Sleep Disorders

University of Zagreb School of Medicine Zagreb, Croatia Volume 4, Number 3–4, pp. 249–361 July–December 2017

UDC 616.8 UDC 616.89 UDC 159.9 UDC 612 ISSN 1849-5427 (Online) ISSN 2459-5233 (Print) Volume 4, Number 3–4, pp. 249–361 July–December 2017 249–361 July–December pp. Number 3–4, 4, Volume Gyrus

sleep disorders

Rhythmic variations What color are your Menstrual cycle and Pediatric hydrocephalus: of mood letters? – an insight cognitive functions causes, symptoms and Disorders Sleep into synesthesia treatment modalities p. 304 p. 319 p. 343 p. 355

sleep disorders

impressum IMPRESSUM founded 2013 zagreb, croatia UDC 616.8 UDC 159.9 ISSN 1849-5427 (Online) volume 4, number 3 – 4, pp. 249 – 361 UDC 616.89 UDC 612 ISSN 2459-5233 (Print) july – december 2017

EDITOR-IN-CHIEF/ GLAVNA UREDNICA Barbara Tomić University of Zagreb, School of Medicine

DEPUTY EDITOR-IN-CHIEF/ ZAMJENIK GLAVNE UREDNICE Ivan Mlinarić University of Zagreb, School of Medicine

ASSOCIATE EDITORS/ PRIDRUŽENI UREDNICI Mislav Čaić University of Zagreb, School of Medicine Marta Dugonjić University of Zagreb, School of Medicine Nina Fajs University of Zagreb, School of Medicine Bea Hohšteter University of Zagreb, School of Medicine Ida Ivek University of Zagreb, School of Medicine Vinka Kugelman University of Zagreb, School of Medicine Niko Njirić University of Zagreb, School of Medicine Karlo Toljan University of Zagreb, School of Medicine Luka Turkalj University of Zagreb, School of Medicine Ivan Vukelić University of Zagreb, School of Medicine Ivana Car University of Zagreb, Faculty of Humanities and Social Sciences, Department of Psychology Emina Horvat Velić University of Zagreb, Faculty of Science, Department of Biology

WEB EDITOR/ WEB UREDNIK Nikola Prpić University of Zagreb, School of Medicine

VISUAL IDENTITY & LAYOUT/ VIZUALNI IDENTITET I PRIJELOM Ljubica Golubić Monika Vodopija Antonija Vuletić

ADVISORY BOARD/ UREDNIČKI SAVJET SENIOR EDITORIAL BOARD/ VIŠI UREDNIČKI KOLEGIJ Ema Bokulić, MD Sonja Mikulec, MD Monika Mudrovčić, MD EDITORIAL CONSULTANTS/ SAVJETNiCI UREDNIČKOG KOLEGIJA Božidar Nikša Tarabić, MA Marko Zorić, MD FIRST EDITORIAL BOARD/ PRVO UREDNŠTVO ČASOPISA // HONOURABLE MEMBERS Tomislav Ćaleta, MD Vinka Knezović, MD Ines Martinec, MD Marko Petrić, MD Dora Sedmak, MD MENTOR/ MENTOR Goran Sedmak, MD, PhD, Assistant Professor Croatian Institute for Brain Research University of Zagreb, School of Medicine gyrus | vol. 4 | no. 3 – 4 | july – december 2017 I sleep disorders impressum

REVIEWERS/ RECENZENTI Domagoj Džaja, MD, PhD Ivana Hromatko, PhD, Assistant Professor Dragutin Ivanec, PhD, Professor Vinka Knezović, MD Darija Mahović Lakušić, MD, PhD, Associate Professor Alma Mihaljević-Peleš, MD, PhD, Professor Dinka Pavičić Baldani, MD, PhD, Associate Professor Željka Petelin Gadže, MD, PhD, Associate Professor Marina Raguž, MD Goran Sedmak, MD, PhD, Assistant Professor Marina Šagud, MD, PhD, Assistant Professor Meri Tadinac, PhD, Professor Marko Zorić, MD

PROOFREADER/ LEKTOR Thomas Klarić, PhD

VISUAL CONCEPT/ VIZUALNI KONCEPT Ljubica Golubić Stella Grabarić Marijana Šimag

ADDRESS OF THE EDITORIAL BOARD/ ADRESA UREDNIŠTVA Šalata 12, Zagreb, Croatia

PUBLISHER/ IZDAVAČ University of Zagreb Check out Gyrus’ website School of Medicine http://gyrus.hiim.hr/ Šalata 3, Zagreb, Croatia

FOR THE PUBLISHER/ ZA IZDAVAČA Contact us via email Marijan Klarica, MD, PhD, Professor [email protected]

PRINT / TISAK Find us on Facebook Printera Grupa d.o.o. https://www.facebook.com/gyrus.unizg/ Ul. dr. Franje Tuđmana 14A, Sveta Nedelja, Croatia www.printera.hr Follow us on Twitter https://twitter.com/gyrusjournal NUMBER OF COPIES/ NAKLADA 500 Join us on LinkedIn https://www.linkedin.com/company/gyrus-journal

Gyrus is student scientific journal which publishes review articles, Gyrus je studentski stručni časopis koji objavljuje pregledne i stručne mainly from the fields of fundamental neuroscience, neurology, članke, ponajprije iz područja bazične neuroznanosti, neurologije, psychiatry and psychology, and neurosurgery. It was founded by psihijatrije i psihologije te neurokirurgije. Osnovala ga je Studentska Student Society for Neuroscience at the University of Zagreb School sekcija za neuroznanost Medicinskog fakulteta Sveučilišta u Zagrebu of Medicine. The journal is published quarter-yearly. te se objavljuje svaka tri mjeseca. The publication of this journal is financially supported by the University Časopis izlazi uz financijsku potporu Medicinskog fakulteta of Zagreb School of Medicine. Sveučilišta u Zagrebu. We would like to thank the Management Board of the University of Zahvaljujemo Upravi Medicinskog fakulteta Sveučilišta u Zagrebu što Zagreb School of Medicine for permission to use the official logo of nam je ustupila na korištenje službeni logotip povodom obilježavanja the 100th anniversary of the founding of our School. 100. godišnjice osnutka našeg Fakulteta.

Financial support for the print of previous issue (Gyrus Vol. 4, No. 2) Tisak prethodnog broja časopisa (Gyrus Vol. 4, No. 2) financijski je was provided by the Students’ Council of the University of Zagreb. potpomogao Studentski zbor Sveučilišta u Zagrebu.

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table of contents TABLE OF CONTENTS

Gyrus, Vol. 4, No. 3 – 4, pp. 249 – 361 ISSN 1849-5427 (Online) july – december 2017 ISSN 2459-5233 (Print) Zagreb, Croatia

I IMPRESSUM III TABLE OF CONTENTS

249 FOREWORD FROM THE EDITORS

251 TIMELINE

263 NEWS AND EDUCATION

264 NEUROSCIENCE FOR ENGINEERS, KSET NEUROZNANOST ZA INŽENJERE, KSET Krešimir Friganović

265 TEDDY BEAR HOSPITAL Matea Škoro Iva Topić

267 UTRECHT SUMMER SCHOOL: NEURAL CIRCUIT DEVELOPMENT AND PLASTICITY Nikola Prpić

269 6TH CROATIAN NEUROSCIENCE CONGRESS 6. HRVATSKI NEUROZNANSTVENI KONGRES Ivan Mlinarić Barbara Tomić

271 ZOOM INTO THE PSYCHE ZOOM NA PSIHU Ana Kraljević Sara Lončar

273 BOOK / MOVIE REVIEW

274 A DIFFERENT BRAIN Emina Horvat Velić

275 INTERVIEW

275 INTERVIEW WITH RAPHAEL BÉNÉ Nikola Prpić

277 CASE REPORT

278 NEW CONCEPTS IN REHABILITATION OF CHILDREN WITH CEREBRAL PALSY Rašeljka Batelić Dragić

285 EDITOR’S CHOICE

286 DEVELOPING BRAIN REGIONS IN CHILDREN HARDEST HIT BY SLEEP DEPRIVATION Ivana Starčević gyrus | vol. 4 | no. 3 – 4 | july – december 2017 III sleep disorders table of contents

287 LATE NEURONAL MIGRATION – NEW FINDINGS SUGGEST A KEY ROLE IN HUMAN BRAIN DEVELOPMENT Luka Ćusek

288 NEURAL NETWORK UNDERLYING HUMAN CONSCIOUSNESS DISCOVERED Ida Ivek

289 HOW CONSTANT SOCIAL DEFEAT MODIFIES OUR BEHAVIOR: IS THE PERSON NEXT TO YOU SIMPLY DULL, AGGRESSIVE, EXTREMELY INTROVERTED OR IS THERE MORE TO THE STORY? Bea Hohšteter

291 VIRTUAL REALITY IN MANAGEMENT OF SCHIZOPHRENIA Ana Bardak,

293 FORGETTING Tomislav Smoljo

issue Topic

299 THIS IS YOUR BRAIN ON DREAMS Vana Vukić

304 RHYTHMIC VARIATIONS OF MOOD Augustin Mutak

311 SLEEP DISORDERS AND HEALTH RISKS Elizabeth Nedić

315 SOMNAMBULISM Dora Dragčević Fundamental Neuroscience

319 WHAT COLOR ARE YOUR LETTERS? – AN INSIGHT INTO SYNESTHESIA Andrea Paulik

323 THE PRION PROTEIN AND CREUTZFELDT-JAKOB DISEASE Dora Franka Zelić neurology

329 THE PATHOPHYSIOLOGY OF MIGRAINE Josipa Popović

335 TRIGEMINAL NERVE STIMULATION (TNS) Emina Horvat Velić

339 EPILEPSY AND PREGNANCY Ivana Starčević Psychiatry and Psychology

343 MENSTRUAL CYCLE AND COGNITIVE FUNCTIONS Anamaria Novak

348 BRIGHT LIGHT THERAPY (BLT) IN DEPRESSION Jana Radić

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table of contents Neurosurgery

355 PEDIATRIC HYDROCEPHALUS: CAUSES, SYMPTOMS AND TREATMENT MODALITIES Alisa Junaković Erratum

361 ERRATUM TO: RESEARCH ON FACTORS THAT CONTROL THE ACTIVATION OF SPINAL CORD ENDOGENOUS STEM CELLS Ana Dekanić

VI KEYWORD AND AUTHOR INDEX VII ACKNOWLEDGEMENT TO THE REVIEWERS ZAHVALA RECENZENTIMA VIII GUIDE FOR AUTHORS X SUBSCRIPTION

gyrus | vol. 4 | no. 3 – 4 | july – december 2017 V sleep disorders foreword from the editors FOREWORD FROM THE EDITORS

Dear Readers,

I am more than grateful for the opportunity to address you once again at the beginning of new Gyrus Journal issue, this time especially dedicated to sleep disorders.

As human beings, we spend approximately one third of our lives sleeping. Sleep and its architecture are of vital importance for psychological, as well as physiological processes. However, modern way of life (e.g. exposure to screen-light), just like certain health conditions, can affect our circadian rhythm and stages of sleep to a great extent.

It is well known that sleep deprivation can lead to disruption in cognitive functioning and changes in emotional abilities. Moreover, scientific studies revealed associations of perpetual short sleep duration with adverse health effects, such as hypertension and other cardiovascular diseases, diabetes, obesity, and depression.

In this issue you can discover the influence of sleep deprivation on developing brain regions in children. Moreover, you can find out more about the relationship of sleep disorders and quality of life, especially the harmful effects of sleep deficiency and related health risks. In addition, you can unravel the mystery of somnambulism, popularly known as sleepwalking.

People have always been fascinated with dreams, trying to understand these peculiar experiences, especially in order to find out their meanings, and reaching to grasp their origins in human psyche. To learn more about the scientific background of this interesting matter we recommend reading the article “This is your brain on dreams”. If you are interested in the influence of circadian and other rhythms, season alteration and working days-weekend interchange on our affect, we gladly direct you to the article “Rhythmic variations of mood”. Apart from the articles related to the issue topic, as always, there are the ones related to certain neuroscientific fields.

One of the topics that makes us worry, especially as we approach the older age, is forgetting. Young people rarely think about it, apart from problems they are facing while studying for exams. On the other hand, the elderly are often in doubts trying to differ physiological forgetting from early signs of dementia, a serious neurological illness. You can learn more by reading the article of the homonymous title “Forgetting”. Furthermore, if you are interested in ambiguous phenomena, we recommend the article “What color are your letters? – an insight into synesthesia”, dealing with this extraordinary perceptual association of senses. We also present a student-project with noble purpose of helping the youngest overcome their fear of doctors and their equipment, such as stethoscopes and syringes. Considering the necessity of physician’s approach to a child in need, as well as the fact that fear, as one of the strongest emotions, could in this context be a destructive stressor by itself, one can easily assume the potential risk of this reaction to the child’s wellbeing. Fortunately, this can easily be prevented by the effort of young people elaborated in the article “Teddy Bear Hospital”.

You can also read about what happens when people from two different “worlds” join forces for common good. In other words, when future neuroscientists and electrical engineers, both neuro-enthusiasts, decide to exchange their knowledge. In addition, you can find out what does an initiative established by psychology students and photography artist look like when they’re trying to diminish the stigma of mental illness.

We are now leaving you to discover a dashing variety of new interesting facts and realizations hidden among the pages in front of you.

Sapere aude!

On behalf of Gyrus Editorial Board,

Barbara Tomić, Editor-in-Chief

249 july – december 2017 | gyrus | vol. 4 | no. 3 – 4 TEMA BROJA sleep disorders

foreword fromNAZI theV CJELeditorsINE Autor i administrativni podaci

Human brain frontal lobe, child 3 months old, Gallyas staining showing distribution of axons in the white matter. This image is property of Zagreb Neuroembriological Collection, Croatian Institute for Brain Research, University of Zagreb School of Medicine. For details see Kostović et al. 1991; Judaš et al. 2011.

gyrus || vol.vol. 4 4 | |no. no. 3–4 3 – | december4 | july – december 2017 2017 250 sleep disorders timeline TIMELINE – LENTA VREMENA legend legenda humanitarian / public health actions humanitarne / javnozdravstvene akcije symposium / congress simpozij / kongres lecture / workshop predavanje / radionica student lecture / workshop studentsko predavanje / radionica journal / book club journal / book Club other (gatherings, art etc.) ostalo (druženja, umjetnost itd.)

30. 3. – 14. 6. 2017. Organizer: Izložba – „Anamneza – povijest bolesti u antičkom svijetu” Archaeological Museum in Zagreb – Arheološki muzej u Zagrebu, Hrvatska / Exhibition – “Anamnesis – Medical History in the Ancient World” Partners: – Archaeological Museum in Zagreb, Croatia University of Zagreb School of Medicine http://amz.hr/home/virtual-walk/temporary-exhibitions.aspx Croatian Academy of Sciences and Arts High School for Nursing Vinogradska University of Applied Health Sciences Zagreb Holding subsidiaries – Zagreb Pharmacies, Vodoopskrba i odvodnja, Zrinjevac

12. 4. – 31. 5. 2017. Organizator: Izložba – „Muzejski vremeplov: Zbirka narodne medicine kao Hrvatski muzej medicine i farmacije HAZU-a okosnica izložbenog postava prvog hrvatskog muzeja medicine” – Strossmayerova galerija starih majstora HAZU-a, Zagreb, Hrvatska Katalog:http://info.hazu.hr/upload/File/Kal17/10_05_MV_deplijan.pdf

22. 4. 2017. Organizatori: Dan otvorenih vrata Medicinskog fakulteta Medicinski fakultet Sveučilišta u Zagrebu Sveučilišta u Zagrebu Studentski zbor Medicinskog fakulteta http://mef.unizg.hr/dan-otvorenih-vrata-medicinskog-fakulteta-sveucilista-zagrebu-subota-22-4-2017-g Sveučilišta u Zagrebu Studentske udruge osnovane pri Medicinskom fakultetu Sveučilišta u Zagrebu

24. 4. 2017. Organizator: Noć knjige 2017. u Središnjoj medicinskoj knjižnici: MEF „Studentski život 1917. i 2017.” http://mef.unizg.hr/100-obljetnica-mefa-noc-knjige-2017-sredisnjoj-medicinskoj-knjiznici-24-travnja-2017-17-sati?bn

26. 4. – 2. 6. 2017. Organizatori: Izložba “Medicina Sacra – Štovanje svetaca zaštitnika i Medicinski fakultet Sveučilišta u Zagrebu duhovna dimenzija medicine” Hrvatski muzej medicine i farmacije HAZU-a Hrvatsko katoličko liječničko društvo, Podružnica Branimir Richter Zagreb http://mef.unizg.hr/100-obljetnica-mefa-otvorenje-izlozbe-medicina-sacra-stovanje-svetaca-zastitnika-duhovna-dimenzija-medicine?pid=17597

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timeline

28. 4. 2017. Organizer: Lecture – Tutankhamun and other mummies: A medical Archaeological Museum in Zagreb (as a part of perspective – Prof. Dr. Dr. med. Frank Rühli, Institute of the exhibition “Anamnesis – Medical History in Evolutionary Medicine (IEM), Zurich the Ancient World”) http://mef.unizg.hr/100-obljetnica-mefa-tutankhamun-and-other-mummies-a-medical-perspective?pid=17597 http://mef.unizg.hr/wp-content/uploads/2017/04/e-pozivnica_Tutankamon_Anamneza.pdf

2. 5. 2017. NEWS AND Predavanje – „Neuroznanost za inženjere” – SSNZ EDUCATION Nikola Prpić, Krešimir Friganović, mag. ing. Klub studenata elektrotehnike (KSET) FIND OUT MORE! Kugelman V. New advances in brain-computer interface (BCI) technologies. Gyrus. 2017;4(2):186-190. http://gyrus.hiim.hr/images/gyrus12/final_web_highq_Part3.pdf 3. 5. 2017. Studentsko predavanje – „Uvod u duboku mozgovnu SSNZ stimulaciju (DBS)” – Ivan Vukelić FIND OUT MORE! Vukelić I. DBS – infographic. Gyrus. 2017;4(2):177-178. http://gyrus.hiim.hr/images/pdfgyrus/Gyrus12.pdf

4. 5. 2017. Predavanje – „Bolesti zagrebačkih mumija” – Arheološki muzej u Zagrebu doc. dr. sc. Mislav Čavka, dr. med. https://www.facebook.com/events/290448188076911/?acontext=%7B%22ref%22%3A%223%22%2C%22ref_newsfeed_story_ type%22%3A%22regular%22%2C%22action_history%22%3A%22null%22%7D 4. – 6. 5. 2017. 2nd Regional DBS meeting “Deep brain stimulation: Organized by New Horizons in Neurology and Psychiatry” University Hospital Dubrava, Zagreb – Referral – Zagreb, Croatia Centre of the Croatian Ministry of Health for In association with Stereotactic and Functional Neurosurgery UCL Institute of Neurology, Sobell Department of Motor Clinical Department of Neurology, University Neuroscience & Unit of Functional Neurosurgery, Queen Hospital Centre Rijeka Square, London, UK University of Zagreb School of Medicine University of Rijeka, Faculty of Medicine Program: dbs.exclusivecroatia.hr/wp-content/uploads/2nd-Regional-DBS-meeting-final-program.pdf 4. – 6. 5. 2017. 3. SPIRI – Regionalni susret studenata psihologije Udruga studenata psihologije Psirius – „Skepticizam i kriticizam” http://ffri.hr/spiri/ Program: https://drive.google.com/file/d/0B6G66MBIPgm_cFJtQUpVcWNXVVU/view 5. 5. 2017. Nacionalni dan osoba s cerebralnom paralizom https://www.hzjz.hr/sluzba-javno-zdravstvo/5-svibanj-nacionalni-dan-osoba-s-cerebralnom-paralizom/ 6. – 7. 5. 2017. Autism-Europe (AE) Annual General Assembly and Croatian Union of Associations for Autism Council of Administration meetings, Zagreb, Croatia (CUAA) http://www.autismeurope.org/ https://www.facebook.com/pg/autismeurope.AE/photos/?tab=album&album_id=1447590041982802 8. 5. 2017. Predavanje povodom Svjetskog dana multiple Radna skupina za sigurnosne informacije i skleroze – „Multipla skleroza i planiranje obitelji” klinička ispitivanja Hrvatskog farmaceutskog društva (HFD-a) http://www.farmaceut.org/novosti/hrvatska/povodom-svjetskog-dana-multiple-skleroze-organiziraju-se-predavanja-na-temu-multipla-skleroza-i-planiranje-obitelji http://www.farmaceut.org/kalendar-dogadjanja/predavanja/multipla-skleroza-i-planiranje-obitelji-261

gyrus | vol. 4 | no. 3 – 4 | july – december 2017 252 sleep disorders timeline

10. – 13. 5. 2017. Croatian Medical Association – Croatian Association for Psychotherapy, Psychosocial 22nd School of Psychotherapy of Psychoses – Methods and Early Prevention of Psychotic Disorders, Program: Dubrovnik, Croatia Croatian Association for Clinical Psychiatry http://www.psihijatrija.hr/site/wp-content/uploads/2017/03/Programme-22.-School-2017.pdf Croatian Academy of Medical Sciences Institute of Group Analysis 11. 5. 2017. 7. Rhotonova anatomija glave i kirurški pristupi – SSNZ „Transsilvijevi i drugi temporalni pristupi” https://www.facebook.com/events/662724463920782/ 17. 5. 2017. Ciklus predavanja „Od bazike do klinike: Bol” SSNZ – „Eksperimentalna glavobolja” – dr. sc. Ivica Matak Studentska sekcija za anesteziologiju 17. 5. 2017. Lecture – „Ubiquitin, cell identity and tumorigenesis, University of Zagreb School of Medicine from flies to humans” – Professor Amir Orian, MD, PhD Croatian Institute for Brain Research http://mef.unizg.hr/predavanje-ubiquitin-cell-identity-and-tumorigenesis-from-flies-to-humans-prof-amir-orian?bn Emed (Student Council for the Medical Studies 22. 5. 2017. in English program, Zagreb) Team 5 event https://www.facebook.com/events/1653004398062928/?acontext=%7B%22ref%22%3A%223%22%2C%22ref_newsfeed_story_type%22%3A%22regu- lar%22%2C%22action_history%22%3A%22null%22%7D https://www.facebook.com/mse.emed/

24. 5. 2017. Zagrebački institut za kulturu zdravlja Predavanje – „Izazovi psihijatrije u 21. stoljeću” http://zikz.hr/ – prof. dr. sc. Norman Sartorius

25. 5. 2017. Etnografski muzej u Zagrebu Predavanje – „Psihološke koristi od kućnih ljubimaca” Sklonište za nezbrinute životinje grada Zagreba – dr. sc. Predrag Zarevski (Azil Dumovec) https://www.facebook.com/events/764046813775582/

26. 5. 2017. MEF Dan doktorata 2017. / PhD Day 2017 Predavanja / Lectures: “Mossy fiber synapses in the hippocampus have their individual memories” – Prof. Michael Frotscher, Universitätsklinikum Hamburg-Eppendorf “Botulinum neurotoxin (BoNT) treatment for pain syndromes” – Prof. Bahman Jabbari, MD, FAAN, Yale University “Correlation of molecular and morphologic classification of breast cancer” – Prof. Fattaneh A. Tavassoli, MD, Yale University http://mef.unizg.hr/100-obljetnica-mefa-dan-doktorata-26-svibnja-2017-g?bn Program: mef.unizg.hr/wp-content/uploads/2017/05/Program-Dana-doktorata-2017.pdf NEWS AND EDUCATION EMSA Zagreb (European Medical Students' Association Zagreb) 27. 5. 2017. SSHLZ (Student Society of the Croatian Medical Association) Bolnica za medvjediće / Teddy Bear Hospital https://www.facebook.com/events/1879000762354392/

30. 5. 2017. SSNZ 8. Rhotonova anatomija glave i kirurški pristupi – „Separacija kraniopagus sijamskih blizanaca” https://www.facebook.com/events/833779800102952/

31. 5. 2017. Udruga MS TIM HRVATSKA – udruga oboljelih Svjetski dan multiple skleroze od multiple skleroze – 3. Hrvatski MS Walk – Hodaj za MS https://www.facebook.com/events/703492776496788/?acontext=%7B%22ref%22%3A%224%22%2C%22feed_story_ type%22%3A%22308%22%2C%22action_history%22%3A%22null%22%7D http://mstim.hr/ https://www.facebook.com/hodajzaMs/

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31. 5. 2017. Medicinski fakultet Sveučilišta u Zagrebu Kroz logore do slobode Studentski zbor Medicinskog fakulteta https://www.facebook.com/szmef.unizg/posts/816570051829297 Sveučilišta u Zagrebu

1. 6. 2017. Hrvatsko društvo za dječju i adolescentnu psihi- Simpozij o aktualnim pitanjima dječje i adolescentne jatriju i psihoterapiju Hrvatskog psihijatrije i psihoterapije – Maja Beck-Dvoržak: liječničkog zbora „Aktualni dijagnostički pristupi i specifičnost liječenja u Klinika za psihološku medicinu Medicinskog dječjoj i adolescentnoj psihijatriji i psihoterapiji” fakulteta Sveučilišta u Zagrebu KBC Zagreb http://www.psihijatrija.hr/site/?p=2978 Program: www.psihijatrija.hr/site/wp-content/uploads/2017/05/HDDAPP-simpozij.program.proljece.2017-1.pdf

2. 6. 2017. Knjižnica Bogdan Ogrizović, Zagreb Svjetski dan akcije poremećaja u prehrani Udruga Nada www.hope.hr

5. 6. 2017. Akademija medicinskih znanosti Hrvatske Okrugli stol o doktrini “One Health Medicine” Škola narodnog zdravlja „Andrija Štampar” – Čitajući Štampara Medicinskog fakulteta Sveučilišta u Zagrebu http://mef.unizg.hr/okrugli-stol-doktrina-one-health-medicine-citajuci-stampara?bn

6. 6. 2017. Klinika za psihijatriju Vrapče Okrugli stol: Prava osoba s duševnim smetnjama u Hrvatskoj Hrvatsko psihijatrijsko društvo u kontekstu „Liste prava osoba s duševnim smetnjama” Hrvatsko društvo za forenzičku psihijatriju HLZ-a http://www.psihijatrija.hr/site/?p=2993

7. 6. 2017. Medical Information Conference Croatia 2017 (MICC 2017) Središnja medicinska knjižnica Medicinskog – “Current trends in scholarly communication in medicine” / fakulteta Sveučilišta u Zagrebu „Mijenja li se struktura medicinske literature?” – Zagreb, Croatia http://ark.mef.hr/MICC/MICC13.htm

8. 6. 2017. Arheološki muzej u Zagrebu (u sklopu Predavanje – „Voda u glavi” – prof. dr. sc. Marijan Klarica, izložbe „Anamneza – povijest bolesti u prof. dr. sc. Miroslav Vukić antičkom svijetu”) https://www.facebook.com/events/1494149183993083/?acontext=%7B%22ref%22%3A%223%22%2C%22ref_newsfeed_story_type%22%3A%22regu- lar%22%2C%22action_history%22%3A%22null%22%7D http://mef.unizg.hr/100-obljetnica-mefa-voda-glavi-predavanje-sklopu-izlozbe-anamneza?pid=17597 http://mef.unizg.hr/100-obljetnica-mefa-voda-glavi-predavanje-sklopu-izlozbe-anamneza?bn 8. 6. 2017. NEWS AND Predavanje – „Neuroznanost za inženjere 2: Brain-Computer SSNZ EDUCATION Interface” – Nikola Prpić, Krešimir Friganović, mag. ing. Klub studenata elektrotehnike (KSET) 8. 6. 2017. Dan sive vrpce – Svjetski dan oboljelih od tumora na mozgu https://www.hzjz.hr/aktualnosti/dan-sive-vrpce-svjetski-dan-oboljelih-od-tumora-na-mozgu/ 9. 6. 2017. Organizatori: 5. Simpozij Hrvatskog društva za spinalnu kirurgiju Klinika za neurokirurgiju KBC-a Sestre milosrdnice „Kirurško i nekirurško liječenje bolne kralježnice” Hrvatsko spinalno društva Hrvatskog liječničkog zbora – Zagreb, Hrvatska Udruga neurokirurga jugoistočne Europe (SeENS) Pokrovitelj: Razred za medicinske znanosti HAZU-a http://info.hazu.hr/hr/novosti_i_dogadanja/5-simpozij-hrvatskog-drustva-za-spinalnu-kirurgiju-kirursko-i-nekirursko,4004.html gyrus | vol. 4 | no. 3 – 4 | july – december 2017 254 sleep disorders timeline

9. 6. 2017. Ciklus predavanja „Od bazike do klinike: Bol” Organizatori: Predavanja: SSNZ „Suvremeni pristup liječenju kronične boli” Studentska sekcija za anesteziologiju – doc. dr. sc. Zoran Lončar, prim. dr. med. „Liječenje boli u djece” – dr. sc. Diana Butković, prim. dr. med. 29. 6. 2017. Studentska radionica (I. dio) – „Ispravno navođenje i citiranje Gyrus literature” – Barbara Tomić, Ivan Mlinarić 5. 7. 2017. Studentska radionica (II. dio) – „Fotografije, slike, grafikoni: Gyrus što i kako?” – Barbara Tomić, Ivan Mlinarić

5. 7. 2017. Medicinski fakultet Sveučilišta u Zagrebu Svečani skup: 35 godina osnivanja Instituta za klinička Institut za klinička medicinska istraživanja i medicinska istraživanja i nastavu KBC Sestre milosrdnice nastavu KBC-a Sestre milosrdnice http://mef.unizg.hr/svecani-skup-35-godina-osnivanja-instituta-za-klinicka-medicinska-istrazivanja-i-nastavu-kbc-sestre-milosrdnice?bn 1. – 30. 9. 2017. Svjetski mjesec borbe protiv Alzheimerove bolesti https://www.cdc.gov/features/worldalzheimersday/index.html

13. – 15. 9. 2017. Tehnički fakultet Sveučilišta u Rijeci Asistivna tehnologija i komunikacija – Konferencija o Edukacijsko-rehabilitacijski fakultet naprednoj tehnologiji za djecu s teškoćama u razvoju i Sveučilišta u Zagrebu osobe s invaliditetom Tvrtka E-Glas http://www.ataac.eu/hr/

14. 9. 2017. University of Zagreb School of Medicine Lectures – scientists from Leibniz Institute for Neurobiology Croatian Institute for Brain Research (Magdeburg, Germany) Lecture titles: “A Gene-switch for memories: neuroplastin ablation causes retrograde amnesia and cognitive deterioration” – Prof. Dirk Montag “Past, Present and Future of the Cell adhesion molecule neuroplastin” – Rodrigo Herrera-Molina, PhD https://www.facebook.com/gyrus.unizg/posts/1602288423149184

16. – 18. 9. 2017. Organizers: 6th Croatian Neuroscience Congress with International Croatian Society for Neuroscience Participation, Osijek, Croatia / Department of Anatomy and Neuroscience and 6. Hrvatski neuroznanstveni kongres s međunarodnim Department of Medical Biology and Genetics at sudjelovanjem, Osijek, Hrvatska the Josip Juraj Strossmayer University of Osijek Faculty of Medicine Croatian Academy of Sciences and Arts http://www.hiim.unizg.hr/index.php/24-naslovnica/373-vi-kongres-hdn https://www.osijek.hr/6-hrvatski-kongres-neuroznanosti/ Croatian Brain Council http://www.osijek031.com/osijek.php?najava_id=68817 http://info.hazu.hr/hr/novosti_i_dogadanja/novosti/16---18-09-6-hrvatski-kongres-neuroznanosti,2550.html http://www.mefos.unios.hr/images/vijesti/2017/07/marija_kongres/PRELIMINARNI_PROGRAM.pdf

18. 9. 2017. Outreach seminar za studente – ciklus seminara: Hrvatsko psihoanalitičko društvo „Što je psihoanaliza?” http://www.hpsg.hr/ http://www.hpsg.hr/psihoanaliticari/

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21. 9. 2017. Svjetski dan Alzheimerove bolesti Etnografski muzej, Zagreb Predavanje – „Psi – čuvari uspomena” FIND OUT MORE! https://www.youtube.com/watch?v=WcbjVrKdFQw https://www.ncbi.nlm.nih.gov/pubmed/28699394 https://www.ncbi.nlm.nih.gov/pubmed/24814254 https://www.ncbi.nlm.nih.gov/pubmed/21356158 21. 9. – 10. 11. 2017. Projekt „Album” – zajednički program kojim se kod osoba Tiflološki muzej s Alzheimerovom bolesti nastoje pomoću muzejskih Etnografski muzej predmeta potaknuti i prizvati zaboravljena sjećanja Tehnički muzej Nikola Tesla http://www.tifloloskimuzej.hr/news.aspx?idNews=446&Page=9 http://www.culturenet.hr/default.aspx?id=79119 26. 9. 2017. Lecture – “Munchausen syndrome by proxy” MEF – Prof. Roger Byard, MD, PhD FIND OUT MORE! https://www.ncbi.nlm.nih.gov/pubmed/29938745 https://www.ncbi.nlm.nih.gov/pubmed/28750264 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4341319/ 29. – 30. 9. 2017. Poslijediplomski tečaj stalnog medicinskog Medicinski fakultet Sveučilišta u Zagrebu usavršavanja I. kategorije Referentni centar za poremećaje pokreta i – „Liječenje uznapredovalog stadija neurodegenerativne bolesti Ministarstva zdravstva RH Parkinsonove bolesti” i Klinike za neurologiju KBC-a Zagreb Hrvatska udruga bolesnika s poremećajima pokreta Program tečaja: mef.unizg.hr/wp-content/uploads/2017/07/TECAJ-program-2017.doc

3. 10. 2017. Škola narodnog zdravlja „Andrija Štampar” 90 godina Škole narodnog zdravlja „Andrija Štampar” Medicinskog fakulteta Sveučilišta u Zagrebu – Stručno-znanstveni skup „Zdravlje i zdravstvo: izazovi i Ministarstvo zdravstva RH mogućnosti – susret profesije i politike” Razred za medicinske znanosti HAZU-a http://mef.unizg.hr/90-godina-snz-a-zdravlje-zdravstvo-izazovi-mogucnosti-susret-profesije-politike?bn http://mef.unizg.hr/90-godina-snza-obilljezena-obljetnica-skole-narodnog-zdravlja-andrija-stampar-organizacijom-strucno-znanstvenog-skupa-zdravlje-zdravstvo-izazovi-mogucnosti-susret-profesije-politike?bn Program skupa: https://mef.unizg.hr/wp-content/uploads/2017/09/Dan-SNZ-2017.pdf 5. 10. 2017. Gyrus – postani i ti dio ekipe! :) Gyrus

10. 10. 2017. Svjetski dan mentalnog zdravlja http://www.bolime.hr/Dan-mentalnog-zdravlja-10-10-2017 11. 10. 2017. Uvodni sastanak Studentske sekcije za neuroznanost SSNZ

13. 10. 2017. Katedra za neurologiju Medicinskog fakulteta Poslijediplomski tečaj stalnog medicinskog Sveučilišta u Zagrebu usavršavanja I. kategorije – „Dijagnostički i terapijski Klinika za neurologiju KBC-a Zagreb pristup bolesniku s epilepsijom” Referentni centar Ministarstva zdravstva RH za epilepsiju Hrvatsko društvo za EEG i kliničku neurofiziologiju HLZ-a Hrvatska liga protiv epilepsije Hrvatska udruga za epilepsiju Društvo za pomoć neurološkim bolesnicima „SPES” Program tečaja: http://www.epilepsija.hr/wp-content/uploads/epilepsije_te%C4%8Daj.pdf

16. 10. 2017. Hrvatska akademija znanosti i umjetnosti Znanstveni skup „Molekularna genetika – novosti u Razred za prirodne znanosti dijagnostici i terapiji” Odbor za primijenjenu genomiku http://mef.unizg.hr/19224?bn Hrvatsko društvo za laboratorijsku medicinu Hrvatsko društvo za humanu genetiku Društvo za kliničku genetiku Hrvatske Hrvatsko društvo za biotehnologiju Hrvatsko društvo za biosigurnost i biozaštitu gyrus | vol. 4 | no. 3 – 4 | july – december 2017 256 sleep disorders timeline

ISSUE TOPIC 19. 10. 2017. SSN Journal Club – „Cirkadijani ritam” SSNZ

21. 10. 2017. Milenijske fotografije povodom 100 godina Studentski zbor Medicinskog fakulteta Medicinskog fakulteta Sveučilišta u Zagrebu Sveučilišta u Zagrebu http://mef.unizg.hr/100-obljetnica-mefa-milenijska-fotografija-povodom-100-godina-medicinskog-fakulteta?bn http://mef.unizg.hr/100-obljetnica-mef-a-milenijske-fotografije?bn https://www.facebook.com/events/120584871957723/ 26. 10. 2017. 1. neuroanatomske vježbe – „Uvod u živčani sustav” SSNZ 27. 10. 2017. Predavanje – „Rad s ovisnostima iz perspektive gestalt Gestalt centar Homa psihoterapije” – Kevin McCann, MIACP http://gatla.org/couples-faculty/ 29. 10. 2017. Svjetski dan moždanog udara https://www.hzjz.hr/aktualnosti/svjetski-dan-mozdanog-udara-2017/ 30. 10. 2017. Studentska radionica (I. dio) – „Ispravno navođenje i Gyrus citiranje literature” – Barbara Tomić, Ivan Mlinarić https://www.facebook.com/events/135982360383037/ 31. 10. 2017. Rhoton neurokirurška radionica – Uvod SSNZ https://www.facebook.com/events/182386702325314/

2. 11. 2017. 2. neuroanatomske vježbe – „Mikroskopska građa SSNZ živčanog sustava” 3. 11. 2017. Dies academicus – Dan Sveučilišta u Zagrebu Sveučilište u Zagrebu FIND OUT MORE! Informacije o znanstvenoj produktivnosti Sveučilišta u Zagrebu http://mef.unizg.hr/unizg-informacije-znanstvenoj-produktivnosti-sveucilista-zagrebu?bn

3. – 5. 11. 2017. 11. susret Dječje filmsko i videostvaralaštvo u funkciji MEF javnog zdravstva / 7. Dječji filmski kamp ŠNZ „Andrija Štampar” http://mef.unizg.hr/javno-zdravstvo-11-susret-djecje-filmsko-videostvaralastvo-funkciji-javnog-zdravstva-7-djecji-filmski-kamp?bn

15. – 30. 11. 2017. MEF Brkati studeni na Štamparu ŠNZ „Andrija Štampar” Poster: www.snz.unizg.hr/app/uploads/2017/11/Brkati-studeni-2017-poster.pdf KBC Zagreb 6. 11. 2017. Ciklus predavanja „Nobel na ‘Ruđeru’” – „Molekularni Institut Ruđer Bošković mehanizmi biološkog dnevnog ritma” – dr. sc. Jasminka Štefulj https://www.facebook.com/events/885095024979884/ 9. 11. 2017. 3. neuroanatomske vježbe – „Vanjska morfologija mozga” SSNZ

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9. 11. 2017. Knjižnica i čitaonica Bogdana Ogrizovića Predavanje – „Koliko traju rast i razvoj ljudskog mozga?” (Knjižnice grada Zagreba) – prof. dr. sc. Miloš Judaš

10. 11. 2017. SSNZ SSN Journal Club – „ANS” Gyrus https://www.facebook.com/events/130108597652210/ 11. 11. 2017. Stručni skup o art terapiji „UMjetnost” Klubovi studenata psihologije Sveučilišta u – predavanja i radionice Zagrebu – STUP (Filozofski fakultet) i Feniks (Hrvatski studiji) https://www.facebook.com/events/1976775549207128/ https://www.facebook.com/UMjetnost.radionice/ 14. 11. 2017. Studentska radionica (II. dio) – „Fotografije, slike, Gyrus grafikoni: što i kako?” – Barbara Tomić, Ivan Mlinarić 14. 11. 2017. Rhoton #2: Telovelar Approach to the Fourth Ventricle SSNZ 17. 11. 2017. 4. neuroanatomske vježbe – „Vaskularizacija, SSNZ limfa i ovojnice mozga”

17. 11. 2017. Zavod za kemiju i biokemiju Medicinskog 5. dan Frana Bubanovića fakulteta Sveučilišta u Zagrebu http://mef.unizg.hr/pozivnica-5-dan-frana-bubanovica?bn Pozivnica i program: mef.unizg.hr/wp-content/uploads/2017/11/Pozivnica-5.-Dan-FB.pdf

18. 11. 2017. Studentski zbor Medicinskog fakulteta Dan sjećanja – putovanje u Vukovar Sveučilišta u Zagrebu https://www.facebook.com/events/1996468787256006/

19. 11. 2017. Pjevački zbor studenata Medicinskog fakulteta u Koncert povodom 100. obljetnice osnutka Medicinskog Zagrebu „Lege artis” fakulteta Sveučilišta u Zagrebu „Sto ti je godina tek” Jazz sastav „Greenhill Club” Zagrebački liječnici pjevači Zbor medicinskih sestara i tehničara „KBC Zagreb” http://mef.unizg.hr/100-obljetnica-mefa-koncert-povodom-100-obljetnice-osnutka-medicinskog-fakulteta-sveucilista-zagrebu?bn Videosnimka koncerta u Hrvatskom glazbenom zavodu: http://mef.unizg.hr/100-obljetnica-mefa-videosnimka-koncerta-hrvatskom-glazbenom-zavodu-19-11-povodom-obiljezavanja-100-godina-medicinskog-fakulteta?bn

20. 11. 2017. NEWS AND Studentsko predavanje – „Neuroznanost za inženjere 3: SSNZ EDUCATION Vizualna percepcija” – Nikola Prpić Klub studenata elektrotehnike (KSET) https://www.facebook.com/events/700606300135771/ 20. 11. – 16. 12. 2017. Akcija „Medicinari velikog srca” STUDMEF uz potporu studentskih organizacija i zaposlenika Medicinskog fakulteta Sveučilišta u Zagrebu te ostalih https://www.facebook.com/Medicinari-velikog-srca-1781534588812875/ 21. 11. 2017. 5. neuroanatomske vježbe SSNZ – „Ventrikularni sustav i likvor”

23. – 25. 11. 2017. EMSA Zagreb Zagreb International Medical Summit 17 (ZIMS 17) Studentska sekcija HLZ-a – Zagreb, Croatia https://www.facebook.com/zims.hr/ https://www.facebook.com/emsaZageb1/ gyrus | vol. 4 | no. 3 – 4 | july – december 2017 258 sleep disorders timeline

NEWS AND 23. – 25. 11. 2017. Organizatori: EDUCATION 1. međunarodni transdisciplinarni simpozij Znanstveni centar izvrsnosti za integrativnu bioetiku „Bioetika i aporije psihe” – Zagreb, Hrvatska / Hrvatsko bioetičko društvo 1st International Transdisciplinary Symposium Sveučilišni centar za integrativnu bioetiku “Bioethics and Aporia of Psyche” Sveučilišta u Zagrebu Centar za integrativnu bioetiku Filozofskog Programska publikacija skupa / Book of Abstracts: fakulteta Sveučilišta u Zagrebu www.bioetika.hr/wp-content/uploads/2017/11/BiAPs-publikacija.pdf Udruga „Ludruga”, Zagreb Projekt „Zoom na psihu” (FFZG) 23. – 25. 11. 2017. Smotra Sveučilišta u Zagrebu Sveučilište u Zagrebu Program: http://smotra.unizg.hr/fileadmin/smotra2017/program.html 24. 11. 2017. Mini simpozij „Europski certificirani farmakolog Hrvatsko društvo farmakologa – EuCP Program” http://mef.unizg.hr/mini-simpozij-europski-certificirani-farmakolog-eucp-program?bn 28. 11. 2017 Rhoton #3: Retrosigmoid approach SSNZ 29. 11. 2017. 6. neuroanatomske vježbe SSNZ – „Bazalni gangliji i živčani putevi” 29. 11. 2017. 1. Kviz općeg znanja studenata biomedicinskog područja Studentski zbor MEF-a https://www.facebook.com/events/241954759672589/ Studentski zbor FBF-a Studentski zbor SFZG-a Udruga studenata veterinarske medicine (USVM) 30. 11. 2017. Ponavljanje za neuroanatomski kolokvij – kolegij Temelji neuroznanosti (TNZ) SSNZ

30. 11. 2017. TeaTime – Prof. dr. sc. Bruno Baršić „Jazz me up! STUDMEF (Jazz i medicinari se vole dugo i javno)” http://mef.unizg.hr/teatime-prof-dr-sc-bruno-barsic-jazz-me-up-jazz-medicinari-se-vole-dugo-javno?bn

1. 12. 2017. Studentski zbor Medicinskog fakulteta 100. brucošijada Medicinskog fakulteta Sveučilišta u Zagrebu https://www.facebook.com/events/1465674216881305/

1. – 2. 12. 2017. Buđenje – udruga za razumijevanje ADHD-a 1. međunarodna konferencija o ADHD-u pod nazivom Edukacijsko-rehabilitacijski fakultet Sveučilišta „Od stigme do uspjeha” – Zagreb, Hrvatska u Zagrebu https://adhdconferencecroatia.com/arhiva/ ADHD Europe Knjiga sažetaka: https://adhdconferencecroatia.com/wp-content/uploads/2017/09/knjiga-sa%C5%BEetaka.pdf

4. 12. 2017. Hrvatska pošta pušta u optjecaj prigodnu poštansku marku povodom 100 godina našeg Fakulteta http://mef.unizg.hr/100-obljetnica-mef-a-hrvatska-posta-pusta-optjecaj-prigodnu-postansku-marku-povodom-100-godina-naseg-fakulteta?bn

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4. 12. 2017. Božić na MEF-u STUDMEF https://www.facebook.com/events/379752869129128/

6. 12. 2017. – 28. 2. 2018. Hrvatski muzej medicine i farmacije HAZU-a Izložba “Diplome hrvatskih liječnika iz Zbirke diploma Medicinski fakultet Sveučilišta u Zagrebu i povelja Hrvatskog muzeja medicine i farmacije HAZU “ http://mef.unizg.hr/100-obljetnica-mefa-otvorenje-izlozbe-diplome-hrvatskih-lijecnika-iz-zbirke-diploma-povelja-hrvatskog-muzeja-medicine-farmacije-hazu?bn 7. 12. 2017. 7. neuroanatomske vježbe – „Moždano deblo” SSNZ

8. 12. 2017. Svečano obilježavanje 25. obljetnice osnutka Uredništvo časopisa CMJ časopisa Croatian Medical Journal http://mef.unizg.hr/cmj-svecano-obiljezavanje-25-obljetnice-osnutka-casopisa-croatian-medical-journal?bn 8. – 9. 12. 2017. Treća edukativna konferencija o Alzheimerovoj bolesti Hrvatska udruga za Alzheimerovu bolest „EdukAl 2017” – Zagreb, Hrvatska Zbornik sažetaka: https://edukal.alzheimer.hr/application/files/1715/2639/7808/Edukal_2017_zbornik-web.pdf

8. – 10. 12. 2017. Škola narodnog zdravlja „Andrija Štampar” Simpozij „Mladi i mentalno zdravlje: Slušam te” Medicinski fakultet Sveučilišta u Zagrebu – ljubav i mentalno zdravlje Agencija za odgoj i obrazovanje https://www.facebook.com/events/1191289831015107/ Međunarodna udruga studenata medicine Hrvatska (CroMSIC) Dom zdravlja Zagreb – Zapad Grad Zagreb 9. 12. 2017. Simpozij “Dan Frana Mihaljevića” – Sto godina Klinika za infektivne bolesti „dr. Fran Mihaljević” Medicinskog fakulteta Sveučilišta u Zagrebu http://mef.unizg.hr/100-obljetnica-mefa-simpozij-dan-frana-mihaljevica-sto-godina-medicinskog-fakulteta-sveucilista-zagrebu?bn 11. 12. 2017. 8. neuroanatomske vježbe – „Mali mozak” SSNZ 13. 12. 2017. Rhoton – Special session: Harvey Cushing and SSNZ birth of modern neurosurgery FIND OUT MORE! Gojković S. Rhoton Cranial Anatomy and Surgical Approaches Course. Gyrus. 2017;4(2):237-238. http://gyrus.hiim.hr/images/pdfgyrus/Gyrus12.pdf

14. 12. 2017. Promocija monografije Medicinskog fakulteta, MEF poštanske marke Hrvatske pošte te izložba udžbenika Medicinskog fakulteta „Knjige pričaju o 100 godina Medicinskog fakulteta” http://mef.unizg.hr/100-obljetnica-mefa-promocija-monografije-postanske-marke-udzbenika?bn 15. 12. 2017. Lecture – “Precision medicine in EGFR-mutated MEF non-small cell lung cancer” – Prof. Igor Štagljar, PhD

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15. 12. 2017. Prezentacija dokumentarnog filma o 100 godina MEF Medicinskog fakulteta Sveučilišta u Zagrebu Galerija fotografija: https://www.facebook.com/pg/studmef/photos/?tab=album&album_id=1935542426486403

16. 12. 2017. MEF Humanitarni koncert na Europskom trgu STUDMEF – završnica akcije „Medicinari velikog srca” Turistička zajednica grada Zagreba https://www.facebook.com/events/799012426951617/ http://mef.unizg.hr/100-obljetnica-mefa-humanitarni-koncert-europskom-trgu-zavrsnica-akcije-medicinari-velikog-srca?bn

17. 12. 2017. Svečana sjednica Fakultetskog vijeća MEF povodom 100. godišnjice Medicinskog fakulteta Sveučilišta u Zagrebu http://mef.unizg.hr/100-obljetnica-mefa-svecana-proslava-jubilarne-100-obljetnice-postojanja-medicinskog-fakulteta-sveucilista-zagreb?bn Galerija fotografija: https://www.facebook.com/pg/MedicinskifakultetZagreb/photos/?tab=album&album_id=137834063593917

18. 12. 2017. – 18. 2. 2018. Izložba „Tehnika i zdravlje Tehnički muzej Nikola Tesla u Zagrebu – Medicinska tehnika kroz povijest” http://mef.unizg.hr/100-obljetnica-mefa-otvorenje-izlozbe-tehnika-zdravlje-medicinska-tehnika-povijest-tehnicki-muzej-nikola-tesla-zagrebu?bn 20. 12. 2017. 9. neuroanatomske vježbe SSNZ – „Autonomni živčani sustav”

20. 12. 2017. Gyrus Božićno druženje ~ Gyrus i SSN SSNZ

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http://mef.unizg.hr/100-obljetnica-mefa-svecana-proslava-jubilarne-100-obljetnice-postojanja-medicinskog-fakulteta-sveucilista-zagreb?bn Galerija fotografija: https://www.facebook.com/pg/MedicinskifakultetZagreb/photos/?tab=album&album_id=137834063593917

http://mef.unizg.hr/100-obljetnica-mefa-otvorenje-izlozbe-tehnika-zdravlje-medicinska-tehnika-povijest-tehnicki-muzej-nikola-tesla-zagrebu?bn

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However, a considerable amount of time and effort has been invested in creating this journal in order to eradicate plagiarism and intellectual property theft of any nature whatsoever, as well as to prevent and correct any possible errors.

Human fetal brain 26 postconceptional weeks, Alcian section through the middle of the hemisphere at the level of thalamus showing extracellular matrix (blue). This image is property of Zagreb Neuroembriological Collection, Croatian Institute for Brain Research, University of Zagreb School of Medicine. For details see Kostović et al. 1991; Judaš et al. 2011.

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Human brain frontal lobe, 6 years old child; Gallyas staining showing axonal bundles entering cerebral cortex. This image is property of Zagreb Neuroembriological Collection, Croatian Institute for Brain Research, University of Zagreb School of Medicine. For details see Kostović et al. 1991; Judaš et al. 2011.

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news and education NEUROSCIENCE FOR ENGINEERS, KSET NEUROZNANOST ZA INŽENJERE, KSET

Krešimir Friganović, mag. ing., assistant at the Department of Electronic Systems and Information Processing University of Zagreb, Faculty of Electrical Engineering and Computing

Brain-computer interfaces (BCIs), explo- School of Medicine, organized lectures sion with the audience brought up many ration of mind and thoughts, and tenden- hoping to give students of electrical engi- interesting questions and ideas. Special cy to understand brain in the same way neering and computing a basic introduc- guest of the first lecture was Professor as we understand computer machines tion to brain functions and morphology, Mario Cifrek, PhD, who has mentored are topics undergoing intense studies and vice versa – to give medical students many students on their master and doc- (well-known companies, such as Face- a basic introduction to techniques be- toral thesis on this subject (vol.12(2) 2017 book, revealed plans on investigating hind brain-computer interface systems. of “Engineering Power”, bulletin of the the subjects, such as the possibility of Croatian Academy of Engineering, is ded- typing by thoughts). This research field is On May 2nd and June 8th, two lectures icated to the topic “Brain electrical sig- multidisciplinary, meaning that advance were held in crowded students’ club KSET nals – measurement, processing, analysis, knowledge of computer science and en- by Nikola Prpić, a medical student, and and application”, with prof. Cifrek as the gineering, as well as neurology and neu- Krešimir Friganović, a PhD student at Guest-Editor). Prof. Cifrek held a greet- roscience, is needed. Often students don’t the Faculty of Electrical Engineering and ing speech and expressed his joy over so have the opportunity, or time, to study Computing, both members of KSET. many students attending lectures of this subjects that aren’t in the main scope of type, held by students for students. their faculty’s curriculum. To try to bridge The topic of the first lecture was a basic that gap, the Electrical Engineering and introduction to neuroscience, while the In the future, KSET is planning to reor- Computing Students’ Club (known as second lecture was mainly focused on ganize “Neuroscience for Engineers” by KSET, Cro. Klub studenata elektrotehnike), brain-computer interfaces and the mech- turning lectures into workshops, in order together with the Student Society for anism behind the bioelectrical activity to provide students with practical knowl- Neuroscience at the University of Zagreb of the brain. After each session, a discus- edge and experience in BCI field.

FIND OUT MORE:

Kugelman V. New advances in brain-computer interface (BCI) tech- Figure 1. Greeting speech (Prof. Mario Cifrek, Krešimir Friganović, Nikola Prpić). nologies. Gyrus. 2017;4(2):186-190. Copyright © 2017 Fotosekcija KSET-a gyrus | vol. 4 | no. 3 – 4 | july – december 2017 264 sleep disorders timeline TEDDY BEAR HOSPITAL

Matea Škoro University of Zagreb, School of Medicine

Iva Topić University of Zagreb, School of Medicine

Although we still do not know everything dy Bear Hospital, a project organized by The physicians who work there have a lot of about its neurobiological background, fear two student associations – EMSA Zagreb instruments and medicines which allow is an emotion known even to the youngest (European Medical Students’ Association them to diagnose and treat just about each of children. Red face, swollen eyes, “vocal Zagreb) and SSHLZ (Student Society of the and every disease, ranging from sore throat chords training” and hiding behind parents’ Croatian Medical Association). This Hospital to an injured leg. They always make time legs is a common sight in the practice of is specially designed for preschool children not only for teaching children about the almost every doctor who works with children. as the most sensitive health care users, with importance of washing their hands and the aim of introducing them to basic medical teeth, healthy diet, sports, but also for short That’s why a specially designed mobile procedures, eliminating fear of white coats, conversations about their best friends and hospital, which specializes in treatment of and overcoming barriers between doctors favourite cartoon characters. After the visit, these serious problems, was established. Its and toddlers through playing and treating each child receives a special “Courage Di- waiting list is short and the waiting room plush toys. ploma” by Teddy Bear Hospital Zagreb for is always filled with patient little patients. recognition and as a reminder of their own Their doctors are professionals who receive The Teddy Bear Hospital Zagreb visits Za- courage during the treatment of their toy. an unique and most valuable form of pay- greb’s kindergartens throughout the aca- ment – a child’s smile – as a reward for their demic year and, once a year, it hosts children We are especially proud of and grateful to work. If you are tempted to give up on your and their plush toys in Zrinjevac Park. Be it our doctors. All of them are students at the dream of becoming a neurosurgeon and in their kindergartens or at Zrinjevac Park, University of Zagreb School of Medicine, who decide to pursue this career path, the fact all patients must first spend some time in dedicate their spare time to our cause and that a doctor’s job in this hospital requires the waiting room and wait for their turn. who are happy to volunteer with children. nothing more than good will and free time As soon as a doctor is available, a plush toy The project’s emphasis is on children’s fear, might feel liberating. This is about the Ted- and his little escort enter the doctor’s office. however, young physicians also experience

Figure 1. Official event poster of Teddy Bear Hospital Zagreb that took place at Zrinjevac Park on May 27, 2017. (Teddy bears are wondering who is still afraid of the doctor.) Copyright © 2017 TBH Zagreb

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timeline the same emotion, as they are deeply con- cerned about the right approach to a child who is frightened. Therefore, this project also helps future doctors tailor their approach to pediatric patients and improve their communication skills.

As this is a nonprofit student volunteer project, the assistance of the School of Medicine in Zagreb, which has recognized the potential and effort of the Hospital and which supports this project from the very beginning, is of vital importance.

Finally, once all patients are cured and the equipment and medicaments carefully stored in pink medical bags, the doctors can finish their shifts. Cheerful faces and the sound of children’s songs that remain in their ears for the rest of the week are the best rewards for a job well-done. Figure 2. “Courage Diploma” received for recognition and a long memory of courage in treating plush toys. Copyright © 2017 TBH Zagreb “Doctor, I’m scared of the needle I’m afraid I’m gonna shut my eyes Above the fear I will rise!”

Figure 3. Teddy Bear Hospital Zagreb, Zrinjevac Park. Copyright © 2017 TBH Zagreb gyrus | vol. 4 | no. 3 – 4 | july – december 2017 266 sleep disorders timeline UTRECHT SUMMER SCHOOL: NEURAL CIRCUIT DEVELOPMENT AND PLASTICITY

Nikola Prpić University of Zagreb, School of Medicine

University of Utrecht is located in the small was designed as a series of 3 lectures in the from axonal growth cones to novel research town of Utrecht south-east of Amsterdam, morning and a workshop in the afternoon techniques. Lectures combined a useful just 20 minutes by train. From 10th to 15th aimed primarily at master and PhD students overview of current research and the labs of July the University organized a set of Sum- from all over the world. Lectures were held best practices and techniques. Afternoon mer schools covering all areas of academ- by international scientists and principal workshops ranged in style so there was time ia, including several neuroscience schools. investigators from well known universities to get to know the lecturers, experience life Neural Circuit Development and Plasticity such as University of California San Diego, in Utrecht’s laboratories and come up with course was set up by Jeroen Pasterkamp and Oxford, University College London – all work- and present a unique research proposal on his colleagues working in neural plasticity ing in cellular biology and neural plasticity. Friday 15th. Perhaps the most impressive and axonal growth. The summer school Each day covered a different topic ranging part of the summer school were the super

Figure 1. STED vs Confocal microscopy. Source: Stimulated Emission Depletion Microscopy (STED) | PicoQuant. https://www.picoquant.com/applications/category/life-science/sted. Accessed August 12, 2017.

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timeline resolution lectures covering new STORM and the diffraction limit of light microscopes. STED microscopy techniques. Both have res- On the other hand Stimulated Emission olution far better than confocal microscopy, Depletion (STED) provides real-time su- however each with its own problems. During per resolution microscopy by deactivating Stochastic Optical Reconstructive Microsco- neighboring fluorophores thus increasing py (STORM) the specimen is suspended in its resolution while working with normal a special buffering solution allowing the buffering solutions and in real time. The fluorescent molecules to emit photons in- summer schools will be held again the next termittently rather than continuously. This summer and everyone is invited to join. procedure allows the cameras to capture point-spread functions of light-emitting molecules and, using postprocessing, artifi- cially pinpoint the position of the molecule. Superimposing processed photos taken in time give a much clearer image bypassing

Figure 2. STORM and conventional microscopy. Source: There’s a STORM brewing! – Science Brainwaves. http://www.sciencebrainwaves.com/theres-a-storm-brewing/. Accessed August 12, 2017. gyrus | vol. 4 | no. 3 – 4 | july – december 2017 268 sleep disorders timeline 6TH CROATIAN NEUROSCIENCE CONGRESS 6. HRVATSKI NEUROZNANSTVENI KONGRES

Ivan Mlinarić University of Zagreb, School of Medicine

Barbara Tomić University of Zagreb, School of Medicine

The 6th Croatian Neuroscience Congress with in Health and Disease” and Presidential and Department of Neuroscience at the International Participation (Cro. 6. Hrvatski Symposium “From Molecules to Cortical Johns Hopkins University School of Medicine neuroznanstveni kongres s međunarodnim sud- Maps” were also held within the Congress. (Baltimore, USA). His lecture was entitled jelovanjem) was held in Osijek, Croatia, from There were also two poster sessions, with “Gangliosides in axon stability, regeneration September 16th to 18th, 2017. Its organizers posters divided in several groups: basic and synaptic plasticity”. were Croatian Society for Neuroscience, neuroscience, clinical neuroscience, cogni- Department of Anatomy and Neuroscience tive neuroscience, molecular neuroscience, Lecturers of the Presidential Symposium and Department of Medical Biology and neurodegenerative disorders, neurodevel- were esteemed guests: Professor Paško Genetics at the Josip Juraj Strossmayer Uni- opmental basis of cognitive, mental and Rakić, MD, PhD (Yale University School of versity of Osijek Faculty of Medicine, Croatian neurological disorders, neuropharmacology, Medicine, New Haven), Associate Professor Academy of Sciences and Arts, and Croatian and sleep. Mladen-Roko Rašin, MD, PhD (Department Brain Council. of Neuroscience & Cell Biology, Rutgers Presidential lecture of the 6th Croatian Neu- University, Robert Wood Johnson Medical International Society for Neuroscience roscience Congress was held by Professor School, New Jersey), Professor Emeritus Symposium “Frontiers in Neurochemistry: Ronald L. Schnaar, PhD, from the Department Harry Uylings, PhD (Department of Anatomy Crosstalk of Membrane Proteins and Lipids of Pharmacology and Molecular Sciences and Neurosciences, VU University Medical

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Center, Amsterdam) and Professor Karoly Mirnics, MD, PhD (University of Nebraska Medical Center, Omaha, and director of the Munroe-Meyer Institute).

The Welcome Cocktail was held at the Mu- seum of Fine Arts (Cro. Muzej likovnih umjetnosti) were we had the opportunity to make acquaintances with other participants of the Congress while enjoying “Traces” (Cro. “Trago- vi”) art exhibition by Lana Ključarić. Another opportunity to meet other participants, as well as enjoy delicious local cuisine was at the Farewell Dinner, held at the Hotel Waldinger Restaurant and Lounge Bar.

During the third day of the Congress, a half an hour lecture called “Students in neuroscience” was held by the members of Student Societies for Neuroscience, both from Osi- jek and Zagreb. Work and achievements of our students, especially within the Student Academic Journal Gyrus, were presented by Barbara Tomić, Editor-in-Chief, and Ivan Mlinarić, Deputy Editor-in-Chief.

We would like to thank our professors and mentors for giving us this unique opportunity to enjoy first-class neuroscience. Our special thanks go to Professor Marija Heffer, MD, PhD, President of the Organizing Committee of the 6th Croatian Neuroscience Congress with International Participation, for her hospitality.

Figure 3. During our time in Osijek, we were enjoying in Osijek’s beautiful architecture, culture and landscape. a) Old hospital building (today a part of the University Hospital Center Osijek) b) Pedestrian bridge. Copyright © 2017 Gyrus gyrus | vol. 4 | no. 3 – 4 | july – december 2017 270 sleep disorders timeline ZOOM INTO THE PSYCHE ZOOM NA PSIHU

Ana Kraljević University of Zagreb, Faculty of Humanities and Social Sciences, Department of Psychology

Sara Lončar University of Zagreb, Faculty of Humanities and Social Sciences, Department of Psychology

Zoom na psihu (Zoom into the psyche) is a discussion which would hopefully raise be evoked with friendly communication. We project firstly established by psychology awareness about psychological diseases, soon realized that we have more in common students from the Faculty of Humanities and diminish the stigma people who have than we initially presumed. and Social Sciences in Zagreb. Our initial such diseases are burdened with. The second week of our project started with idea arose from the discussion about the Our project started in May 2017, when we a series of lectures about different types of frequently negative and inaccurate portrayal held the first workshops in which all team psychological disorders, such as ADHD/ of mental diseases and people with psy- members, especially psychology students ADD, autism, schizophrenia, depression, chological disorders within popular media and photographers, had a chance to meet anxiety and eating disorders, which were such as films, series, and social media. We each other and exchange ideas and knowl- organized by psychology students with the realized, since popular media do have a rapid edge from their fields of expertise. During help of their professors. During that period and great impact on a wide population, that that week psychology students prepared the psychology students created an open in fact it should be used to educate, inform lectures and workshops dealing with topics and educational environment, which was and destigmatize. Since all of us do respond from their field of study that could have had soon filled with different questions about to visual stimuli more actively than to any a practical use to photographers (nonverbal certain myths and misconceptions about other, the combination of psychology and and verbal communication, motivation and psychological disorders and the role popular photography should be able to create the creativity). Photographers organized lectures media plays in creating such an image. biggest impact. which improved the team’s knowledge and Since our goal was to create a different The main aim of our project is to create series skills in photography. The lectures were “image”, an image which will portray the of photographs with the cooperation of our followed by interesting discussions about facts about psychological disorders and multidisciplinary team (psychology students photography and its purpose as an art form, how people live with them daily, we felt and professors, acting and photography as well as the motivation that lies behind that our team was now ready to create a students, photographers, and people with each photographer’s enthusiasm: their at- series of photographs which will aid the psychological diseases), followed by their tempts to capture the essence of a human, destigmatization process of our society. exhibition, and accompanied by an open their personality which at certain times must We thrive to leave an impact on the public, not only with the upcoming exhibition but also through our social network engagement on Facebook and Instagram. Our goal is multidimensional, the priority is to raise awareness and educate the public on the presence and variety of psychological disorders in daily life, as well as to remove the taboo from the need to ask for professional help. We find it very important to show the functionality and beauty of people that deal with psychological diseases, and in this way remove the stigma not only from the very disorder but the person as well. We do not wish to present psychological disorders as something romantic, fun and attractive, nor do we tend to label such people as abnormal or socially maladjusted. What we hope is to make the public realize with the help of the powerful media, photography, that psychological disorders are one of the many human sub-dimensions. People themselves Figure 1. At the end of the last day everyone shared their experiences and by tossing a wool ball are not responsible for having a psychological created a web which symbolizes all the new friendships that we created. disorder, and they do suffer in certain situa- Copyright © 2017 David Petar Balaban tions, but they also cope and live with their

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timeline disorders, and that in fact, their coping and general quality of life will definitely be less difficult if they live in a well informed and destigmatized society. It is somehow easier for all of us to understand and sympathize with people who deal with visible, physical wounds, but to glance into someone else’s mind, to zoom in, hear and understand their pain, is what requires humanity and empathy which we all possess. Our project is nothing but an attempt to awaken these human Figure 2. Having a blast during teambuildings characteristics of ours. between workshops. On the photo: Matej Sušanj, psychology student. Copyright © 2017 Lorna Kijurko

Figure 4. Stela Vilhar, psychology student, held a workshop about the dark triad. Copyright © 2017 Philipp Tomaš gyrus | vol. 4 | no. 3 – 4 | july – december 2017 272 sleep disorders timeline BOOK / MOVIE REVIEW

Golgi slide of human fetal brain showing stained blood vessels (black lines) and astrocytes (cells with stellate processes). This image is property of Zagreb Neuroembriological Collection, Croatian Institute for Brain Research, University of Zagreb School of Medicine. For details see Kostović et al. 1991; Judaš et al. 2011.

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book / movie review A DIFFERENT BRAIN

Emina Horvat Velić University of Zagreb, Faculty of Science, Department of Biology 0000-0002-8861-2719

“A different brain” is an hour-long BBC docu- “A different brain” is his latest take on the that is unfortunately not possible. Their reha- mentary by the appraised British television complicated subject, and in it, he explores bilitation is exhausting, and even though it presenter Louis Theroux. Theroux is famous the lives of patients who suffered a sort of is helpful in some aspects, the documentary for his many documentaries that explore traumatic brain injury that caused direct shows us that there are obstacles modern unusual and controversial topics, such as damage to the brain which further caused medicine still cannot do. Medical profession- different aspects of religion, religious sects, unusual and odd behaviour in those pa- als are just minor characters in this movie, diverse lifestyles, and otherwise intriguing tients. In all four patients followed through and patients’ conditions are not explained on subjects. His documentaries are easy to the documentary, we observe them exhibit any scientific level, apart from mentioning watch and strive to bring understanding of new behaviour and the way it affects their what kind of brain trauma happened (a car the topic to the public, often to raise aware- families and loved ones. As with his previ- crash, a fall during horseback riding, etc.). ness and educate the masses. However, that ous works, Theroux’s calm demeanour often Although many documentaries strive to raises the question of legitimacy and depth helps in diffusing possible conflicts, and his present the possible outcomes and hope, “A of his work, since making and producing presence is minimal – he only helps steering different brain” only records events as they such a large number of movies (of any kind) the conversation and lets them explain them- happen, and tries to present what patients could mean the lack of quality or insufficient selves and share their wishes for progress. are going through, without some grand preparation in research and execution of Without spoiling the cases, some scenes conclusion in mind. Still, it works, because it the task at hand. are simply heartbreaking to watch, but still gives us the rare grasp of the family struggle Lately, Theroux focused on the human brain show helpful insight into the lives, suffering, – how to unconditionally love and support as well, with two documentaries about au- and everyday problems of people who fight a person who is fundamentally changed? tism and dementia (Extreme Love: Autism to become independent individuals again, and Extreme Love: Dementia). despite us viewers knowing something like

Figure 1. Louis Theroux. Source: Image “Louis Theroux at Nordiske Medied- ager 2009” by Nordiske Mediedager, modified by Zscout370 – from Wikimedia Commons, public domain. https://commons.wikimedia.org/?curid=10008707 Published April 14, 2010. Accessed November 16, 2017. gyrus | vol. 4 | no. 3–4 | july – december 2017 274 sleep disorders timeline INTERVIEW

Human brain midbrain region, late embryonic period, Golgi staining showing early glial cells. This image is property of Zagreb Neuroembriological Collection, Croatian Institute for Brain Research, University of Zagreb School of Medicine. For details see Kostović et al. 1991; Judaš et al. 2011.

INTERVIEW WITH RAPHAEL BÉNÉ

Nikola Prpić University of Zagreb, School of Medicine

1) TELL US YOUR LIFE STORY! in the field of neurology, especially neurore- very proud of my cooperation with Professor WHAT ARE YOUR RESEARCH habilitation, which caught my interest, with Krešimir Ćosić of the University of Zagreb Professor Vida Demarin, FCA. Medicines treat Faculty of Electrical Engineering and Com- GOALS? the damaged part of the brain, but we, as phy- puting and Professor Zdravko Radman of I was born in 1980 in São Paulo, Brazil, and sicians, also have to take care of the healthy the Institute of Philosophy, Zagreb. lived there for a year and a half. After that I part of the brain, create new synapses and went to Lyon. My dad’s French. When I was use neural plasticity. Twitter is of great help because it makes it 20, I moved to Croatia. My mother’s Croatian, easy to connect with other scientists who from Split. I began studying medicine at the I currently teach Fundamentals of Neuro- are exploring different areas of neuroscience. University of Zagreb School of Medicine in science, Fundamentals of Medical Skills and The other thing that is of help to me is “MIND 2000. Two years later, after I had passed the Medical Ethics courses in Medical Studies in & BRAIN – International Neuropsychiatric Fundamentals of Neuroscience exam, I be- English (MSE) program at the University of Congress” in Pula, Croatia, which I am for- came a student teaching assistant. I started Zagreb School of Medicine. tunate enough to be a part of. This is where working in neuroscience with Professor Mi- neurology and psychiatry collide. They are loš Judaš and I won the Rector’s Award for My idea is to connect neuroscience and com- both on the same spectrum and this is best my work at the Croatian Institute for Brain munication, to find out how to activate brain illustrated by V. S. Ramachandran. Research (CIBR) in 2006. After earning my structures using verbal communication and MD and finishing my internship, I worked use placebo effect to help my patients. I’m

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interview

2) HOW DID YOU DECIDE TO the music industry started contacting us and for us, there are a lot of world-class athletes STUDY MEDICINE AND WHY saying they can finally listen to music normally. in Croatia. We had been missing a way to When you’re working with tinnitus, you come combine EEG and video, so Ivan Fabek de- DID YOU CHOOSE CROATIA across a lot of pseudoscientific approaches, veloped Brainalyzer, which we used to record OVER FRANCE? but ours is based in neuroscience and that is top both athletes and amateurs. Right now why we have such good results. we’re looking for EEG patterns that appear Ever since I was a boy I knew I wanted to during their activities and we are trying to work in medicine. My grandfather was Duško Another therapy we are developing at Core help athletes reach their maximum potential. Katunarić, MD, PhD, a radiology specialist, a Interface is mirror therapy, which V. S. Ram- Professor at the University of Zagreb School achandran described in his book Phantoms in The Core Interface team was recognized as of Dental Medicine and a famous water polo the Brain: Probing the Mysteries of the Human one of top 20 neuroscience startups in 2015. player. He implanted this passion in me. When Mind in 1998. The therapy is based on the sym- Our team was the only one out of 20 teams I was 15 or 16, I lived in Lyon and my biology metrical properties of our body movements, that wasn’t based in the USA. We were also teacher showed me how fascinating the brain which are lacking in patients who suffered a named one of the top 50 most innovative is and that’s when I knew neuroscience was stroke. We put a mirror in the medial sagittal companies in sports in 2016, which is a great my discipline. However, I was always fasci- plane in front of patients, and we tell them to achievement for us. nated by the fact that my grandfather was a repeat the same movements with both arms. Professor in Croatia. Croatia is a wonderful Because of the mirror, patients, while looking 4) WHAT ARE YOU MOST country. If I had stayed in France, I don’t know at their healthy arm, have a feeling they are PROUD OF? if I would have had opportunities like this. I moving their disabled arm, thereby targeting was lucky enough to work with world-class neural networks around the unhealthy cortex. I’m most proud of my family and my children. scientists like Professor Judaš, who has taught Patients have great responses to this form of This isn’t connected to neuroscience, but they me a lot and opened a lot of doors for me. Pro- therapy. They often say: “I finally feel like I’m always come first. On the other hand, I’m fessors Judaš and Demarin sucked me into exercising my brain and not my arm.” Using also very proud of my team and how we’ve this world. Ever since then I’ve been reading these mirrors we accomplished something managed to connect different disciplines and a lot of books related to neuroscience, such no one else had. We devised a rehabilita- create our startup. as In Search of Memory: The Emergence of a New tion system for paraplegic patients in which Science Of Mind by Eric R. Kandel. patients look at their therapists’ hands and 5) DO YOU HAVE A MESSAGE think they are their own. We are working with FOR OUR READERS? 3) TELL US ABOUT CORE the Special Hospital for Medical Rehabilita- INTERFACE! tion Varaždinske Toplice and developing a Being an MD makes you very interesting video-based scale that will take less time to to investors, especially if you work with the During my first Anatomy class I met and be- assess motor function than currently most brain. My advice to everyone who has plans came best friends with Natko Beck, who later used Fugl-Meyer Assessment (FMA) scale. to become a researcher in Croatia is to work became a specialist in radiology. We always abroad, at least for a little while, to see how talk about how to combine medicine and On our sports side, we have joined forces with research is done in places outside of Croatia. technology. Technology progresses very fast Ivan Fabek, an electrical engineer who is ac- They could learn a lot. The main problem here and medicine is struggling to keep up with it. tively engaged in EEG analysis and has already is that everything moves at a slow tempo and We are especially interested in brain-comput- amassed a lot of experience in this field, and there is a lot of bureaucracy, but, with enough er interfaces. They are our passion. The science Marin Mindoljević, a great basketball player enthusiasm and patience, you can establish behind them is fascinating. Core Interface and coach. We’ve also been cooperating with your own lab and succeed in Croatia. Proac- was founded at the end of 2014. We created a fitness center. Until recently, our focus has tivity is the key to success. a couple of methods for encouraging and di- been on radiology, but now we also record recting neural plasticity. The startup has two athletes’ EEG using neurofeedback. Luckily branches, the medical one and the sports one.

On the medical side, our greatest success is tinnitusOFF, as can be seen in the newspa- pers and on television. Tinnitus is a disorder in which some receptive cells in the ears become “nutty” and the person hears a constant buzzing. A couple of articles came out that stated that, while listening to music using FIND OUT MORE: top-down and bottom-up regulation, the brain neuroplastically integrates this noise Nedeljković V, Staničić A. Start-up in medicine. Gyrus. 2017;4(2):137-138. and corrects the disbalance of the whole au- Kugelman V. New advances in brain-computer interface (BCI) technologies. Gyrus. ditory receptive system. Around 280 people 2017;4(2):186-190. with tinnitus downloaded our app with in- Both available at: http://gyrus.hiim.hr/index.php/2016-01-10-18-08-09/arhiva/ credible results and that’s how we’ve managed details/4/15. to create a large base of them. People like listening to music via our app and they say Follow the link to learn how TinnitusOFF works: it’s more pleasant that way. What surprised https://www.youtube.com/watch?v=HCV0ZQKPF5g us most is when DJs and people working in gyrus | vol. 4 | no. 3 – 4 | july – december 2017 276 sleep disorders case report CASE REPORT

Human fetal brain at the level of hippocampus, 26 PCW; Nissl staining showing neurons and glial cells. This image is property of Zagreb Neuroembriological Collection, Croatian Institute for Brain Research, University of Zagreb School of Medicine. For details see Kostović et al. 1991; Judaš et al. 2011.

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case report Batelić Dragić R. New concepts in rehabilitation of children with cerebral palsy. pp. 278 – 284 NEW CONCEPTS IN REHABILITATION OF CHILDREN WITH CEREBRAL PALSY

Rašeljka Batelić Dragić, dipl. physioth. E-mail: [email protected] 0000-0002-0623-6706

ABSTRACT

Cerebral palsy is a major burden for the affected person, their family, health insurance, educational institutions and society in general. In the past few years, new rehabilitation concepts which could offer better results on the activity/participation level and better functional skills of everyday life are being discussed. The Therasuit® therapy is a new concept in rehabilitation, based on the theory of motor learning and motor control, individualized progressive strength training, primitive reflex integration, used in combination with other well-known neurophysiotherapy techniques. A case study outcome using Therasuit® therapy on a 7.5-year-old child with spastic cerebral palsy, one month after multiple Ulzibat fibrotomy, will be presented in this article.

Keywords: cerebral palsy, strength training, primitive reflex integration, Therasuit®

INTRODUCTION

Cerebral palsy (CP) is a common name used The main goals and problems of rehabilita- However, new evidence has been found that for different disorders of the postural system tion dealing with the described population isolated strength training with increased caused by a non-progressive damage to the are multiple and the number of different replication of motoric tasks and activities brain in its early stages of developement.1 types of intervention used around the world does not increase spasticity13,14 nor co-con- Around the world, a large number of children is very large, starting with drugs, orthopedic tractions of antagonistic muscles,15 but in- are diagnosed with CP, about 1.5 to 4 on 1000 procedures, orthotics, occupational therapy, stead normalizes the muscle tone and pos- live births. In the USA, 10.000 children are speech therapy, cognitive-behavioral thera- itively affects walking, functional activities diagnosed with CP every year.2 The preva- py, neurofeedback, nutritionism, different and participation.14-18 lence in Europe is the same as in the rest of alternative treatments and physiotherapy, When speaking of reactions commonly the world and the epidemiological data for which includes hydrotherapy, hippotherapy known as primitive reflexes, traditional Croatia are poor and incomplete, but can be and neurodevelopmental concepts such as theories define them as primitive reactions compared with the rest of the world.3,4 Re- Bobath,7 Vojta,8 Doman-Delacato,9 Jane Ay- which must be cortically inhibited through search shows that 77.4% of children with CP res’ Sensory integration10 and many others. normal development.8,10,19 New theories such have spasticity or hypertonic musculature, Research in rehabilitation of children with as the Masgutova’s theory,20 which is based 35–50% have epileptic seizures and some CP has been focused on physiotherapy in- on the physiological research conducted level of mental retardation, difficulties with terventions, strength training methods and by Pavlov, Sechenov, Vygotsky, Bernstein, learning, sight, hearing and speech. 6.9% of treatments since the ‘60s of the past century. Sherrington, Luria and Anokhin, give evi- affected children show symptoms within the In the past two decades, researchers’ in- dence that primitive reflexes, besides their autistic spectrum and 40–45% display poor terest has been piqued by new controver- protective role, also play a very important coordination and motor control, which lim- sial methods based on new theories about role in supporting neurogenesis, synapto- its them in participation and activities such strength training and the integration of genesis, and myelination, as neurophys- as crawling, independent walking, running primitive reflexes. iological foundation for higher levels of and playing.5 A study reported that 31% of Karol and Berta Bobath and many other ther- motoric, emotional and cognitive devel- children with CP use special equipment like apists who followed their theories, stated opment. Masgutova stated that primitive walkers, crutches or wheelchairs.6 that isolated strengthening of spastic mus- reflexes are always present as genetic codes CP represents a major burden for the affected cles could lead to increased co-contractions, or natural afferent-efferent motor patterns child, the family, health insurance, educa- spasticity and associated reactions with which are not inhibited by cortical develop- tional institutions, and society in general.4 consequences of poorer motor control.7,11,12 ment, but integrated as a link between lower gyrus | vol. 4 | no. 3–4 | july – december 2017 278 sleep disorders case report Batelić Dragić R. New concepts in rehabilitation of children with cerebral palsy. pp. 278 – 284 and higher centers of our central nervous connected to facilitate or inhibit muscle Indications: system during its development.20,21 Associ- activity. The suit with rubber cables gives a 1. CP ated reactions, according to the primitive strong proprioceptive input and loading at 2. Developmental delays reflex integration theory, can be defined as the same time. The theory behind the suit 3. Balance and coordination delays and reflexive genetically conditioned answers therapy is that it induces a strong afferent, disorders that emerge when the nervous circuits have proprioceptive input which stimulates the 4. Traumatic brain injury been disrupted. This disruption inhibits the formation of cerebral systems whose post- 5. Stroke next level of sensory-motor development natal development has been delayed. The 6. Hypertonicity and cognitive function. Masgutova’s theory elastic cables provide the body and articu- 7. Hypotonicity practitioners commonly call the primitive lations with a vertical loading of about 15 to 8. Dyskinesia: ataxia, athetosis and dystonia reflexes the missing link in the facilitation 45 kg (33 to 88 pounds), which is significant 9. Non-progressive neurological disorders of development.21 to patients that have no appropriate stimu- and syndromes: spina bifida, spinal cord New theories about isolated strength train- lation from their own soft tissue because of injury, Down syndrome ing and the integration of primitive reflexes abnormal muscle tone. The Therasuit® with complement and enrich the neurophysiolog- its individualized placing of rubber cables Contraindications: ical concepts, such as Vojta, Bobath, propri- becomes a dynamic orthosis which can give 1. Progressive and genetic metabolic oceptive neuromuscular facilitation (PNF), support and stabilize correct posture in a syndromes P. and G. Dennison and Ayres.21,22 natural way. At the same time, it facilitates 2. Severe degeneration of bones and and strengthens correct functional patterns articulations The Therasuit® concept of movement by providing dosed resistance. 3. Severe osteopenia/osteoporosis Along with new evidence of the effective- The concept of the described intervention fol- 4. Loss of integrity on the level of body struc- ness of strengthening exercises for children lows neurophysiological principles, training ture (severe subluxations, scoliosis and with CP, new concepts have begun to devel- theories and antioxidant diet principles to structural fixed contractures) op. The Therasuit® concept was developed support the functioning of the neural tissue in 2002 by husband and wife Izabela and and the musculoskeletal system. It is also Precautions: Richard Koscielny, parents of a child with characterized by a constant increase of the 1. Hypertension, hemodynamic disorders CP, who are both physiotherapists from Po- number of exercise repetitions, increase of 2. Uncontrolled epileptic seizures land. The Therasuit® concept was based on resistance and change of contraction types.23 3. Subluxations the idea of Russian researchers in 1971 and According to the Koscielny physiotherapists23 4. Metabolic disorders their modified version of a cosmonaut suit the positive effects, indications, contraindi- 5. Hydrocephalus (VP shunt) called “Penguin”, developed to prevent the cations, precautions and goals of the Thera- 6. Kidney damage detrimental effects of hypokinesis in the suit® treatment are the following: 7. Poor bone mineralization weightless conditions in space. 8. Status post botox or alcohol injections Therasuit® is a rehabilitation concept that integrates different manual, myofascial Positive effects: Goals: and neurodevelopmental techniques in the 1. Provides deep proprioceptive and tac- 1. Support for weak structures (trunk) Universal Exercise Unit (UEU) (Figure 1) that tile input 2. To provide resistance (for deeper proprio- accentuates progressive strength training 2. Stimulates the reorganization of the cen- ceptive input and strengthening) and repetitive functional activities while tral nervous system 3. Reeducation of pathologic synergies and wearing a specially designed suit. The pro- 3. Enables ontogenic development and cen- patterns of movement gram is highly intensive because it is carried tral activation 4. Facilitation of new functional and eco- out for five days a week, 3–4 hours a day and 4. Enables external activation of muscles nomic patterns for at least 3–4 weeks. needed in stabilization 5. Reflex integration According to the Therasuit® concept, the pa- 5. Normalizes muscle tone providing the tient is first prepared with manual, myofas- sense of center of gravity, inhibiting hy- cial techniques, massage, soft tissue mobili- pertonicity, affecting vestibular nuclei The Therasuit® was approved by the Ameri- zations, activation of core muscles and reflex and activating postural muscles can Food and Drug Administration (FDA) and integration. The preparation is followed by 6. Changes posture the Brazilian National Health Surveillance intensive isolated strength training in the 7. Provides dynamic correction Agency (ANVISA) registered Therasuit® as UEU. The UEU is a three-dimensional cage 8. Corrects patterns of walking and move- a medical device. that serves as a suspension and pulley system ment in general in which every movement and muscle group 9. Affects balance and coordination can be isolated and gravitational forces elim- 10. Affects uncontrolled movements in ataxia, inated. The system facilitates the patient in athetosis and dystonia motor learning and increasing the range of 11. Supports the control of the head and trunk motion, centimeter by centimeter, through 12. Affects the density and mineralization concentric, static and eccentric contractions of bones through dynamic activation of against or/and without the gravitational muscle groups force. The strength training is continued 13. Contributes to conversion of muscle fibers wearing the Therasuit® special suit, which serves as an exoskeleton made of a vest, shorts and additions for the head, elbows, wrists and knees with rubber cables that can be

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case report Batelić Dragić R. New concepts in rehabilitation of children with cerebral palsy. pp. 278 – 284 CASE STUDY

Name/Surname: N. N.* Gender: M Diagnosis: CP, tetraparesis spastica, GMFM III

Anamnesis: The patient is a first child and child. At the age of 10 months the subject was Six weeks after the operation the child start- born from the mother’s first pregnancy. able to rotate from supine to prone position ed an intensive rehabilitation program based Mother* and father* are both healthy and without selectivity of movement. When he on the Therasuit® concept. without medical history. At 8 weeks of ges- was 1 year old, he was crawling using bent tation the mother was hospitalized due to elbows and legs in extension and by the age First evaluation before Therasuit® vaginal bleeding, after which the pregnancy of 2 he was able to maintain diagonal sitting treatment: was without complications. The child was position, stand on all four limbs and move Functional diagnosis: hypertonus (pro- born in term via cesarean section because of with poor coordination and jumping. At the nounced on lower limbs), lack of muscle pelvic presentation. Birth mass was 3000 g, age of 3 the subject was able to crawl with strength postoperatively (Ulzibat fibrotomy), birth length 50 cm, and Apgar 9/10. When better coordination, but with lower limbs in poor balance during walking. he was 2 months old, the child underwent internal rotation and equinovarus of both Six weeks after fibrotomy, the subject is an ultrasound examination of the head feet. At the age of 4 he was able to maintain able to crawl with internal rotation of lower because of hypertonicity and the findings high kneeling position and at the age of 5.5 limbs and feet above the ground. He stands were within normal limits, without visible he finally started walking in a tetraparetic up independently with the right leg in front, abnormalities. pattern with legs in internal rotation and which is in adduction and internal rotation. When he was 4 months old, a specialist tiptoe support. Since then, the subject was He is unable to do it with the left leg. He is of physical medicine and rehabilitation at able to walk with very poor balance just for also able to walk several meters (4–5 m) the University Hospital Center Osijek (at a few meters with high risk of falling and with internal rotation and adduction of that time Clinical Hospital Osijek) reported upper extremities always in abduction. He both legs, left heel above the ground, and that the child had poor spontaneous gen- needed a wheelchair for appropriate mo- upper limbs in abduction, which is causing eral movements, undeveloped radiopalmar bility for distances longer than 2 meters. him to lose balance and fall. The boy stands grasping on the left hand, that his head did The subject was constantly undergoing a up from a stool by swinging the upper limbs not follow the trunk in traction, and that complex rehabilitation program with NDT and knees together. elevated muscle tone of lower limbs was Bobath, Vojta, Halliwick and equine-assisted Observing the posture in frontal and sagittal found. Consequently, it was recommended activities, as the parents own horses at home. plane, while he stands, the following is noted: for him to undergo neurodevelopmental At the age of 7.5, the subject underwent visible weakness of the trunk, accentuated treatment, using Bobath and Vojta meth- Ulzibat fibrotomy on several muscles: m. lumbar lordosis, asymmetrical position of ods. The specialist also recommended an pronator teres, mm. flexores carpi et digitorum, the pelvis, which is inclined (Figure 2). MRI of the head, but the mother objected m. quadriceps femoris, m. semitendinosus, mm. because of fear of too much stress for the adductores, m. gracilis, m. soleus.

Figure 1. Universal Exercises Unit. Figure 2. Posture and walking pattern in the first Source: Método TheraSuit em BH: Gaiola. http://therasuitbh.blogspot.com/p/gaiola.html. Accessed week. January 19, 2017. Copyright © 2017 Rašeljka Batelić Dragić gyrus | vol. 4 | no. 3–4 | july – december 2017 280 sleep disorders case report Batelić Dragić R. New concepts in rehabilitation of children with cerebral palsy. pp. 278 – 284

Observing the posture from behind, he has visible kyphosis of the thoracic spine with scapulas in abduction and prominent lower corners, which speaks for weakness of serratus anterior and rhomboideus muscles on both sides. The evaluation of primitive reflex integration revealed that the Moro, tonic labyrinthine, Galant and asymmetrical tonic neck reflex are not fully integrated. The subject finished the first grade of regular education in a public school in his hometown with the help of a school assistant. He has complete use of both hands in all activities of everyday life and is able to write at sufficient speed. The left elbow is slightly bent at 20°, which can be corrected passively.

Flexors of left elbow on the Ashworth scale = +1 Pediatric balance scale (PBS) = 45/56

The goals of the treatment were: – primitive reflex integration, – activation and strengthening of core muscles and extremities, – coordination and balance training, and Figure 3. Correction of posture on a vibrating Figure 4. Walking in Therasuit®. – reeducation of walking. platform. Copyright © 2017 Rašeljka Batelić Dragić Copyright © 2017 Rašeljka Batelić Dragić Treatment plan: The subject was submitted to a Therasuit® treatment for a total of 45 hours (3 weeks, 3 properly aligned, extension of knees, full The process of motor learning of the new hours a day, 5 days a week), which included: loading and full support of the feet with walking pattern is not completely automatic – a preparation of soft tissue with massage heels on the floor. The pelvis is symmetrical, and when he tries to walk faster the left leg and specific mobilizations for 30 min, less inclined and upper extremities relaxed is still moving in internal rotation, but on a – exercises for primitive reflex integration and in proper alignment. conscious level, when he slows down, he and core activation for 15 min, The subject is also able to crawl with feet on activates his external rotators and obtains – 60 min of strengthening of trunk muscles, the ground and without internal rotation better balance which enables him to walk upper and lower extremities using all three of the thighs. He stands up independently longer. His upper limbs are relaxed, in prop- types of muscle contraction, but giving ad- from the ground, stepping forward with left er alignment and the elbows are not flexed vantage to isometric and eccentric work or right leg. The knees are still somewhat in anymore, which can be seen on photos and in supine, prone, lateral and quadruped adduction, but when he gets up from a stool video materials. position in the UEU® (the focus was on or chair, the legs are properly aligned and In the final evaluation the subject scored strengthening of the trunk, abductors he is able to walk 300 meters in a correct 54/56 on the PBS, which means that there and external rotators of the thighs and manner. After walking approximately 300 is less risk of falling, and the muscle tone of scapula stabilizers), meters he reports he feels tired. the flexors of the left elbow scored 1 on the – 15 min of correction of posture on a vibrating platform with and without the suit (Figure 3), and – 45 min of walking reeducation, along with Monday to Friday other functional activities wearing the suit (Figure 4). 9:00–9:30 Soft tissue mobilization 9:30–9:45 Reflex integration and core stability training The schedule of treatment activities is shown in Table 1. 9:45–10:45 UEU The treatment was carried out in a progressive way by increasing the number of rep- 10:45–11:00 Pause for antioxidant and alkalizing liquid meal etitions, resistance to movement and level 11:00–11:15 Therasuit® wearing of motor task or activity. 11:15–11:30 Correction of posture on vibrating platform Results 11:30–12:15 Walking reeducation and functional activities After three weeks of treatment the patient is able to maintain the upright position with good balance and lower extremities Table 1. Schedule of the Therasuit® treatment activities.

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case report Batelić Dragić R. New concepts in rehabilitation of children with cerebral palsy. pp. 278 – 284

Ashworth scale. Discussion results and progress in participation in every- The positive results of the treatment are also For the past few years strength training has day life. visible on the level of participation because, been in the center of discussion as a possible The restrictions of this case study are the lack when the child went back home, he was able treatment with positive effects on subjects of more detailed measurements (e.g., muscle to join the taekwondo sport club with oth- with CP. Several studies reported increased strength measured with a dynamometer, a er children and was completely integrated range of movement, strength, better func- measured range of movement) and a need in recreational activities. The mother sent tion and decrease in spasticity without signs for a greater number of additional functional photos of him training taekwondo three of abnormal movement patterns as a reactivity tests to be included. months later (Figures 5a and 5b). sult of progressive strength training in this population.13,14,16,24,25 Conclusion The positive effects mentioned above are In neurophysiotherapy, through five decades, in agreement with the results obtained in the dominant clinical treatment methods subjects after stroke.26,27 have been Bobath, Vojta and PNF. Strength A lot of different strength training programs training was being questioned for a long are being questioned and studied in regard time because it was believed that the ef- to duration, frequency, type of muscle con- fort needed for strength training could in- traction, exercises in open or closed muscle crease spasticity, co-contractions, associated chain, the use of different equipment and reactions and abnormal movement pat- the impact on activity/participation level.28 terns. However, new studies conducted in The results show that these strength train- the domains of motor control and learning, ing programs and treatments for subjects human biomechanics and training theory, with CP should be highly individualized to revealed that there is no evidence to support ensure better outcomes on activity/partic- such claims. These studies, on the contrary, ipation level.28 brought proof of major positive effects on At the same time, different devices, suits and the development of strength, new motor dynamic orthoses that control abnormal mus- functional skills, better motor control and cle tone, stabilize posture and additionally regulation of muscle tone. a) affect the increment of motor function,29,30,31 The Therasuit® concept combines neuro- like the Therasuit®, are being discussed. physiotherapy techniques and methods With the intent to give detailed and exact known from earlier times and upgrades evidence, Bailes, Greve, Burch et al.32 analyz- them using new clinical evidence of effec- ed the effects of the Therasuit®, but did not tiveness of recently developed treatment find statistically important difference in the programs. It is important to emphasize improvement of the motor function between that physiotherapists should always be an intensive physiotherapy treatment with open-minded in their clinical work, always the suit and an intensive treatment without try to combine their knowledge without the suit. However, they stated that the study prejudice and include all evidence-based lacked one more control group that was techniques. For example, it could be of a not submitted to any or at least to a classic great benefit to patients to combine a vir- treatment. They think that in future stud- tual technology, such as Nintendo Wii, with ies researchers should focus on additional the Therasuit® program because it could evaluation procedures of postural changes motivate children even more. in children with CP with different functional The Therasuit® concept is a highly individu- abilities and that even case studies could realized treatment program, which includes veal some changes not noticed in their study. a comprehensive, task oriented method of The results obtained in this case study of a strengthening body structures and functions b) 7.5-year-old boy mirror the effects of simi- through a distinct period of time (3–4 hours lar studies. The decrease in spasticity and a day, at least for 21 days) to enable motor increase in range of motion can be attrib- learning and to cover multiple elements of Figure 5 (a and b). The boy training taekwondo, uted to the combination of the fibrotomy a therapeutic session needed for the acqui- completely integrated. procedure that was followed by the inten- sition of new skills and their application in Copyright © 2017 Rašeljka Batelić Dragić sive and progressive Therasuit® treatment. everyday life. The decrease in spasticity of the left elbow For future studies, it would be interesting flexors, the changes in PBS and Ashworth to compare the effects of different neuro- scoring can be attributed to the Therasuit® physiotherapy treatment programs, e.g., 1) treatment only, as it is a highly individual- a classic treatment carried out for a longer ized treatment concept combining different period of time (6 to 12 months, 3 times a methods based on neurophysiology and week with 1 hour session a day), 2) a more neurodevelopmental science with signifi- frequent classic treatment carried out in a cant impact on function and participation. shorter period (3 months, 5 days a week for The photos and video materials from the 1 hour session a day) and 3) the Therasuit® later integration of the child in average sport treatment program (4 weeks, 5 days a week, activities give strong evidence of long-term 3 to 4 hour session a day). gyrus | vol. 4 | no. 3–4 | july – december 2017 282 sleep disorders case report Batelić Dragić R. New concepts in rehabilitation of children with cerebral palsy. pp. 278 – 284

REFERENCES: 1. Koberda JL, Akhmatova N, Akhmatova E, Bienkiewicz A, Nowak N, Nawrocka H. Masgutova Neurosensorimotor Reflex Integration (MNRI) Neuromodulation Technique Induces Positive Brain Maps (QEEG) Changes. J Neurol Neurobio. 2016;2(4):1-8. doi:10.16966/2379-7150.130. 2. Centers for Disease Control and Prevention (CDC), USA. Data and Statistics for Cerebral Palsy. https://www.cdc.gov/ncbddd/cp/data. html. Published 2016. Accessed January 3, 2017. 3. Cans C. Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy surveys and registers. Dev Med Child Neurol. 2000;42(12):816- 824. doi:10.1111/j.1469-8749.2000.tb00695.x. 4. Mejaški-Bošnjak V. Neurološki sindromi dojenačke dobi i cerebralna paraliza. Paediatr Croat. 2007;51(Supl 1):120-129. http://www.hpps. com.hr/sites/default/files/Dokumenti/2007/pdf/dok26i33.pdf. Accessed January 19, 2017. 5. Winter S, Autry A, Boyle C, Yeargin-Allsopp M. Trends in the Prevalence of Cerebral Palsy in a Population-Based Study. Pediatrics. 2002;110(6):1220-1225. doi:10.1542/peds.110.6.1220. 6. Boulet SL, Boyle CA, Schieve LA. Health Care Use and Health and Functional Impact of Developmental Disabilities Among US Children, 1997-2005. Arch Pediatr Adolesc Med. 2009;163(1):19-26. doi:10.1001/archpediatrics.2008.506. 7. Bobath K, Bobath B. The neurodevelopmental treatment. Management of Motor Disorders of Children with Cerebral Palsy. Blackwell Scientific Publications Ltd, Denmark; 1984. 8. Vojta V. Current methods of rehabilitation in the treatment of motor disorders in perinatal encephalopathy. Cesk Neurol. 1964;27:81-86. 9. The Doman-Delacato Treatment of Neurogically Handicapped Children. Dev Med child Neurol. 1968;10(2):243-246. doi:10.1111/j.1469-8749.1968. tb02879.x. 10. Ayres AJ. Characteristics of types of sensory integrative functions. Am J Occup Ther. 1971;25(7):329-334. 11. Bobath K. A Neurophysiological Basis for the Treatment of Cerebral Palsy. 2nd ed. London, England: Wiliam Heinimann Medical Books Ltd, 1980. 12. Bassoe Gjelsvik BE. The Bobath Concept in Adult Neurology. Thieme, Stuttgart, New York, 2008. 13. Fowler EG, Ho TW, Nwigwe AI, Dorey FJ. Effect of Quadriceps Femoris Muscle Strengthening Exercises on Spasticity in Children with Cerebral Palsy. Phys Ther. 2001;81(6):1215-1223. doi:10.1093/ptj/81.6.1215. 14. MacPhail HE, Kramer JF. Effect of Isokinetic Strength-Training on Functional Ability and Walking Efficiency in Adolescents with Cer- ebral Palsy. Dev Med Child Neurol. 1995;37(9):763-775. doi:10.1111/j.1469-8749.1995.tb12060.x. 15. Damiano DL, Abel MF. Functional Outcomes of Strength Training in Spastic Cerebral Palsy. Arch Phys Med Rehabil. 1998;79(2):119-125. doi:10.1016/S0003-9993(98)90287-8. 16. Damiano DL, Kelly LE, Vaughn CL. Effects of Quadriceps Femoris Muscle Strengthening on Crouch Gait in Children with Spastic Di- plegia. Phys Ther. 1995;75(8):658-667. doi:10.1093/ptj/75.8.658. 17. Wiley ME, Damiano DL. Lower-Extremity Strength Profiles in Spastic Cerebral Palsy. Dev Med Child Neurol. 1998;40(2):100-107. doi:10.1111/j.1469-8749.1998.tb15369.x. 18. Carr JH, Shepherd RB. Training Motor Control, Increasing Strength and Fitness and Promoting Skill Acquisition. In: Neurological Re- habilitation: Optimizing Motor Performance. Oxford: Butterworth-Heinemann; 1998:23-46. 19. Goddard S. Reflexes, learning and behaviour: A window into the child`s mind: a non-invasive approach to solving learning and behavior problems. Eugene, OR, USA: Fern Ridge Press, 2005. 20. Shackleford P. MNRI® – Neurotypical Development and Reflex Integration Disorder. In: Reflexes: Portal to Neurodevelopment and Learn- ing. Svetlana Masgutova Educational Institute® for Neuro-Sensory-Motor and Reflex Integration, SMEI (USA); 2015:31-40. https:// informedchoicesinhealth.org/mnri-neurotypical-development-and-reflex-integration-disorder/. Accessed January 19, 2017. 21. Shackleford P. MNRI® – Historical Approach on Reflex Integration. In: Reflexes: Portal to Neurodevelopment and Learning. Svetlana Mas- gutova Educational Institute® for Neuro-Sensory-Motor and Reflex Integration, SMEI (USA); 2015:22-30. https://informedchoicesinhealth.org/mnri-historical-approach-on-reflex-integration/. Accessed January 19, 2017. 22. Akhmatov E, Buraczewski J, Masgutov D. The Leg Cross Flexion-Extension Reflex: Biomechanics, Neurophysiology, MNRI® Assessment, and Repatterning. In: Reflexes: Portal to Neurodevelopment and Learning. Svetlana Masgutova Educational Institute® for Neuro-Senso- ry-Motor and Reflex Integration, SMEI (USA); 2015:41-57. http://masgutovamethod.com/_uploads/_media_uploads/_source/Theo- ry-And-History-Of-MNRI-Reflex-integration-02.24.15.pdf. Accessed January 19, 2017. 23. Koscielny I, Koscielny R. Manual Therasuit Method® Training Course. 2002-2014 Therasuit LLC, USA. 24. Blundell SW, Shepherd RB, Dean CM, Adams RD, Cahill BM. Functional strength training in cerebral palsy: a pilot study of a group circuit training class for children aged 4-8 years. Clin Rehabil. 2003;17(1):48-57. doi:10.1191/0269215503cr584oa. 25. Morton JF, Brownlee M, McFadyen AK. The effects of progressive resistance training for children with cerebral palsy. Clin Rehabil. 2005;19(3):283-289. doi:10.1191/0269215505cr804oa. 26. Sharp SA, Brouwer BJ. Isokinetic Strength Training of the Hemiparetic Knee: Effects on Function and Spasticity. Arch Phys Med Rehabil. 1997;78(11):1231-1236. doi:10.1016/S0003-9993(97)90337-3. 27. Teixeira-Salmela LF, Nadeau S, Mcbride I, Olney SJ. Effects of muscle strengthening and physical conditioning training on temporal, kinematic and kinetic variables during gait in chronic stroke survivors. J Rehabil Med. 2001;33(2):53-60. doi:10.1080/165019701750098867. 28. Dodd KJ, Taylor NF, Damiano DL. A systematic review of the effectiveness of strength-training programs for people with cerebral palsy. Arch Phys Med Rehabil. 2002;83(8):1157-1164. doi:10.1053/apmr.2002.34286. 29. Bar-Haim S, Harries N, Belokopytov M, et al. Comparison of efficacy of Adeli suit and neurodevelopmental treatments in children with cerebral palsy. Dev Med Child Neurol. 2006;48(5):325-330. doi:10.1017/S0012162206000727. 30. Bailes AF, Greve K, Schmitt LC. Changes in Two Children with Cerebral Palsy After Intensive Suit Therapy: A Case Report. Pediatr Phys Ther. 2010;22(1):76-85. doi:10.1097/PEP.0b013e3181cbf224. 31. Turner AE. The efficacy of Adeli suit treatment in children with cerebral palsy. Dev Med Child Neurol. 2006;48(5):324. doi:10.1017/ S0012162206000715.

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32. Bailes AF, Greve K, Burch CK, Reder R, Lin L, Huth MM. The Effect of Suit Wear During an Intensive Therapy Program in Children with Cerebral Palsy. Pediatr Phys Ther. 2011;23(2):136-142. doi:10.1097/PEP.0b013e318218ef58.

NOVI PRISTUPI U REHABILITACIJI DJECE S CEREBRALNOM PARALIZOM

Sažetak Cerebralna paraliza predstavlja veliko opterećenje za oboljele, njihovu obitelj, zdravstveni sustav, odgojno-obrazovne ustanove i društ- vo u cjelini. Posljednjih godina raspravlja se o drugačijim pristupima u rehabilitaciji, koji bi imali veće učinke na razini aktivnosti, par- ticipacije i funkcionalnih sposobnosti u svakodnevnom životu. U radu su prikazani rezultati Therasuit® intervencije na djetetu od 7,5 godina sa spastičnim oblikom cerebralne paralize mjesec dana nakon višestrukih fibrotomija po Ulzibatu. Therasuit® koncept spada u novije rehabilitacijske pristupe koji počivaju na teoriji motoričkog učenja i kontrole, individualnog progresivnog jačanja muskulature, integraciji primitivnih refleksa i kombinaciji ostalih neurofizioterapijskih tehnika.

Ključne riječi: cerebralna paraliza, integracija primitivnih refleksa, Therasuit®, trening snage

*Personal information is known to the Editorial Board. Parental informed consent for publication of the clinical details and clinical images was obtained in written form from the patient’s mother prior to publishing.

Received June 19, 2017. Accepted July 27, 2017.

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Knezić J. Bobath therapy. Gyrus. 2017;4(2):136.

gyrus | vol. 4 | no. 3–4 | july – december 2017 284 sleep disorders editor´s choice EDITOR’S CHOICE

Human brain cerebellum, adult, hemalau-eozin staining showing cerebellar cortex with Purkyne cells and granular cells. This image is property of Zagreb Neuroembriological Collection, Croatian Institute for Brain Research, University of Zagreb School of Medicine. For details see Kostović et al. 1991; Judaš et al. 2011.

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editor´s choice DEVELOPING BRAIN REGIONS IN CHILDREN HARDEST HIT BY SLEEP DEPRIVATION

Ivana Starčević 0000-0002-8333-6831 University of Zagreb, School of Medicine

It's needless to say that sleep is vital for our that show how lack of sleep in children can brain like it does in adults, but rather in the daily functioning and, more important- cause future problems in cognitive behav- parietal and occipital lobes.This effect may ly,brain development. But what happens ior. Brain plasticity is higher during brain only be temporary and occur during sensi- if we lack sleep? The brain waves, caused development and highly affected by sleep tive developmental phases in childhood or by sleep deprivation,are quantified as an deprivation (as proven by number of stud- adolescence.Even though the important increased slow-wave activity (as monitored ies conducted on animals). question - can sleep affect our behavior on sleep-eeg). Those swa are predominant in and our future personality may still be left the prefrontal cortex, brain region in charge This particular research consisted of deter- unanswered, it is more than important for of higher brain functions as planning and mining the myelin-content in 13 healthy children to get an adequate amount of cognitive thinking, which explains why sleep children aged 5–12 years with magnetic res- sleep, especially during childhood. deprivation causes incompetence of atten- onance imaging and then monitoring their tion and working memory. Recent studies swa in 2 occasions. On the first monitoring, conducted by researchers from University children were sleeping in accordance to their of Zürich tried to determine how sleep dep- normal habits and the other monitoring rivation affects developing brain regions was conducted after the sleep deprivation. in children. The results have shown that sleep depri- The experiment was to determine the ef- vation mostly affects more myelinated re- fect of sleep deprivation on brain devel- gions of the brain. The slow-wave activity opment. It was based on the new studies does not appear in the front regions of the

REFERENCE: 1. Kurth S, Dean DC, Achermann P, et al. Increased Sleep Depth in Developing Neural Net- works: New Insights from Sleep Restriction in Children. Front Hum Neurosci. 2016;10:456. doi:10.3389/fnhum.2016.00456.

gyrus | vol. 4 | no. 3 – 4 | july – december 2017 286 sleep disorders editor´s choice LATE NEURONAL MIGRATION – NEW FINDINGS SUGGEST A KEY ROLE IN HUMAN BRAIN DEVELOPMENT

Luka Ćusek 0000-0002-7946-1154 University of Zagreb, School of Medicine

During the development of the human ventricles. They used viruses tagged with Given that the most of these late arriving brain, most neurons go through a dynam- a glowing protein to label these neurons neurons become inhibitory neurons and ic process in which they migrate from deep in tissue samples donated and collected the fact that the imbalance between ex- within the brain where the proliferative immediately after infants’ death. MRI citatory and inhibitory neurons is found in zones lie, to their destination in the cere- showed an arc-like trajectory of neurons many neurological diseases, ranging from bral cortex. This phenomenon was consid- from the subventricular zone toward the autism to schizophrenia, the question that ered to take place before birth. However, surface of the frontal lobe. After they have arises is – could a disruption in this process researchers at uc San Francisco have pub- settled, they mostly differentiate into in- play a role in these diseases? A follow-up lished a paper in which they have present- hibitory neurons. The research team found is in plan to explore this possibility and to ed evidence that the migration continues that the peak of the migration happens deepen the knowledge on this complex even months after birth. Their research about 1.5 months after birth but continues topic. suggests this could provide a basis for de- to up to 3 months. This time is critical for velopmental plasticity and the disruption appropriate brain development as this is of migration to neurodevelopmental dis- the time when infants being to interact orders. with the environment and starts to engage with emotions. Therefore, the arrival The researches have identified popula- of these cells could play an important role tions of immature neurons in subven- in setting up the basis for the human cog- tricular zone around the anterior lateral nition.

REFERENCES:

1. Nogueira ab, Nogueira ab, Veiga jce, Teixeira mj. Letter: Extensive Migration of Young Neurons Into the Infant Human Frontal Lobe. Neurosurgery. 2017;81(2):e16-e18. doi:10.1093/neuros/nyx202. 2. Paredes mf, James D, Gil-Perotin S, et al. Extensive migration of young neurons into the infant human frontal lobe. Science. 2016;354(6308):aaf7073. doi:10.1126/science.aaf7073.

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editor´s choice NEURAL NETWORK UNDERLYING HUMAN CONSCIOUSNESS DISCOVERED

Ida Ivek 0000-0001-8381-7128 University of Zagreb, School of Medicine

Probably no other aspect of human mind voxel-based lesion-symptom mapping. In wakefulness, while VENs takes part in intrigues so many great thinkers as con- addition, using resting state functional sustaining self-awareness. That being said, sciousness does. Questions in terms of connectivity MRI a group managed to de- brainstem lesions which disconnect brain- consciousness occupy human intellect fine a network associated with coma-caus- stem-AI-pACC network lead to impaired and answers to this are expected from ing brainstem region in healthy volunteers. awareness disorder. modern neuroscience. Lastly, it was necessary to look into the functional connectivity of the identified These findings are important for a better Traditionally, the presence of wakefulness network in comatose patients. understanding of human consciousness and awareness has been considered a pos- and were recognised by American Acade- tulate for this brain function. It was also Finally, the outcomes of this study showed my of Neurology. believed that the center of consciousness overlapping of coma-causing injuries in is located in the reticular formation, but all rostral dorsolateral pontine tegmentum. in all details were poorly understood. This coma-causing region showed functional connections with left ventral an- A group of scientists led by neurologists terior insula (AI) and pregenual anterior at Beth Israel Deaconess Medical Center cingulate cortex (pACC). The study also (bidmc) succeeded in closely explaining showed a lack of connectivity between the brain network responsible for main- these cortical regions in patients with dis- taining consciousness, a discovery pub- orders of consciousness. lished in November 2016 in Neurology. A group recreated coma-causing and con- Ai and pACC are parts of a default mode trol non-coma-causing brainstem on a network and are histologically alike due brain template in order to precisely local- to spindle-shaped neurons called von ize coma-causing region. They have em- Economo neurons (VENs) found in both. ployed two different methods: subtraction Scientists at bidmc suggest that pontine non-coma from coma-causing lesions and tegmentum plays a role in maintaining

REFERENCES:

1. Insight into the seat of human consciousness | Neuroscience News & Research from Technology Networks. https://www.technologynetworks.com/neuroscience/news/insight-seat-human-consciousness-284723. Accessed October 6, 2017. 2. Fischer DB, Boes AD, Demertzi A, et al. A human brain network derived from coma-causing brainstem lesions. Neurology. 2016;87(23):2427-2434. doi:10.1212/ WNL.0000000000003404.

gyrus | vol. 4 | no. 3 – 4 | july – december 2017 288 sleep disorders editor´s choice HOW CONSTANT SOCIAL DEFEAT MODIFIES OUR BEHAVIOR: IS THE PERSON NEXT TO YOU SIMPLY DULL, AGGRESSIVE, EXTREMELY INTROVERTED OR IS THERE MORE TO THE STORY?

Bea Hohšteter 0000-0002-3361-3298 University of Zagreb, School of Medicine

It is quite logical that the master mediator occurred. For instance, increase in social the two structures is attenuated after ex- of our behavior, the prefrontal cortex (pfc), avoidance was also present when a female posure to social defeat, similar to what is is somehow connected with columns in mouse was placed behind the wire-barrier, found in states such as major depression. periaqueductal gray (pag), motor areas but not during the presence of inanimate Lastly, the structural and functional fea- crucial for basic social interaction such as novel object. tures of targeted PAG neurons were ex- defense or approaching. However, the pre- amined, and results demonstrated that cise location or structural features of such In the Y-maze test (short-term memory glutamatergic Vglut2+ neurons in dPAG projection have not yet been described. tb test which relies on pfc-function) a sig- were major target for mPFC afferents. As Franklin et al. managed to track down the nificant increase in same arm returns was figure 1 demonstrates, dPAG neurons- in exact pyramidal, glutamatergic neurons measured, indicating deterioration of the tegrate impulses deriving from PFC and projecting directly from the layer 5 of the working memory which strongly indicates those from medial hypothalamic regions. medial pfc (mpfc) to dorsal and lateral that social defeat causes weakening of Defensive behavior manifested through columns within the periaqueductal gray mpfc-pag connections. recoiling, social avoidance, freezing or sub- (pag). mission, could be perceived as a variant of In order to confirm such premise, addi- our basic survival instinct. Since there is The main behavioral experiment in this tional tests such as pharmacological rever- no chance for fight (because of the - obvi study examined how subchronic social sal of avoidance or inhibition of mpfc-pag ous superiority of our opponent) or flight defeat reflects on specific aspects of mice were performed and results supported (closed cage), the solution which will the behavior. Examined mouse was placed in it: ketamine, used in antidepressant most likely result in our survival is obvious the cage with another, aggressive mouse treatment, increased time which socially demonstration of our inferiority to the ag- every day for 15 minutes. Firstly, for 5 min- defeated mouse spent investigating his gressor. This act could cause intruder’s loss utes, they were divided by a safety net, and newly arrived cage neighbor, whereas of interest or encourage him to reanalyze then, the partition was removed and mice pharmacogenetic inhibition of mpfc-pag the purpose of the attack. Similar behav- were able to freely interact the follow- connection induced behavior similar to ior could also be seen among ducks: when ing 10 minutes. Such limitless conditions those in socially defeated mouse (short- threatened, they tend to fall within the allowed the aggressive mouse to repeat- ened time spent investigating an un- behavioral pattern called tonic immobility edly attack the examined, weaker mouse. known neighbor resident). or, in other words “play dead”. Since limbic During this 7 days lasting procedure, num- system is our “base”, ground for survival, bers or duration of attacks did not change, Moreover, measuring of the local field po- and our PFC evolutionary “upgrade of the but behavior of the submissive mouse tentials (lfp) between mpfc and pag system”, behavior provided by hypothal- changed notably: he spent significant- showed significant decrease in functional amus may be seen as a “default”: when ly less time examining the bully during connectivity in defeated mice when com- there is no other impulses, like those from the “safe”, “wired” period and increased in pared to those in control group. PFC, organism will act in accord with that maintaining “frozen” and defensive pos- basic limbic impulse. Therefore, mPFC ture. The exact cause of decrease in lfp connec- projections are considered to provide an tivity was also investigated and results inhibitory impulse which will suppress ex- Except from behavioral changes listed suggested it originates from weakened af- citatory afferents from hypothalamus. above, which we may perceive as expect- ferent neuronal input to pfc. pfc receives ed attempts of pain avoidance, other, not strong input from thalamic medial dorsal This research also suggests the existence so easily predictable modifications also nucleus (mdt) and connection between of small, special PAG neuronal subclass,

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editor´s choice which receives direct, excitatory PFC cated in defensive behavior. Furthermore, impulses. Its purpose was not furtherly in psychiatry by noticing the declined LFP examined, but it would certainly be inter- potential between MDT-mPFC, which esting to investigate whether they might illustrates how social defeat modifies act as an antipode, promoting explorative thalamic and to some extent PFC activity. behavior and increased interest for an en- This may be of great importance in under- vironment, both inanimate and social. standing some pathological states such as The great significance of this research lies depression or in a study of influences of so- in its pluripotent contributions. In basic cial environment on cognitive impairment. neuroscience, by morphologically, pharmacologically and functionally character- izing the exact neuronal pathways impli-

Figure 1. Integration of impulses in dPAG neurons. Orange projections from mPFC are inhibitory, whereas purple – medial hypothalamic ones, are excitatory. In the absence of mPFC projections, output is purely a result of limbic projections. Based on references 1 and 4. Copyright © 2017 Bea Hohšteter

REFERENCES:

1. Franklin TB, Silva BA, Perova Z, et al. Prefrontal cortical control of a brainstem social behavior circuit. Nat Neurosci. 2017;20(2):260-270. doi:10.1038/nn.4470. 2. Deciding When Not To Act On Instinct. https://www.technologynetworks.com/tn/news/ deciding-when-not-to-act-on-instinct-278892. Published January 10, 2017. Accessed October 14, 2017. 3. Arnaud I, Mignon-Grasteau S, Larzul C, Guy G, Faure J-M, Guémené D. Behavioural and physiological fear responses in ducks: genetic cross effects. animal. 2008;2(10):1518-1525. doi: 10.1017/S1751731108002784. 4. Parnaudeau S, O’Neill P-K, Bolkan SS, et al. Inhibition of Mediodorsal Thalamus Disrupts Thalamofrontal Connectivity and Cognition. Neuron. 2013;77(6):1151-1162. doi:10.1016/j. neuron.2013.01.038.

gyrus | vol. 4 | no. 3 – 4 | july – december 2017 290 sleep disorders editor´s choice VIRTUAL REALITY IN MANAGEMENT OF SCHIZOPHRENIA

Ana Bardak 0000-0002-8909-9216 Josip Juraj Strossmayer University of Osijek, Faculty of Medicine

Stjepan Kovačević 0000-0002-7779-9805 Josip Juraj Strossmayer University of Osijek, Faculty of Medicine

Nowadays, virtual reality (VR) is a really In the past, VR was mainly used for train- raphobia, body image disturbances, binge popular term, mainly in the gaming indus- ing pilots, astronauts and military person- eating disorders, fear of flying, etc.2 try. The media is filled with videos of peo- nel. In the 1990s, however, VR found its ple playing unbelievably realistic games application in medicine. Impressive inven- The most interesting application is in diag- with VR. There are many definitions of VR, tions allowed healthcare professionals to nosing and treating schizophrenia. Using one of them being: “Virtual reality refers learn new skills as well as refreshing exist- the virtual environment, psychiatrists try to immersive, interactive, multi-sensory, ing ones in a safe environment. Addition- to convince patients that their halluci- viewer-centered, three-dimensional com- ally, this has been allowed without causing nations are not real, and that they suffer puter generated environments and the any danger to patients.2 from an illness that requires treatment. combination of technologies required to They also hope that confronting patients build these environments.”1 Therefore, the Today, apart from being a simulation tool, with their own psychoses in this way will fact that the gaming industry is using this VR became an interaction tool used in be- help when drug therapy fails, teaching device is really not that surprising. Howev- havioral medicine. In psychology VR has them to ignore hallucinations in real life, er, are games the only purpose of VR? Of been verified in the treatment of acropho- just as virtual reality is already helping course not. bia, spider phobia, panic disorder and ago- patients with phobias about spiders or

Figure 1. Virtual reality demonstration. Source: Gear VR Saw One Million Users Last Month - UploadVR. https://uploadvr.com/gear-vr-saw-one-million-users-last-month/. Published May 11, 2016. Accessed November 29, 2017.

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editor´s choice heights. During psychotic episodes, pa- ing social events. They are prone to anxiety, strain, reduced limb and postural control, tients with schizophrenia can experience which can lead to fear of people, as well as a decreased sense of presence, excessive a wide range of hallucinations. One in ten misinterpretation of their actions. In the sweating, increased salivation, discom- people is eventually driven to suicide.3 end, they turn to isolation and avoidance. fort and the development of responses Targets of the treatment are to reduce inappropriate to the real world. Although One of the most interesting usages of VR symptoms, improve coping and increase Virtual Reality slowly marches its way into is certainly its potential to present certain activity, and thus improve the patient’s life the mainstream, questions still remain social encounters and environments that in the modern, social world.4 about its long-term side effects.4 would possibly trigger responses in patients suffering from schizophrenia and The major side effect of this technology thus allowing better understanding and is a VR-induced sickness which can pres- treatment of their psychosis. Schizophren- ent itself with a wide array of symptoms ics experience a lot of difficulties regard- such as nausea, dizziness, headache, eye

REFERENCES:

1. Novák-Marcinčin J. Technology of virtual reality in industrial systems. Sci Bull Ser C. 2008;XXII(1). Paper presented at: International Conference of the Carpathian Eu- ro-Region Specialists in Industrial Systems, 7th edition. http://www.nordtech.ubm.ro/ issues/2008/2008.01.59.pdf. Accessed November 29, 2017. 2. Välimäki M, Hätönen HM, Lahti ME, et al. Virtual reality for treatment compli- ance for people with serious mental illness. Cochrane Database Syst Rev. 2014;(10). doi:10.1002/14651858.CD009928.pub2. 3. VR hallucinations used to treat schizophrenia | New Scientist. https://www.newscientist. com/article/dn2459-vr-hallucinations-used-to-treat-schizophrenia/. Published July 1, 2002. Accessed November 29, 2017. 4. Freeman D. Studying and Treating Schizophrenia Using Virtual Reality: A New Para- digm. Schizophr Bull. 2008;34(4):605-610. doi:10.1093/schbul/sbn020.

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editor´s choice Smoljo T. Forgetting. pp. 293 – 295 FORGETTING

Tomislav Smoljo 0000-0002-4067-5649 University of Zagreb, School of Medicine

ABSTRACT Learning is one of the most studied processes in the brain, while the opposite process of forgetting remains unclear although it is at least as important as learning. We can observe this process from a few different perspectives. People have been testing memory for a long time and the most famous paper on this topic is Ebbinghaus’ publication from 1885 which produced the famous forgetting curve. Nowadays scientists are investigating molecular mechanisms of forgetting. Control of the process may be immensely useful for treatment of some diseases, but also for all healthy individuals. The above stated is a good reason to investigate the process of forgetting and the possible modulatory factors.

Keywords: learning, memory, memory disorders, neurogenesis, synapses

Mechanism of forgetting Importance of forgetting that the curve jump is caused by sleep, an unclear but important factor that moder- The loss of memory is a process called for- Exploring this field has been interesting for ates mentioned processes which should be getting. Memory could be viewed as a neural a long time. The most famous experiment is investigated.4 But why did the curve fall off circle which contains information. Therefore Ebbinghaus’ experiment from 1880 to 1885. exponentially? The reason may be overload. we can explain forgetting as a change of Considering that the original experiment Numerous inputs interflow in our nervous neural circles caused by dying of neurons, was made on a single subject, the author system every second, but most of them we retreating of axons or dendrites, and re- himself, it is interesting to replicate it so that do not process consciously. Even with that finement of the synapses. There are a few we can minimize subjective mistakes. Graph- amount of unprocessed information, our causes of these processes. Decay over time ic analyses show exponential forgetting over consciousness receives many useless signals is a process that can be induced by several time, but the curve isn’t smooth because it that could impede the vitally important factors as pathological processes, fluctua- shows a jump after a single day retention thoughts and interrupt learning. It is shown tion of hormones, and metabolic changes. interval (Figure 1). There is an assumption that forgetting old experience improves Recently it was proven that interference from new irrelevant information can interrupt existing information. Interfering is typical for extrahippocampal memory because the circuits are overlapping, while hippocampal memory patterns are separated. Also, we can assume where certain information is memorized by comparing confidence of remembering. Low- confidence memory is a familiarity-based type related to extrahippocampal memorizing while high-confidence memory is recollection-based type situated in hippocampus.1 Extrahippocampal processing includes semantic content and emotions contained in the information.2 Furthermore, recall can cause a phenomenon called retrieval-induced forgetting.3 It’s important to note that decay and interference are insep- arable. While we test interference, time is passing and metabolic processes are Figure 1. Curves of forgetting according to Ebbinghaus’ experiment and replications. going on, including decay. On the other Source: Murre JMJ, Dros J. Replication and Analysis of Ebbinghaus’ Forgetting Curve. PLoS One. hand, while we are waiting for the decay, 2015;10(7):e0120644. doi:10.1371/journal.pone.0120644. information is flowing into the brain so Copyright © 2015 Murre, Dros. interference is unavoidable. Available under the CC BY 4.0 International license (https://creativecommons.org/licenses/by/4.0/).

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editor´s choice Smoljo T. Forgetting. pp. 293 – 295

learning new words.5 That rejection of the divide was used. Those animals did exercise, The use of new discoveries about forgetting information isn’t considered forgetting. but their results were similar to the wild type Usually the term forgetting considers an animals without exercise. The conclusion is New discoveries about forgetting, neurogen- amount of facts that we used consciously. that neurogenesis is the main mediator of esis, memory consolidation and conservation Connections of neural circle containing the the processes described above. Furthermore, could be used in the treatment of numerous information with emotions or another infor- there is another view on coherence between diseases. Usually the first thought is the mation in specific order helps to preserve learning, forgetting and emotions, because prevention of forgetting observed in some that information over a longer period of depression is interconnected with decreased pathological conditions. According to the time. Repetition has a similar effect which hippocampal neurogenesis12 while exercise WHO, in 2015 there were 46.8 million people is interconnected with the update of synaps- promotes hippocampal neurogenesis and worldwide suffering from dementia and es and entanglement of new information good mood.13 Besides the hippocampus, it is predicted that this number will grow preventing decay. the cerebral cortex is also responsible for up to 74.7 million in 2030.16 Most of them the establishment of working memory and are suffering from Alzheimer’s disease, but long-term memory.14 But even scientists who there are also other types including Lewy Hippocampal neurogenesis effects study neurogenesis in the cerebral cortex body dementia, frontotemporal dementia, have not explained it: “sections focus on the pseudodementia and vascular dementia The occurrence of neurogenesis in certain hippocampus because a higher density of among others.16 Nowadays the research is parts of the adult brain (in rats), including new neurons is generated there and more focused on genes and proteins involved in the hippocampus, has been known for a long is known about them“.11 neuronal pathology including hyperphos- period of time.6 This process is affected by phorylated tau protein,17 amyloid beta18 several factors. While some of them have the and apolipoprotein E.19 The prevention of potential to increase the generation of new Synaptic changes forgetting may not be the only way of using neurons, like antidepressants7 and exercise,8,9 new findings. For instance, vivid traumatic others, like opiates, corticosteroids, chronic Changes in synapses are not completely PTSD memories cause suffering among stress and inflammation, are detrimental.10,11 defined because synapses are composed of patients and it would be convenient to al- Many signaling molecules that control dif- many different receptors, enzymes, signaling leviate them. A third use of new discoveries ferent phases of neuronal proliferation and molecules and other proteins. Another rea- could be used for boosting mental skills in maturation are the central interest of many son is the qualitative and quantitative vari- healthy people, but that seems far away scientists.11 Neurogenesis in the adult sub- ations of the synapses. New findings about from the current perspective. granular zone of the hippocampus results the above mentioned processes should lead in an increased formation of new memories to improved pharmacological treatment of and loss of old ones. Adding newly gener- neurological diseases. Our understanding of ated neurons into existing neural circuits the consolidation of new memories is much is considered the neurobiological basis for better than our understanding of the process this. Scientists have noticed that mice who of losing of existing ones. Research on the lived in an environment that provides more decay of long-term memories suggests that physical activity were worse at recalling it is a normal process, considering that the old memories but better in forming new blocking of normal proteins, like NMDA conflicting ones, than mice with less phys- receptors and AMPA receptors which allow ical activity.8 In the experiment, a group of influx of Ca 2+ and activation of calcineurin, genetically modified animals whose hip- prevents forgetting in some parts of the pocampal neurons don’t have the ability to brain.15

REFERENCES:

1. Sadeh T, Ozubko JD, Winocur G, Moscovitch M. Forgetting Patterns Differentiate Between Two Forms of Memory Representation. Psychol Sci. 2016;27(6):810-820. doi:10.1177/0956797616638307. 2. Ozubko JD, Seli P. Forget all that nonsense: The role of meaning during the forgetting of recollective and familiarity-based memories. Neuropsychologia. 2016;90:136-147. doi:10.1016/j.neuropsychologia.2016.06.026. 3. Anderson MC, Bjork EL, Bjork RA. Retrieval-induced forgetting: Evidence for a recall- specific mechanism. Psychon Bull Rev. 2000;7(3):522-530. doi:10.3758/BF03214366. 4. Murre JM, Dros J. Replication and analysis of Ebbinghaus’ forgetting curve. PloS One.2015;10(7):e0120644. doi:10.1371/journal pone.0120644. 5. Barrett J, Zollman KJ. The role of forgetting in the evolution and learning of language. J Exp Theor Artif Intell. 2009;21(4):293-309. doi:10.1080/09528130902823656. 6. Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol. 1965;124(3):319-335. doi:10.1002/cne.901240303. 7. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000;20(24):9104-9110. doi:10.1523/JNEUROSCI.20-24-09104.2000.

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8. Epp JR, Mera RS, Köhler S, Josselyn SA, Frankland PW. Neurogenesis-mediated forgetting minimizes proactive interference. Nat Comm. 2016;7:10838. doi:10.1038/ncomms10838. 9. Van Praag H, Shubert T, Zhao C, Gage FH. Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci. 2005;25(38):8680-8685. doi:10.1523/JNEUROSCI.1731-05.2005. 10. Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003;302(5651):1760-1765. doi:10.1126/science.1088417 11. Gross CG. Neurogenesis in the adult brain: death of a dogma. Nat Rev Neurosci. 2000;1(1):67-73. doi:10.1038/35036235. 12. Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301(5634):805-809. doi:10.1126/science.1083328. 13. Dinas PC, Koutedakis Y, Flouris AD. Effects of exercise and physical activity on depression. I J Med Sci. 2011;180(2):319-325. doi:10.1007/ s11845-010-0633-9. 14. Courtney SM, Ungerleider LG, Keil K, Haxby JV. Object and spatial visual working memory activate separate neural systems in human cortex. Cereb Cortex. 1996;6(1):39-49. 15. Sachser RM, Santana F, Crestani AP, et al. Forgetting of long-term memory requires activation of NMDA receptors, L-type voltage-dependent Ca2+ channels, and calcineurin. Sci Rep. 2016;6:22771. doi:10.1038/srep22771. 16. Tomasović S, Sremec J, Košćak J, Klepac N, Draganić P, Bielen I. Epidemiological Characteristics of Dementia Treatment in Croatia. Psychiatr Danub. 2016;28(2):170-175. 17. Guo Y, Wang L, Zhu M, et al. Detection of hyperphosphorylated tau protein and α- synuclein in spinal cord of patients with Alzhei- mer’s disease. Neuropsychiatr Dis Treat. 2016;12:445-452. doi:10.2147/NDT.S90735. 18. Breydo L, Kurouski D, Rasool S, et al. Structural differences between amyloid beta oligomers. Biochem Biophys Res Commun. 2016;477(4):700-705. doi:10.1016/j.bbrc.2016.06.122. 19. Rezeli M, Zetterberg H, Blennow K, et al. Quantification of total apolipoprotein E and its specific isoforms in cerebrospinal fluid and blood in Alzheimer’s disease and other neurodegenerative diseases. EuPA Open Proteom. 2015;8:137-143. doi:10.1016/j.eu- prot.2015.07.012.

ZABORAVLJANJE

Sažetak Učenje spada među najistraživanije procese u neuroznanosti, dok je suprotni proces zaboravljanja sla- bo poznat, iako je barem jednako važan kao i učenje. Zaboravljanje proučavamo s različitih gledišta. Ljudi gotovo oduvijek testiraju pamćenje, a najpoznatiji rad na ovu temu je Ebbinghausova publikacija iz 1885. u kojoj je rezultate prikazao krivuljom zaboravljanja. Današnji znanstvenici proučavaju molekularne mehanizme zaboravljanja. Nadziranje ovog procesa bilo bi neizmjerno korisno za liječen- je određenih bolesti, ali i primjenjivano za poboljšanje funkcija zdravih osoba. Navedeni razlozi potiču znanstvenike na daljnje istraživanje zaboravljanja i čimbenika koji na njega utječu.

Ključne riječi: neurogeneza, pamćenje, poremećaji pamćenja, sinapse, učenje

Received November 20, 2016. Accepted August 18, 2017.

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gyrus | vol. 4 | no. 3 – 4 | july – december 2017 298 sleep disorders issue topics Vukić V. This is your brain on dreams. pp. 299 – 303 THIS IS YOUR BRAIN ON DREAMS

Vana Vukić 0000-0003-0003-3729 University of Zagreb, School of Medicine

Abstract Dreams are highly unpredictable events that sometimes go even beyond human imagination. A dream is created entirely by the brain, with no help from the outside. Dreaming occurs while we sleep, mostly, but not exclusively, in the REM (rapid eye-movement) phase. The REM phase is similar to the waking state by EEG presentation as well as by high activity of some brain regions involved in both wakefulness and some features of the dream. On the other hand, some brain regions are deactivated during REM phase and the cholinergic system dominates. Dreams are mostly visual but they might depend on the dominant sense used in daily life, as was shown in studies of blind people’s dreams. Blind people dream with sounds, touch, smell, and taste. Research of different characteristics of dreams throughout childhood led to the definition of dreaming as a developing process. But the question why we dream is still out of reach, although different theories circulate. Freud speculated that we dream to fulfil our deepest, forbidden wishes. Relatively newer theories propose that dreaming is a preprogramed process and simply a result of the activation of the forebrain by the brain stem neurons. Dreams are also hypothesized to be involved in memory consolidation. Hopefully, further experiments will uncover the purpose of dreaming.

Keywords: activation-synthesis hypothesis, dreaming, memory consolidation, psychoanalytic theory, REM

INTRODUCTION the dopaminergic system is related to motivational states and feelings of pleasure, this theory could be the confirmation Every night people experience unique, mysterious magic. of Freud`s idea about desires as the foundation of dreams, A dream. A proof that our brains can do amazing things. which will be discussed in detail later. Dreaming can occur Create pictures, scenes, and stories without any external without REM. Studies on patients with brain lesions show stimuli. When we close our eyes, when the brain shuts the that, for example, patients with brainstem lesions lost the gates to the outside world, an internal, personal journey begins. capacity for REM sleep but continued to dream. Why does that happen? Do dreams have deep meaning or are they just an outcome of accidental brain connections? Non-REM sleep is characterized by diminishing of the aminergic activity and peripheral autonomic activity; synchronized EEG and presence of delta and theta rhythms. Researchers PHYSIOLOGY OF SLEEP AND DREAMING showed that the thalamus and cerebral cortex have the most significant role in non-REM dream generation. Interest- Traditionally, sleep is divided into two phases, the REM ingly, impulses from peripheral nerves and spinal cord can (Rapid Eye Movement) and NREM (Non-Rapid Eye Move- increase EEG synchronization and modify other charac- ment) phase. They interchange a few times during one teristics of electrical activity in this phase of sleep. Other night. REM sleep comprises around 20% of sleep and most structures, such as basal forebrain, anterior hypothalamus, of the dreaming. It would be incorrect to equate REM sleep cerebellum and caudal brain stem are also involved in NREM and dreaming, because dreaming also occurs in NREM. regulation.2 Dreams that occur in this phase of sleep are In fact, according to some scientists, REM sleep is controlled realistic, thought-like and constructed from the previous by the cholinergic activity in the brainstem, and dreaming is, day’s experiences.3 On the other hand, REM dreams are on the other hand, generated by the dopaminergic circuits of vivid, hallucinatory, bizarre, visual, highly emotional (fear, the ventromedial forebrain. Dopaminergic fibers originate anxiety, joy, anger) and are reported to use a high number of in the mesolimbic-mesocortical system, pass through the words.1 This type of dreaming could be explained by activation ventromedial forebrain, which involves the ventral tegmental and deactivation of specific brain areas in REM. Activated area of the mesencephalon, nucleus accumbens, hypothalamus, brain regions are the pontine tegmentum, amygdala, left prefrontal cortex, and anterior cingulate cortex.1 Given that thalamus, cingulate cortex, right parietal operculum and

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Figure 1. Comparison between EEG presentation and neurotransmitter dominance in wakefulness, NREM and REM sleep. Source: Nir Y, Tononi G. Dreaming and the brain: from phenomenology to neurophysiology. Trends Cogn Sci. 2010;14(2):88-100. doi:10.1016/j.tics.2009.12.001. Copyright © 2010 Published by Elsevier Inc. associative visual cortex, among others. The primary visual role of REM, mice that were deprived of it lost weight and and prefrontal cortex are deactivated. This could explain the temperature control. So, it is not impossible that REM sleep rich visual experience (activation of associative visual cortex), is required for body weight and temperature maintenance.4 and the fact we so often forget our dreams (deactivation of When do people start to dream? When does dreaming as prefrontal cortex). The neuromodulatory milieu also changes we adults know it begin to happen? It is interesting that depending on the state of mind. In the waking state, the the sleep of newborns, and even fetuses, has a REM phase. aminergic system dominates. NREM is characterized by In fact, REM occupies the greatest portion of sleep in the fading of the monoaminergic influence, whereas moving to last trimester of pregnancy and in early periods of life. But, the REM phase definitely suppresses this influence and the as was earlier mentioned, dreaming is not equal to REM.4 cholinergic activity becomes more prominent. This change If we define dreaming as a conscious experience based on of neurotransmitters is consistent with the characteristics internal rather than on external stimuli, what would be the of REM dreams described above. The limbic and paralimbic basis for an infant`s dream since they have no memories areas, responsible for vivid, hallucinatory dreams and emo- and no knowledge? Could it be that infants still dream tional experiences, are innervated by acetylcholine and thus some kind of a dream – only it differs from ours because activated during REM. On the other hand, the dorsolateral their dreams are based mostly on the external world?5 On prefrontal cortex, important for making plans and decisions, the other hand, what if they dream a “real” dream but are is dependent on the monoaminergic innervation which is not aware of it?6 For the simple reason that young children diminished during REM sleep. Other physiological features cannot report what they experience while sleeping, it is not of REM sleep are muscle paralysis, preventing a dreamer from an easy field to research. However, research of dreams of acting out their dreams, and rapid eye movements, which children from 3 years of age onwards prove that dreaming are involuntary saccadic eye movements.2 EEG in REM sleep is a developing process. In fact, the development of dream- shows desynchronization and rapid, low-voltage electrical ing correlates with the development of a child`s cognitive rhythms in the cortex which are similar to the waking state. capacities.3 Between the age of 3 to 5 children do not dream often, but when they do, their dreams lack social interactions, active self-participation and movement, which are the main DEVELOPMENT OF DREAMING characteristics of an adult`s dream. Dreaming about animals and body state dominates this phase of development. REM sleep appeared recently in evolution. It has evolved sep- Explanation for animals appearing in dreams could be the arately in mammals and birds, which are both homeothermic habit of using metaphors involving animals when explaining animals. In experiments designed to discover the possible life to kids. Indeed, when asked to tell a story, a child will gyrus | vol. 4 | no. 3 – 4 | july – december 2017 300 sleep disorders issue topics Vukić V. This is your brain on dreams. pp. 299 – 303 often tell one with animals in it. Contrary to popular belief, ing, painful, and disturbing. For the person`s own good, children do not usually experience frightening dreams for it must be disguised. This is where “the censor” operates. they do not dream of feelings. The appearance of feelings is It “translates” the latent into the manifest content using four a characteristic of a later phase of development. What might mechanisms. The first one is Condensation. It fuses a few frighten the child is the confusion when waking up and different elements from latent content into one unity that exchanging the dream for reality. In the period between the becomes present in the manifest content. This is the way to ages of 5 to 9 major changes happen which take the dreams express similarity between objects/subjects, although the to an adult level. Dream reports become longer and include main characteristic that makes them alike is not present. social interactions and motion, whereas until the age of 7, The second mechanism is called Displacement. This means active participation is still lacking. This could be explained that the essential idea, feeling, desire behind the dream is by kids’ current inability to imagine themselves as active represented in manifest content as a small, insignificant participants in the world. From 7 years of age onwards, along detail, whereas those things that are truly unimportant are with self-participation, happy feelings and thoughts about represented as the most meaningful. Freud describes this dream events come into the dream. Play takes central place as “transvaluation of all values”, using Nietzsche`s phrase. in both everyday life and dreaming. Knowing that dreams This mechanism may be the explanation why we usually dream are not daytime reflections, but one`s own interpretation of of the previous day’s experiences. A few associations between them, suggests that emotions experienced during playing are day experience and dream thought are usually enough for an important factor in the development of a child. Another representing a dream thought in dreams. Regression is the intriguing fact is that dream development correlates with third dream making mechanism, meaning the return of a the development of visuo-spatial skills rather than that of dreamer in a dream to primary mental processes. This sounds memory or vocabulary. Visuo-spatial skills depend on the reasonable if we consider that vision is dominant process in parietal cortex which is not fully myelinated till the age of 7. dreams. There is no intellectual operation in dream making. The years between 9 and 15 bring fully active participation The last mechanism is Secondary Elaboration. That simply and great pleasure into dreams. Since this period is essential means that a dreamer, when recalling a dream, changes it to for the creation of a young person, their ideals, opinions and be more comprehensible.9 In other words, we try to reconcile personality are reflected in their dreams.5 our (sub)consciousness with a dream.

DO BLIND PEOPLE DREAM? ACTIVATION-SYNTHESIS HYPOTHESIS

Since visual imagery dominates the dreams of people capa- The central idea of activation-synthesis hypothesis is that ble of seeing, questions have been raised about what blind dreaming is a preprogramed, essential brain process. Gen- people dream about. Researches on blind people’s dreams erators of a dream are giant cells in the pontine tegmentum. found that congenitally blind, as well as people blind since They activate the reticular, vestibular and oculomotor neu- the age of 4 or 5 years, show no elements of vision in their rons. The reticular system is responsible for the activation of dreams. They dream with the senses they use in daily life, the forebrain, whereas oculomotor and vestibular neurons such as hearing, taste, smell, and touch. Auditory sensation induce eye movements and inform the forebrain about them. is present in abundance, but that is similar in sighted peo- The forebrain then uses that internal information to create a ple. On the other hand, the prevalence of taste/smell/touch dream, to synthesize it. So, eye movements during dreaming sensations is higher. People who become blind later in life are not due to “following images that pass before our eyes”, continue to dream visual dreams.7,8 So, yes, blind people do but they actually precede the appearance of visual imagery dream, only with different tools. in the brain. Dreaming occurs periodically throughout sleep. This is due to the interaction between reciprocally activated cholinergic and aminergic cells (the former called D-ON/ WHY DO WE DREAM? – DREAM THEORIES OFF cells, and latter REM-ON/OFF cells). D-ON cells, which are in fact giant pontine cells, activate themselves as well as Questions about the function and genesis of dreams have D-OFF cells which in turn inhibit themselves and D-ON cells.10 been puzzling the human mind for centuries. Impressive Thanks to the improvement of research techniques in neu- theories have emerged, each brilliant in its own way. A few roscience, the hypothesis has been further developed into of them will be presented here. Freud`s theory of dreams AIM model (Activation – Input source – Modulation).11 This Sigmund Freud was an Austrian neurologist. He discovered model brings better identification of the brain regions acti- psychoanalysis, a therapy with the central idea of a dialogue vated during dreaming and stresses the role of the thalamic between a therapist and a patient. He brought emotions and nuclei as key sites which transmit endogenous stimuli to the desires into medicine. He believed them to be the cause of forebrain. PGO (ponto-geniculate-occipital) waves have been illness and a basis for dreams. According to Freud, dreams identified as endogenously generated signals that serve as an are fulfilment of the dreamer`s deepest wishes. These desires input source for a dream and also prevent external stimuli are subconscious and can enter the consciousness only by from interfering with dreaming. Another group of scientists means of psychoanalysis.9 When dreaming, we are aware found the cells that generate PGO waves to be glutamater- of what is called the manifest content. That is an allegorical gic.4 The third element of the model, modulation, describes presentation of latent content or a dream thought. It is of- cholinergic dominance during REM. In fact, research on ten absurd, illogical, and hallucinatory. On the other hand, the molecular level confirmed the existence of REM-ON dream thought is a “logical and integral part of the subject`s and REM-OFF cells with the former being the cholinergic mental life”, it is a “hidden desire”, stressful, embarrass- pedunculopontine tegmental neurons and the latter being

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the serotonergic dorsal raphe nucleus and noradrenergic MEMORY CONSOLIDATION HYPOTHESIS locus coeruleus neurons. This theory is much more complex than presented here and its details are beyond the scope of There is a lot of evidence that dreaming enhances learning. this review. However, there is one new update to this theory Experiments showed that brain activation during learning that is worth mentioning. Although REM sleep appears very is “replayed” during sleep, although it is not an exact copy early in human development it is thought that the brain is not of it. The process that goes on in dreaming is incorporation sufficiently developed to dream an adult dream. The question and storing of new information in the network of existing that comes to mind is what the brain does in REM if it does knowledge and experience. Dreaming may be influenced by not dream. The theory of protoconsciousness proposes that memory consolidation, but dream content does not have to the brain prepares itself for its future functions, the main reflect it, or even be functional.12 one being consciousness. During the dreamless REM phase the brain creates a virtual reality, with intrinsic predictions of time and space which are later modified by experiences in external world.4

CONCLUSION

Déjà vu, despite numerous studies, is still relatively unknown phenomenon. Although present in the population as a normal psychological event, as well as a direct indicator of various pathophysiological states of the brain, such as temporal lobe epilepsy and migraine, it is not clear with an absolute certainty which mechanisms are responsible for its forming. When it comes to déjà vu experiences as a part of a neurological condition, different explanations have been offered, and it is only clear that hippocampus and parahippocampal gyrus, in connection to the temporal neocortex, play significant role. Furthermore, prolonged duration, and higher frequency of the occurring of the déjà vu phenomenon, have also been indicated as symptoms that appear in person with temporal lobe epilepsy, rather than in individuals with otherwise non-affected brains. Déjà vu, in spite of many definitions, and startling the minds of countless scientists and laymen, still remains a mystery, since new studies and equipment that we still do not possess are needed in order to reveal its true origin, as well as meaning.

REFERENCES:

1. Cheniaux E. Dreams: Intergrating Psychoanalytic and Neuroscientific views. Rev Psiquiatr do Rio Gd do Sul. 2006;2(2):169-177. doi:10.1590/S0101-81082006000200009. 2. Eiser, A.S. Physiology and Psychology of dreams. Seminars in Nerology.2005;25(1) . 3. Andrés I De, Garzón M, Reinoso-suárez F. Functional anatomy of non-REM sleep. 2011;2(November):1-14. doi:10.3389/fneur.2011.00070. 4. Hobson JA. REM sleep and dreaming: towards a theory of protoconsciousness. Nat Rev Neurosci. 2009;10(11):803-813. doi:10.1038/ nrn2716. 5. Foulkes D. Children’s Dreaming and the Development of Consciousness.; 1999. 6. Nir Y, Tononi G. Dreaming and the brain: from phenomenology to neurophysiology. Trends Cogn Sci. 2010;14(2):88-100. doi:10.1016/j. tics.2009.12.001. 7. Hurovitz CS, Dunn S, Domhoff GW, Fiss H. The Dreams of Blind Men and Women : A Replication and Extension of Previous Findings. Dreaming. 1999;9(2):183-193. doi:10.1023/A:1021397817164. 8. Kerr NH, Domhoff GW. Do the Blind Literally “See” in Their Dreams? A Critique of a Recent Claim That They Do. Dreaming. 2004;14(4):230-233. doi:10.1037/1053-0797.14.4.230. 9. Jones E. Freud’s Theory of Dreams. Am J Psychol. 1910;21(2):283-308. doi:10.2307/1413004. 10. Hobson JA, McCarley RW. The brain as a dream state generator: an activation-synthesis hypothesis of the dream process. Am J Psychiatry. 1977;134(12):1335-1348. doi:10.1176/ajp.134.12.1335. 11. Hobson JA, Pace-Schott EF. The cognitive neuroscience of sleep: neuronal systems, consciousness and learning.Nat Rev Neurosci. 2002;3(9):679-693. doi:10.1038/nrn915. 12. Wamsley EJ. Dreaming and offline memory consolidation. Curr Neurol Neurosci Rep. 2014;14(3). doi:10.1007/s11910-013-0433-5.

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MOZAK I SNOVI

Sažetak Snovi su nezaobilazni dio života svakog ljudskog bića. Mozak nekoliko puta tijekom noći kreira svoju vlastitu stvarnost bez pomoći vanjskog svijeta. Sanjamo i u REM i u NREM fazi sna. REM faza sna i stanje budnosti povezani su sličnim EEG prikazima i visokom aktivnošću određenih regija mozga. S druge strane, druge regije mozga, aktivne u budnosti, u REM fazi su deaktivirane, uz dominaciju kolinergičkog sustava. Snovi su uglavnom vizualne naravi, ali istraživanja snova osoba slijepih od rođenja pokazuju da se sanjati može i drugim osjetima : sluhom, okusom, dodirom i mirisom. Također je pokazano da se snovi razvijaju usporedo s razvojem dječjih kognitivnih sposobnosti. No pitanje zašto uopće sanjamo još uvijek ostaje nedovoljno razjašnjeno. Ipak, brojne teorije nude zanimljiva objašn- jenja. Psihoanalitička teorija tvrdi da sanjanjem ispunjamo najdublje želje kojih se sramimo, koje su potisnute u nesvjesno i koje u stvarnosti ne možemo realizirati. Nasuprot toj teoriji izdiže se druga po kojoj je sanjanje već unaprijed programiran proces koji je rezultat aktivacije neurona iz moždanog debla koji podražuju prefrontalni korteks. Mozak onda od sve te zbrke pokuša stvoriti nešto iole smis- leno što doživljavamo kao san. Druga, istraživanja ukazuju na to da bi san mogao imati važnu ulogu u procesu konsolidacije pamćenja.

Ključne riječi: hipoteza aktivacije-sinteze, konsolidacija pamćenja, psihoanalitčka teorija, REM, snovi

Received July 13, 2017. Accepted October 16, 2017.

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issue topic Mutak A. Rhytmic variations of mood. pp. 304 – 310 RHYTHMIC VARIATIONS OF MOOD

Augustin Mutak 0000-0001-9003-1166 University of Zagreb, Faculty of Humanities and Social Sciences, Department of Psychology

Abstract In this article, an overview of studies on circadian (daily), circaseptan (weekly) and circannual (yearly) variations of positive affect, negative affect and total mood is given. Studies on circadian mood rhythms, which were mostly focused on fluctuations of positive and negative affect, indicate that positive affect displays circadian variations, while negative affect does not. Such findings are linked to predictive and reactive homeostasis, respectively. The function of positive affect could be to energize the organism to be more active during the middle of the day, while the function of negative affect could be to respond to immediate threats which can appear during any time of the day. Research on circaseptan mood rhythms often also explored total mood in addition to positive and negative affect. Current findings show that mood is higher during the weekend than during the working week. It is possible that such variations are culturally determined, however, more research is needed to reach stable conclusions. Studies on circannual mood rhythms were mostly focused on seasonal affective disorder (SAD). SAD rates are highest in the winter, although a smaller number of patients report depressive symptoms during the summer months. Predictive homeostasis is also thought to be the underlying evolved mechanism responsible for SAD since SAD makes the organism less active, thus reducing the quantity of food the organism needs to consume in the winter months when the sources of food are scarce. An overview of differences between yearly fluctuations of SAD rates and suicide rates is given.

Keywords: affect, circadian clocks, circaseptan, periodicity, seasonal mood disorder

INTRODUCTION and are less likely to be known by the person experiencing the affective state. For example, a person may become fright- In psychological science, mood is a construct which is, along ened because of the imminent danger which poses a threat with emotions, encompassed within a broader term called to his/her well-being, sad because of a loss of a loved one, affect. Although all intrapsychical processes are interlaced, angry because another person usurped his rightful interests. affects are distinct from cognitive (e.g. thinking, perception) On the other hand, a person may be in a bad mood throughout and conative (e.g. personality traits) constructs because they the day without clear reasons for such mood and the rea- possess a subjective component. In other words, affects are sons may even be unknown to the person experiencing the composed of characteristic “feelings” that can be experienced described mood. Thirdly, emotions are of shorter duration only from the first-person perspective and are difficult to than mood. While emotions are usually quick to appear and verbalize or explain to other persons. This subjective quality fade, the duration of mood is significantly longer. Modern is mutually shared between emotions and mood. research shows that, unlike emotions, mood actually never ceases to be present and can be felt in any moment from the first-person perspective.1 MOOD AND EMOTIONS Research has shown that mood consists of two separate Mood is, however, distinct from emotions in several important dimensions: positive and negative affect. Positive affect is characteristics. Firstly, emotions are more intensive than characterized by pleasant, happy, joyful and energized mood, mood. Both measures of subjective feelings and measures while negative affect is characterized by unpleasant feelings of physiological reactions clearly show that emotions elicit of subtle anger, fear, sadness and anxiety. The finding that stronger psychological and physiological reactions than these two dimensions are separate was unusual to many mood. Secondly, emotions are triggered by significant life laypeople and scientists alike because the conventional events, while the determinants of mood are more dispersed viewpoint held that the positive and negative affect are two gyrus | vol. 4 | no. 3 – 4 | july – december 2017 304 sleep disorders issue topics Mutak A. Rhytmic variations of mood. pp. 304 – 310 poles of the same continuum.2 At first, researchers insisted the optimal body temperature by sweating if the temperature that the positive and negative affect are two completely is too high or by shivering if the temperature is too low). separate, orthogonal dimensions. However, newer studies It can be divided into two types: reactive homeostasis, which have shown that, while these two dimensions indeed are aims to restore the balance after it has been disrupted and separate, they are not completely distinct, but are instead predictive homeostasis, which aims to alter the state of an in a low-to-moderate negative correlation. Thus, these two organism in anticipation of an event that can disrupt the dimensions are sometimes referred to as quasiorthogonal.3 balance so that the balance doesn’t get disrupted once the Some self-report instruments for measurement of mood event occurs.19 Studies in evolutionary psychology have shown have separate measures for positive and negative affect and that the evolutionary function of happiness is to motivate the measure of “total affect” is mathematically calculated the organism to approach potentially rewarding stimuli.20 as the difference between positive and negative affect.2 The idea of a prospective experience of a pleasant emo- Apart from self-report inventories, behavioral indicators tional state after completing a certain behavior motivates can also be used as a measure of a person’s current mood. the organism to take part in said behavior. Moreover, the For example, laughter and sobbing are reliable indicators of experience of a pleasant emotional state after completing positive and negative affect, respectively. However, studies a certain behavior keeps the prospective expectation real- that have used behavioral indicators as a measure of mood istic and relevant. Since humans are a diurnal species, the are rare, because the data collection process is difficult and potential function of circadian variations of positive affect time-consuming. Recently, there have been developments is to motivate the organism to be active during the daytime, in implicit measurements of mood (e.g. a person is asked to when the opportunities for finding positive stimuli are the rate the emotional valence of non-existent words). While the greatest, and less active during mornings and evenings.3,14,21 results of the first validation studies were promising, more There is currently no known methodology which could be studies are needed to fully validate this type of measure, applied to measure mood while the organism is sleeping. which is why implicit mood measures have not yet been used However, evolutionary psychologists have also devised a hy- in other studies besides the validation studies.4 pothesis which holds that the evolutionary functions of sleep is to force the organism to be inactive during the nighttime, when the opportunities for finding useful objects are lesser.19 TYPES OF RHYTHMIC VARIATIONS OF MOOD In other words, the functions of circadian rhythmicity of positive affect and sleep-wakefulness cycles are mutually Given the fact that mood is a constant state which never adverse. Because of this, certain authors believe that deep disappears from the intrapsychical world of each person, sleep represents the nadir of the daily fluctuation of positive researchers have turned their interests to the fluctuations affect; it is its lowpoint that currently cannot be measured.21 of mood in time. Biology has shown that many processes in the human body show daily (circadian), weekly (circaseptan), Studies of negative affect, on the other hand, show that neg- monthly (circalunar) or yearly (circannual) rhythmicity. ative affect displays no circadian fluctuations. This finding Perhaps the most cited example of a rhythm is the sleep-wake- was replicated in many studies.3,12,14,17 Certain studies have fulness rhythm which exhibits a clear circadian rhythm.5 detected circadian rhythmicity in negative affect, but they Some other examples include body temperature6 and height,7 have found that the rhythm of negative affect is much less which exhibit a circadian rhythm; synthetization of certain prominent than the rhythm of positive affect,13 or that the substances in the immune system,8 which exhibits a cir- goodness-of-fit measures indicate that the detection of caseptan rhythm; menstrual cycle,9 which is perhaps the a significant circadian rhythm of negative affect could be most famous example of a circalunar rhythm and testos- a statistical artifact.18 Modern theorists rely on evolutionary terone production in males, which shows both circadian10 functions of emotions to explain these findings. Many nega- and circannual11 fluctuations. tive emotional states (e.g. fear, anger) temporarily raise the activation level of an organism to allow for more efficient behavioral coping with threatening or unfriendly stimuli. Fear CIRCADIAN RHYTHMS OF MOOD can mobilize the energy of the organism for faster escape or more efficient defense against an attacker. Anger can also The greatest number of studies examining rhythmic fluc- mobilize the energy and allow the organism to attack other tuations of mood were oriented on investigating circadian hostile organisms. Since it is unpredictable when the need mood variability. Most studies examined either positive for such mobilization of organism will occur (e.g. dangerous and negative affect separately, or only examined one of animals can also attack in the morning), negative affect needs these two dimensions, while a smaller number of studies to be more flexible and ready for activation at any time of the examined the variability of total affect. Studies of positive day, which is why the function of the variations of negative affect revealed that it exhibits clear circadian fluctuations, affect is linked to reactive homeostasis.3,22 For this reason, appearing to be low in the mornings and evenings and negative affect displays no circadian variations and the reaching its peak during afternoon hours. This conclusion rhythmicity of negative affect is thought to be exogenous was reached by virtually all studies investigating circadian rather than endogenous. While mood is usually measured rhythms of positive affect.3,12-18 Modern theories hold that through self-report inventories, some studies that have used the circadian rhythmicity of positive affect is endogenous behavioral indicators to measure mood have also concluded and such variations are linked with predictive homeostasis. that positive affect exhibits circadian variations, while neg- Homeostasis is an umbrella term for a group of biological ative affect does not. For example, it was found that people functions whose purpose is to maintain the balance of the level laugh mostly during the middle of the day, with less laughs of certain characteristics of the organism (e.g. to maintain in the mornings and evenings, while the frequency of sighing

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issue topic Mutak A. Rhytmic variations of mood. pp. 304 – 310 does not depend on the time of the day.23 for the hypothesis that these two regulatory mechanisms are Studies of circadian variation of total affect are rare. In one two sides of the same coin that regulates the activation level study it was found that total affect displays a circadian rhythm of an organism (Figure 1). in a similar manner to positive affect; the peaks of total affect coincided with the peaks of positive affect. However, being composed of both positive and negative affect, total CIRCASEPTAN RHYTHMS OF MOOD affect displayed greater deviations from sinusoidality than positive affect and the rhythm was much less prominent. A smaller number of studies investigated how mood varies on It was also found that the extraversion/introversion person- a weekly basis. Initial results showed that total affect 13,25 and ality trait may have an impact on the sinusoidality of total positive16 and negative13 affect display a circaseptan rhythm, affect. While a significant circadian rhythm was found in with total affect and positive affect being higher during the introverts, it was not found in extraverts, which may be weekend and lower during the working week, while negative explained with the known findings that extraverts are more affect displayed an opposite trend. Differences between prone to sensation-seeking behaviors, which may result in introverts and extraverts were also found, with the same outcomes that unsystematically impact the mood of extra- trend of results as in circadian rhythms. Rhythm of total verts and make their mood rhythm less sinusoidal. Such affect was more pronounced in introverts than in extraverts.25 differences between extraverts and introverts were not found But, from a general viewpoint, the number of studies of in positive affect, which is why future studies should focus circaseptan mood rhythms was small and theoretical debates on investigating differences in the exogenous fluctuations about the causes of such rhythmicity emerged. The propo- of negative affect between these two groups.18 nents of the cultural viewpoint argued that the circaseptan variations of mood are determined by the structure of the Disruptions in circadian mood rhythms are also linked to week. Since people are preoccupied by obligations during the personality trait of neuroticism. One study found that the working week, their mood is lower and since they are the people with high results on measures of neuroticism did relatively free during the weekends, they have the ability to not display a circadian rhythm of positive affect, while those engage in activities they find interesting and joyful, which who scored lower did display such a rhythm24. It is interesting is why their mood is increased on weekends. On the other that the group with high results on neuroticism measures hand, theorists who favored a biological viewpoint insist- also displayed a weaker amplitude of circadian rhythm of ed that the circaseptan variations of mood are innate and body temperature, which suggests that the general circadian endogenous. The support for this argument was found in rhythmicity may be lower as neuroticism increases.24 Some of the results of certain chronobiological studies which found the yet unverified explanations hypothesize that lower levels that some non-psychological variables, such as the number of gamma-aminobutyric acid (GABA) lead to disruption of of erythrocytes26 and the response of the immune system to activity in suprachiasmatic nucleus, which is responsible endotoxins27, also display a circaseptan rhythm. The structure for regulating circadian rhythms.24 Lower levels of GABA of the week, according to these theorists, was not a determi- are also found in depressed patients. It is also known that nant of the mood. Instead, the structure of the week itself GABA is one of the essential neurotransmitters that induce was determined by innate circaseptan variations.25 sleep, which is why disruptions in mood may be linked with One study,28 although its sample size was small, was conducted disruptions in the sleep-wakefulness cycle.24 This similarity to test which of these two opposing viewpoints is true. In this in disturbances between circadian mood rhythms and cir- research, mood was measured using a self-report inventory cadian sleep-wakefulness rhythms provides further support each day in November, when the structure of the week is clear

Figure 1. Diurnal pattern of Positive Affect (PA) and Negative Affect (NA) in Studies I and II. Source: Clark LA, Watson D, Leeka J. Diurnal variation in the Positive Affects. Motiv Emot. 1989;13(3):205-234. doi:10.1007/BF00995536. Copyright © 1989 Plenum Publishing Corporation

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CIRCANNUAL RHYTHMS OF MOOD and in July, when the differences between the working week Whereas studies of circadian and circaseptan variations of and the weekend are much less pronounced. The results of mood typically measured mood in a population of healthy this research showed that mood, as was expected, exhibited individuals, with research only later being extended to a circaseptan rhythm in November, but did not exhibit a measure relations between disrupted circadian variations circaseptan rhythm in July. These findings suggest that the of mood and some psychiatric entities, studies of circannual circaseptan variations of mood are not innate, which is in variations of mood almost exclusively focus on depressive concordance with the cultural viewpoint and is aligned with symptoms. It is important to distinguish between depressive the fact that there is no external marker which would mark mood and negative affect. Negative affect is a broader term the passing of a week and which would allow circaseptan that may also include angry, fearful and other unpleasant rhythmicity to appear in humans through natural selection. feelings, while depressive symptoms are mostly linked with There are potentially important clinical implications of these sadness and anxiety. Seasonal affective disorder (SAD) is results. It is possible that the aforementioned circaseptan a well-documented mood disorder encompassed in Inter- rhythmicity of non-psychological variables is in fact influenced national Statistical Classification of Diseases and Related by variations of mood. In other words, it is possible that those Health Problems (ICD-10) under F33 (recurrent depressive circaseptan variations are also not endogenous. Physicians and disorder) and the Diagnostic and Statistical Manual of Men- other medical personnel who rely on circaseptan rhythmicity tal Disorders (DSM-5) recognizes a specifier “with seasonal in, for example, diagnostic procedures and determining the pattern” for major depressive disorder (296.xx). Studies of optimal dose of medications to administer should be cautious SAD have shown that in most people suffering from this in these procedures, especially if the patient is examined or disorder, the frequency and intensity of depressive symptoms treated during the part of the year in which the boundary are highest in the winter.30 To explain this finding, scientists between the weekend and the working week is dispersed.28 have again turned to predictive homeostasis. The function of depressive symptoms may be opposite to the function of One well-known phenomenon is related to circaseptan fluc- positive affect. While positive affect energizes the organism tuations of mood: the “blue Monday” phenomenon. A great and stimulates it to engage in activities, depressive persons number of movies, music and works of literature depict are often exhibiting symptoms of avolition and anhedonia. characters who complain about their extremely low mood The potential function of lowered mood in winter months on Mondays. It is not uncommon to hear people in everyday may be to reduce the activation level of organism, which in life reporting how they feel the worst on Mondays either. turn severely lowers the amount of calories the organism However, empirical results show no support for this phe- needs to intake to function. This type of an evolved mecha- nomenon. Studies show that the mood on Mondays is not nism would be adaptive since food is generally more difficult significantly lower than on the other days of the working to obtain in winter due to unbefitting weather conditions. week 13,16,25 and that the actual nadir of the mood may be This hypothesis is supported by empirical tests which show closer to Tuesday.28 An interesting finding showed that mood, that the availability of the serotonin transporter (5-HTT) measured through self-report inventories, was equally low on in the brain shows circannual variations.31 Some theorists Monday as on the other days of the week, but the participants view hibernation, which can be observed in some animal of the research still insisted that the Monday was their worst species, as an extreme form of such an evolved mechanism. day of the week. There are currently no empirically tested In accordance with this hypothesis, empirical research has hypotheses which could explain such disparities. One of the found that the prevalence of SAD increases as the geographical possible options is that the difference in mood is greatest latitude is further from 0° (the equator).32 SAD can be very between Sunday and Monday and that the participants are rarely (if ever) found among the inhabitants of the tropical actually complaining about this sudden drop when reporting climate zone, which does not experience winter.33 On the about their lowered mood on Mondays29 (Figure 2). other hand, the prevalence of SAD is greater among the inhabitants of Scandinavian countries, Alaska and northern parts of Canada.34

Figure 2. Fluctuations of mood show a clear circaseptan pattern in November (right panel), but not in July (left panel). Source: Mutak A. Kako struktura tjedna utječe na naše raspoloženje? Paper presented at the 5th Psihozij conference; May 13-15, 2017; Zagreb, Croatia. Copyright © 2017 Augustin Mutak

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Theories and research still need to examine the prevalence the society become more active and more socially engaged, of SAD within the Arctic and the Antarctic circle, which, like while depressive people remain inactive and are even more tropical climate, also deviate from “conventional” change socially isolated. It is hypothesized that this increase in the of seasons. subjective felling of “being left out” can lead to higher sui- However, certain individuals display an opposite seasonal cide rates. Some studies have indeed demonstrated that the pattern of depression, with most depressive symptoms oc- spring peak of suicide rates is greater in agricultural than curring during summer. The causes of this pattern are still in industrialized countries.41 A third hypothesis posits that unknown, but research has found that persons suffering from hopelessness, and not depression itself, is a main predictor “summer depression” display more agitated symptoms (e.g. of suicide. Since hopelessness can be a residual symptom irritability, “racing thoughts”, motor agitation) in contrast of depression,42 it is possible that hopelessness increases with sufferers of “winter depression” who display signs of during the remission phase of depression because the person fatigue and lack of energy.35 However, more studies need is fearing that he/she will never “be cured” from depression, to be conducted to explain the phenomenon of “summer which may lead to suicide.43 Clearly more empirical research depression”. More research is also needed to explore the is needed to explain the phase difference between mood and circannual variations of mood in non-depressed individuals. suicide rates (Figure 3).

THE DISPARITY BETWEEN SUICIDE RATES AND SAD RATES

The belief that suicide rates display a clear yearly rhythm which is analogous to the yearly mood rhythm is very popular, which is not surprising since it is known that depression carries a high risk of suicide. However, empirical studies have found different results. A circannual rhythm of suicide was indeed detected; however, suicide rates reached their peak in late-spring and early-summer months. This finding was replicated in many countries.36-39 There is currently no scientific consensus regarding the source of discrepancy between suicide rates and mood and several competing hypotheses are currently available. One hypothesis holds that depressive people ideate suicide in the winter months, but postpone the execution of the act due to societal fes- Figure 3. Plots of the prevalence rates of winter SAD in the USA and tivities (e.g. Christmas, Easter).40 Another hypothesis is Europe in relation to latitude. The straight lines are linear curve-fits. based on the fact that depressive people are more isolated Source: Mersch PP, Middendorp HM, Bouhuys AL, Beersma DG, from social activities due to their lower energy levels. In van den Hoofdakker RH. Seasonal affective disorder and latitude: a review of the literature. J Affect Disord. agricultural societies, the general population is less active 1999;53(1):35-48. doi:10.1016/S0165-0327(98)00097-4. during the winter due to the fact that most crops cannot be Copyright © 1999 Elsevier Science B.V. Published by Elsevier Inc. cultivated in the winter. As the spring starts, members of All rights reserved.

CONCLUSION

Current research shows that positive affect varies on a circadian basis, while negative affect does not. This finding is explained through evolutionary theories which posit that the role of positive affect is to increase the activation level of the organism, which needs to be highest during the afternoon, since humans are a diurnal species, and lower in the mornings and evenings. Negative affect, on the other hand, is associated with states of fear and anger which need to be more flexible to allow for more efficient behavioral responses throughout the day. Studies on circaseptan rhythms of mood show that mood is higher on the weekends and lower during the working week. However, this effect disappears in the parts of the year when the boundaries between the working week and the weekend are less established. Thus, circaseptan rhythmicity of mood is best accounted for by cultural theories. Lastly, research on circannual rhythms of mood has mostly been focused on depressive mood and has shown that depressive symptoms are most prominent in the winter. This finding is also explained with evolutionary theories which hold that the activation level of the organism, which mood is an indicator of, needs to be lower in the winter to decrease the need for food intake in weather conditions which make obtaining food more difficult.

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REFERENCES:

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Diurnal Variation in the Positive Affects. Motiv Emot. 1989;13(3);205-234. doi:10.1007/BF00995536. 13. Cornélissen G, Watson D, Mitsutake G, et al. MAPPING OF CIRCASEPTAN AND CIRCADIAN CHANGES IN MOOD. Scr Med (Brno). 2005;78(2):89-98. http://www.ncbi.nlm.nih.gov/pubmed/18985163. Accessed November 16, 2017. 14. Murray G, Nicholas CL, Kleiman J, et al. Nature’s Clocks and Human Mood: The Circadian System Modulates Reward Motivation. Emotion. 2009;9(5);705-716. doi:10.1037/a0017080. 15. Boivin DB, Folkard S. Complex Interaction of the Sleep-Wake Cycle and Circadian Phase Modulates Mood in Healthy Subjects. Arch Gen Psychiatry. 1997;54;145-152. doi:10.1001/archpsyc.1997.01830140055010. 16. Egloff B, Tausch A, Kohlmann CW, Krohne HW. Relationships Between Time of Day, Day of the Week, and Positive Mood: Ex- ploring the Role of the Mood Measure. Motiv Emot. 1995;19(2);99-110. doi:10.1007/BF02250565. 17. Wood C, Magnello ME. Diurnal changes in perceptions of energy and mood. J R Soc Med. 1992;85(4):191-194. http://www.ncbi.nlm. nih.gov/pubmed/1433057. Accessed November 16, 2017. 18. Mutak A, Pavlović M, Zibar K. Postoje li razlike između introverata i ekstraverata u cirkadijurnim ritmovima raspoloženja? Paper presented at 3rd Regionalni susret studenata psihologije conference; May 4-6, 2017; Rijeka, Croatia. 19. Moore-Ede MC. Physiology of the circadian timing system: predictive versus reactive homeostasis. Am J Physiol. 1986;250(5 Pt 2):R737-52. http://www.ncbi.nlm.nih.gov/pubmed/3706563. Accessed November 16, 2017. 20 Nettle D. Happiness: The Science Behind Your Smile. Oxford, UK: Oxford University Press; 2005. 21. Watson D, Wiese D, Vaidya J, Tellegen A. The Two General Activation Systems of Affect: Structural Findings, Evolutionary Con- siderations, and Psychobiological Evidence. J Pers Soc Psychol. 1999;76(5);820-838. doi:10.1037/0022-3514.76.5.820. 22. Zevon MA, Tellegen A. The Structure of Mood Change: An Idiographic/Nomothetic Analysis. J Pers Soc Psychol. 1982;43(1);111-122. doi:10.1037/0022-3514.43.1.111. 23. Hasler BP, Mehl MR, Bootzin RR, Vazire, S. Preliminary Evidence of Diurnal Rhythms in Everyday Behaviors Associated with Positive Affect. J Res Pers. 2008;42;1537 – 1546. doi:10.1016/j.jrp.2008.07.012. 24. Murray G, Allen NB, Trinder J, Burgess H. Is Weakened Circadian Rhythmicity a Characteristic of Neuroticism? J Affect Disord. 2002;72;281-289. doi:10.1016/S0165-0327(01)00465-7. 25. Larsen RJ, Kasimatis M. Individual Differences in Entertainment of Mood to the Weekly Calendar. J Pers Soc Psychol. 1990;58(1);164- 171. doi:10.1037//0022-3514.58.1.164. 26. Haus E, Lakatua DJ, Swoyer J, Sackett-Lundeen L. Chronobiology in Hematology and Immunology. Am J Anat. 1983;168;467-517. doi:10.1002/aja.1001680406. 27. Levi F, Halberg F. Circaseptan (About 7-Day) Bioperiodicity – Spontaneous and Reactive – and the Search for Pacemakers. Res Clin Lab. 1981;12;323-370. doi:10.1007/BF02909422. 28. Mutak A. Kako struktura tjedna utječe na naše raspoloženje? Paper presented at the 5th Psihozij conference; May 13-15, 2017; Zagreb, Croatia. 29. Stone AA, Hedges SM, Neale JM, Satin MS. Prospective and Cross-Sectional Mood Reports Offer No Evidence of a “Blue Monday” Phenomenon. J Pers Soc Psychol. 1985;49(1);129-134. doi:10.1037/0022-3514.49.1.129. 30. Eagles JM. Seasonal Affective Disorder. Brit J Psychiat. 2003;182(2);174-176. doi:10.1192/bjp.182.2.174. 31. Kalbitzer J, Kalbitzer U, Knudsen GM, Cumming P, Heinz A. How the Cerebral Serotonin Homeostasis Predicts Environmental Changes: A Model to Explain Seasonal Changes of Brain 5-HTT as Intermediate Phenotype of the 5-HTTLPR. Psychopharmacology (Berl). 2013;230(3);333-343. doi:10.1007/s00213-013-3308-1. 32. Mersch PP, Middendorp HM, Bouhuys AL, Beersma DG, van den Hoofdakker RH. Seasonal Affective Disorder and Latitude: A Review of the Literature. J Affect Disord. 1999;53(1);35-48. doi:10.1016/S0165-0327(98)00097-4. 33. Rasool GH, Winnington J. Chapter 5: Mental Health: An Introduction. In: Rassool GH, ed. Dual Diagnosis Nursing. New Jersey, NJ: Wiley-Blackwell; 2006;45-53.

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34. Magnusson A. An Overview of Epidemiological Studies on Seasonal Affective Disorder. Acta Psychiart Scand. 2000;101;176-184. doi: 10.1034/j.1600-0447.2000.101003176.x. 35. Wehr TA, Giesen HA, Schulz PM, Anderson JL, Joseph-Vanderpool JR, Kelly K, Kasper S, Rosenthal NE. Contrasts Between Symptoms of Summer Depression and Winter Depression. J Affect Disorders. 1991;23;173-183. doi: 10.1016/0165-0327(91)90098-D. 36. Maes M, Cosyns P, Meltzer HY, De Meyer, F Peeters D. Seasonality in Violent Suicide but not in Nonviolent Suicide or Homicide. Am J Psychiatry. 1993;150(9);1380-1385. doi:10.1176/ajp.150.9.1380. 37. Bridges FS, Yip PS, Yang KC. Seasonal Changes in Suicide in the United States, 1971 to 2000. Percept Mot Skills. 2005;100;920-924. doi:10.2466/pms.100.3c.920-924. 38. Bazas T, Jemos J, Stefanis K, Trichopoulos D. Incidence and Seasonal Variation of Suicide Mortality in Greece. Compr Psychiatry. 1979;20(1);15-20. doi:10.1016/0010-440X(79)90055-5. 39. Benedito-Silva AA, Pires ML, Calil HM. Seasonal Variation of Suicide in Brasil. Chronobiol Int. 2007;24(4);727-737. doi:10.1080/07420520701535795. 40. Wenz FV. Seasonal Suicide Attempts and Forms of Loneliness. Psychol Rep. 1977;40;807-810. doi:10.2466/pr0.1977.40.3.807. 41. Chew KSY, McCleary R. The Spring Peak in Suicides: A Cross-National Analysis. Soc Sci Med. 1995;40;223-230. doi:10.1016/0277- 9536(94)E0070-9. 42. Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barocka A. Residual Symptoms After Partial Remission: An Important Outcome in Depression. Psychol Med. 1995;25;1171-1180. doi:10.1017/S0033291700033146. 43. Kennedy N, Foy K. The Impact of Residual Symptoms on Outcome of Major Depression.Curr Psychiat Rep. 2005;7(6);441-446. doi: 10.1007/s11920-005-0065-9.

RITMIČKE VARIJACIJE RASPOLOŽENJA

Sažetak

U ovom članku dan je pregled istraživanja o cirkadijurnim (dnevnim), cirkaseptalnim (tjednim) i cirkanualnim (godišnjim) varijacijama pozitivnog afekta, negativnog afekta i ukupnog raspoloženja. Istraživanja cirkadijurnih ritmova raspoloženja, koja su većinom bila usmjerena na fluktuacije pozitivnog i negativnog afekta, ukazuju kako pozitivni afekt pokazuje cirkadijurne varijacije, dok ih negativni afekt ne pokazuje. Takvi nalazi povezuju se s prediktivnom, odnosno reaktivnom homeostazom. Funkcija pozitivnog afekta mogla bi biti da potakne organizam da bude aktivniji tijekom sredine dana, dok bi funkcija negativnog afekta mogla biti odgovaranje na neposredne prijetnje koje se mogu pojav- iti u bilo koje doba dana. Istraživanja o cirkaseptalnim ritmovima raspoloženja često su proučavala i ukupno raspoloženje uz pozitivni i negativni afekt. Trenutni nalazi pokazuju da je raspoloženje više tijekom vikenda nego tijekom radnog tjedna. Moguće je da su takve varijacije kulturalno određene, no potrebno je još istraživanja kako bi se došlo do stabilnog zaključka. Istraživanja cirkanualnih ritmova raspoloženja većinom su bila usmjerena na sezonski afektivni poremećaj (SAP). Stope SAP-a najviše su zimi, premda manji broj pacijenata pokazuje depresivne simptome u ljetnim mjesecima. Smatra se da je prediktivna homeostaza mehanizam koji se nalazi u podlozi SAP-a budući da SAP čini organizam manje aktivnim, čime se smanjuje količina hrane koju organizam treba konzumirati tijekom zimskih mjeseci, kada su izvori hrane oskudni. Dan je pregled razlika između godišnjih fluktuacija stopa SAP-a i stopa samoubojstava.

Ključne riječi: afekt, cirkadijurni satovi, cirkaseptalni, periodičnost, sezonski poremećaj raspoloženja

Received July 10, 2017. Accepted November 29, 2017.

gyrus | vol. 4 | no. 3 – 4 | july – december 2017 310 sleep disorders issue topics Nedić E. Sleep disorders and health risks. pp. 311 – 314 SLEEP DISORDERS AND HEALTH RISKS

Elizabeth Nedić 0000-0003-0946-2060 Josip Juraj Strossmayer University of Osijek, Faculty of Medicine

Abstract This article provides a short overview of the consequences of sleep deprivation, whether they are caused by an illness or lifestyle factors (jobs including night-shifts, staying up all night for studying or party- ing, etc.). Lack of sleep has harmful effects on the whole human body, including the central nervous system, immune and endocrine systems, as well as the gastrointestinal and cardiovascular systems. It also affects psychosocial well-being, causing emotional instability, a constant feeling of tiredness and lack of concentration.

Keywords: cardiovascular system, cognitive disorders, endocrine system, quality of life, sleep deprivation, sleep disorders

INTRODUCTION

Sleep plays an irreplaceable role in a normal human func- sleeps, cognitive slowing, longer response time and decline tioning. Its importance can be recognized by observing the in performance, including short-time memory. consequences we suffer when it’s disturbed. It is well-known These effects have been considered benign for a long time, but that sleep disorders have negative effects on cognition (e.g. it has been proven that sleep-loss induced mistakes, especially reduced attention), but most people do not realise that they those made among workers in medical care, can have serious can lead to more serious consequences, such as increased consequences for patients. In one study, subjects exposed cardiac morbidity.1 Sleep disorders represent a problem that to less than 6 hours of sleep have shown lower cognitive per- can result not only in increased medical costs, but also in formance, but, interestingly, did not recognize their deficit.5 poorer quality of life,2 even in loss of life. Errors that happen due to fatigue among medical residents Sleep deprivation is described as “acquiring sleep that is include poorer lab report and electrocardiogram interpre- inadequate to support daytime alertness”.3 It happens as tation, deterioration in intubation skills and intravenous a consequence of voluntary sleep curtailment or a patho- cannulation. Also, anesthesiologists have reported errors physiological process. The most common sleep disorders made because of fatigue and also falling asleep while working. include insomnia, restless legs syndrome and obstructive Furthermore, surgeries, carried out by both residents and sleep apnea. Among these, insomnia is the most frequent experienced surgeons lasted about 30% longer with higher one.4 Effects of sleep deprivation include a full range of ab- complication rates. What is also affected by loss of sleep is normalities, from those affecting the cardiovascular system quality of communication with patients, which is lowered to those affecting immune function and mood. Also, it can because of episodes of irritability or anger towards patients.7 lead to fatal accidents at work or on the road where approximately 20 percent of car crash injuries could be avoided It seems like habits of shortening sleeping time start appearing by preventing drivers’ sleepiness. Shift-work and longer during college years, and become frequent as students transit working hours, which are common nowadays, have also from puberty to adolescence. There is an association between shown significant negative effects on workers’ performance. poor sleeping patterns and consequently worse academic Although we now understand more about sleep disorders performance in adolescents. It was shown that total sleeping and their effects, they tend to go unrecognized and are time is becoming 40 to 50 minutes shorter from the age of undertreated by patients and physicians alike.5 13 to 19, due to augmented academic obligations. It seems like students’ grades are not proportionally declining, but it is possible that they do not achieve the optimal academic COGNITIVE DISORDERS performance because of sleep related issues. However, the majority of students experience extreme fatigue, sleepiness Almost all types of sleep problems are associated with defi- and mood changes. 3 In cases where the starting time of classes cits in attention, vigilance, and other measures of cognition, was scheduled an hour later, so that students could extend including memory and complex decision making. Sleep their total sleeping time, results have shown more frequent deprived workers show lower attention, involuntary micro attendance of classes and less symptoms of depressed mood.5

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CARDIOVASCULAR SYSTEM ENDOCRINE SYSTEM

Probably the most catastrophic effects caused by the lack of Hormonal secretion is controlled primarily by the suprachi- sleep are seen in the cardiovascular system. Loss of sleep asmatic nucleus (SCN), located in the hypothalamus, which increases the risk of cardiac morbidity.1 is responsible for regulating circadian rhythms in the body. Causes of this may be some of the following: increased sym- However, some hormones are predominantly dependent on pathetic activity, elevated number of inflammation markers, the sleep-wake state. Disorders in both sleep duration and and hormonal changes. All of these factors represent a risk quality of sleep can cause abnormalities in endocrine system.10 for cardiovascular incidents, starting with atherosclerosis. Furthermore, sleep deprivation contributes to the occurrence Usually, cortisol levels decrease in the late hours of the day of hypertension. It is especially dangerous for patients with and reach their lowest level during sleep. The level rises in hypertension or pre-hypertension because even a half night the early morning hours again. If the sleep-wake cycle is of sleep loss increases blood pressure.1 disturbed, it can have an effect on baseline cortisol levels the following night, which can be higher. Also, the maximum Also, since restricted sleep can be a cause of impaired glucose morning level can be lower.9 tolerance and obesity, there is an indirect link between them and cardiovascular events. The risk is even greater with Sleep has an inhibitory effect on thyrotropin (TSH) secretion patients who are sleep-deprived due to an illness, such as and, subsequently, on thyroid hormone secretion. In response obstructive sleep apnea, who are at the highest risk of such to sleep deprivation, TSH rises above the normal level, but it events, including hypertension, cardiac arrhythmias, and seems to be dependent on night and not on daytime-sleep.11 ischemia.7 A large study on 71,617 female health professionals Growth hormone (GH) is strongly dependent on sleep. It is without coronary disease has shown that sleep duration that secreted during sleep, not strictly dependent on time of the day. is either less than 7 or more than 9 hours a day is directly However, its secretion is diminished with sleep deprivation, associated with an increased risk of cardiac events.6 sleep fragmentation and advanced age. Another hormone An effect on coronary vessels is also present: coronary flow dependent on sleep, ghrelin, also enhances GH production.11 is being decreased in cases of sleep deprivation.7 Prolactin is also highly sleep-dependent. Its level peaks in Sleep disorders can represent a risk factor for a stroke. 15 the middle of the sleep period. Therefore, sleep interruption Unrecognized and untreated, disorders contribute to a worse during the night is accompanied by inhibition of prolactin outcome of a stroke.16 secretion.11

Glucose tolerance is biphasic during sleep, resulting in differ- IMMUNE SYSTEM ent thresholds during REM-phase sleep and non-REM phase sleep. As our body has a lower need for energy, tolerance is In people experiencing acute or chronic sleep deprivation, decreased. Switching to REM sleep, the brain needs more the level of C-reactive protein (CRP) was significantly higher glucose and tolerance increases again, as well as insulin compared to people having a normal duration of sleep (~8 sensitivity. These findings suggest that not only duration, hours) where it remained constant. Elevated levels of CRP but the presence of all phases of sleep are required for bal- serve as an inflammation marker, as well as a predictor of anced glucose levels. Such changes in insulin sensitivity and stroke and myocardial infarction.8 glucose tolerance can increase the risk of diabetes mellitus.11 Experimental sleep deprivation in healthy adults has been Gonadotropic hormones secretion is influenced mostly by found to lead to increased peripheral circulation of leuko- circadian rhythm. However, there is some evidence that cytes and interleukin 6 (IL-6). Monocytes, neutrophils and sleep affects some of them, precisely, testosterone. Testos- phagocytic cells in peripheral circulation are also elevated terone levels normally increase at sleep onset, but in sleep as a result of acute loss of sleep.1 deprivation, especially in young men, levels are attenuated.10 These findings lead to the conclusion that stress, a result of prolonged sleep curtailment, invokes chronic low-grade inflammation in the body, and also leads to immunodeficiency.9 PSYCHOSOCIAL EFFECTS

Sleep plays a great role in human well-being. Sleep restric- GASTROINTESTINAL SYSTEM tion causes a decline in sociability and optimism, as well as higher bodily discomfort (increase of generalized body Sleep deprivation has an effect on ghrelin and leptin levels. pain, back pain, and stomach pain), a feeling of tiredness, They are gastrointestinal hormones that have opposing ef- and being more aggressive than usual.2 The presence of in- fects on appetite: leptin, released from adipocytes, promotes somnia can cause many psychological complications, mostly satiety, whereas ghrelin, produced mainly in the stomach, because patients suffering from it can feel symptoms in an promotes increased appetite and reduces fat metabolism. intensified form. It is interesting that poor sleep might not Several studies have shown that partial sleep deprivation always cause objective cognitive problems (tested through is associated with significant decreases in leptin levels and polysomnography), but misperceptions and inaccurate beliefs conversely increases in levels of ghrelin. In the long run, these regarding the daytime consequences of poor sleep may lead combined effects may result in weight gain and obesity.10 to an increased awareness and depressed mood.12 Insomnia is associated with an increased risk of depression, anxiety and suicide11 and its chronic form is significantly associated with a higher risk of subsequent alcohol-related gyrus | vol. 4 | no. 3 – 4 | july – december 2017 312 sleep disorders

issue topics Nedić E. Sleep disorders and health risks. pp. 311 – 314

problems, nicotine dependence and drug abuse or dependence. Furthermore, sleep deprivation produces hyperalgesic changes in patients. It increases generalized body pain and CONCLUSION also augments acute pain.13

There is also a strong link between psychiatric disorders To conclude, it is important to be aware of the and sleep disturbances: it was believed that psychiatric consequences of sleep deprivation, whether it is conditions cause sleep problems, but it has been proven caused by an illness or voluntarily. It has serious that their relationship is more complex. It was shown that negative effects on almost every system in our body, just as treatment of a mental illness helps with sleep prob- including cardiovascular, nervous, gastrointestinal lems, the treatment of sleep disorders can likewise help the and endocrine systems. Inadequate sleep is also outcome of a psychiatric disease.14 Also, sleep problems are associated with cognitive and psychiatric disorders sometimes an important indicator of an illness, such as and remarkably affects quality of life. Therefore, hypersomnia or insomnia present in major depressive dis- sleep-related problems need to be taken more seri- order or hyposomnia in manic episodes of a bipolar disorder. ously and, in order to prevent dangerous outcomes, In generalized anxiety disorder, problems include difficul- treated appropriately. ties falling or staying asleep, as well as in post-traumatic stress disorder. Patients suffering from schizophrenia and alcoholism may have a problem which is best described as a disruption in circadian rhythm, where a person stays awake during the night and sleeps during the daytime. These findings require more research because of a possible better treatment of patients with both illnesses.14

REFERENCES:

1. Mullington, M. J., Haack, M., Toth, M., Serrador, M., Meier-Ewert H. NIH Public Access. Cardiovasc Metab Consequences Sleep Deprivation. 2009;5(4):294-302. doi:10.1016/j.pcad.2008.10.003.Cardiovascular. 2. Haack M, Mullington JM. Sustained sleep restriction reduces emotional and physical well-being. Pain. 2005;119(1-3):56-64. doi:10.1016/j.pain.2005.09.011. 3. Hershner SD, Chervin RD. Causes and consequences of sleepiness among college students. Nat Sci Sleep. 2014;6:73-84. doi:10.2147/ NSS.S62907. 4. Kapur VK. Approach to the Patient with a Sleep Complaint. In: Nathaniel F. Watson MD, Bradley V. Vaughn MD, eds. Clinician’s Guide to Sleep Disorders. ; 2006:1-17. 5. Colten H, Altevogt BBM, Colten. H. Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem.; 2006. doi:10.1097/01. CHI.0000270812.55636.3b. 6. Ayas NT, White DP, Manson JE, et al. A Prospective Study of Sleep Duration and Coronary Heart Disease in Women. Arch Intern Med. 2003;163(2):205. doi:10.1001/archinte.163.2.205. 7. PR OU, Sahota P. Acute and Emergent Events in Sleep Disorders.; 2010. http://books.google.com/books?id=ARlaRwAACAAJ&pgis=1. 8. Meier-Ewert HK, Ridker PM, Rifai N, et al. Effect of sleep loss on C-Reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol. 2004;43(4):678-683. doi:10.1016/j.jacc.2003.07.050. 9. Besedovsky L, Lange T, Born J. Sleep and immune function. Pflugers Arch Eur J Physiol. 2012;463(1):121-137. doi:10.1007/s00424- 011-1044-0. 10. Morgan D, Tsai SC. Sleep and the Endocrine System. Sleep Med Clin. 2016;11(1):115-126. doi:10.1016/j.jsmc.2015.10.002. 11. Gottlieb DJ, Punjabi NM, Newman AB, et al. Association of sleep time with diabetes mellitus and impaired glucose tolerance. Arch Intern Med. 2005;165(8):863-867. doi:165/8/863 [pii]\r10.1001/archinte.165.8.863. 12. Szentkirályi A, Madarász CZ, Novák M. Sleep disorders: impact on daytime functioning and quality of life. Expert Rev Pharmacoecon Outcomes Res. 2009;9(1):49-64. doi:10.1586/14737167.9.1.49. 13. Lautenbacher S, Kundermann B, Krieg JC. Sleep deprivation and pain perception. Sleep Med Rev. 2006;10(5):357-369. doi:10.1016/j. smrv.2005.08.001. 14. Krystal AD. Psychiatric Disorders and Sleep. Neurol Clin. 2013;30(4):1389-1413. doi:10.1016/j.ncl.2012.08.018.PSYCHIATRIC. 15. Ferre A, Ribó M, Rodríguez-Luna D, et al. Strokes and their relationship with sleep and sleep disorders. Neurol (English Ed. 2013;28(2):103-118. doi:10.1016/j.nrleng.2010.09.004. 16. Wallace D, Ramos A, Rundek T. Sleep disorders and stroke. Int J Stroke. 2013;7(3):231-242. doi:10.1111/j.1747-4949.2011.00760.x.Sleep.

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POREMEĆAJI SPAVANJA I ZDRAVSTVENI RIZICI

Sažetak

Ovaj članak predstavlja kratki pregled posljedica nastalih zbog nedostatka sna, uzrokovanog bolešću ili životnim stilom (poslovi koji uključuju noćne smjene, probdijevanje cijele noći zbog učenja ili partijanja itd.). Manjak sna ima štetne učinke na cijeli ljudski organizam, uključujući središnji živčani sustav, imunološki i endokrinološki sustav, kao i na gastrointestinalni te kardiovaskularni sustav. Također utječe na psihosocijalno funkcioniranje pojedinca, uzrokujući emocionalnu nesta- bilnost, neprekidni osjećaj umora i manjak koncentracije.

Ključne riječi: endokrini sustav, kardiovaskularni sustav, kognitivni poremećaji, kvaliteta života, nedostatak sna, poremećaji spavanja

Received August 20, 2017. Accepted September 14, 2017.

gyrus | vol. 4 | no. 3 – 4 | july – december 2017 314 sleep disorders issue topics Dragčević D. Somnambulism. pp. 315 – 318 SOMNAMBULISM

Dora Dragčević 0000-0002-9744-0613 University of Zagreb, School of Medicine

Abstract

Somnambulism, also known as sleepwalking, is a sleep disorder that affects approximately 2.5% of adult population and has slightly higher prevalence in children. The main characteristic of this disorder is the coexistence of both sleep elements and elements of wakefulness. Sleepwalkers have a disrupted sleep pattern, which can cause specific changes in electroencephalogram (EEG) recordings such as cyclic alternating pattern (CAP) change and increased slow wave activity. A few hypotheses claim that a change in serotoninergic and dopaminergic transmission is responsible for sleepwalking, but scientific proof is yet to be found. Various clinical cases show correlation between different drugs (zolpidem, quetiapine) or chemical substances (alcohol, caffeine) and sleepwalking. A positive family history is another known risk factor for somnambulism. Since sleepwalking is most often correlated with various sleep-breathing disorders, the main type of treatment is surgical removal of the tissue causing this problem. Other treatment protocols may include psychiatric help, drugs or changes in sleep routine. Diagnosis is based on anamnestic data and EEG recordings.

Keywords: alcohol, clinical approach, quetiapine, sleepwalking, slow wave activity (SWA), zolpidem

INTRODUCTION MECHANISMS OF SOMNAMBULISM

The aim of this article is to briefly present somnambulism, The sleep cycle lasts approximately 90 min,1 and is divided or sleepwalking, as a sleep disorder grouped with other par- into two major phases NREM (non-rapid eye movement) asomnias that are characterized by a variety of actions not and REM (rapid eye movement). The NREM sleep phase is normally seen in sleep. 1 During the episode of sleepwalking subdivided into 4 stages from 1 to 4 with increasing depth different actions such as eating, driving, talking or various of sleep. Somnambulism occurs during the first sleep cycle violent acts are done unconsciously.1,2 Crimes committed in stages 3 and 4 of NREM sleep, 6,7 and rarely in stage 2.7 during the sleepwalking episode have been a law problem for Sleepwalkers have a different, more disrupted, sleep pattern decades because the episode cannot be proven retrospectively when compared to healthy individuals. Disruption is seen and up until now no absolute solution was found. With the as microarousals, wake after sleep onset (WASO), arousals, advancement of sleep medicine, certain EEG changes are awakenings, or an abnormal amount of cyclic alternating pat- found only in sleepwalkers and are used as a diagnostic tern (CAP A2 and A3).2 In NREM sleep, EEG recordings show parameter and as proof that one has mentioned affliction. high amplitude and low frequency Δ waves whose changes Episodes of sleepwalking occur most often in prepubertal can be seen in patients suffering from sleepwalking as well children, but can also be seen in adults with decreasing fre- as CAP changes. The primary change seen in a sleepwalker’s quency of cases in older age groups.1 Up to 25% of children brain is consistent CAP change which is always present in who have experienced sleepwalking during their childhood EEG recordings, whereas a second measured parameter are troubled with same problem in adulthood.3 These cas- known as slow wave activity (SWA) is not as consistent.2 The es represent almost 90% of sleepwalking cases in adults.4 first measured changes were described as hypersynchronous Somnambulism attacks can be precipitated by taking drugs, delta activity (HSD), but subsequent research showed that alcohol abuse, other sleep disorders or sleep disturbances, this parameter cannot be used for precise classification but in many cases the cause is unknown. When caused by of somnambulism.7 SWA is an EEG-measured parameter known factors, somnambulism is not treated directly, but used for describing sleep dynamics and it describes sleep through treatment of the precipitating cause.3 Other situa- depth and intensity. Researchers have shown that prior to tions require supportive treatment or, rarely, medications.5 the onset of a sleepwalking episode a patient’s EEG will show increased SWA that is different for every individual.7 The reason for this increased activity is still unknown, but may be related to other changes present in the body during the episode. During both major sleep phases sensations and motor functions are inhibited in order to prevent unfortunate events.

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includes dopamine and serotonin antagonists.8,9 Furthermore, different studies have shown involvement of the brain stem and cerebellum in initiation of movement. Confirmation of these findings came from SPECT image of sleepwalkers which have shown activity in mentioned parts of the brain, but negligible activity in cerebrum and cerebral cortex responsible for consciousness.1

CHEMICAL SUBSTANCES AND RISK FACTORS

Sleepwalking episodes may be correlated with other sleep disturbances or an irregular sleep schedule and may be precipitated by the usage of certain medications. A study conducted on 84 symptomatic prepubertal children has shown that 51 children had various sleep problems and 29 of them had a positive family history.6 Another study included 50 symptomatic adults of which 39 had difficulties in breathing.3 Both studies used similar parameters including EEG, psychiatric evaluation, questionnaires and conversation with patients and relatives.3,6 Sleep-disordered breathing, including snoring, asthma, bruxism etc., is the most commonly seen sleep disorder underlying somnambulism in both children and adults.3,6 A group of children with an unknown underlying cause, as well as the group with known problems, had relatives who have suffered sleepwalking throughout their life.6 Recent studies describe the HLA allele DQB1, which is present in 35% of sleepwalkers, but only in 13% of people without this problem, as a gene that could explain the positive family history in sleepwalkers.1 Usage of different medications that affect the central nervous system can cause episodes of sleepwalking as a side effect. Case reports show that this side effect is seen with hypnotics, antipsychotics and antidepressants.9 Zolpidem is a hypnotic-sedative primarily used for treatment of insomnia, but can also be used for migraine relief. Its binding target is on the α1, α2 and α3 subunits of the GABAA receptor, but it has no effect on neurons expressing an α5 subunit.10 As an agonist of the above-mentioned receptors zolpidem stimu- Figure 1. Painting Sleepwalker (1878) by Maximilián Pirner. lates GABA hyperpolarization of specific neurons, resulting Source: Painting “Sleepwalker” by Maximilián Pirner, added by Steve McKay in prolongation and preservation of the NREM sleep phase on Curiator. https://curiator.com/art/maximilian-pirner/sleepwalker. 4 Published January 7, 2017. Accessed September 14, 2017. without the myorelaxant effect. The exact reason why some patients experience sleepwalking after taking zolpidem is still unknown, but considering everything mentioned above Since a sleepwalking episode is characterized by different it seems that it is due to its selectivity for specific subunits types of movement, varying from simple hand movements up of GABAA receptors. to running or driving, it is reasonable to assume that motor function is disinhibited and fully active as in wakefulness. 1 Zolpidem can precipitate sleepwalking episodes when used On the other hand, during the episode the person is com- alone or in combination with other chemical substances such pletely unconscious and once woken up is unable to remem- as alcohol, medical marijuana or various medications for ex- ber any events from that time. Scientists theorize that the ample prednisone, bupropion, ergotamine etc.4,9 Quetiapine, coexistence of wake and sleep elements, often described as a a second-generation antipsychotic, is another drug showing dissociative state,4 can be explained by changes in dopamine a certain correlation with sleepwalking. It is primarily used and serotonin signaling systems. Dopamine pathways regu- for treatment of schizophrenia and bipolar disorder, but is late consciousness throughout projections in the cerebrum nowadays also used in psychiatric disorders with insomnia.9 and cerebral cortex, but also have important projections The precise mechanism of action is unknown, but quetia- in the raphe nuclei located in the brainstem. Impairment pine is known to be a partial agonist of the serotoninergic between the two serotonin pathways, one arising from the 5HT1A receptor and an antagonist of the dopaminergic D2, nuclei raphe in order to regulate consciousness and other serotoninergic 5HT2A, noradrenergic α1 and histaminic H1 descending towards the spinal cord to regulate motor ac- receptors. Some hypotheses claim that quetiapine’s activity tivity, is thought to be responsible for sleepwalking.8 This on serotoninergic receptors is responsible for sleepwalking hypothesis is based on case reports of sleepwalking among episodes, but the mechanism is unknown.9 Several case re- patients with Parkinson’s disease or ones whose treatment ports describe sleepwalking as a side effect of this drug, but gyrus | vol. 4 | no. 3 – 4 | july – december 2017 316 sleep disorders

issue topics Dragčević D. Somnambulism. pp. 315 – 318

an inconsistent period from the first dose to the first episode, CLINICAL ASPECT extremely variable doses which cause this side effect, and sometimes only one episode during therapy make it impossible Diagnosis of sleepwalking is based on physical examina- to establish a doubtless link.9 In the end of this section two tion, anamnestic data and occasionally polysomnography.3 more chemicals, alcohol and caffeine, must be mentioned Anamnestic data is taken from the patient and, if possible, due to their role in society. Various amounts of alcohol are the patient’s bed partner in order to get the best possible consumed in different cultures as a part of daily routine and insight into the problem. The patient’s bed partner is the numerous legal cases used alcohol-induced sleepwalking as only person able to describe actions that happened during a defense for violent crimes. There is no evidence that solely the sleepwalking episode since the sleepwalker is unconscious consumption of acceptable alcohol amounts can influence at the time. The sleepwalker’s complaints include daytime sleep rhythm, prolong SWS or cause a sleepwalking event.11 sleepiness, chronic fatigue and sometimes depression. One Several clinical studies have shown that alcohol intake around major problem is waking up in various places such as the bedtime can worsen sleep-breathing disorders because of its kitchen, car, etc. with different things around them such as ability to decrease tonus in laryngeal musculature.11 Other food leftovers, knife, etc. without the ability to explain what cases have shown that chronic alcoholics and ones sober has happened. The underlying problem in many patients is a for longer periods of time, after consumption of alcohol, sleep-breathing disorder which can be discovered by physical have an increased amount of SWS with greater chance of examination and from anamnestic data.3 Once the particular experiencing sleepwalking. Combined with various drugs problem is found, it is the basis for successful treatment of that have effects on the central nervous system, alcohol sleepwalking.3,6 Polysomnography is a method that combines increases the chance of a sleepwalking episode due to its EEG (electroencephalogram), ECG (electrocardiogram), EOG depressant effect. Caffeine, present in coffee and some soft (electrooculogram), respiration control, measurement of beverages, is an excitatory substance for the central nervous oxygen levels in blood and sometimes videotaping of actions system due to its antagonism on adenosines receptors. It done during sleep.6 When put together, all this data give a is used in the general population to prevent sleep at unde- detailed picture of the patient’s body state during regular sirable moments, but is also known for its effect on sleep. sleep and sleepwalking episodes. Psychiatric disorders are Large amounts of caffeine decrease slow wave sleep (SWS) and also known to precipitate sleepwalking so, if found, they are slow wave activity (SWA) making it hard to maintain sleep in treated to prevent further episodes.3 Whereas treatment of the first sleep cycle when most sleepwalking episodes occur.2 the underlying sleep-breathing disorder can lead to complete remission of symptoms, psychiatric and pharmacological treatment are not as successful and only lower the frequency of events. Drugs available for this indication are benzodiazepines, e.g.. clonazepam, lorazepam etc., and if depression is present different types of antidepressants are used.3

CONCLUSION

Somnambulism, or sleepwalking, is a sleep disorder which happens in the NREM stage of sleep and affects both children and adults. It is characterized by the coexistence of both sleep elements and those of wakefulness. Recent studies show that certain EEG changes can be used as confirmation criteria for this disorder, but the neuronal pathways are still unknown. Clinical studies show that different chemical substances can precipitate sleepwalking episodes. Diagnostic procedures are mostly based on anamnestic data which is supported by certain EEG findings.

REFERENCES:

1. Popat S, Winslade W. While You Were Sleepwalking: Science and Neurobiology of Sleep Disorders & the Enigma ofLegal Responsibility of Violence During Parasomnia. Neuroethics. 2015;8(2):203-214. doi:10.1007/s12152-015-9229-4. 2. Cartwright RD, Guilleminault C. Defending sleepwalkers with science and an illustrative case. J Clin Sleep Med. 2013;9(7):721 726. doi:10.5664/jcsm.2852. 3. Guilleminault C, Kirisoglu C, Bao G, Arias V, Chan A, Li KK. Adult chronic sleepwalking and its treatment based on polysomnography. Brain. 2005;128(5):1062-1069. doi:10.1093/brain/awh481. 4. Poceta JS. Zolpidem ingestion, automatisms, and sleep driving: a clinical and legal case series. J Clin Sleep Med. 2011;7(6):632- 638. doi:10.5664/jcsm.1468. 5. Bharadwaj R, Kumar S. Somnambulism: Diagnosis and treatment. Indian J Psychiatry. 2007;49(2):123-125. doi:10.4103/0019- 5545.33261. 6. Guilleminault C, Palombini L, Pelayo R, Chervin RD. Sleepwalking and Sleep Terrors in Prepubertal Children: What Triggers Them? http://pediatrics.aappublications.org/content/pediatrics/111/1/e17.full.pdf. Accessed September 12, 2017.

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7. Jaar O, Pilon M, Carrier J, Montplaisir J, Zadra A. Analysis of slow-wave activity and slow-wave oscillations prior to somnambulism. Sleep. 2010;33(11):1511-1516. http://www.ncbi.nlm.nih.gov/pubmed/21102993. Accessed September 12, 2017. 8. Fabio D, Poryazova N, Oberholzer R, et al. Sleepwalking, REM Sleep Behaviour Disorder and Overlap Parasomnia in Patients with Parkinson’s Disease. Eur Neurol Eur Neurol. 2013;70(56):297-303. doi:10.1159/000353378. 9. Raja M, Raja S. Sleepwalking in four patients treated with quetiapine. Psychiatr Danub. 2013;25(1):80-83. http://www.hdbp.org/ psychiatria_danubina/pdf/dnb_vol25_no1/dnb_vol25_no1_80.pdf. Accessed September 12, 2017. 10. Crestani F, Martin JR, Möhler H, Rudolph U. Mechanism of action of the hypnotic zolpidem in vivo. Br J Pharmacol. 2000;131(7):1251-1254. doi:10.1038/sj.bjp.0703717. 11. Pressman M, Mahowald M, Schenck C BM. Alcohol-induced sleepwalking or confusional arousal as a defense to criminal behavior: a review of scientific evidence, methods and forensic considerations.J Sleep Res. 2007;16(2):198-212. https://pdfs.seman- ticscholar.org/cfc9/745fc061527469c949f5df3efe93c8deb550.pdf?_ga=2.109861703.313152819.1505377611-318246257.1505377611. Accessed September 14, 2017.

SOMNAMBULIZAM

Sažetak

Mjesečarenje ili hodanje u snu poremećaj je spavanja kojim je zahvaćeno 2,5% odrasle populacije te nešto veći postotak djece. Glavno obilježje ovog poremećaja je istovremeno postojanje elemena- ta spavanja i budnosti. Oboljeli imaju nepravilno i isprekidano spavanje, koje uzrokuje specifične promjene na EEG-u. Spomenute promjene su CAP promjene i povećanje frekvencije sporih valova. Postavljeno je nekoliko hipoteza koje povezuju promjene u serotoninergičkoj i dopaminergičkoj transmisiji s hodanjem u snu, ali znanstvene potvrde još nema. Različita klinička istraživanja pokazuju povezanost pojedinih lijekova (zolpidem, kvetiapin) i drugih kemikalija (alkohol, kofein) sa mjesečarenjem. Genetska podloga je dokazana. Glavni poremećaj u podlozi hodanja u snu je problem dišnih puteva te je stoga kirurški tretman takvih problema glavni način liječenja. Druge metode mogu uključivati psihijatrisko liječenje, lijekove ili promjenu u navikama spavanja. Dijagnoza se temelji na anamnezi i EEG nalazu.

Ključne riječi: alkohol, klinički pristup, kvetiapin, mjesečarenje, sporovalna aktivnost (SWA), zolpidem

Received September 30, 2017. Accepted November 12, 2017.

gyrus | vol. 4 | no. 3 – 4 | july – december 2017 318 sleep disorders

Fundamental neuroscience Paulik A. What color are your letters? - An insight into synesthesia. pp. 319 – 322 WHAT COLOR ARE YOUR LETTERS? – AN INSIGHT INTO SYNESTHESIA

Andrea Paulik 0000-0002-9744-0613 University of Zagreb, Faculty of Education and Rehabilitation Sciences

Abstract Tuesday is a dark shade of blue. The sound of a train tastes like strawberries. For people with synesthesia, sensations in two modalities are experienced when only one is stimulated. Synesthesia can theoreti- cally bind any two senses and there are 60 currently known synesthetic combinations, but research has largely focused on two of the most common variants in which auditory tones and colorless numbers produce vivid colors. It is commonly said that synesthesia is an involuntary, automatic, consistent and idiosyncratic condition, meaning that it does not happen consciously and that sensations evoked by stimuli do not change over time. It also means that no two people will have the exact same experience. For scientists, synesthesia presents an intriguing problem and more research is being conducted with the sole purpose of discovering where it originates from and how it works in the human brain. There are two main competing neurological hypotheses for synesthesia: crossmodal transfer (CMT) and neonatal synesthesia (NS). CMT is based on the idea that different sensory modalities and their functions are located in separated areas or modules of the brain, which are „cross-activated“ in synesthetes. NS is based on an assumption that ordinary neural pruning in human development fails to occur, leaving the individual with an originary, synesthetic brain.

Keywords: cognitive neuroscience, crossmodal transfer, multisensory integration, perception, synesthesia

INTRODUCTION INDUCERS AND CONCURRENTS

For years, the scientific community has been fascinated One of the things that a theory of synesthesia must explain by the neurological phenomenon known as synesthesia. is the pattern of inducers and concurrents. Inducers are Synesthesia (from the Ancient Greek syn, “together”, and the stimuli causing a conscious, involuntary, idiosyncratic, aisthēsis, “sensation”) is an experience in which stimulation and stable (repeatable) experience of an atypical concurrent. in one sensory or cognitive stream leads to associated in- The most common synesthetic inducers are linguistic in na- voluntary experiences in a second, unstimulated stream.1,2 ture: letters, digits, and words – particularly words that form For example, numbers can be perceived in colors or taste may part of a series.4 The most common synesthetic concurrents be experienced when hearing a specific word, as is shown in are visual in nature. This includes color and colored textures. Figure 1. It does not apply to forced or acquired associations, It also includes spatial forms and shapes. However, there is such as the word Christmas having connotations with the a wide spectrum of possible inducers and concurrents, with colors red or green or the smell of cinnamon. The most new combinations still being discovered. Figure 2 represents commonly described forms are grapheme-color synesthesia the most common forms of stimuli and corresponding elic- and chromesthesia (sound to color). The first ever account ited sensations. of this subject was provided by Georg Ludwig Sachs in 1812.3 He was the first to have written a scholastic description of synesthesia when the name itself did not even exist. In his doctoral thesis, he described the colors that he saw in his mind each time he thought of a letter or a number.

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NEURAL BACKGROUND

Synesthesia is often referred to as a neurological condition to emphasize the neural basis of the process. Various neural mechanisms play a role in these different types of synesthesia that may be linked to local cross-activations and re-entrant feedback mechanisms involving processed modalities in different brain areas that create various associations, e.g. word-color, tone-color, grapheme-color, and other forms of synesthesia.8 For instance, a lexical-color synesthesia characterized by observation of an achromatic grapheme is related to specific neural signals from the retina that arrive to lower visual areas. Subsequently, these signals are processed by a shape-processing area (the posterior fusiform gyrus), and finally, they are processed in the area that is in charge of the interpretation of the meaning, in which the anterior fusiform gyrus plays a significant role.9 Among numerous speculations concerning the origins of synesthesia, there are two main competing neurological hypotheses for synesthesia: crossmodal transfer (CMT) and neonatal synesthesia (NS). One arises from the other, but they differ as to the developmental emergence and neurosystemic location of synesthesia.7 CMT is based on the idea that different sensory modalities and their functions are located in separated areas or modules of the brain, which are “cross-activated” in synesthetes. In this model, cognitive abstraction makes sensory cross-modality possible. NS is based on the assumption that normal neural pruning in human development fails to occur, leaving the individual with an originary synesthetic brain. Here, it is suggested that complete nondifferentiation of sensory input supports movement between sensory pathways. These data are in Figure 2. agreement with the description of two basic forms of synes- The frequency of synesthetic inducers and concurrents. thetic experience, “lower” (referring to lower perceptual pro- Based on reference 4. Copyright © 2017 Andrea Paulik cesses) and “higher” (referring to higher cognitive processes), in which the different forms of synesthesia represent different stages of brain processing.6 EPIDEMIOLOGY

According to reported estimations, the prevalence of syn- FORMS OF SYNESTHESIA esthesia is likely at about 5% or less.5 The most widely cited study to date suggests that synesthesia occurs in at least Synesthesia comes in many different forms, with almost 1 in 2000 people, although this is now generally regarded 60 known possible combinations.10 Some of them are shown as an underestimation.2 Subsequent large-scale studies below in Figure 3. However, only three of the more common have suggested the prevalence of synesthesia to be as high types of synesthesia are frequently studied and are better as 1 in 20 across all forms and 1 in 100 for grapheme-color understood, which include grapheme to color and phoneme synesthesia.6 The inconsistency of the data might be the to color synesthesia. It is known that both of these types of aftermath of differences in definitional criteria used by synesthesia activate the fusiform gyrus, or the visual cortex, different researchers. Synesthesia is reported to emerge during synesthetic experiences. in early development and persist throughout life and likely has a genetic component.2 While a proven genetic basis for synesthesia remains elusive, the phenomenon tends to run in families. However, symptoms vary greatly between all individuals with synesthesia, and no two people (not even parent-child pairs who experience the same general type of perceptions) will have the exact same experiences. Early research demonstrated that synesthesia is more common in women than men, leading to the belief that it follows an X-linked dominant mode of inheritance.3 However, recent data shows that the genetic mechanisms that underlie this condition are more complex than the straightforward X-linked Figure 3. Different forms of synesthesia. dominant account.7 Previous findings may have been a result Based on reference 10. of underreporting by male subjects. Copyright © 2017 Andrea Paulik gyrus | vol. 4 | no. 3 – 4 | july – december 2017 320 sleep disorders

Fundamental neuroscience Paulik A. What color are your letters? - An insight into synesthesia. pp. 319 – 322

GRAPHEME-COLOR SYNESTHESIA

Like all forms of synesthesia, grapheme-color synesthesia is Thus, these findings may not generalize to other forms of involuntary, consistent, and memorable. Hubbard & Ram- synesthesia, in which inducer and concurrent are processed achandran (2005) and Hubbard (2007) proposed an inﬂuential in non-adjacent regions in the cortex, such as chromesthesia. two-stage model for it.1,6 According to their model, synesthetic With sounds inducing color concurrents, chromesthesia is experience arises from abnormal crossactivation between the more accurately termed sound-color synesthesia. Individuals grapheme area and the color area in the fusiform gyrus (FG) with sound-color synesthesia are consciously aware of their due to synesthesia-specific local connections. The fusiform synesthetic color associations in daily life. Chromesthesia gyrus has been linked with various neural pathways related evokes strong emotional connections to music because the to recognition. The synesthetic color perceptions driven by listener associates different pitches and tones to certain colors, the FG are then thought to be bound together by top-down which in turn, produces specific feelings.14 Most synesthetes mechanisms controlled by the parietal cortex, this in turn have reported that they don’t encounter color visually when resulting in a kind of “hyperbinding”. This two-stage model listening to music; rather, they feel and experience the color was developed on the basis of several studies that reported that comes with hearing a certain tone. Some researchers neuronal correlates for grapheme–color synesthesia. One suggest that chromesthesia can be acquired by damage to of those studies has noted that the human V4 (hV4) region the retino-cortical pathway.15 in the FG is consistently more active in synesthetes than in The previous studies led some researchers to a new hypothesis: non-synesthetes, when presented with colorless grapheme if color processing in visual association regions and music or stimuli. That is an area responsible for the representation auditory processing in auditory association regions (superior of colors. It was evident in fMRI studies that activation of temporal gyrus, superior temporal sulcus, middle temporal the hV4 region was greater in grapheme-color synesthetes gyrus) are more closely connected, then the white matter than in non-synesthete controls (Figure 4).11 pathways that pass through these regions might be different in colored-music synaesthetes.15 Results showed that people with colored-music synesthesia possess enhanced structural connectivity between the frontal lobe and visual and auditory association areas. Compared to controls, colored-music synesthetes possess different hemispheric patterns of white matter integrity in the inferior fronto-occipital fasciculus (involved in multimodal integration, visual information processing and processing of speech and language input).

CALL FOR RESEARCH

Although fairly prevalent in the general population, synes- Figure 4. fMRI of ventral surface activation in synesthetes and thesia is still an intriguing condition. While scientists have non-synesthete controls during a grapheme stimulus. The hV4 region known about it for nearly two centuries, only recently have is shown in purple and the grapheme area is shown in blue. researchers – across the fields of neuroscience and psychology The grapheme area was equally active for both synesthetes and the – been able to focus their studies in the direction of finding control group, but the hV4 region was active only in synesthetes. Source: Hubbard EM, Arman AC, Ramachandran VS, Boynton GM. Individ- out how the brain of a synesthete works. ual Differences among Grapheme-Color Synesthetes: Brain-Behavior Correla- There were numerous studies regarding synesthesia conduct- tions. Neuron. 2005;45(6):975-985. doi:10.1016/j.neuron.2005.02.008. ed in the previous decade by scientists from the Max-Planck Available under an Elsevier user license (https://www.elsevier.com/about/poli- Institute for Brain Research in Frankfurt. They provided cies/open-access-licenses/elsevier-user-license). us with a different perspective on the subject, proposing Copyright © 2005 Elsevier Inc. All rights reserved. that synesthesia is not a sensory-sensory phenomenon but instead a semantic-sensory one in which the meaning of the stimulus induces perception-like experiences.16 That is why A study conducted by Weiss and Fink12 showed that graph- Dr. Danko Nikolić, a Croatian scientist working in the above eme-color synesthetes have increased grey matter volumes mentioned institute, proposed another term for synesthe- of parietal and fusiform cortex. New studies should address sia: ideasthesia, which is Greek for “sensing concepts”. The the question of whether the observed structural differences theory of ideasthesia is based on evidence for introducing in the FG and intraparietal areas precede or result from a semantic component into the definition of this condition synesthetic experiences. and furthermore proposes a mechanism through which the semantic system contributes to the phenomenon.16 Understanding the development of a synesthetic brain helps CHROMESTHESIA – COLORED HEARING researchers to understand the development of sensory and perception systems. Future research should address syn- While the structural and functional differences in the synesthesia as a foundation from which they could begin to esthete brain provide clear evidence for a neural basis of understand the diversification of human experiences and synesthetic perception, most of these findings come from functions of the human brain. grapheme-color synesthesia, in which inducer and concurrent processing regions may be anatomically adjacent.13

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Fundamental neuroscience Paulik A. What color are your letters? - An insight into synesthesia. pp. 319 – 322 REFERENCES:

1. Hubbard EM. Neurophysiology of Synaesthesia. Curr Psychiatry Rep. 2007;9(3):193-199. doi:10.1007/s11920-007-0018-6. 2. Baron-Cohen S, Burt L, Smith-Laittan F, Harrison J, Bolton P. Synaesthesia: Prevalence and Familiality. Perception. 1996;25(9):1073-1079. doi:10.1068/p251073. 3. Jewanski J, Day SA, Ward J. A Colorful Albino: The First Documented Case of Synaesthesia, by Georg Tobias Ludwig Sachs in 1812. J Hist Neurosci. 2009;18(3):293-303. doi:10.1080/09647040802431946. 4. Simner J, Mulvenna C, Sagiv N, et al. Synaesthesia: The Prevalence of Atypical Cross-Modal Experiences. Perception. 2006;35(8):1024-1033. doi:10.1068/p5469. 5. Ward J. Synaesthesia. Annu Rev Psychol. 2013;64:49-75. doi:10.1146/annurev-psych-113011-143840. 6. Hubbard E, Ramachandran VS. Neurocognitive Mechanisms of Synaesthesia. Neuron. 2005;48(3):509-520. doi:10.1016/j.neuron.2005.10.012. 7. Munster A. An Aesthesia of Networks: Conjunctive Experience in Art and Technology. London, UK: MIT Press; 2013. 8. Neckar M, Bob P. Neuroscience of synesthesia and cross-modal associations. Rev. Neurosci. 2014;25(6):833-840. doi:10.1515/ revneuro-2014-0033 9. Hochel M, Milán EG. Synaesthesia: The existing state of affairs. Cogn Neuropsychol. 2008;25(1):93-117. doi:10.1080/02643290701822815. 10. Day SA. Synaesthesia: A first-person perspective. In: Simner J, Hubbard EM, eds. The Oxford Handbook of Synaesthesia. New York, NY: Oxford: University Press; 2013: 903-923. 11. Hubbard EM, Arman AC, Ramachandran VS, Boynton GM. Individual Differences among Grapheme-Colour Synesthetes: Brain-Behavior Correlations. Neuron. 2005;45(6):975-85. doi:10.1016/j.neuron.2005.02.008. 12. Weiss PH, Fink GR. Grapheme-colour synaesthetes show increased grey matter volumes of parietal and fusiform cortex. Brain. 2009;132(1):65-70. doi:10.1093/brain/awn304. 13. Zamm A, Schlaug G, Eagleman DM, Loui P. Pathways to seeing music: Enhanced structural connectivity in colored-music synesthesia. Neuroimage. 2013;74:359-366. doi:10.1016/j.neuroimage.2013.02.024. 14. Makhlin J. Chromesthesia as Phenomenon: Emotional colors. Writing Programs. 2014; Paper 12. https://digitalcommons.lmu.edu/ arc_wp/12/. Accessed September 26, 2017. 15. Ward J, Huckstep B, Tsakanikos E. Sound-Colour Synaesthesia: to What Extend Does it Use Cross-Modal Mechanisms Com- mon to us All? Cortex. 2006;42(2):264-280. doi:10.1016/S0010-9452(08)70352-6. 16. Nikolić D. Synesthesia / Ideasthesia. http://www.danko-nikolic.com/synesthesia-ideasthesia/. Accessed October 18, 2017.

KOJE SU BOJE TVOJA SLOVA? – UVID U SINESTEZIJU

Sažetak

Utorak je tamno plav. Zvuk prolazećeg vlaka ima okus po jagodama. Za osobe sa sinestezijom, stimulacija jednog modaliteta može dovesti do doživljaja u dva modaliteta. Teoretski, sinestezija može pov- ezati bilo koja dva senzorna modaliteta te danas imamo oko 60 poznatih kombinacija, no istraživanja su se najviše usredotočila na dva najčešća oblika u kojima zvuk ili grafem (slovo ili broj) dovode do percepcije boje. Često se kaže kako je sinestezija nevoljno, automatsko, trajno i idiosinkratsko stanje, što znači da se ne događa na svjesnoj razini i da se doživljaji pobuđeni podražajem ne mijenjaju kroz vrijeme. To također znači da niti jedna dva sinesteta neće proživjeti isto iskustvo. Sinestezija za znanstvenike predstavlja intrigirajući problem te se sve više istraživanja provodi u svrhu određivanja podrijetla ove pojave i kako funkcionira u mozgu. Postoje dvije glavne hipoteze: prva je teorija o kros- modalnom transferu (engl. CMT), a druga o neonatalnoj sinesteziji (engl. NS). CMT je teorija bazirana na činjenici da su različiti senzorni modaliteti i njihove funkcije smješteni u različitim dijelovima mozga te da se kod sinesteta ukršteno aktiviraju. NS je temeljena na pretpostavci da se normalni neu- rorazvojni proces koji se odvija u neonatalnom razdoblju, tzv. sinaptičko obrezivanje (engl. pruning), ne odvije u slučaju sinestezije te osoba doživljava navedene aspekte stanja.

Ključne riječi: kognitivna neuroznanost, križnomodalitetni transfer, multisenzorna integracija, percepcija, sinestezija

Received June 13, 2017. Accepted November 1, 2017.

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Fundamental neuroscience Zelić DF. The prion protein and Creutzfeldt-Jakob disease. pp. 323 – 328 THE PRION PROTEIN AND CREUTZFELDT-JAKOB DISEASE

Dora Franka Zelić 0000-0001-9418-8996 University of Zagreb, School of Medicine

Abstract The prion protein, which stands for proteinaceous infectious particle, has mystified scientists for years. To date we don’t fully understand its physiological role so in this article we’ll be focusing on the pathology. The prion protein causes several diseases in humans: Creutzfeldt-Jakob disease (CJD), Gerst- mann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI), and kuru. They are also called transmissible spongiform encephalopathies (TSEs). Prions don’t cause diseases only in humans - in animals they cause scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) or mad cow disease, and several other encephalopathies. These diseases share a lot of similarities as they are incurable, uniformly fatal, have long incubation times, and cause spongiform vacuolation, neuronal cell loss, astrocytosis, and accumulation of amyloid plaques in the central nervous system (CNS). Signs and symptoms can vary from psychiatric to neurological disorders. Here we will focus on CJD, as it is the most common TSE. Diagnosis of CJD premortem is still a problem for clinicians in part due to the rarity of the condition, similarity to some other neurodegenerative diseases, and lack of specific diagnostic procedures. Current World Health Organisation (WHO) diagnostic criteria date back to 1998 though the Center for Disease Control (CDC) offers newer guidelines published in 2010. Since CJD is incurable, early diagnosis would allow patients and their families to prepare for the expected outcome and possibly help cope with the loss of a loved one.

Keywords: Creutzfeldt-Jakob disease, neurodegeneration, prion, prion disease, transmissible spongiform encephalopathies

INTRODUCTION

Prions (prion proteins or PrP) are infectious particles built disease was acquired we can divide it into 4 types: sporadic entirely out of proteins. The word itself is an abbreviation of CJD (sCJD) caused by a somatic mutation in the PRNP gene proteinaceous infectious particle. PrP exists in different isoforms or a spontaneous conformational change in the PrP, familial which define its behaviour.1 For instance, cell prion protein CJD (fCJD) which is inherited, iatrogenic CJD (iCJD) from (PrPC) exists as a membrane protein in our cells and its various human-to-human implants, and the most recently role is still being investigated, but PrP found in organisms identified type variant CJD (vCJD) acquired by the transmis- with prion diseases, such as in scrapie (PrPSc), is the cause sion of bovine spongiform encephalopathy (BSE) (Table 1).2 of these diseases. Human prion diseases, or transmissible spongiform encephalopathies (TSEs), make an interesting group for they can be sporadic, acquired or genetic and are THE PRION PROTEIN uniformly fatal.2 This article will focus on the most common one, Creutzfeldt-Jakob disease (CJD). Among other TSEs there PrPC is a glycosylated, glycosyl phosphatidyl inositol (GPI) is kuru, which is sporadic, as well as fatal familial insomnia anchored protein of 209 amino acids and a mostly alpha-helical (FFI) and Gerstmann-Sträussler-Scheinker syndrome (GSS), structure (40%).5,6 It can be found in ‘membrane rafts’ rich in which are both genetic.2 cholesterol and sphingolipids. The gene which encodes PrPC, CJD is a fatal progressive neurodegenerative disorder which called the prion protein gene (PRNP), is located on human presents with mostly psychiatric and neurological symptoms chromosome 20. Normal PRNP shows genetic polymorphism accompanied by classical histological findings: spongiform at codon 129, where methionine (M) or valine (V) may be change, neuron loss, and astrogliosis.3 It annually affects one encoded.6 PrPC is highly conserved across species which to two persons per 1,000,000 worldwide.4 Based on how the allows prion diseases to be transmitted between species.7

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Fundamental neuroscience Zelić DF. The prion protein and Creutzfeldt-Jakob disease. pp. 323 – 328

Table 1. Findings in different types of CJD. iCJD is extremely similar to sCJD so it won’t be described separately. Adapted from: Manix M, Kalakoti P, Henry M, et al. Creutzfeldt-Jakob disease: updated diagnostic criteria, treatment algorithm, and the utility of brain biopsy. Neurosurg Focus. 2015;39(5):E2. doi:10.3171/2015.8.FOCUS15328. Copyright © 2015 AANS

The protein contains a single bisulfide bridge, two N-gly- CREUTZFELDT-JAKOB DISEASE cosylation sites, as well as a C-terminal globular domain.5 The physiological role of PrPC is still being examined but some CJD was first described in the 1920s by two German phy- theories have emerged (Table 2). The N-terminal region of the sicians, Hans Gerhard Creutzfeldt and Alfons Maria Jakob, protein contains octapeptide repeat motifs which have five after whom the disease was named.6,13 For a long time it was Cu2+ binding sites.8 The protein’s expression alters copper speculated that a virus causes the disease and to this day there uptake into cells. Therefore, it has been suggested that PrPC are many theories, but the protein only theory which states plays a role in copper metabolism. It may even affect our that PrPSc causes the disease, is mostly accepted. Marked cells capacity to fight oxidative stress through superoxide neuronal loss, spongiform change and astroglyosis, are dismutase (SOD), an enzyme which neutralises superoxide typically found in CJD upon histopathological examination. radical (O2-), whose two out of three human forms require Spongiform change is the most specific and presents with copper to properly function.9 Another proposed role is that a fine vacuolation, mostly in dendrites, of the grey matter PrPC acts as a scaffold protein meaning that it binds several with round or oval vacuoles containing curled membrane members of a signalling pathway optimizing downstream fragments and amorphous material. Neuronal loss seems signal transfer, for instance by regulating the activity of to mostly affect GABAergic neurons and usually spares the phosphatidylinositol 3-kinase (PI 3-kinase), which is an hippocampus and dentate gyrus, which are considered to be enzyme that’s part of an intracellular signalling pathway most vulnerable. Clinical presentation differs between each important in regulating the cell cycle.10 Some researchers type and subtype of CJD but typically we can see a progressive even speculate that PrPC may play a role in maintaining encephalopathic illness with dementia, cerebellar ataxia and long-term memory.11 So what makes PrPSc so different from myoclonus.3 General diagnostic criteria for CJD by the World PrPC? Although they have the same primary structure, PrPSc Health Organisation (WHO) are shown in Table 4 and the has a 45% beta-sheet structure (Table 3).6 This is enough to Center for Disease Control (CDC) guidelines are in Table 5. make it resistant to degradation by proteases and highly We will now discuss each type in more detail. insoluble.12 If PrPC is structurally altered and converted into a proteinase K-resistant form in vitro it’s called pro- tease-resistant PrPSc-like protein (PrPres). How can PrPSc SPORADIC CJD replicate if it’s made only of amino acids? PrPSc converts normal PrPC molecules into it’s own misfolded form. The Sporadic CJD (sCJD) is the most common form of the dis- conversion process is not yet fully understood but PrPSc seems ease with a prevalence of 85%.6 The etiology is probably a to serve as a template and autocatalyses the process which somatic mutation in the PRNP gene or a random structural can occur in a cell-free system.2 Accumulated PrPSc then change in the PrPC causing it to change into PrPSc. It affects forms amyloid aggregates which can be found histologically.6 mostly the middle-aged and elderly with a median survival gyrus | vol. 4 | no. 3 – 4 | july – december 2017 324 sleep disorders

Fundamental neuroscience Zelić DF. The prion protein and Creutzfeldt-Jakob disease. pp. 323 – 328

of around 4 months from the onset of the disease. sCJD is divided into six subtypes based on the two types of human PrPSc and on the polymorphism of codon 129 of the PRNP gene. Type 1 prion has a relative molecular mass of 21kDa and Type 2 of 19kDa.3 The most common sCJD subtype is MM1 which presents with cognitive impairment, myoclonus, cerebellar ataxia and psychiatric symptoms.6 There are also some clinical variants such as the Heidenhain variant where the patient presents with diplopia, blurred vision, cortical blindness and/or visual hallucinations within the first week of illness, or the Oppenheimer-Brownell variant in which there are no cognitive or visual impairments in the first week, only ataxia. The Heidenhain variant is found only in the MM1 subtype.14 Periodic sharp wave complexes (PSWCs) are an EEG finding specific for sCJD and can be observed in most patients during the duration of the illness, with the exception of the VV1 subtype.6,15 Cerebrospinal fluid (CSF) can be tested for 14-3-3 protein, which appears after neuronal destruction and is positive in almost all patients and in all types of sCJD.6 This biomarker, unlike PSWCs, is not specific to sCJD and can be found in other conditions where neurons are being destroyed.6

IATROGENIC CJD

Iatrogenic CJD (iCJD) has been linked to intracerebral electrodes, corneal transplantations, dura mater grafts, and growth hormone injections.6,16,17 The incubation period reflects the site of inoculation; for instance, the incubation time when contaminated electrodes were placed directly into the brain was 16-28 months, whereas peripheral growth hormone injections from contaminated cadavers took 5-30 years to bring about iCJD.6 There are cases of probable vCJD transmission via blood transfusions.18 This alarmed the Food and Drugs Administration (FDA) which banned blood donation from people who have spent 6 months or more in the UK between 1980 and 1996.19 Clinically it resembles sCJD with a different age of onset depending on the age at which the patient received a contaminated transplant or implant.6

FAMILIAL CJD

Familial CJD (fCJD) is caused by an inherited mutation in the PRNP gene which encodes the prion protein. Since there are many different mutations that can occur, there are also many presentations of the disease but it mostly resembles sCJD. It’s transmitted in an autosomal dominant pattern meaning that first-degree relatives have a 50% chance of 20 Table 2. Proposed physiological roles of the prion protein. inheriting the disease. Two other diseases are caused by a Source: Linden R. The Biological Function of the Prion Protein: A Cell mutation in the PRNP gene; Gerstmann-Sträussler-Scheinker Surface Scaffold of Signaling Modules. Front Mol Neurosci. 2017;10:77. (GSS) syndrome and fatal familial insomnia (FFI). GSS is doi:10.3389/fnmol.2017.00077. distinguished histologically by widespread, large, multi- Copyright © 2017 Linden centric amyloid plaques within the cerebral cortex.21 FFI is Available under the CC BY 4.0 International license caused by a mutation at position 178 (D178N) accompanied (https://creativecommons.org/licenses/by/4.0/). by a methionine at codon 129 of the mutated allele, whereas fCJD is accompanied by a valine at the same codon on the mutated allele.22 Age of onset differs but for fCJD it’s around 60 years of age.6

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VARIANT CJD

Variant CJD was first described in the UK in the 1990s following a BSE epidemic.23 People were infected by eating food contaminated with BSE. It differs from other types of CJD by a younger mean age of onset, 28 years, and a longer period of illness duration of 14 months.3 The incubation period is about 11-12 years. At the beginning of the disease, symptoms are mostly psychiatric with more classical CJD symptoms, such as ataxia, appearing later on.6 EEG doesn’t show PSWCs and CSF 14-3-3 is positive in less than 50% of patients.3 Spongiform change with gliosis is most Table 3. Differences between PrPC and PrPSc. prominent in the basal ganglia and cerebellum, especially Based on references 6 and 8. in the pulvinar.6 This change is consistent with the characteristic hyperintensity in the posterior thalamus shown on an MRI which is thus called the ‘Pulvinar Sign’. The sign is positive in 90% of cases.3 PrPSc forms florid plaques and accumulates throughout the cerebral cortex, but even more intriguing is the accumulation of PrPSc in the lymphoreticular system which is only seen in vCJD. After a person eats a prion contaminated product, PrPSc is transported through the intestinal epithelium by M-cells to Peyer’s patches. There, PrPSc accumulates within dendritic cells and dissem- inates via the blood stream to the rest of the lymphoreticular system. Autonomic nerves or lymphoid tissue carry the PrPSc to the central nervous system.2 To date, all vCJD cases have been in individuals with methionine homozygosity at codon 129 of PRNP.6

TREATMENT

Many drugs, such as antiviral medications, amphotericin B, flupirtine, quinacrine, pentosan polysulphate, doxycycline and more, have been tested for treating CJD but there are none that stop or slow down the progression of the disease to this day.24,25 The search for a cure continues, but until it’s found we can only hope to alleviate pain and make patients as comfortable as possible.

Table 4. WHO diagnostic criteria for CJD from 1998. Source: Global surveillance, diagnosis and therapy of human Trans- missible Spongiform Encephalopathies: Report of a WHO consultation. Geneva, Switzerland, February 9-11, 1998. https://www.who.int/csr/ resources/publications/bse/whoemczdi989.pdf. Accessed May 1, 2017.

Table 5. CDC diagnostic criteria for sCJD from 2010. Source: Diagnostic Criteria | Creutzfeldt-Jakob Disease, Classic (CJD) | Prion Disease | CDC. https://www.cdc.gov/prions/cjd/diagnostic-criteria.html. Updated February 11, 2015. Accessed May 1, 2017.

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CONCLUSION

CJD includes a very wide set of clinical manifestations which vary in duration and age of onset in different types. For this and many other reasons, such as a lack of definite diagnostic tests and similarity to some other neurodegenerative diseases (Alzheimer’s disease, Lewy body dementia, frontotemporal dementia…), it usually passes unrecognized during the patient’s life. Although there is no cure for CJD so far, correct diagnosis is important to help patients and their families prepare for the disease outcome. Improving the patient’s life and the lives of those around them should be a priority. There is yet much to be discovered regarding the prion protein, both in PrPC and PrPSc form, and hopefully one day we’ll get closer to changing the fatal outcome of CJD.

REFERENCES:

1. Pan KM, Baldwin M, Nguyen J, et al. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci. 1993;90(23):10962-10966. doi:10.1073/pnas.90.23.10962. 2. Hilton DA. Pathogenesis and prevalence of variant Creutzfeldt-Jakob disease. J Pathol. 2006;208(2):134-141. doi:10.1002/path.1880. 3. Sikorska B, Knight R, Ironside JW, Liberski PP. Creutzfeldt-Jakob disease. In: Ahmad SI, ed. Neurodegenerative Diseases. 1st ed. Springer US; 2012:76-90. doi:10.1007/978-1-4614-0653-2. 4. Kojima G, Tatsuno BK, Inaba M, Velligas S, Masaki K, Liow KK. Creutzfeldt-Jakob disease: a case report and differential diagnoses. Hawaii J Med Public Health. 2013;72(4):136-139. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3689509&tool=pm- centrez&rendertype=abstract. 5. Linden R, Cordeiro Y, Lima LMTR. Allosteric function and dysfunction of the prion protein. Cell Mol Life Sci. 2012;69(7):1105-1124. doi:10.1007/s00018-011-0847-7. 6. Manix M, Kalakoti P, Henry M, et al. Creutzfeldt-Jakob disease: updated diagnostic criteria, treatment algorithm, and the utility of brain biopsy. Neurosurg Focus. 2015;39(5):E2. doi:10.3171/2015.8.FOCUS15328. 7. Martins VR, Brentani RR. The biology of the cellular prion protein.Neurochem Int. 2002;41(5):353-355. doi:10.1016/S0197-0186(02)00054-2. 8. Zomosa-Signoret V, Arnaud J-D, Fontes P, Alvarez-Martinez M-T, Liautard J-P. Physiological role of the cellular prion protein. Vet Res. 2008;39(4):9. doi:10.1051/vetres:2007048. 9. Fukai T, Ushio-Fukai M. Superoxide Dismutases: Role in Redox Signaling, Vascular Function, and Diseases. Antioxid Redox Signal. 2011;15(6):1583-1606. doi:10.1089/ars.2011.3999. 10. Linden R. The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules.Front Mol Neurosci. 2017;10:77. doi:10.3389/fnmol.2017.00077. 11. Shorter J, Lindquist S. Prions as adaptive conduits of memory and inheritance. Nat Rev Genet. 2005;6(6):435-450. doi:10.1038/nrg1616. 12. Trevitt CR, Singh PN. Variant Creutzfeldt-Jakob disease : pathology , epidemiology , and public health implications 1 – 4. 2003;1986(3):3-8. 13. Jakob A. Uber eigenartige Erkrankungen des Zentralnervensystems mit bemerkenswertem anatomischen Befunde. 1921. 14. Appleby BS, Appleby KK, Crain BJ, Onyike CU, Wallin MT, Rabins P V. Characteristics of established and proposed sporadic Creutzfeldt-Jakob disease variants. Arch Neurol. 2009;66(2):208-215. doi:10.1001/archneurol.2008.533. 15. Wang P-S, Wu Y-T, Hung C-I, Kwan S-Y, Teng S, Soong B-W. Early detection of periodic sharp wave complexes on EEG by independent component analysis in patients with Creutzfeldt-Jakob disease. J Clin Neurophysiol. 2008;25(1):25-31. doi:10.1097/ WNP.0b013e318163a7d5. 16. Duffy P, Wolf J, Collins G, DeVoe AG, Streeten B, Cowen D. Possible person-to-person transmission of Creutzfeldt-Jakob disease. 1974. 17. Brown P, Preece M, Brandel JP, et al. Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology. 2000;55(8):1075-1081. doi:10.1212/WNL.56.7.987. 18. Llewelyn CA, Hewitt PE, Knight RSG, et al. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet. 2004;363(9407):417-421. doi:10.1016/S0140-6736(04)15486-X. 19. Questions and Answers on “ Guidance for Industry : Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease ( CJD ) and Variant Creutzfeldt-Jakob Disease ( vCJD ) by Blood and Blood Products .” https://www. fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm074100.htm. Accessed April 30, 2017. 20. Clift K, Guthrie K, Klee EW, et al. Familial Creutzfeldt-Jakob Disease: Case report and role of genetic counseling in post mortem testing. Prion. 2016;10(6):502-506. doi:10.1080/19336896.2016.1254858. 21. Collins S, McLean CA, Masters CL. Gerstmann-Straussler-Scheinker syndrome,fatal familial insomnia, and kuru: a review of these less common human transmissible spongiform encephalopathies. J Clin Neurosci. 2001;8(5):387-397. doi:10.1054/jocn.2001.0919. 22. Llorens F, Zarranz J-J, Fischer A, Zerr I, Ferrer I. Fatal Familial Insomnia: Clinical Aspects and Molecular Alterations. Curr Neurol Neurosci Rep. 2017;17(4):30. doi:10.1007/s11910-017-0743-0.

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Fundamental neuroscience Zelić DF. The prion protein and Creutzfeldt-Jakob disease. pp. 323 – 328

23. Will R., Ironside J., Zeidler M, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet. 1996;347(9006):921-925. doi:10.1016/S0140-6736(96)91412-9. 24. Appleby BS, Lyketsos CG. Rapidly progressive dementias and the treatment of human prion diseases. Expert Opin Pharmacother. 2011;12(1):1-12. doi:10.1517/14656566.2010.514903. 25. Damkier HH, Brown PD, Praetorius J. Cerebrospinal fluid secretion by the choroid plexus. Physiol Rev. 2013;93(4):1847-1892. doi:Doi 10.1152/Physrev.00004.2013.

PRIONSKI PROTEIN I CREUTZFELDT-JAKOBOVA BOLEST

Sažetak

Prioni, zarazne proteinske čestice, već godinama zbunjuju znanstvenike. Do danas ne znamo točnu fiziološku ulogu priona pa ćemo se koncentrirati više na patologije koje uzrokuju. U ljudi uzrokuju: Creutzfeldt-Jakobovu bolest (engl. Creutzfeldt-Jakob disease, CJD), Gerstmann-Sträussler-Scheinkerov sindrom, smrtonosnu obiteljsku nesanicu i kuru. Zajedno ih nazivamo transmisibilnim spongi- formnim encefalopatijama. Prioni ne uzrokuju bolesti samo u ljudi, već i u nekih životinja kao što su ovce, koze u kojih uzrokuje grebež (engl. scrapie), goveđu spongiformnu bolest ili kravlje ludilo i nekoliko drugih encefalopatija. Nabrojene bolesti dijele dosta sličnosti: neizlječive su, smrtonosne, imaju dug period inkubacije i uzrokuju spongiformnu promjenu, gubitak neurona, astrocitozu i akumulaciju amiloidnih plakova u središnjem živčanom sustavu. Simptomi su psihijatrijske i neurološke naravi. U ovom članku usredotočit ćemo se na CJD kao najčešću spongiformnu ence- falopatiju. Dijagnosticiranje CJD-a prije smrti problem je s kojim se kliničari susreću zbog malog broja takvih slučajeva, sličnosti sa drugim neurodegenerativnim bolestima i nedostatka specifičnog dijagnostičkog testa. Trenutne dijagnostičke smjernice Svjetske zdravstvene organizacije su iz 1998. Američki Centar za kontrolu bolesti nudi nešto novije smjernice iz 2010. Pošto je CJD neizlječiva bolest, točna rana dijagnoza omogućila bi pacijentima i njihovim obiteljima više vremena da se pri- preme za očekivani ishod te bi se bolje nosili s bolešću.

Ključne riječi: Creutzfeldt-Jakobova bolest, neurodegeneracija, prijenosne spongiformne encefalopatije, prioni, prionske bolesti

Received May 1, 2017. Accepted September 29, 2017

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NEUROLOGY Popović J. The pathophysiology of migrane. pp. 329 – 334 THE PATHOPHYSIOLOGY OF MIGRAINE

Josipa Popović 0000-0002-3834-5261 University of Zagreb, School of Medicine

Abstract

Migraine, as one of the most common medical disorders nowadays, affects both the young and elderly population and causes great disabilities in everyday functioning. Its pathophysiology has not been clearly resolved yet. There are many conflicting hypotheses regarding its pathogenesis. The first theory explaining migraine was the vascular theory, but after new findings, the neuronal theory followed. The vascular theory proposes that vasodilatation of cerebral arteries, especially the middle meningeal artery, stimulates nociceptive trigeminal nerve fibers causing excruciating headache. On the other hand, the neuronal theory disproves the vascular theory and suggests that the cause of migraine attacks is brain hyperexcitability. This theory is confirmed by measuring high glutamate and low γ-aminobutyric acid (GABA) concentrations. Furthermore, researchers from Harvard University have proposed a series of brain circuits and structures, such as the trigeminal nucleus caudalis, anterior cingulate cortex and periaqueductal gray matter, as generators of migraine attack. Scientists supporting the neuronal theory assume that calcitonin gene-related peptide (CGRP) would help a great deal in explaining migraine pathophysiology. They demonstrated that CGRP, like vasodilatation, stimulates trigeminal nerve fibers. CGRP is considered to be one of the most significant initiators and moderators of migraine. However, it may be that radical, new theories, such as the genetic theory or the theory of thermoregula- tion will ultimately answer the mystery of migraine pathogenesis. Once its pathophysiology is resolved, researchers will be able to put an end to symptomatic treatment of chronic migraine.

Keywords: calcitonin gene-related peptide (CGRP), migraine, migraine aura, neuronal theory, vascular theory

INTRODUCTION because it is not linked to any underlying condition, such as hydrocephalus, brain tumor or inflammation. Moreover, Pain is described as an unpleasant feeling associated with migraine is often triggered by and associated with sensi- threat. It can be physical or emotional. Pathogenetically, tivity to light, sound or movement. It is initiated by many pain can be nociceptive, neuropathic, and psychosomatic triggers, such as glare, bright light, sound, hunger, excess depending on the origin. The brain itself cannot “feel” any stress, physical exertion, hormonal fluctuations, lack of sleep, pain due to a lack of sensory innervation, but there are excessive alcohol consumption, etc.3 Although migraine is a several structures, especially the dura mater and cerebral rather common disorder, its pathophysiology is still unclear. arteries, which can be described, in the sense of a headache, as There are several theories which try to explain its cause. “receptors”, while the trigeminal nerve acts as a transmitter Vascular, neuronal, and its combination, neurovascular of pain signals.1 theory, are theories traditionally supported by scientists. There are two types of headaches – primary and secondary. In this article, they are going to be discussed, but also new, Primary headaches occur due to functional disturbance in controversial, migraine theories are going to be presented. one’s brain. Migraine, as a primary headache, is a chronic, complex medical condition defined as a unilateral pulsating headache, often combined with a so-called aura, a state MIGRAINE AURA anticipating the migraine, which consists of nausea, vomiting, photophobia, and phonophobia. It lasts from four to Migraine headaches can be classified into two groups: 72 hours and its intensity is moderate to severe. Migraine those accompanied by aura and migraine without an aura. is the second most common type of headache, after tension Migraine aura typically begins 5 to 20 minutes before the headache.1 The prevalence of migraine headache is 18% among onset of migraine and lasts 5–55 minutes. Aura symptoms the population.2 It occurs approximately twice as often in are reversible, unlike those of brain stroke which are often women than in men. It is classified as a primary headache similar to migraine aura symptoms.1

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Aura symptoms can be divided and described as atypical activity with constant blood flow. Another possible inter- shining, crenelated shapes and scintillation as positive symp- pretation they could offer is that increased venoconstriction toms, and scotomas and loss of sight as negative symptoms. could increase BOLD levels. They are not quite sure whether Besides visual symptoms, auras can be accompanied by a specific region in the occipital lobe initiates the spreading numbness, paraesthesia, aphasia or dysphasia. Scintillations event, but they found that area V3A is extremely sensitive to are followed by a decrease in blood flow progressing from motion and luminance contrast and they believe that neu- central to peripheral visual fields in the occipital lobe – this ronal firing in this area might produce scintillations during mechanism is known as cortical spreading depression (CSD).1 a typical visual aura.6 Moreover, they noticed that hyperemia It has been suggested that CSD is responsible for migraine in the visual cortex is followed by mild hypoperfusion. This aura.4 This theory has been offered to explain how a change hypoperfusion is described many minutes after the aura had in excitability causes migraine attack. occurred. Also, they were able to measure the spread of BOLD More precisely, CSD is a slowly propagating wave of de- throughout the gray matter and discovered that this spread polarization followed by inhibition of brain activity.3 Ions is consistent with previous measures of CSD. and neurotransmitters, such as glutamate, are being accumulated extracellularly and cause steady potential changes Another study conducted by Bolay et al. also tried to find a in the occipital lobe.5 Simultaneously, cortical blood flow, link between CSD and migraine attacks.5 They performed especially in the middle meningeal artery is being increased an experiment on animals (rats) in which they induced CSD and dramatically decreased afterwards.5 and monitored blood flow in the middle meningeal artery, Clinicians previously noticed visual symptoms that antici- cerebral cortex, and pial vessels with laser speckle-contrast pate a headache, but till nowadays they did not succeed in imaging. After pharmacologically inducing CSD with the explaining the neuroscientific connection between the two. statistically significant increase in the middle meningeal According to a study from Harvard University, there is a artery blood flow lasting 10 minutes a 10% enlargement of relationship between CSD and migraine aura. This corre- the vessel diameter was noticed. To be more specific, they lation is based on the uniquely slow spread of clinical and measured two blood flow peaks, an early one 5 minutes after electrophysiological events. Scientists wanted to prove this induction and a long-lasting one which returned to its base- linkage experimentally, but this was not an easy task. line within 45 minutes. Blood flow changes only occurred in Although, CSD has never been directly demonstrated in the the affected hemisphere.5 human cortex, researchers noted that CSD is associated with To investigate the link between middle meningeal artery blood spreading hypoperfusion of occipital lobes or with blood flow and trigeminal nerve stimulation, they transected the oxygenation level-dependent (BOLD) signal changes. trigeminal branch innervating the meninges and examined BOLD reflects the balance between oxygen delivery and ox- blood flow shifts. By doing so, the long-lasting elevation was ygen consumption. Scientists who worked on the previously abrogated, but the early peak remained unchanged. mentioned study tried to track temporal and spatial events Secondly, knowing that trigeminal stimulation causes menin- in the human visual cortex in order to map the progression geal inflammation due to the secretion of various neuropep- of the BOLD changes during migraine aura. Changes were tides (e.g. calcitonin gene-related peptide (CGRP), substance detected by magnetic resonance imaging (MRI).6 P, neurokinin A), they argued that these neuropeptides could The study investigated three patients during five episodes of be measured in plasma. As expected, CSD caused ipsilateral visual aura. They were trying to find out which brain areas plasma protein leakage.5 are included in visual migraines aura and, more precisely, to discover which of these neuronal cycles is responsible for its initiation. They used MRI to detect specific parameters DIFFERENT HYPOTHESES OF MIGRAINE associated with migraine. Before each of the imaging tests, PATHOPHYSIOLOGY subjects were told to think of something that induced their migraine attack in the past. The patient needed to push the 1. Vascular hypothesis button every time he or she experienced the beginning of the visual aura, the end of the visual aura, and the beginning of The first, rather primitive theory for migraine pathophysi- the headache.6 ology was the vascular theory which claimed that migraine occurs due to vasodilatation of intracranial blood vessels In the migraine attacks with visual aura, BOLD signals were which are innervated by the trigeminal nerve. The concept similar. They detected abnormal blood flow in the occipital that migraine is mainly caused by vasodilatation has been lobe during migraine aura. Also, they revealed neurovascular expanded nowadays. The vascular theory purports that events in the occipital lobe that resembled CSD. These events abnormal dilatation of brain blood vessels is the primary are: an initial cortical gray hyperemia with characteristic du- cause of migraine headaches. Vasoconstriction, which is ration and velocity, followed by hypoperfusion. They showed a cause of aura, is followed by vasodilatation and the start an attenuated response to visual activation and a recovery to of migraine headache. However, it has never been properly baseline mean level and a concurrent recovery of the stimulus explained whether extracranial or intracranial arteries are driven activation. Furthermore, they discovered that this generating these migrainous symptoms. Still, results from phenomenon, just like CSD, did not cross prominent sulci.6 various investigations are not uniform. There are many which They argued that the source of those initial responses was an confirm but, on the other hand, also negate vascular theory. increase in blood flow that caused the shining, scintillating, There are many cranial arteries in the scalp, pia, and dura migrating visual aura. The data they collected are not specific which activate trigeminal nerve fibers by vasodilatation. because the mean MRI signal increase that they saw could Wolff is the researcher who observed and published that the reflect low oxygen consumption due to decreased neuronal superficial temporal artery becomes dilated, edematous, and gyrus | vol. 4 | no. 3 – 4 | july – december 2017 330 sleep disorders

NEUROLOGY Popović J. The pathophysiology of migrane. pp. 329 – 334 partially damaged during migraine attacks. He is the first Recent studies are in opposition to the old ones because they one who suggested vasoconstriction as the cause of the aura.7 have shown that headache typically begins during the hypop- Further support for the vascular theory comes from calci- erfusion and ends when hyperperfusion starts resolving.3 tonin gene-related peptide (CGRP) and histamine. Asghar Many neuroimaging studies were conducted in order to et al., reported that CGRP causes dilations of the middle explain and confirm this migraine-causing theory. In favor meningeal artery in healthy volunteers, but it is unknown of hyperperfusion and vasodilatation as the trigger and whether headache is induced by CGRP itself or vasodila- cause of migraine-headache are the studies that investigated tation of the middle meningeal artery. They also noticed vasodilatation as a product of vasodilating drugs, such as unilateral dilatation of the middle meningeal artery during nitroglycerin. Also, they confirmed that usage of some drugs unilateral headaches and bilateral dilatation during bilateral that cause vasodilatation did not cause migraine. Because headaches. The dilatation was significant in extracerebral of that finding they concluded that vasodilatation is not and intracerebral blood vessels. Also, the headaches ceased necessary for migraine progression.16 when the vasoconstrictor sumatriptan was used.8 On the Another perspective on vasodilatation and vasoconstriction contrary, a study using high-resolution imaging did not detect has been offered recently, which states that the vasoconstric- any changes in middle meningeal artery diameter during tive effect of caffeine, ergotamines, and triptans can also migraine headaches. Furthermore, a study administrating explain their anti-migraine effect. These assumptions have vasoactive intestinal polypeptide and adrenomedullin, both not been accepted because it has been shown that triptans, highly effective vasodilatative agents, showed that, despite for example, can work at multiple sites along the trigeminal dilatation of the middle meningeal artery, CGRP did not cause nerve to inhibit nociceptive signalling.17 Activation of the a migraine.9 Thirdly, Doppler sonography was conducted by trigeminal nucleus results in the release of CGRP at vascular Friberg et al. in another study that provides evidence against terminations of the trigeminal nerve.10 vascular hypothesis. They compared blood flow velocity in the middle cerebral artery on the headache and non-headache side of the head and noticed that blood flow on headache 2. Genetics side was much lower.10 Pourshoghi et al., tried to explain vascular theory by giving patients three different agents: Like in any other disease, genetics may play smaller or magnesium sulfate, sodium valproate, or dihydroergotamine greater role in the pathogenesis of migraine. A genetic pre- (DHE) and monitoring cerebrovascular dynamics using disposition has been speculated. Scientists have proposed a near-infrared spectroscopy (NIRS). Their results weren’t in genetic model for familial hemiplegic migraine (FHM). Three favor of the vascular theory; both magnesium sulfate and different mutations for FHM have been found in the human DHE had the same effect on pain management, even though genome. These mutations cause an increase in excitatory magnesium sulfate works as a vasodilatative drug and DHE neurotransmitter release via alterations in Na/K-ATPase that is a vasoconstrictor. Sodium valproate, which has no effect reduce the function of this enzyme and lead to an increase in on vascular tonus, improved pain significantly, suggesting extracellular potassium. Also, mutation of a sodium channel that the neuronal theory might be the proper explanation gene causes an increase in action potential frequency. These for migraine pathophysiology.11 mutations increase neuronal excitability which is thought to lead to migraine.3 However, the search for genes related Schoonman et al., conducted a study in which they did not to other types of migraine is still in progress. find any correlation between intracranial vasodilatation and migraine. They measured the diameter of the middle meningeal artery, though they did not take into account its 3. Sensory hypersensitivity intradural part, and the external carotid artery before its bifurcation. The diameter of these vessels was unchanged Patients who suffer from migraines often experience symp- during attacks. However, they did not measure the diameter toms affecting the sensory systems. They are hypersensitive of the superficial temporal artery, so conclusions about the to light, sound, smell and touch. Studies have shown that vascular theory are not valid.12 many patients experience allodynia during migraine attack There are several pieces of evidence supporting Wolff’s and that the severity of allodynia is correlated with migraine theory that dilation of the extracranial arteries is the cause duration.3 Scientists hypothesize that allodynia is the result of migraine. The pulse of the external carotid artery in of primary dysregulation of central sensory processing which migraine patients was twice that of the control group. Also, may also be the cause of other sensory symptoms. they noticed a decrease in the headache intensity when the This dysregulation is the consequence of the cortex, thalamus pulse of the external carotid artery was lower. In addition, and brainstem activation.3 during headache blood flow was increased when attacks were occurring and the increase was on the painful side of the head if headache was unilateral.13 After the administration 4. Neuronal theory of ergotamine, blood flow suddenly decreased if patients re- sponded to ergotamine – if not, blood flow stayed elevated.14 Scientists that support the neuronal theory are keen to Secondly, high levels of CGRP were detected in the external consider vascular theory rather primitive. New theories jugular vein during migraine attacks in the same study. After propose that vasodilatation is definitely not necessary for triptan was given, CGRP levels dropped.15 Thirdly, extracranial causing migraine attacks. Firstly, basic neuronal pathways artery compression alleviates pain. A study revealved that need to be explained. Trigeminal nerve afferent fibers from bilateral compression of the frontal branches of the super- the trigeminal ganglion innervate pial and dural meningeal ficial temporal artery was successful in pain management. blood vessels. Its efferent projections synapse with sec-

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NEUROLOGY Popović J. The pathophysiology of migrane. pp. 329 – 334 ond-order neurons in the trigeminal nucleus caudalis (TNC) axonal membranes of primary afferent neurons, leading to in the brainstem. TNC neurons project to the thalamus and plasma leakage and headache.5 higher cortical areas that are included in pain processing. Furthermore, there are many discussions about neuroan- An increase in middle meningeal artery blood flow stimulates atomical structures incorporated in pain processing and trigeminal parasympathetic nerve fibers. According to the modulation, so scientists Borsook and Burstein tried to neuronal theory, trigeminal nerve fibers and inflammation explain why the brainstem and periaqueductal gray matter mediators play a great role in starting and prolonging attacks (PAG) are not the most promising examples of migraine of migraine headache. Inflammatory mediators stimulate generators, despite a lot of evidence in favor of this.19 nerve fibers and cause pain. Nowadays, CGRP is considered The theory that supports the notion of the PAG as a migraine to be one of the most significant moderators and initiators generator states that abnormal PAG functioning can enhance of pain during migraine. CGRP’s role in an organism is not pain transmission. Imaging studies of the rostral brainstem limited to migraine initiator. It is involved in regulation of during spontaneous migraine attacks are in favor of this the cardiovascular and gastrointestinal systems, neurogenic theory. Raskin et al., noticed that electrical stimulation of inflammation modulation, and nociceptive input.15 the PAG did not initiate a headache, moreover, it produced pain relief in 160 of 175 patients. Also, in their opinion, PAG Studies reported elevated CGRP levels in jugular vein blood activation was a consequence of trigeminal nerve activation, during migraine attacks. Also, elevated CGRP levels were thus it cannot be a migraine generator.20 detected in saliva and serum, and were reduced by triptans Weiller et al. investigated nine patients with migraine us- afterwards in the study. CGRP receptor antagonists are ing positron emission tomography (PET). They correlated effective in treating migraine headache. Because of that, increased blood flow in brain areas with hyperexcitability. CGRP becomes an important starting point to investigate Increased blood flow during migraine attack was measured the neuronal pathophysiology of migraine.15 bilaterally in the cingulate cortex, inferior anterocaudal cingulate cortex, auditory association cortex, brainstem, Another study conducted by Beccera et al., investigated the and visual association cortex. However, it was only in the idea of hyperexcitable brain measuring γ-aminobutyric brainstem that high blood flow persisted after administra- acid (GABA) and glutamate levels in patients with episodic tions of sumatriptans. It was proven that the brainstem has migraine. Their area of interest was the anterior cingulate a crucial role in prolonging migraine attack.21 cortex (ACC) because of its putative role in migraine. The ACC was imaged using MRI, then gray matter was extracted and each voxel was spectroscopically analyzed. They noticed that 5. Controversial theories levels of these metabolites were lower in migraine patients, but they did not get statistically significant results.18 Besides these common explanations for the pathophysiology of migraine, some untraditional ones have emerged nowadays. Investigations are also being undertaken to understand the Researches from Nanjing Medical University tried to em- premonitory symptoms, like nausea, vertigo and autonomic phasize understanding of neuronal hyperexcitability during symptoms, occurring during migraine. They indicate that migrainous attacks. They conducted a case-control study on these symptoms are associated with the hypothalamus and 29 women suffering migraine. Brain activity was imaged brainstem. Recent positron emission tomography (PET) during attacks. They analysed significant waveforms in the studies have showed that laterality of pontine activation magnetoencephalogram (MEG) after participants heard corresponds with laterality of pain. Also, they suggested a sound of a certain frequency range at which time they that changes in metabolism in the brainstem can cause would tap a button with their index finger. MEG detected chronic migraine.19 Other brain structures are involved in brain activity in the primary and supplementary motor migraine-headache, such as the trigeminal nucleus caudalis area after use of the index finger. It was noticed that the which is activated by CSD, and the locus coeruleus which can latencies in the MEG were delayed in the migraine group reduce cerebral blood flow.6 when compared to the control group. Their results were as follows: migrainous patients have increased cortical activa- Bolay et al. performed an experiment in which they used laser tion in the ipsilateral primary motor area and higher odds speckle-contrast imaging in order to map cortical, pial, and of developing this activity in the supplementary motor area dural blood vessels. They observed medial meningeal artery in comparison to the control group. The conclusion of this blood flow in order to determine whether CSD stimulates study was that many other brain areas can be included in the trigeminovascular system. Trigeminal activation was the initiation of the migraine attack.22 Furthermore, new observed after CSD. CSD caused unilateral plasma protein studies have presented a correlation between the patient’s leakage and they showed that CSD irritates axon collateral foramen ovale and the prevalence of migraine, saying that nociceptors in the pia and dura leading to migraine visual microemboli or other factors crossing from the right-to-left aura and the genesis of unilateral head pain. They confirmed circulation can trigger migraine attacks.3 that medial meningeal artery blood flow depends on intact trigeminal and parasympathetic innervation. This was proven by noticing that trigeminal rhizotomy blocks the medial meningeal artery response following CSD. Also, they demonstrated that CSD activates trigeminal nerves, triggers headache and reflex middle meningeal vasodilatation. This is explained by an increase in epicortical potassium levels which is needed to relax smooth muscle and depolarize gyrus | vol. 4 | no. 3 – 4 | july – december 2017 332 sleep disorders

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CONCLUSION

Although migraine is a rather common medical condition, scientists have not found a consensus about its pathophysiology. Vascular and neuronal theories are the first ones that emerged and they have not been fully explained yet. Despite that, new, controversial hypotheses and theories are coming to light every day. Nowadays, great advantages for medical research are afforded by neuroimaging techniques. PET and functional MRI (fMRI) studies have confirmed that migraine attacks are accompanied by waves of blood flow that arouse trigeminal nerve fibers and high brain activity which leads to migraine-headache. In spite of such evidence, the pathophysiology of migraine cannot be only associated with vasodilation even though there are many theories in favor of it. For example, triptans, as vasoconstrictive agents make symptoms of migraine manageable. But, triptans, also reduced CGRP levels in the studies. CGRP has been discussed as the main neuromodulatory agent in neuronal theories, although scientists are not sure whether CGRP is a product of brain inflammation which causes vasodilatation, or whether it is the vasodilatation itself that causes headache. Nevertheless, it is clear that increased CGRP levels were measured in migrainous patients. Furthermore, it is still discussed whether the vasodilatation of extracranial or intracranial blood vessels is cause of migraine attack. Most studies agree that CSD is relevant for the explanation of migraine aura although there are studies which disproved the link between middle meningeal artery blood flow and CSD. Moreover, new theories suggest the implication of genetics and body temperature in the pathophysiology of migraine. An explanation of the pathophysiology of migraine and migraine aura still remains out of reach. On the one hand, one could not claim the vascular theory to be absolutely obsolete. But on the other hand, despite many new findings, scientists investigating the neuronal theory have not offered an unambiguous solution yet.

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PATOFIZIOLOGIJA MIGRENE

Sažetak

Migrena, jedno od medicinskih stanja s najvećom prevalencijom, pogađa i mlađu i stariju populaci- ju. Usprkos tome, patofiziologija migrene do danas nije u potpunosti razriješena iako mnogi znanstvenici predlažu teorije o njezinu nastanku. Hipoteze često nisu u potpunoj podudarnosti. Jedna od njih je vaskularna teorija kojom je objašnjeno na koji način vazodilatacija cerebralnih arterija, posebice srednje meningealne arterije, podražuje vlakna trigeminalnog živca koja prenose osjet boli te na taj način uzrokuje glavobolju. S druge strane, neuronska teorija, u svojoj srži ne podržava va- skularnu teoriju, već predlaže hiperekscitabilnost mozga kao inicijatora migrene. Teza je potvrđena mjerenjima koncentracija gama-aminomaslačne kiseline (engl. γ-aminobutyric acid, GABA) i gluta- mata u pojedinaca koji pate od kronične migrene. Nadalje, znanstvenici koji podupiru neuronsku teoriju smatraju kako postoje određeni neuronski krugovi i moždane strukture koji mogu generirati migrenski napadaj kao što su to, primjerice, anteriorni cingulatni korteks i periakveduktalna siva tvar. Također, peptid vezan uz kalcitoninski gen (engl. calcitonin gene-related peptide, CGRP) je stavl- jen u središte zbivanja neuronske teorije kao jedan od značajnih moderatora migrenske glavobolje. Dokazano je kako CGRP, jednako kao i vazodilatacija, stimulira nociceptivna vlakna trigeminalnog živca te uzrokuje glavobolju. Osim navedene dvije, zadnjih godina znanstvenici su iznjedrili i, mnogima za sada, radikalne teorije kao što je teorija termoregulacije i „pregrijavanja“ mozga za vrijeme glavobolje. Moguće je kako će jedna od novih teorija objasniti izvor napadaja migrene i stati na kraj isključivo simptomatskom liječenju te bolesti.

Ključne riječi: migrena, migrena s aurom, neuronska teorija, peptid vezan uz kalcitoninski gen (CGRP), vaskularna teorija

Received March 27, 2017. Accepted June 1, 2017.

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NEUROLOGY Horvat Velić E. Trigeminal nerve stimulation (TNS). pp. 335 – 338 TRIGEMINAL NERVE STIMULATION (TNS)

Emina Horvat Velić 0000-0002-8861-2719 University of Zagreb, Faculty of Science, Department of Biology

Abstract Trigeminal nerve stimulation is a non-invasive approach that aims to help patients suffering from a wide range of illnesses such as epilepsy and major depressive disorder. The basis of the treatment lies in the externally applied electrodes through which electrical pulses that stimulate the final branches of the trigeminal nerve are emitted. Preliminary studies showed promising results despite being conducted on a small number of patients, but large scale studies are necessary in order to prove whether trigeminal nerve stimulation (TNS) is indeed a valuable method of treatment.

Keywords: epilepsy, major depressive disorder (MDD), trigeminal nerve, trigeminal nerve stimulation (TNS)

INTRODUCTION skull through different openings (mental foramen – mental nerve, branch of mandibular nerve, infraorbital foramen – External trigeminal nerve stimulation (TNS) is a new, non-in- infraorbital nerve, branch of maxillary nerve, and supraorbital vasive approach that uses electrical stimulation in order to notch – supraorbital nerve, branch of ophthalmic nerve) alleviate symptoms of certain neurological illnesses. Pilot and innervate different regions of the face (Figure 1), with studies showed that TNS can be helpful in the management almost no overlap.3 of epilepsy, post-traumatic stress disorder (PTSD), and major depressive disorder (MDD). Vagus nerve stimulation (VNS) In the treatment itself, cutaneous branches of the trigeminal is another treatment that uses electrical pulses in order nerve are stimulated externally with electrodes – the first to stimulate the cranial nerve with similar outcomes, but due studies were conducted on rats and several pilot studies on to some side effects, emphasis has been currently put on the humans have also shown positive results.1 An important investigation and development of TNS.1 Although the exact study to mention is the study published in The Journal of mechanism of TNS is relatively unknown, Schulze-Bonhage Neuroscience in 2000. The scientists first induced epilepsy proposes in the 2016 study that this sort of neuromodulation in rats and then connected the trigeminal stimulator in such inactivates targeted brain tissue by “activation of GABA-ergic fashion that stimulation of the trigeminal nerve would start inhibitory neurons and alters extracellular potassium con- at the same time as the epileptic seizure. This study and its centrations.” This kind of high frequency stimulation could positive results paved the way for human studies.4 A 2010 also “desynchronize neural activities and lower the recruita- study on BOLD (blood oxygen level-dependent) effects and bility of neurons to epileptic rhythm”. Schulze-Bonhage also responses to TNS on the rat barrel cortex showed activity briefly discusses advantages of low frequency stimulation, in the primary somatosensory barrel cortex, the secondary by mentioning that it could lead to the reduction of excita- somatosensory cortex, and the motor cortex.5 These findings bility (inducement of long term depression).2 later helped in the interpretation of results from various studies conducted on human subjects.

METHOD OF STIMULATION AND INITIAL STUDIES In one of the first human studies, conducted by DeGiorgio et al. in 2003, two patients with complex partial seizures The trigeminal nerve is the fifth cranial nerve and is re- (CPS) were chosen in order to investigate effects of TNS. For sponsible for both sensory and motor functions in the face. stimulation, a neurostimulator was used for pulses at 120 It originates in the trigeminal nuclei in the pons, and has Hz that lasted 20 to 30 seconds, with 20 to 30 seconds off three main branches that stem from the trigeminal (semi- periods, with silver gel electrodes placed on the skin of the lunar) ganglion, which lies above the carotid canal and near face – positive ones just over the infraorbital foramen and the apex of the anterior surface of the petrous part of the negative ones above the nasal-labial fold. The strength of the temporal bone. The first two branches (ophthalmic nerve current was gradually increased to identify patients’ percep- and maxillary nerve) are strictly sensory branches, while tion and pain, in order to avoid discomfort and unwanted the third (mandibular nerve) contains both sensory and side effects such as muscle contraction. That study showed motor fibers. After their intracranial path, they leave the pronounced minimization of the seizures during the period

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NEUROLOGY Horvat Velić E. Trigeminal nerve stimulation (TNS). pp. 335 – 338

Figure 1. Dermatome distribution of the trigeminal nerve. Source: Image “Gray784.png” by Henry Vandyke Carter, originally from bartleby.com – from Wikimedia Commons, public domain. https://commons.wikimedia.org/?curid=531758

FURTHER STUDIES of six months in which TNS was applied.1 Another study by After pilot studies showed that TNS has beneficial effects on DeGiorgio et al., this one conducted in 2006 and involving epilepsy seizures, further studies were conducted focusing seven patients, yielded similar results; stimulated areas (with on potential benefits of the treatment of MDD and PTSD. alternating right and left side) that included infraorbital In 2014 and 2015 Shiozawa conducted two studies concern- foramen were the same as in the initial study, but another ing the possible treatment of MDD with TNS. The use of was added as well – simultaneous bilateral stimulation of stimulators was shorter here in comparison with previously the supraorbital part of the face. Patients did not feel any mentioned studies (30 minutes per day, over the course of discomfort, but reported tingling sensations in the forehead 10 days total). Both studies showed positive effects on the and canines, as well as improved tolerance over time, with alleviation of the symptoms, without any severe side effects heart rate, blood pressure, and pulse monitored throughout present. The first study was a small study involving eleven the first 24 hours after the initiation of the treatment and patients while the second was a sham-controlled study with continued afterwards; all vital signs remained within nor- 40 patients randomized into two groups (20 active, 20 sham). mal limits. Of seven patients, four experienced reduction of In both studies, only supraorbital branches of the ophthalmic seizures over 50%, while five patients continued with TNS nerve were stimulated, with psychiatric follow ups, and in for six months, with four of them also displaying the same both studies a positive conclusion was reached. When it decrease in seizures. It is also important to note that out of comes to the anatomical explanation of the data, several seven patients, six opted for 24-hour long treatments, and neuroimaging studies showed changes in neuronal activity the seventh chose to wear the stimulator for 12-hours per of the amygdala, insula, precentral gyrus, hippocampus, and night because the seizures happened only during nighttime thalamus. 8,9 The precise mechanism of action, once again, or in early mornings.6 However, another study conducted in is still unknown, apart from the fact that there are changes 2013 by Pack showed that TNS might not be effective in the in cortical excitability in the aforementioned subcortical treatment of all types of epilepsy (the study was focused on sites.8 TNS was also proved to be a good therapy option refractory partial seizures), since the end results did not in the treatment of irritable bowel syndrome in an elderly support previous findings.7 female patient with MDD. After ten days of receiving bilateral supraorbital stimulation, the patient reported lessening of the symptoms. 10 Furthermore, a 2015 study involving twelve patients with PTSD and MDD showed significant increase of the quality of life after an eight-week trial.11 gyrus | vol. 4 | no. 3 – 4 | july – december 2017 336 sleep disorders

NEUROLOGY Horvat Velić E. Trigeminal nerve stimulation (TNS). pp. 335 – 338

Figure 2. Dermatome distribution of the trigeminal nerve. Source: Image “Gray784.png” by Henry Vandyke Carter, originally from bartleby.com – from Wikimedia Commons, public domain. https://commons.wikimedia.org/?curid=531758 Available under the GNU Free Documentation License (GFDL), Version 1.2 or any later version and under the CC BY-SA 1.0, 2.0 and 2.5 Generic license as well as under the CC BY-SA 3.0 Unported license (https://creativecommons.org/licenses/by-sa/3.0/deed.en). Published June 24, 2007. Accessed October 15, 2017. Original image adapted by Emina Horvat Velić and available under the CC BY-SA 3.0 Unported license (https://creativecommons.org/licenses/by-sa/3.0/deed.en).

CONCLUSION

Despite unknown mechanisms, empirical evidence shows that TNS helps in managing of the symptoms of multiple illnesses, such as epilepsy, major depressive disorder, and post-traumatic stress disorder. It seems as a good supplement for medication, especially since it is non-invasive and easy to apply, in addition to observed reduction of the frequency of seizures. The issue, however, lies in the fact that almost all conducted studies involved a small number of patients, with some even dropping out of the study entirely before finishing. Although showing promising potential, more studies involving a larger sample of patients are necessary in order to confirm or disprove preliminary findings.

REFERENCES:

1. DeGiorgio CM, Shewmon DA, Whitehurst T. Trigeminal nerve stimulation for epilepsy. Neurology. 2003;61(3):421-422. doi:10.1212/01.WNL.0000073982.42650.57. 2. Schulze-Bonhage A. Brain stimulation as a neuromodulatory epilepsy therapy. Seizure – Eur J Epilepsy. 2017;44:169-175. doi:10.1016/j.seizure.2016.10.026. 3. Krmpotić-Nemanić J, Marušić A. Anatomija čovjeka. Zagreb: Medicinska naklada; 2007. 4. Fanselow EE, Reid AP, Nicolelis MAL. Reduction of Pentylenetetrazole-Induced Seizure Activity in Awake Rats by Sei- zure-Triggered Trigeminal Nerve Stimulation. J Neurosci. 2000;20(21):8160–8168. doi:10.1523/JNEUROSCI.20-21-08160.2000. 5. Just N, Petersen C, Gruetter R. BOLD responses to trigeminal nerve stimulation. Magn Reson Imaging. 2010;28(8):1143-1151. doi:10.1016/j.mri.2010.02.002. 6. DeGiorgio CM, Shewmon A, Murray D, Whitehurst T. Pilot Study of Trigeminal Nerve Stimulation (TNS) for Epilepsy: A Proof-of-Concept Trial. Epilepsia. 2006;47(7):1213-1215. doi:10.1111/j.1528-1167.2006.00594.x. 7. Pack AM. Trigeminal Nerve Stimulation May Not be Effective for the Treatment of Refractory Partial Seizures: Efficacy of Trigeminal Nerve Stimulation. Epilepsy Curr. 2013;13(4):164-165. doi:10.5698/1535-7597-13.4.164. 8. Shiozawa P, Duailibi MS, da Silva ME, Cordeiro Q. Trigeminal nerve stimulation (TNS) protocol for treating major depression: An open-label proof-of-concept trial. Epilepsy Behav. 2014;39:6-9. doi:10.1016/j.yebeh.2014.07.021.

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9. Shiozawa P, da Silva ME, Netto GTM, Taiar I, Cordeiro Q. Effect of a 10-day trigeminal nerve stimulation (TNS) protocol for treating major depressive disorder: A phase II, sham-controlled, randomized clinical trial. Epilepsy Behav. 2015;44:23- 26. doi:10.1016/j.yebeh.2014.12.024. 10. Trevizol AP, Cordeiro Q, Cook IA, Barros MD, Shiozawa P. Trigeminal Nerve Stimulation (TNS) for the Treatment of Irri- table Bowel Syndrome in an Elderly Patient with Major Depressive Disorder: A Case Study. Brain Stimul Basic, Transl Clin Res Neuromodulation. 2015;8(6):1235-1236. doi:10.1016/j.brs.2015.09.001. 11. Cook IA, Abrams M, Leuchter AF. Trigeminal Nerve Stimulation for Comorbid Posttraumatic Stress Disorder and Major Depressive Disorder. Neuromodulation Technol Neural Interface. 2016;19(3):299-305. doi:10.1111/ner.12399.

VANJSKA STIMULACIJA TRIGEMINALNOG ŽIVCA

Sažetak

Vanjska stimulacija trigeminalnog živca je neinvazivni pristup s ciljem pomoći pacijentima koji pate od širokog spektra bolesti kao što su epilepsija i depresija. Temelj liječenja leži u elektrodama koje se prislanjaju na vanjsku stranu lica, i kroz koje se emitiraju električni impulsi koji stimuliraju završne grane trigeminalnog živca. Preliminarne studije pokazale su obećavajuće rezultate unatoč tome što su provedene na malom broju pacijenata, ali potrebna su istraživanja koja uključuju veći broj pacijenta kako bi se dokazalo je li stimulacija trigeminalnog živca (TNS) zaista učinkovita metoda liječenja.

Ključne riječi: epilepsija, trigeminalni živac, vanjska stimulacija trigeminalnog živca (TNS), veliki depresivni poremećaj (MDD)

Received October 24, 2016. Accepted October 15, 2017.

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NEUROLOGY Starčević I. Epilepsy and pregnancy. pp. 339 – 342 EPILEPSY AND PREGNANCY

Ivana Starčević 0000-0002-8333-6831 University of Zagreb, School of Medicine

Abstract Epilepsy, as a chronic neurological disease, affects women during their fertile period. Due to a variety of clinical manifestations, patients who suffer from epilepsy usually require medication - antiepileptics. It has been proven that certain antiepileptic drugs (AEDs) cause different types of fetal abnormalities, and there are many indications that the rest of these drugs may cause the same complications. The seizures themselves cause different difficulties, which often increase during pregnancy. Deciding whether to prescribe AEDs or risk the complications of seizures is a problem which physicians encounter on a daily basis. This article compares the risks and complications caused by epilepsy with the possible adverse effects of the AEDs during the pregnancy, also considering their effect during the lactation period.

Keywords: antiepileptics, complications, epilepsy, pregnancy, seizure

INTRODUCTION DANGERS OF SEIZURES - HOW DO THEY AFFECT PREGNANCY AND CHANGE DURING PREGNANCY? Epilepsy is a chronic neurological disease whose cause is mostly unknown. The main indicators of the disease are the The changes in hormonal balance that normally occur during regular or isolated seizures, caused by the increased activity pregnancy can often increase neuronal activity, which can of neurons in different parts of the brain’s cortex. Epilepsy oc- further increase both the frequency of seizures and their curs in approximately one million women of childbearing age, variations in severity (both are side effects in 15-32% of women who later deliver around 24 000 babies every year.1 Epilepsy with prediagnosed epilepsy).2,1 Estrogen increases the risk negatively impacts women by decreasing fertility, increasing of seizures, while progesterone has an inhibitory effect.2 the risk of polycystic ovary syndrome, abnormal menstrual The only type of seizure that can affect pregnancy is the cycles, and altered antiepileptic drug (AED) metabolism.2 tonic-clonic seizure. The tonic-clonic type of seizure often causes falling and loss of breath where physical disturbance and a temporary lack of oxygen inevitably cause damage to DOES EPILEPSY AFFECT CONCEPTION? the mother and the fetus. Epileptic seizures occur in 20-36% of pregnant women with Considering epilepsy’s diverse origins (genetic, brain inju- prediagnosed epilepsy. It is important to mention that wom- ries, tumors), it has not been proven that epilepsy or AEDs en who have not shown any signs of attacks 9 months prior themselves significantly affect conception. Nevertheless, to pregnancy have a high chance of remaining seizure-free they do affect the female reproductive system. Around half during pregnancy. That also includes keeping them on their of all epileptic women have menstrual abnormalities and current AED therapy.2 a higher frequency of anovulatory cycles. The results of the recent study done in India have shown that infertility was least common (7.1%) in epileptic women who were not on AEDS: RISKS, ADVANTAGES, WHICH ONES ARE IN USE AEDs. Comparing those who were not on AEDs with women who were exposed to AEDs, the results showed a significant It has been proven that use of different AEDs results in in- difference in ability to conceive, which was correlated to the creased seizure frequency. This unfortunate side effect may number of AEDs used: 31.8% of women who were on mon- occur as a result of the drug overdose. The other mechanism otherapy (one AED exposure) experienced difficulties with of the increased seizure frequency is considered to be the conceiving, 40.7% of women experienced difficulties when adverse activity of the drug. This applies to a specific type of two AEDs were used, 60.3% of women had difficulties with epilepsy or different types of seizures. The drugs reported conceiving when three or more different AEDs were used).3 to aggravate the seizures are carabamazepine, phenytoin, vigabatrin and sometimes benzodiazepines.5 It has also been shown that pre-conception counseling is necessary for successful family planning. That includes A recent study conducted in North America came to the counseling about the AEDs, a possible change or reduction conclusion that the new AEDs are less associated with birth in the dose of the therapy, and plainly educating women and malformations - for example, lamotrigine or levetiracetam preparing them for the possible outcomes.4 (often used together in form of polytherapy). The ‘’older’’

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NEUROLOGY Starčević I. Epilepsy and pregnancy. pp. 339 – 342

AEDs, valproate and phenobarbital, are connected with a born to women with epilepsy, out of those which often oc- higher risk of malformations, such as cleft lip.6 cur in the general population, were cardiac and neural tube There is also a 10% risk of postpartal hemorrhage in chil- defects as well as hypospadias.10 dren exposed to AEDs in utero, with a potential mortality Due to the increased incidence of neural tube defects, recom- rate of 30%.7,8 The risk of bleeding is reduced by taking the mendations advise women with prediagnosed epilepsy to take recommended quantity of vitamin K at a dose of 10 mg per up to 5 mg of folic acid daily preconceptionally and during day during the last month of pregnancy. the first trimester, whereas healthy women in childbearing Patients often continue valproate or phenobarbital treat- age should receive around 0,4 mg of folic acid.11 ment when their epilepsy is under control and they may The possible outcomes of pregnancy in women with epilepsy be reluctant to switch AEDs because of the risk of seizure include maternal death (80 deaths per 100 000 pregnan- recurrence. New AEDs are usually prescribed to patients cies), prolonged stay in the hospital, increased possibility who were not responding to traditional drugs. Also, there are of necessity for cesarean delivery, hypertension, premature pharmacokinetic changes during pregnancy due to increased delivery, and preeclampsia. Other maternal outcomes vary clearance, which can be particularly pronounced for specific from different types of hemorrhage to chorioamnionitis. AEDs resulting in the increase of the risk of seizures. Still, it One possible fetal outcome could be poor growth. There is is intriguing that less effective AEDs, meaning less effective also the possibility of stillbirth.12 seizure control during pregnancy, turns out to be safer for fetal development.6 There has been a lot of discussion in considering monotherapy AFTER THE PREGNANCY – THERAPY DURING over polytherapy in treating pregnant women with epilepsy. LACTATION Despite polytherapy allowing better control over seizures, it is easy to conclude that the risk for teratogenicity increases After the delivery and during lactation, it is important to just by using more AEDs at the same time (by combining all restore AED intake back to normal levels, regardless of the of their side effects). intake being stopped or reduced during the pregnancy. That is due to changes the body experiences after bringing the hormonal level back to normal.13 MALFORMATIONS, MATERNAL MORTALITY Even though to date there have not been a lot of papers published that show how much of the AEDs actually reaches the When one considers monotherapy over polytherapy, the child through breastfeeding, it is widely accepted that the studies have shown that the risk of major congenital malfor- effects on the child’s psychomotor development that may mations increases not only by the type of AED, but also with have been affected by AEDs are consequently compensated by the antiepileptics’ dose – as shown in studies concerning the benefits of breastfeeding. A study conducted in the USA carbamazepine, lamotrigine, valproate, and phenobarbital.9 followed the children who were exposed to AEDs in utero up Different studies compared the risk of malformations in the to 3 years after their birth. There was no difference between general population with the risk in children born to mothers the breastfed and non-breastfed children in psychomotor with epilepsy. The most frequent abnormalities in children development.14

Table 1. Guidelines for the use of antiepileptic drugs during pregnancy. Adapted from: Morrell MJ. Epilepsy in women. Am Fam Physician. 2002;66(8):1489-1494. Available at: https://www.aafp.org/afp/2002/1015/p1489.html. Accessed July 18, 2017. Copyright © 2002 by the American Academy of Family Physicians. gyrus | vol. 4 | no. 3 – 4 | july – december 2017 340 sleep disorders

NEUROLOGY Starčević I. Epilepsy and pregnancy. pp. 339 – 342

CONCLUSION

The use of AEDs during pregnancy is, depending on the frequency of seizures, often inevitable. There is always a question regarding changes in therapy during the pregnancy. The possibility of a seizure and the risks it may carry are tough to compare with the advantages of AEDs usage. Even though there is a variety of AEDs, some patients do not respond well to them, which is complicated by the fact that some patients change their response during the pregnancy. The policy that is conducted in many hospitals is to give women with epilepsy extra care and attention with frequent check ups from the beginning of their pregnancies. The only universally safe option is planned parenthood in women who are seizure-free for a while, while the correct and least harmful AED therapy is still yet to be discovered.

REFERENCES:

1. Beach RL, Kaplan PW. Seizures in pregnancy: diagnosis and management. Int Rev Neurobiol. 2008;83(8):259-271. doi:10.1016/ S0074-7742(08)00015-9. 2. Morrell MJ. Epilepsy in women. Am Fam Physician. 2002;66(8):1489-1494. 3. Sukumaran SC, Sarma PS, Thomas S V. Polytherapy increases the risk of infertility in women with epilepsy. Neurology. 2010;75(15):1351-1355. doi:10.1212/WNL.0b013e3181f73673. 4. Betts T, Fox C. Proactive pre-conception counselling for women with epilepsy - Is it effective? Seizure. 1999;8(6):322-327. doi:10.1053/seiz.1999.0325. 5. Perucca E, Gram L, Avanzini G, Dulac O. Antiepileptic drugs as a cause of worsening seizures. Epilepsia. 1998;39(1):5-17. doi:10.1111/j.1528-1157.1998.tb01268.x. 6. Hernández-Díaz S, Smith CR, Shen A, et al. Comparative safety of antiepileptic drugs during pregnancy. Neurology. 2012;78(21):1692-1699. doi:10.1212/WNL.0b013e3182574f39. 7. Liporace J, D’Abreu A. Epilepsy and women’s health: family planning, bone health, menopause, and menstrual-related seizures. Mayo Clin Proc. 2003;78(4):497-506. doi:10.4065/78.4.497. 8. Yerby M, Collins SD. Pregnancy and the mother. In: Engel J Jr, Pedley TA, eds. Epilepsy: A Comprehensive Textbook. Vol 2. Philadelphia, Pa: Lippincott-Raven Publishe1998:2027-2035. 9. Tomson T, Battino D, Bonizzoni E, et al. Dose-dependent risk of malformations with antiepileptic drugs: An analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 2011;10(7):609-617. doi:10.1016/S1474-4422(11)70107-7. 10. Tomson T, Xue H, Battino D. Major congenital malformations in children of women with epilepsy. Seizure. 2015;28:46-50. doi:10.1016/j.seizure.2015.02.019. 11. Talaulikar VS, Arulkumaran S. Folic Acid in Obstetric Practice: A Review. Obstet Gynecol Surv. 2011;66(4):240-247. doi:10.1097/ OGX.0b013e318223614c. 12. MacDonald SC, Bateman BT, McElrath TF, Hernández-Díaz S. Mortality and Morbidity During Delivery Hospitalization Among Pregnant Women With Epilepsy in the United States. JAMA Neurol. 2015;72(9):981-988. doi:10.1001/jamaneurol.2015.1017. 13. Anderson GD. Using pharmacokinetics to predict the effects of pregnancy and maternal-infant transfer of drugs during lactation. Expert Opin Drug Metab Toxicol. 2006;2(6):947-960. doi:10.1517/17425255.2.6.947. 14. Meador KJ, Baker GA, Browning N, et al. Effects of breastfeeding in children of women taking antiepileptic drugs. Neurology. 2010;75(22):1954-1960. doi:10.1212/WNL.0b013e3181ffe4a9.

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EPILEPSIJA U TRUDNOĆI

Sažetak

Epilepsija, kronična neurološka bolest, u jednakim se razmjerima pojavljuje kod svih spolova i dobi. To također uključuje i žene u fertilnom periodu. Zbog razlika u intenzitetu napadaja, pacijenti ovise o lijekovima. Dokazano je da određeni antiepileptici uzrokuju različite fetalne abnormalnosti, a ta- kođer postoje indikacije da puno širi spektar tih lijekova ima sličan učinak. Sami epileptični napadaji uzrokuju razne poteškoće čije su posljedice tijekom trudnoće još izraženije. Problem s kojim se li- ječnici redovito susreću jest biranje između liječenja antiepileptičkim lijekovima i prihvaćanja rizika mogućih napadaja u trudnoći. Ovaj članak uspoređuje rizike i komplikacije uzrokovane epilepsijom u trudnoći s prednostima i nedostatcima korištenja lijekova, također uzevši u obzir njihov učinak tijekom perioda laktacije ili dojenja.

Ključne riječi: antiepileptici, epilepsija, komplikacije, napadaj, trudnoća

Received July 18, 2017. Accepted October 16, 2017.

FIND OUT MORE:

Epilepsy Foundation of America – Epilepsy and Pregnancy https://www.epilepsy.com/living-epilepsy/women/epilepsy-and-pregnancy

Royal College of Obstetricians and Gynaecologists – Epilepsy in Pregnancy https://www.rcog.org.uk/globalassets/documents/guidelines/green-top-guidelines/ gtg68_epilepsy.pdf

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Psychiatry and Psychology Novak A. Menstrual cycle and cognitive functions. pp. 343 – 347 MENSTRUAL CYCLE AND COGNITIVE FUNCTIONS

Anamaria Novak 0000-0002-0665-4756 University of Zagreb, School of Medicine

Abstract Menstrual cycle is characterized by fluctuations of the main ovarian sex hormones, estradiol and progesterone. Estradiol reaches its peak around day 12 of the average 28-day cycle, during the late follicular or preovulatory phase, while progesterone peaks in the mid luteal phase. In animals, estradiol has been shown to induce neurogenesis and increase spinal density in the hippocampus, as well as potentiate dopaminergic signaling in the prefrontal cortex. In women, studies have shown that sex hormones, while not effecting overall learning ability, do modulate certain cognitive functions. Most prominent of these is the preference for response strategy in 4/8 virtual maze task during early and late follicular phase, as opposed to spatial strategy, which women are statistically more likely to use during mid to late luteal phase. In addition, when tested on a verbal memory test, women in the ovulatory phase, when estradiol levels are high, recalled significantly more words during the first five trials, after interference trial and after time delay when compared to women in luteal phase of the cycle. This suggests that high estradiol levels are associated with beneficial effects on working memory, which could, in part, be explained by its agonist-like effects on dopamine signaling in prefrontal cortex.

Keywords: cognition, estradiol, progesterone, spatial memory, working memory

INTRODUCTION MENSTRUAL CYCLE

While there are no differences in overall intelligence between 1. Hypothalamic-pituitary-gonadal axis women and men, studies have shown certain differences in their cognitive abilities.1 Most prominent of these being The reproductive period of a woman, from menarche to men- male’s advantage on some visuospatial tasks, such as spatial opause, is filled with repetitive monthly cycles – menstrual rotation and target accuracy tasks, and female’s advantage cycles, lasting, on average, 28 days. These cycles encompass on verbal fluency, visual memory and fine motor control cyclic changes in two organs, the ovaries and endometrium, tasks.2 Many of these have been analyzed and confirmed, which are known as an ovarian and endometrial cycles, not only in humans, but also in rodents and non-human respectively. These monthly cycles are driven by the hypo- primates. A much less noticeable, but nonetheless striking, thalamic-pituitary-gonadal axis. Hypothalamic gonado- phenomenon is the difference in female performance on tropin-releasing hormone (GnRH) neurons are located in certain tasks throughout the menstrual cycle. In normally the nucleus arcuatus (ARC) and preoptic area (POA), with cycling women, the influence of the menstrual cycle phase on those in the ARC generating an “hourly” rhythm, with pulses cognition is associated with estradiol (E2) and progesterone spaced 60 to 90 minutes apart, and those in POA generating a (P4) concentrations in specific brain regions.3 Furthermore, monthly rhythm of GnRH secretion, with a massive increase studies show that female monkeys’ brains express a greater at mid-cycle responsible for a luteinizing hormone (LH) number of dopaminergic D2 receptors during the luteal phase peak.7 Released GnRH is transported by the portal vessels in comparison to the follicular phase of the menstrual cycle.4 to the anterior pituitary, where it stimulates the synthesis Based on the suggestion that E2 also increases the number of of gonadotropins, follicle-stimulating hormone (FSH) and dopaminergic (DA) projections from the ventral tegmental luteinizing hormone (LH) from the gonadotrophs. FSH stim- area (VTA) to the prefrontal cortex (PFC), as shown by tests ulates folliculogenesis in the first phase of the ovarian cycle, done on rats, some scientists postulate that E2 influences which is hence termed the follicular phase. LH, on the other cognitive tasks reliant on DA signaling in the PFC.5 Much hand, reaching its peak around day 14 of the cycle, triggers less is known about the influences of P4 on cognitive perfor- ovulation and luteinization of granulosa and theca interna mance. However, an active P4 metabolite, allopregnanolone, cells, which then form the corpus luteum. At the moment has shown anti-depressant effects in rats.6 The aim of this of ovulation, the ovarian cycle has entered its final, luteal review is to highlight the role of E2 and P4 in modulation phase (Figure 1).7 of cognitive performance through different phases of the menstrual cycle.

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then convert to E2. The serum E2 concentration steadily rises during the follicular phase and reaches its peak in the preovulatory phase, around day 12 of the cycle. During the luteal phase of the cycle, the biochemistry of granulosa and theca cells is changed. Due to the invasion of blood vessels toward the granulosa-lutein cells, as well as LH stimulation of both granulosa-luteal and theca-luteal cells, the action of taking up and processing of cholesterol is facilitated. As a result, serum concentrations of progesterone (P4) rise and peak in the mid luteal phase, around day 21 of the cycle (Figure 1).7

Figure 1. Course of the hormonal concentrations within the ovarian cycle. OVARIAN STEROIDS AND THE HIPPOCAMPUS Source: Image “Estradiol.Cycle” by Ekem – from Wikimedia Commons. Available under the GNU Free Documentation License (GFDL), E2 has been shown to influence adult neurogenesis in the Version 1.2 or any later version and under the CC BY-SA 3.0 subgranular zone of the rat’s dentate gyrus by increasing Unported license (https://creativecommons.org/licenses/by-sa/3.0/deed.en). Published June 6, 2006. Accessed April 30, 2017. cell proliferation rate, as well as dendritic spine number and synaptic density in the Cornu Ammonis 1 (CA1) region of the hippocampus (Figure 2).8,9 This, in turn, is associated with 2. Ovarian steroids modulation of hippocampus-dependent cognitive functions. However, the relationship between E2 levels and performance The precursor for ovarian steroids, cholesterol, is taken on tasks that measure these functions is not linear, but up from the blood or synthetized de novo inside the ovary, rather of an inverted “U” shape. Therefore, both lowest and depending on the vascularization of the cell’s immediate highest levels of E2 correlate with impaired performance on environment. Theca cells convert cholesterol into androgens, hippocampus-dependent tasks.2 dehydroepiandrosterone (DHEA) and androstenedione, Even though no task is dependent purely on a single neural which are then taken up by the granulosa cells, containing system, there are tasks which predominantly activate hip- FSH-induced P-450 aromatase (P-450arom) enzyme, and pocampal or some other brain regions.2 Spatial memory is converted by it into estrone (E1), which is then converted one of the hippocampus-dependent cognitive functions,10 by 17β-hydroxysteroid dehydrogenase (17β-HSD) to a more and it can be divided into spatial working memory, which potent estrogen, E2, the primary circulating estrogen in involves trial-specific information and hence also recruits nonpregnant females. Alternatively, 17β-HSD can convert prefrontal cortex (PFC), and spatial reference memory.2 androstendione to testosterone, which the aromatase can The classic test for studying spatial learning and memory is

Figure 2. Structure of the hippocampus. Neurogenesis takes place in subgranular zone of dentate gyrus (DG). Estradiol (E2) increases spinal and synaptic density of Cornu Ammonis 1 (CA1) pyramidal cells. Source: Image “CajalHippocampus (modified)” by Santiago Ramón y Cajal (original) and Looie496 (derivative) – from Wikimedia Commons, public domain. Published 1911 (original) and April 19, 2008 (derivative). Accessed April 30, 2017.

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Psychiatry and Psychology Novak A. Menstrual cycle and cognitive functions. pp. 343 – 347 the Morris water maze task, in which the subject is placed inside a water-filled pool surrounded by high walls labeled with visual cues that serve as reference points. Using these visual cues, the subject must find a hidden platform that it can climb onto.11 Studies on rodents show that males outperform females in proestrous (high estradiol), but not in diestrous (low estradiol) on the standard Morris water maze task.12 Behavioral task studies reviewing the selection between a striatal-mediated response strategy and a hippocampal-dependent spatial strategy show differences in strategy preference through different menstrual cycle phases. To test this selection, a 4 on 8 virtual maze (4/8 VM) was created using a computer game and made to resemble the structure of a radial arm maze (Figure 3). At the end of each arm were stairs leading to a pit, with four of them containing an object, while the landscape surrounding the maze contained cues Figure 3. Radial arm maze. The structure was taken as a basis for 4/8 to be used as reference points. Every trial consisted of two virtual maze (4/8 VM), created using a computer game. parts. In Part 1, four arms were barred and the objects were Source: Image “Simple_Radial_Maze” by Mcole13~commonswiki – from placed in the pits at the end of the unbarred arms, whereas Wikimedia Commons. Available under the CC BY-SA 3.0 Unported license (https://creativecommons.org/licenses/by-sa/3.0/deed.en). in Part 2, all eight arms were unbarred and the objects were Published July 13, 2008. Accessed April 30, 2017. placed at the end of arms that had been blocked in the Part 1. In each trial, the pattern of unbarred and barred arms was different. After finishing the task, the participants were asked to explain how they solved it. If the used approach Performance is measured by the number of words recalled was based on counting or recognizing a specific pattern (i.e. after an interference trial and 30 min delay. Results revealed open, open, blocked arm), they were categorized as response that women tested during the preovulatory phase, when E2 learners, whereas if it was based on using surrounding land- levels are high, recalled considerably more words after each marks, without any counting or pattern identification, they of the five acquisition trials, after the interference trial, and were categorized as spatial learners.13 Women tested during after a 30 min delay than women tested in mid luteal and the early follicular and preovulatory phase predominantly early follicular phase. In addition, women tested during the used a response strategy, while women tested during mid or early follicular phase recalled significantly fewer words after late luteal phase mostly used spatial strategy. Furthermore, a 30 min delay, compared to women in mid luteal phase.15 women in preovulatory phase were even more likely to use In sum, these results suggest a positive correlation between a response strategy when compared to women in early fol- E2 levels and verbal working memory. licular phase. This indicates that women in the luteal phase, when P4 concentrations are high and E2 levels moderately high, are more likely to use a more cognitively demanding ESTRADIOL (E2) AND DOPAMINE (DA) spatial strategy, whereas women in follicular phase are more likely to use a response strategy.14 As reviewed before, in animals, E2 increases the number of dopaminergic projections to the PFC and could thus influence The fact that highest E2 levels, achieved in the preovulatory working memory, a PFC-dependent function that is highly phase, are not associated with preferential hippocampus-de- reliant on DA signaling.5,16,17 However, it is important to pendent spatial strategy selection, even though E2 has been note that the relationship between PFC function and DA also shown to increase hippocampal synaptic density, could be follows an inverted “U” shape, meaning that the maximal PFC explained by progesterone’s attenuating effect on E2-induced function is achieved with optimal DA levels.16,17 Furthermore, neurotrophic actions. In essence, some studies indicate that it has been suggested that taking the baseline DA into account an acute P4 injection after E2 treatment, antagonizes the is essential for understanding E2 effects on working mem- E2-induced increase in hippocampal spine density.15 ory. In essence, whether the E2 effects on PFC-dependent cognitive functions will be favorable or harmful depends on catechol-O-methyltransferase (COMT) genotype, such that OVARIAN STEROIDS AND THE PREFRONTAL E2 potentiated DA signaling in individuals with Val158Met CORTEX (PFC) genotype, and COMT enzymatic activity.17

The PFC is implicated in higher cognitive and emotional processes, such as short-term/working memory, including hippocampus-dependent spatial working memory. A standard verbal memory test is the Rey Auditory Verbal Learning Test (RAVLT). The participants are read a list of 15 words (List A) for five trials and then asked to recall as many words as they can, after which they are read a list of 15 different words (List B) and again asked to recall as many words as they can. After this interference trial, participants are asked to recall the words from the List A and again after a 30 min delay.

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CONCLUSION

Menstrual cycle hormones, namely estradiol and progesterone, impact cognitive function by modulating the preference between spatial and response strategy, depending on whether the woman is in the luteal or follicular phase, respectively. A lesser difference in response strategy selection between early and late follicular phase suggests that progesterone levels, rather than estradiol levels, determine the preference toward spatial strategy. Estradiol levels, on the other hand, correlate positively with performance in working memory test, possibly through their effects on dopamine signaling.

REFERENCES:

1. Halpern DF, LaMay ML. The Smarter Sex: A Critical Review of Sex Differences in Intelligence. Educ Psychol Rev. 2000;12(2):229- 246. doi:10.1023/A:1009027516424. 2. Hamson DK, Roes MM, Galea LAM. Sex Hormones and Cognition: Neuroendocrine Influences on Memory and Learning. Compr Physiol. 2016;6(3):1295-1337. doi:10.1002/cphy.c150031. 3. Toffoletto S, Lanzenberger R, Gingnell M, Sundström-Poromaa I, Comasco E. Emotional and cognitive functional imaging of estrogen and progesterone effects in the female human brain: A systematic review. Psychoneuroendocrinology. 2014;50:28- 52. doi:10.1016/j.psyneuen.2014.07.025. 4. Czoty PW, Riddick NV, Gage HD, et al. Effect of Menstrual Cycle Phase on Dopamine D2 Receptor Availability in Female Cynomolgus Monkeys. Neuropsychopharmacology. 2009;34(3):548-554. doi:10.1038/npp.2008.3. 5. Shansky RM, Lipps J. Stress-induced cognitive dysfunction: hormone-neurotransmitter interactions in the prefrontal cortex. Front Hum Neurosci. 2013;7:123. doi:10.3389/fnhum.2013.00123. 6. Nin MS, Ferri MK, Couto-Pereira NS, et al. The effect of intra-nucleus accumbens administration of allopregnanolone on δ and γ2 GABAA receptor subunit mRNA expression in the hippocampus and on depressive-like and grooming behaviors in rats. Pharmacol Biochem Behav. 2012;103(2):359-366. doi:10.1016/j.pbb.2012.09.002. 7. Boron WF, Boulpaep EL. The Female Reproductive System. In: Medical Physiology: A Cellular and Molecular Approach. Phil- adelphia, PA: Elsevier; 2017:1109-1129. 8. Duarte-Guterman P, Yagi S, Chow C, Galea LAM. Hippocampal learning, memory, and neurogenesis: Effects of sex and estrogens across the lifespan in adults. Horm Behav. 2015;74:37-52. doi:10.1016/j.yhbeh.2015.05.024. 9. Woolley CS. Estrogen-Mediated Structural and Functional Synaptic Plasticity in the Female Rat Hippocampus. Horm Behav. 1998;34(2):140-148. doi:10.1006/hbeh.1998.1466. 10. O’Keefe J, Nadel L. The Hippocampus as a Cognitive Map. Oxford, UK: Clarendon Press (Oxford University Press); 1978. 11. Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc. 2006;1(2):848-858. doi:10.1038/nprot.2006.116.Morris. 12. Frye CA. Estrus-associated decrements in a water maze task are limited to acquisition. Physiol Behav. 1995;57(1):5-14. doi:10.1016/0031-9384(94)00197-D. 13. Bohbot VD, Gupta M, Banner H, Dahmani L. Caudate nucleus-dependent response strategies in a virtual navigation task are associated with lower basal cortisol and impaired episodic memory. Neurobiol Learn Mem. 2011;96(2):173-180. doi:10.1016/j. nlm.2011.04.007. 14. Hussain D, Hanafi S, Konishi K, Brake WG, Bohbot VD. Modulation of spatial and response strategies by phase of the menstrual cycle in women tested in a virtual navigation task. Psychoneuroendocrinology. 2016;70:108-117. doi:10.1016/j.psyneuen.2016.05.008. 15. Tanapat P, Hastings NB, Gould E. Ovarian steroids influence cell proliferation in the dentate gyrus of the adult female rat in a dose- and time-dependent manner. J Comp Neurol. 2005;481(3):252-265. doi:10.1002/cne.20385. 16. Cai JX, Arnsten AFT. Dose-Dependent Effects of the Dopamine D1 Receptor Agonists A77636 or SKF81297 On Spatial Working Memory in Aged Monkeys. J Pharmacol Exp Ther. 1997;283(1):183-189. 17. Jacobs E, D’Esposito M. Estrogen shapes dopamine-dependent cognitive processes: Implications for women’s health. J Neurosci. 2011;31(14):5286-5293. doi:10.1523/JNEUROSCI.6394-10.2011.

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Psychiatry and Psychology Novak A. Menstrual cycle and cognitive functions. pp. 343 – 347

MENSTRUALNI CIKLUS I KOGNITIVNE FUNKCIJE

Sažetak

Menstrualni ciklus karakteriziraju promjene u serumskim koncentracijama glavnih spolnih hormo- na jajnika, estradiola i progesterona. Ako se kao prosječno trajanje ciklusa uzme period od 28 dana, koncentracija estradiola vrhunac doseže oko 12. dana cikusa, u kasnoj folikularnoj, odnosno preovu- latornoj fazi. Progesteron, s druge strane, postiže maksimalnu koncentraciju tijekom luteinske faze ciklusa. Studije na životinjama pokazale su da estradiol inducira neurogenezu i povećava gustoću dendritičkih trnova u hipokampusu te potencira učinak dopamina unutar prefrontalnog korteksa. Iako ženski spolni hormoni ne utječu na sveobuhvatnu sposobnost učenja, studije na ženama pokazale su kako ipak moduliraju određene kognitivne funkcije. Najizraženije jest preferiranje određenog tipa strategije u rješavanju virtualnog navigacijskog zadatka (4/8 virtualni labirint). Pokazalo se da žene u ranoj i kasnoj folikularnoj fazi češće biraju strategiju odgovora, dok se one u luteinskoj fazi koriste prostornom strategijom. Rezultati testiranja verbalne memorije pokazali su da su žene u kasnoj folikularnoj fazi ciklusa sposobne zapamtiti veći broj riječi tijekom prvih pet pokušaja, nakon interferencije i nakon vremenske odgode. Rezultati pokazuju da su visoke razine estradiola povezane s boljim ishodom na testovima koji ispituju radnu memoriju, što bi se dijelom moglo objasniti po- tencirajućim učincima estradiola na dopaminergičke signalne puteve unutar prefrontalnog korteksa.

Ključne riječi: estradiol, kognicija, progesteron, prostorna memorija, radna memorija

Received April 30, 2017. Accepted October 27, 2017.

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Psychiatry and Psychology Radić J. Bright light therapy (BLT) in Depression. pp. 348 – 354 BRIGHT LIGHT THERAPY (BLT) IN DEPRESSION

Jana Radić 0000-0001-6790-5929 University of Zagreb, Faculty of Humanities and Social Sciences, Department of Psychology

Abstract Depression is considered among the most prevalent of all mental health diagnoses. Besides pharmacotherapy and psychotherapy, extending the daily photoperiod with artificial bright light (bright light therapy – BLT) has been reported as being useful in treating mood disorders. The aim of this article is to analyze the available data in the literature and discuss the efficacy of BLT in both seasonal affective disorder (SAD) and non-seasonal major depressive disorder. We analyzed 20 studies covering the problems of efficacy of BLT versus placebo and antidepressants, its side-effects, predictive factors which suggest better therapeutic response, as well as unclarified questions. For SAD, data show well-established efficacy of BLT. Artificial light exposure consistently improves symptoms compared to placebo, with remission rates comparable to those seen for antidepressant medication. Regarding the predictive factors, morning treatment is shown to be superior to evening treatment, reflecting the hypothesis of phase-delayed circadian rhythms that underlie disordered mood. Also, atypical vegetative symptoms are shown to predict better therapeutic response. With high therapeutic benefits, and a favorable side-effect profile, it is considered as an appropriate alternative to antidepressants. On the other hand, data regarding the efficacy of BLT in non-seasonal depression show a high level of inconsistency. Although some studies confirm the therapeutic use of BLT in non-seasonal depression, meta-analyses express that the therapeutic benefits seem to be fleeting. Also, it is expressed that general quality of evidence seems to be poor, due to considerable methodological problems. To conclude, data from the literature support the efficacy of BLT in depression with seasonal pattern and recommend it as a first-line choice in this case. To evaluate BLT for non-seasonal depression more rigorous studies are necessary, with a focus on long-term-effects, larger groups, controlled group allocation, and adequate placebo treatment.

Keywords: bright light therapy (BLT), circadian rhythm, depressive disorder, seasonal affective disorder

INTRODUCTION

Depression is considered to be one of the most prevalent Moreover, it has been shown that exposure to light of the mental health diagnoses, affecting approximately 5% of the appropriate intensity and duration, at an appropriate time general population with lifetime prevalence estimated at of day, can have substantial positive effects on the affective 14%.1 Recent findings by Hidaka2 indicate rising prevalence and physical symptoms of a depressive illness.5 and an increased lifetime risk, referring to depression as a The development of bright light therapy (BLT) is related to the ‘disease of modernity’, which negatively affects quality of original description of seasonal affective disorder (SAD). In life and increases the risk of mortality. In the treatment of 1984, Dr Norman Rosenthal and colleagues5 described SAD, depression, both biological and psychological treatments a condition characterized by recurrent depressive episodes are applied, with the most common approaches including that occur in fall or winter and spontaneously remit during antidepressant drug therapy and psychotherapy. the following spring or summer seasons, with symptoms including depressed mood, profound lack of energy, hyper- When it comes to the etiology of depression, a wide range phagia with carbohydrate craving and weight gain. of theories proposed an association of disrupted biological Besides the lack of environmental light as a major cause of factors, as well as of environmental and personal vulnera- SAD, according to Rosenthal6 there are two other leading bilities with disordered mood.3 According to one biological causes: biological predisposition, and stress. People who theory, imbalance in circadian biological rhythms has been have a predisposition for developing SAD include those suggested to play a causal role in affective disorders.3,4 with family members with the condition, as well as other gyrus | vol. 4 | no. 3 – 4 | july – december 2017 348 sleep disorders

Psychiatry and Psychology Radić J. Bright light therapy (BLT) in Depression. pp. 348 – 354 forms of depression. Additionally, gender and age are also Another clinical trial14 administered BLT (10, 000 lux, 30 risk factors. It is shown that SAD occurs four times more minutes a day) over a 2–4 week period to patients with SAD in women than in men.7-9 It is also more prevalent among (N = 124, 99 female, 25 male, aged 18–59 years). Subjects were the young population with the age of onset estimated to be required to abstain from psychotropic medication, alcohol between 18 and 30 years.8,10 Regarding the stress factor, it and recreational drugs. Additional exclusion criteria were is shown that people with SAD are less capable of handling another Axis I disorder, suicidal attempt within past 3 years stress (such as having to get up early in the morning, meeting and habitual sleep onset later than 1 AM or awakening later deadlines, working long hours) during winter months than than 9 AM. Similar to Eastman’s results, it has been found that they are at other times of year.6 bright light was superior to placebo condition in producing clinical remissions. Also, morning light exposure has been In accordance with the lack of daily light as a main cause of shown to be superior to evening light exposure. the condition, studies consistently show increased prevalence of SAD at the more northern latitudes.7,8,11 For example, it is Regarding the importance of the particular daily treatment found that in the United States, the prevalence of SAD was schedule, research consistently confirms the superiority of 1.5% in Florida, in Alaska 9%, whereas in New Hampshire it morning exposure to bright light,15 as it produces significantly was almost 10.2%.8 higher remission rate (83%), than evening (53%) or midday (32%) exposure.16 In the study of Terman and colleagues,15 a Besides the explanation of the condition, in their initial re- high intensity fluorescent lighting system was tested under port Rosenthal and colleagues described the application of two random crossover protocols in winter-depressed patients bright light therapy for the treatment of SAD, showing that (N = 34, 26 female, 8 male): 30-minute sessions at (1) 3,000 lux extension of the daily photoperiod (by means of exposing a vs. 10,000 lux in early morning, and (1) morning vs. evening patient to artificial light) had an antidepressant effect. The sessions at 10,000 lux. Exclusion criteria were presence of preliminary findings sparked an interest in both clinicians other Axis I disorders, current treatment with psychotropic and the scientific community. This resulted in a considerable medications, recent history of suicide attempt, panic disor- number of studies on bright light therapy (BLT) for depression der unrelated to depression, skin cancer, cataract glaucoma, conducted since then. The main purpose of this article is to retinal pathology, current treatment with beta-adrenergic integrate findings of empirical studies that concentrated blockers and extreme delayed sleep phase disorder. After on the efficacy of BLT in the treatment of SAD, as well as in 10 to 14 days of each experimental condition, patients were non-seasonal depressive disorder. evaluated by a blind rater. An overall remission rate of 75% was found for morning light at 10,000 lux. The rates for evening light (25%) and 3,000 lux morning light (19%) were BRIGHT LIGHT THERAPY IN significantly lower. SEASONAL AFFECTIVE DISORDER Well-established therapeutic benefits of morning light expo- 1. Hypothalamic-pituitary-gonadal axis sure reflect the hypothesis of circadian rhythm misbalance as a causal factor of depression. Although the mechanism The reproductive period of a woman, from menarche to men- of action of light therapy is not yet completely understood, opause, is filled with repetitive monthly cycles – menstrual according to Lewy et al.3 the circadian rhythms of people cycles, lasting, on average, 28 days. These cycles encompass with winter depression are seen as phase delayed, with late cyclic changes in two organs, the ovaries and endometrium, onset of melatonin secretion – a pattern that can poten- which are known as an ovarian and endometrial cycles, tially be corrected with morning light exposure. Following respectively. These monthly cycles are driven by the hypo- this, it is suggested that the antidepressant effect of light thalamic-pituitary-gonadal axis. Hypothalamic gonado- is induced by phase-advance resetting of the internal clock tropin-releasing hormone (GnRH) neurons are located in to morning light.4 the nucleus arcuatus (ARC) and preoptic area (POA), with those in the ARC generating an “hourly” rhythm, with pulses When it comes to the comparison of light therapy with an- spaced 60 to 90 minutes apart, and those in POA generating a tidepressant drugs, Ruhrmann and colleagues17 conducted monthly rhythm of GnRH secretion, with a massive increase a randomized, parallel design trial, with patients and rater at mid-cycle responsible for a luteinizing hormone (LH) blind to treatment conditions. One week of placebo (phase I) peak.7 Released GnRH is transported by the portal vessels was followed by 5 weeks of treatment (phase II) with fluox- to the anterior pituitary, where it stimulates the synthesis etine (20 mg per day) and a placebo light condition versus of gonadotropins, follicle-stimulating hormone (FSH) and bright light (3000 lux, 2 hours per day) and a placebo drug. luteinizing hormone (LH) from the gonadotrophs. FSH stim- There were 42 patients (33 female, 9 male; age between 18 and ulates folliculogenesis in the first phase of the ovarian cycle, 65 years) suffering from seasonal affective disorder (SAD). which is hence termed the follicular phase. LH, on the other Exclusion criteria were serious suicidal risk, concurrent hand, reaching its peak around day 14 of the cycle, triggers clinically significant medical illness which is not stabilized, ovulation and luteinization of granulosa and theca interna eye diseases, organic brain disease, history of psychosis cells, which then form the corpus luteum. At the moment and drug/alcohol abuse within the past 6 months, and use of ovulation, the ovarian cycle has entered its final, luteal of MAOIs, anticonvulsants and neuroleptics within 2 weeks. phase (Figure 1).7 At the beginning of the placebo week, 26 patients had been free of psychotropic medication for more than 6 months. The other 16 patients were equally distributed among both treatment groups.

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Psychiatry and Psychology Radić J. Bright light therapy (BLT) in Depression. pp. 348 – 354

Figure 1. Bright light therapy lamp. Source: Photo “Bright light lamp” by Mysid – from Wikimedia Commons, public domain. https://commons.wikimedia.org/w/index.php?curid=1626229. Published February 2, 2007. Accessed May 1, 2017.

contrary to the previous study. Patients showed steady im- Results suggested that light therapy and pharmacotherapy provement during the course of 8 weeks, which is a pattern are comparably effective treatments for patients with SAD, more similar to a medication effect. with no differences in final depression scores and clinical response. Yet, it has been showed that the light treatment Systematic reviews generally support the efficacy of light has a slightly faster appearance of benefits. therapy.19,20 According to a meta-analysis by Golden and colleagues,19 BLT is an efficacious treatment of SAD, with effect In the recent controlled study trial by Raymond and col- sizes comparable to those found in many antidepressant trials. leagues,18 96 patients (32 male, 64 female; 18–65 years old) However, it has also been argued that the most trials on the who had major depressive episodes with seasonal (winter) effects of BLT have considerable methodological limitations, pattern were randomly assigned to 8 weeks of double-blind including brief treatment periods with restriction to the treatment with either: 1) exposure to 10,000 lux light treatment short-term effects, small sample sizes, inadequate placebo and a placebo capsule; or 2) 100 lux light treatment (placebo) conditions, difficulties with ‘blinding’ the subject regarding and fluoxetine, 20 mg/day. Subjects were excluded from the experimental intervention and the subject’s anticipation of study if they used other psychotropic drugs including lith- an improvement with bright light. Since these factors limit ium, L-tryptophan or melatonin, were currently using beta the conclusions that can be drawn from BLT, future studies blocking drugs, had used antidepressants or mood-altering with improved design are needed. Despite methodological medications within 7 days of baseline, had been treated drawbacks, research consistently favors its application in previously with fluoxetine and/or BLT. treating depression with seasonal pattern. What is more, according to Martensson and colleagues,20 BLT is recom- The results showed that there were no differences in outcomes mended as a first-line treatment for SAD. for patients with SAD who received active light treatment and those who received fluoxetine. Benefits of light treatment However, a significant number of non-responders and partial were apparent in both interviewer-rated and patient-rated responders still remains,16 so predictive factors of antidepres- outcome scales and in the typical and atypical symptom sant outcome of BLT should be identified. Generally, there is subscales. However, the response to light therapy in this considerable evidence that features associated with a good trial was not significantly faster than fluoxetine response, response to light therapy mainly include atypical neurovege- gyrus | vol. 4 | no. 3 – 4 | july – december 2017 350 sleep disorders

Psychiatry and Psychology Radić J. Bright light therapy (BLT) in Depression. pp. 348 – 354 tative symptoms.21,22 Nagayama and colleagues21 administered period of one week is too short to make clear conclusions. phototherapy to 24 patients (16 female, 8 male) with SAD of Another trial of patients (N = 32, 24 female, 8 male; ages which 62% showed improvements of 25–50%, based on the 22–65) with chronic recurrent major depressive disorder Hamilton rating scale for depression for SAD (HAMSAD). (MDD) included a different type of exposure (10,000 lux, 1hour a day) and longer treatment duration (5 weeks).24 Although the improvement rate in HAMSAD correlated signif- Subjects were excluded if they had seasonal pattern of disease, icantly with the pretreatment severity of atypical symptoms had another Axis I disorder (i.e. all psychological disorders of depression, such as increased appetite with carbohydrate except mental retardation and personality disorders), had craving, winter weight gain and hypersomnia, it did not a recent history of suicide attempt, habitual waking after correlate with that of typical symptoms. This suggests that 9 AM or bedtime after 1 AM, and past treatment with light phototherapy is a useful treatment in SAD and that respon- or ions. It was found that BLT produced clinical remission siveness to phototherapy in SAD can possibly be predicted by (SIGH-SAD score improvement) in 53.7% of chronically de- the atypical depressive symptoms before treatment. pressed patients, which is similar to remission rates for SAD,14 According to Thompson,22 whenever those typical winter while there were no remissions under placebo conditions symptoms predominate, it is more likely that light therapy (low-density ions). Contrary to Yamada et al.,23 the results would be beneficial and should be the treatment of first choice. support previous findings regarding SAD, suggesting that On the other hand, when patients describe non-seasonal morning presentation of bright light is superior to evening recurrences, antidepressants should be advised. exposure. However, the presence of atypical neurovegetative symptoms did not presage success for patients with chronic When it comes to the side effects of artificial light exposure, depression, which is inconsistent to findings regarding the a comprehensive analysis by Terman16 has been performed. response predictors identified for SAD.21,22 Besides infrequent headaches, nausea and irritability, mild visual complaints have been reported, including blurred vi- A recent study25 included a comparison of BLT effects with sion, eyestrain and spot-seeing. Also, cases of light-induced an antidepressant (fluoxetine) and with the combination agitation and hypomania have been noted. According to of both treatments in patients with non-seasonal MDD. Terman, the side effect profile is considered advantageous in Participants were 122 patients (76 female, 56 male, aged 19 comparison to pharmacotherapy, with no contraindications to 60 years), who were psychotropic drug-free for at least for BLT besides retinopathy.16 2 weeks prior to the baseline visit. Patients were excluded due to treatment resistance during the current episode Despite methodological limitations of many studies, there or for using other concurrent treatments for depression, is a firm basis for the conclusion that BLT is an efficacious including psychotherapy. They were randomly allocated treatment for seasonal affective disorders. With well-es- to one of the 4 treatment conditions: 1) light monotherapy tablished therapeutic benefits and a favorable side-effect using a fluorescent light box plus placebo pill, 2) fluoxetine profile, it should be considered as a treatment of first choice monotherapy using an inactive ion generator, 3) placebo in therapy of SAD. treatment with an inactive ion generator plus placebo pill, 4) combined treatment using a light box plus fluoxetine. The main result is that both light monotherapy and the BRIGHT LIGHT THERAPY IN TREATING combination treatment had significant benefits compared to NONSEASONAL DEPRESSION placebo condition. The benefits of the combination treatment were apparent in both interviewer-rated and patient-rated Beyond its established application for recurrent annual outcomes. Also, there was steady improvement with both depressive episodes, recent studies go beyond the treatment light conditions throughout the 8 weeks. Those results are of SAD, and discuss the utility of artificial light exposure in similar to those from a previous study,26 which found that non-seasonal depression treatment. sertraline hydrochloride (50 mg/day) combined with bright The study of Yamada et al.23 showed that BLT significantly light (10,000 lux, for 1 hour/day) was superior to sertraline reduced the severity of depression in patients with non-sea- combined with placebo dim light. sonal depression (measured by Hamilton Rating Scale for Depression). Light therapy was given to 27 patients with Generally, systematic reviews have yielded equivocal and non-seasonal depression (17 female, 10 male), who did not conflicting evidence for the efficacy of BLT in non-seasonal receive any medication during the course of the study and depression. A review by Tunnainen27 confirms the therapeutic 16 control volunteers, without history of mental illness. use of bright light boxes for non-seasonal depression, with Exclusion criteria included acute suicidal tendencies. Also, benefit being modest, but promising. On the other hand, no subject included in the study showed any pathological some meta-analyses suggest that treatment with bright signs upon medical and neurological examination, including light showed effects on depression score, but followed over routine laboratory tests. time, they seem to be of a transient nature.20,28 Also, they point out that the overall evidence for the efficacy of BLT Patients exposed to a light box (2,500 lux, 2 hours a day) ob- in non-seasonal depression is poor due to limited data and tained a benefit of 24% over the patients exposed to dim light, heterogeneity of studies (differences in treatment design, after 1 week of treatment. Contrary to previous findings, the timing duration, intensity and spectrum of light, and sever- therapeutic effect of bright light did not depend on the time ity of depression). Following this, there is no clear rationale of day, with both evening and morning exposure to bright for using BLT as a monotherapy in treating non-seasonal light being sufficient for therapeutic effect. However, these depression. However, a considerable number of studies results should be considered with caution, since the treatment demonstrated that BLT may be helpful as adjuvant therapy

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for antidepressant medication, which can further enhance clinical response.27,28 Thus, for now it should be considered CONCLUSION as an optional and additional treatment. The analysis of literature shows that BLT is generally Although a considerable number of studies provide evidence considered to be effective and is recommended as in favor of the efficacy of BLT in non-seasonal MDD, the a first-line treatment when it comes to depression conclusion that BLT as a stand-alone treatment improves with seasonal pattern (SAD). Morning light treat- depressive symptoms in non-seasonal depression remains ments consistently produce a significantly higher controversial. Contrary to SAD, in non-seasonal depression antidepressant response compared to evening treat- there is no consensus as to the optimal time of the treatment, ments, which suggests that the mechanism by which with some studies suggesting that morning administration bright light is capable of ameliorating the symp- is likely to benefit in the treatment,16,24 while others show toms in patients with SAD lays in phase-advance that morning exposure showed no difference in therapeutic resetting of disordered circadian rhythms. Factors response.23 that have been found to predictably correlate with better antidepressant outcomes include atypical According to Terman,16 it is possible that treatment param- neurovegetative symptoms. eters such as longer daily exposure duration, higher light In contrast to the well-established benefits for SAD, intensity, and longer course of treatment are needed to en- when it comes to non-seasonal depression, the hance light response in non-seasonal depression. Additional evidence seems to be equivocal, with some studies randomized, controlled trials with appropriate numbers of confirming its therapeutic use, while others express subjects and longer treatment duration are needed. Also, the doubts. Based on the analyzed literature, BLT is studies should focus on specific subgroups of patients with for now considered to be appropriate as a potent MDD who respond to light therapy, as well as the timing and adjunct to an antidepressant treatment, but there length of light exposure needed to provide therapeutic benefits. is still no clear evidence for its use as an alternative to pharmacotherapy in treating non-seasonal depression. In addition to the efficacy of light therapy for non-seasonal depression, several issues such as timing and length of light treatment, as well as factors which predict better therapeutic response, are not yet fully understood. Regarding this, future well-designed studies are needed.

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1. Warraich P, Goldner EM, Somers JM, Hsu L. Prevalence and incidence studies of mood disorders: a systematic review of the literature. Can J Psychiatry. 2004;49(2):124-38. doi:10.1177/070674370404900208. 2. Hidaka BH. Depression as a disease of modernity: explanations for increasing prevalence. J Affect Disord. 2012;140(3):205-14. doi: 10.1016/j.jad.2011.12.036. 3. Lewy AJ, Sack RL, Miller S, Hoban TH. Antidepressant and Circadian Phase-Shifting Effects of Light. Science. 1987;235(4786):352- 354. doi:10.1126/science.3798117. 4. McClung CA. Circadian rhythms and mood regulation: Insights from pre-clinical models. Eur Neuropsychopharmacol. 2011;21(Suppl 4):S683-S693. doi:10.1016/j.euroneuro.2011.07.008. 5. Rosenthal NE, Sack DA, Gillin JC, et al. Seasonal affective disorder: A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry. 1984;41(1):72-80. doi:10.1001/archpsyc.1984.01790120076010. 6. Rosenthal NE. What is seasonal affective disorder? Answers from the doctor who first described the condition. Norman Rosenthal Website. http://www.normanrosenthal.com/seasonal-affective-disorder/. Accessed August 11, 2017. 7. Magnusson A. An overview of epidemiological studies on seasonal affective disorder. Acta Psychiatr Scand. 2000;101(3):176- 84. doi:10.1034/j.1600-0447.2000.101003176.x. 8. Melrose S. Seasonal Affective Disorder: An Overview of Assessment and Treatment Approaches. Depress Res Treat. 2015;2015:178564. doi:10.1155/2015/178564. 9. Eagles JM. Seasonal affective disorder. Br J Psychiatry. 2003;182(2):174-176. doi:10.1192/bjp.182.2.174. 10. Swedo SE, Pleeter JD, Richter DM, et al. Rates of seasonal affective disorder in children and adolescents. Am J Psychiatry. 1995;152(7):1016-1019. doi:10.1176/ajp.152.7.1016. 11. Rosen LN, Targum SD, Terman M, et al. Prevalence of seasonal affective disorder at four latitudes. Psychiatry Res. 1990;31(2):131- 144. doi:10.1016/0165-1781(90)90116-M. 12. Westrin Å, Lam RW. Seasonal Affective Disorder: A Clinical Update. Ann Clin Psychiatry. 2007;19(4):239-246. doi:10.1080/10401230701653476. 13. Eastman CI, Young MA, Fogg LF, Liu L, Meaden PM. Bright Light Treatment of Winter Depression. Arch Gen Psychiatry. 1998;55(10):883-889. doi:10.1001/archpsyc.55.10.883.

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14. Terman M, Terman JS, Ross DC. A Controlled Trial of Timed Bright Light and Negative Air Ionization for Treatment of Winter Depression. Arch Gen Psychiatry. 1998;55(10):875-882. doi:10.1001/archpsyc.55.10.875. 15. Terman JS, Terman M, Schlager D, et al. Efficacy of brief, intense light exposure for treatment of winter depression. Psy- chopharmacol Bull. 1990;26(1):3-11. 16. Terman M, Terman JS. Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and side effects. CNS Spectr. 2005;10(8):647-663. doi:10.1017/S1092852900019611. 17. Ruhrmann S, Kasper S, Hawellek B, et al. Effects of flouxetine versus bright light in the treatment of seasonal affective disorder. Psychol Med. 1998;28(4):923-933. doi:10.1017/S0033291798006813. 18. Lam RW, Levitt AJ, Levitan RD, et al. The Can-SAD Study: A Randomized Controlled Trial of the Effectiveness of Light Ther- apy and Fluoxetine in Patients With Winter Seasonal Affective Disorder. Am J Psychiatry. 2006;163(5):805-812. doi:10.1176/ ajp.2006.163.5.805. 19. Golden RN, Gaynes BN, Ekstrom RD, et al. The Efficacy of Light Therapy in the Treatment of Mood Disorders: A Review and Meta-Analysis of the Evidence. Am J Psychiatry. 2005;162(4):656-662. doi:10.1176/appi.ajp.162.4.656. 20. Mårtensson B, Pettersson A, Berglund L, Ekselius L. Bright white light therapy in depression: A critical review of the evidence. J Affect Disord. 2015;182:1-7. doi:10.1016/j.jad.2015.04.013. 21. Nagayama H, Sasaki M, Ichii S, et al. Atypical depressive symptoms possibly predict responsiveness to phototherapy in seasonal affective disorder. J Affect Disord. 1991;23(4):185-189. doi:10.1016/0165-0327(91)90099-E. 22. Thompson C. Evidence-based treatment. In: Partonen T, Magnusson A, eds. Seasonal Affective Disorder: Practice and Research. Oxford: Oxford University Press; 2001:151-158. 23. Yamada N, Martin-Iverson MT, Daimon K, Tsujimoto T, Takahashi S. Clinical and chronobiological effects of light therapy on nonseasonal affective disorders. Biol Psychiatry. 1995;37(12):866-873. doi:10.1016/0006-3223(94)00221-N. 24. Goel N, Terman M, Terman JS, Macchi MM, Stewart JW. Controlled trial of bright light and negative air ions for chronic depression. Psychol Med. 2005;35(7):945-955. doi:10.1017/S0033291705005027. 25. Lam RW, Levitt AJ, Levitan RD, et al. Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With Nonseasonal Major Depressive Disorder. JAMA Psychiatry. 2016;73(1):56-63. doi:10.1001/jamapsychiatry.2015.2235. 26. Martiny K, Lunde M, Unden M, Dam H, Bech P. Adjunctive bright light in non-seasonal major depression: results from clinician-rated depression scales. Acta Psychiatr Scand. 2005;112(2):117-125. doi:10.1111/j.1600-0447.2005.00574.x. 27. Tuunainen A, Kripke DF, Endo T. Light therapy for non-seasonal depression. Cochrane Database Syst Rev. 2004;(2):CD004050. doi:10.1002/14651858.CD004050.pub2. 28. Even C, Schröder CM, Friedman S, Rouillon F. Efficacy of light therapy in nonseasonal depression: A systematic review. J Affect Disord. 2008;108(1-2):11-23. doi:10.1016/j.jad.2007.09.008.

PRIMJENA TERAPIJE JARKIM SVJETLOM U LIJEČENJU DEPRESIJE

Sažetak

Depresija je jedan od najučestalijih psihijatrijskih poremećaja. Osim farmakoterapije i psihoterapije, kao korisnom terapijom u depresiji pokazalo se produljivanje dnevnog foto-perioda izlaganjem um- jetnom svjetlu, tzv. terapija jarkim svjetlom (engl. bright light therapy, BLT). Cilj ovog rada bio je ana- lizirati dostupne podatke iz literature vezane uz učinkovitost terapije jarkim svjetlom u sezonskom afektivnom poremećaju i velikom depresivnom poremećaju. Analizirali smo 20 istraživanja koja su ispitivala učinkovitost terapije jarkim svjetlom u odnosu na placebo i antidepresive, nuspojave terapije te faktore predviđanja boljeg terapijskog odgovora. Što se tiče sezonskog afektivnog poremećaja, analizirani podaci sugeriraju čvrsto utemeljenu učinko- vitost terapije jarkim svjetlom. Istraživanja konzistentno pokazuju da izlaganje svjetlosnoj kutiji značajno ublažava simptome depresije u odnosu na placebo, uz stope remisije usporedive onima koje prate terapiju antidepresivima. Što se tiče prediktivnih faktora, jutarnji tretman pokazao se značajno učinkovitijim nego večernji, što odražava hipotezu o odgođenim cirkadijanim ritmovima u podlozi poremećaja raspoloženja. Također, prisutnost atipičnih vegetativnih simptoma pokazala se prediktivnom za bolji terapijski odgovor. S visokom razinom terapijskih prednosti te povoljnim profilom nuspojava, terapija jarkim svjetlom smatra se prikladnom alternativom farmakoterapiji u liječenju sezonskog afektivnog poremećaja.

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Psychiatry and Psychology Radić J. Bright light therapy (BLT) in Depression. pp. 348 – 354

Što se tiče učinkovitosti terapije jarkim svjetlom depresije bez sezonskog obrasca, podaci su nekonzis- tentni. Iako neka istraživanja govore u prilog njenoj terapijskoj učinkovitosti, meta-analize sugeriraju da su terapijski učinci u ovom slučaju prolazni. Također, značajne su kritike usmjerene na metodološ- ka ograničenja brojnih studija, što za sad ograničava donošenje zaključaka vezanih uz učinkovitost terapije svjetlom u tretmanu velike depresije. Zaključno, podaci iz literature podržavaju učinkovitost terapije jarkim svjetlom u sezonskom afektivnom poremećaju, pri čemu se ona preporuča kao prvi izbor tretmana. U slučaju depresije bez sezonskog obrasca, podaci iz literature nisu jednoznačni. U tom kontekstu nužna su buduća istraživanja koja bi uključila veće uzorke, bolju kontrolu svrstavanja sudionika u tretmanske grupe, prikladan placebo tretman te usmjerenost na dugoročne efekte tretmana.

Ključne riječi: cirkadijani ritam, depresivni poremećaj, sezonski afektivni poremećaj, terapija jarkim svjetlom (BLT)

Received May 1, 2017. Accepted August 13, 2017.

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Neurosurgery Junaković A. Pediatric hydrocephalus: causes, symptoms and treatment modalities. pp. 355 – 360 PEDIATRIC HYDROCEPHA- LUS: CAUSES, SYMPTOMS AND TREATMENT MODALITIES Alisa Junaković 0000-0002-6505-5075 University of Zagreb, School of Medicine

Keywords: cerebrospinal fluid (CSF), endoscopic ventriculostomy, intracranial pressure, neurosurgery, pediatric hydrocephalus, ventriculoatrial shunt, ventriculoperitoneal shunt

INTRODUCTION functional impairment of arachnoid Pacchioni’s granulations, but impaired reabsorption usually emerges due to meningitis Hydrocephalus can be defined as an abnormal increase in the or subarachnoid hemorrhage.3 amount of cerebrospinal fluid (CSF) within the ventricles of the brain.1 It involves dilatation of the cerebral ventricular system as well as corresponding compressive effects on the CLINICAL PRESENTATION OF HYDROCEPHALUS parenchyma.2 It can be divided into two main types – obstructive and communicating. If the main cause is the obstruction Clinical features of hydrocephalus depend on the patient’s of the outflow of CSF, usually in the cerebral aqueduct (also age, causes of hydrocephalus, rapidity of onset, and site of known as aqueduct of Sylvius) or foramina Luschka and obstruction if the type is obstructive hydrocephalus. The Magendie (where CSF can exit from the brain ventricles to the usual physical manifestation in infants is head enlargement subarachnoid space), it is called obstructive hydrocephalus. because of the excess CSF and enlarged ventricles. Head en- Communicating (non-obstructive) hydrocephalus can occur largement is defined as a head circumference above the 98th due to impaired CSF reabsorption which can be caused by percentile for the infant’s age. The patient usually presents

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Neurosurgery Junaković A. Pediatric hydrocephalus: causes, symptoms and treatment modalities. pp. 355 – 360 with increased irritability, vomiting, and poor feeding. They ETIOLOGY OF HYDROCEPHALUS can also have headaches due to skull rigidity. If we were to perform a physical examination, we would be able to pal- Hydrocephalus can be congenital (recognized at birth) or pate disjunction of the skull sutures and we would be able acquired during the lifetime. The incidence of congenital to see dilated and prominent scalp veins. The patient will hydrocephalus is about 0.2–0.5/1000 live births, with a higher also present with a bulging and tense anterior fontanelle on incidence reported in elderly primiparous mothers.2 One of the top of the head. Due to increased intracranial pressure the important congenital causes of hydrocephalus in children (ICP), the eyes will deviate downward and the infant will is a type of brainstem malformation, aqueductal stenosis present with persistent downward gaze, the upper eyelids (stenosis of mesencephalic aqueduct of Sylvius), which is can be retracted and upward gaze is completely paralyzed – responsible for about 10 % of cases in newborns. Some other this is called a setting-sun sign and it is an ophthalmologic congenital syndromes that may lead to hydrocephalus are sign of hydrocephalus, but it can also be benign in healthy Dandy-Walker malformation and Arnold-Chiari malformation infants and represent immaturity of the reflex systems that type 1 and type 2. Dandy-Walker malformation is primarily control eye movements. Hydrocephalus can easily stretch the described as cerebellar hypoplasia, dilatation of the fourth periventricular pyramidal tract fibers and cause spasticity ventricle and enlarged posterior fossa where macrocephaly of the lower limbs. is the most frequent manifestation. Arnold-Chiari mal- In children, if the ICP is increased due to hydrocephalus, a very formation is a developmental defect that usually involves dangerous physical manifestation may be papilledema, optic the cerebellum. Type I is defined as the protrusion of the disc swelling secondary to elevated ICP, which often presents cerebellum into the foramen magnum, while type II (classic as blurry vision. If papilledema is not treated well it can lead Chiari malformation) is often combined with spina bifida to optic atrophy and vision loss, so it is a medical emergency. in newborns and consists of a protrusion of the cerebellum Like infants, children may also experience a sun-setting phe- and part of the brain stem through the foramen magnum. nomenon or failure of the upward gaze. It appears secondary Agenesis of the foramen Monroi, which is a communication to high pressure on the tectal plate through the suprapineal between lateral ventricles of the brain can lead to congenital recess. One more clinical sign that is important in diagnosing hydrocephalus because CSF cannot circulate through the hydrocephalus is called the Macewen sign and it is usually ventricles as it normally does. described as a „cracked pot“ sound due to percussion of the head near the junction of the frontal, temporal and parietal On the other hand, hydrocephalus can develop after birth bone. If the test is positive, it indicates separated sutures and then it is defined as acquired. It can develop due to which is a common finding in hydrocephalus. Patients may overproduction, poor absorption, or obstruction of the present with an unsteady gait which is related to lower limb outflow of CSF. Choroid plexus papillomas and carcinomas spasticity. Children’s heads will be unusually large, but with can secrete excess CSF and rarely lead to hydrocephalus closed sutures, unlike infants. If ICP is chronically elevated, due to CSF overproduction. The most common reasons for it can lead to progressive macrocephaly and, secondary to obstruction in the brain ventricles or between ventricles increased ICP, unilateral or bilateral sixth cranial nerve palsy and subarachnoid space are brain tumors (such as ependy- may occur and it usually presents as double vision (diplopia). momas that are located in the ventricles and develop from Some additional symptoms in children are stunted growth the ependymal tissue or medulloblastomas), hematomas, or and sexual maturation because of the third ventricle dilation intraventricular hemorrhage that can occur in prematurely and it can lead to precocious puberty or obesity. Dilation born babies or due to vascular malformations in the brain of the third ventricle may also lead to Parinaud syndrome that lead to a predisposition to bleed heavily. Subarachnoid which manifests as an inability to move eyes upwards and hemorrhage (SAH) can block reabsorption of CSF in the sub- downwards. If a patient suffers from neck pain, it can be a arachnoid space leading to excess CSF in the brain ventricles. sign of a tonsillar herniation. Similarly to children, adults SAH is a very common reason for hydrocephalus in adults, suffering from hydrocephalus may present with papilledema, including tumors and head injury.1 Intramedullary tumors the inabililty to move the eyeballs upwards and impaired eye commonly present as hydrocephalus and other nonspecific accommodation, truncal and limb ataxia, an enlarged head symptoms, which can lead to a delayed diagnosis in children. which is very common, and palsy of the sixth cranial nerve Although rare, hydrocephalus may be an initial manifestation may occur and present with horizontal diplopia. NPH, or of spinal cord tumors.5 normal pressure hydrocephalus, has diverse symptoms and often occurs in the elderly, which means that we can rarely Infections, especially bacterial meningitis, can induce de- see NPH in patients younger than 60 years old. The triad velopment of hydrocephalus. Also, hypervitaminosis A can of symptoms, also known as Hakim’s triad, is defined by be an iatrogenic cause because it increases production of incontinence, gait apraxia which gets worse with time, and cerebrospinal fluid and it can also increase the permeability dementia. Parkinsonism and personality changes may also of the blood-brain barrier and in that way lead to hydroceph- occur.1,3 Another, albeit rare, complication of hydrocephalus alus. It can also lead to increased ICP.1 is sensorineural hearing loss. Jamshidi et al. have reported a case of a 10-month old infant presenting with a bilateral sensorineural hearing loss of moderate severity, diagnosed IMAGING TECHNIQUES IN DIAGNOSING after failing newborn hearing screening. Subsequent imaging HYDROCEPHALUS demonstrated obstructive hydrocephalus, which was treated by inserting a ventriculoperitoneal (VP) shunt. Afterwards, the The most commonly used imaging techniques for diagno- patient had immediate improvement of her hearing, which sis of hydrocephalus are CT and MRI.1 CT (computerized indicates hydrocephalus was the cause of this condition.4 tomography) is a form of X-ray examination where a higher gyrus | vol. 4 | no. 3 – 4 | july – december 2017 356 sleep disorders

Neurosurgery Junaković A. Pediatric hydrocephalus: causes, symptoms and treatment modalities. pp. 355 – 360 radiation dose is received than with some other conventional X-ray techniques.6 It is very useful for measuring the size of the ventricles of the brain and planning the surgery. When CT with contrast is used, tumors or infections that cause obstruction can easily be visualized.1 MRI (magnetic resonance imaging) is one of the diagnostic imaging techniques whose major advantage over CT is the lack of X-rays which reduces exposure to ionizing radiation and reduces the risk of overexposure to radiation.6 MRI is very useful for evaluating Chiari malformation or cerebellar tumors and it provides better imaging of the posterior cranial fossa than CT. In general, a CT scan is used to visualize bone injuries, to diagnose lung diseases and to detect tumor masses, while an MRI is suited for examining soft tissues (tendons and ligaments), brain tumors or spinal cord injuries. An MRI is an examination that takes more time than a CT scan which is usually done in only 5 minutes, so a CT is used more often Figure 1. Mickey mouse sign seen on a CT scan, ballooning of the fron- in an Emergency Room. An MRI, on the other hand, can tal horns of the lateral ventricles and dilatation of the third ventricle. take up to half an hour. Also, CT will give us more details Source: Mohamed M.A. Zaitoun. Diagnostic Imaging of Hydrocephalus & Pneumocephalus [PowerPoint Presentation]. in bony structures, while MRI gives higher detail in soft https://www.slideshare.net/meshmesh2013/diagnostic-imaging-of-hydroceph - tissue. Another advantage of MRI is its ability to change alus-pneumocephalus. Published December 29, 2015. the imaging plane without moving the patient. If we have Accessed August 4, 2017. to detect a tumor mass, MRI would be a superior choice, but CT is faster, less expensive and the person is rarely sedated during scanning.7 Some of the CT/MRI criteria for acute hydrocephalus include some of these findings: upward bowing of the corpus callosum which we are able to see on sagittal MRI and it is an indicator of acute hydrocephalus, ballooning of the frontal horns of the lateral ventricles and ballooning of the third ventricle (often called “Mickey mouse” ventricle) – it may indicate aqueductal stenosis. Normally, temporal horns of the lateral ventricles are barely visible, but in case of hydrocephalus, they are clearly visible and usually bigger than 2 mm. CT/MRI criteria for evaluating chronic hydrocephalus include; atrophy of the corpus callosum between two brain hemispheres, erosion of the sella turcica, sometimes herniation of the third ventricle in the sella turcica, and the temporal horns of the lateral ventricles may be visible but are less prominent than in acute phase. Also, macrocrania is one of the findings in the chronic phase.1 Another imaging method that is used for diagnostics in infants is ultrasonography through the anterior fontanelle for evaluating intraventricular or subependymal hemorrhage. Neonatal cranial ultrasound is used in neonatal intensive care units. One of the novel imaging techniques is DTI – diffusion tensor imaging, which allows recognition of some microstructural defects in the periventricular white matter Figure 2. Obstructive hydrocephalus seen on a CT scan, dilation of the which is edematous in the acute phase (edema may be present lateral ventricles. Obstructive hydrocephalus. 1 Case courtesy of Dr. Paul Simkin, rID 30453, as a histological finding). Radiopaedia.org. Cerebral angiography is not often used, except in cases of major venous anomalies or vein of Galen malformations. Cerebral arteries are visualized as hyperplastic, occluded TREATMENT MODALITIES OF HYDROCEPHALUS and elongated on angiograms.2 If a seizure occurs, the patient may be sent for an EEG to check Hydrocephalus can be treated either with medications or the electrical activity of the brain. No specific blood tests are surgery. Most patients are treated surgically and shunts needed to diagnose hydrocephalus. Sometimes, CSF evalua- are performed. A shunt provides an alternative CSF path- tion is helpful in posthemorrhagic and postmeningitic hydro- way as a bypass between the brain and a drainage cavity. cephalus and lumbar puncture (LP) can be used for measuring In that way, CSF can bypass the obstruction in the brain intracranial pressure. If X-linked hydrocephalus is considered ventricles. A shunt usually serves as a communication be- as a potential diagnosis, genetic testing is recommended. tween brain ventricles (or spinal canal) and a drainage cavity It develops when there is a mutation in the gene for neural such as the peritoneum, pleura, right cardiac atrium etc. cell adhesion molecule L1 and it is inherited recessively.1,3 The most commonly used shunt is ventriculoperitoneal shunt (VP) where CSF from the lateral brain ventricle as a

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Neurosurgery Junaković A. Pediatric hydrocephalus: causes, symptoms and treatment modalities. pp. 355 – 360 proximal location is drained in the peritoneum as a distal cinereum) that allows the excess CSF to flow to the basal location and the abdomen should be able to absorb the cistern, thus bypassing the obstruction in the brain. The excess CSF.1 A VP shunt is the gold standard of treatment.2 major advantage of ETV over cerebral shunting is decreased Patients who are unable to have distal abdominal catheters risk for infections since it avoids the use of a foreign body.8 because of big abdominal surgeries, malabsorptive peritoneal Hoshide et al. have recently reported a 16.6 % incidence of cavity, abdominal pseudocyst, obesity, peritonitis, undergo injuries to neural structures during ETV in North America. the ventriculoatrial shunting, which is also called vascular A robot-assisted endoscopic third ventriculostomy system shunting. The catheter is located in the brain ventricle and (ROSA system) was introduced to improve the trajectories carries excess CSF through the jugular vein to the superior of the endoscope stereotactically, thereby reducing the risk vena cava and into the right atrium which represents the for injuries and providing stabilization for the endoscope.9 drainage cavity in this case. Fluoroscopic guidance is need- Possible complications of the ETV procedure are hemorrhages ed in this procedure to prevent cardiac arrhythmias (long from the basilar artery if it ruptures and damage to some brain distal catheter used) and catheter thrombosis (short distal structures such as the hypothalamus, pituitary gland etc.10 catheter used). The procedure has some side effects and it is A single-institution experience from Great Ormond Street not really harmless. Every shunting procedure carries risks Hospital for Children in London included 286 pediatric cases of infections. Some serious complications are renal failure of intraventricular endoscopic procedures. ETV was performed and vein thrombosis. Aside from the most commonly used in 159 cases, and endoscopic fenestration in 64 patients. Some VP and ventriculoatrial shunts, the lumboperitoneal shunt of the complications included: postoperative seizures, CSF is also performed in case of communicating non-obstructive leakage, CSF infection and intracranial hemorrhage, while hydrocephalus. The Torkildsen shunt (also named internal no perioperative deaths were reported. Intraventricular shunt) is rarely performed because it is valid only in the case endoscopy was concluded to be a safe procedure in the pedi- of acquired obstructive hydrocephalus and it shunts CSF atric population, although it was associated with increased from the brain ventricles to the cisternal place. One more shunt rates, especially in infants. Higher failure rates are possible drainage cavity is the pleura, hence one more poten- expected in younger infants.11 Nishiyama et al. reported that tial shunt is the ventriculopleural shunt which is performed the success rate for ETV in shunt malfunction is really high, when other shunts are contraindicated. Shunts function on around 80%, and therefore patients with hydrocephalus who the mechanism of valves which act as on-off switches. If the were not successfully treated using shunts are candidates for pressure between the valves is increased, then the flow is ETV. They also report how endoscopic aqueductoplasty (EAP) also increased, so, the pressure difference across the valve is an alternative to ETV because it can avoid severe arterial is the valve’s opening pressure.1,6 hemorrhage, but it is also considered a riskier procedure due to the risk of destroying some midbrain structures and One more procedure other than shunting that may be done leading to neurologic deficits such as oculomotor nerve palsy.12 is called endoscopic third ventriculostomy (ETV), which is If rapid-onset hydrocephalus with increased intracranial often used as an alternative to shunting.1,8 It is performed pressure occurs, it is a medical emergency. Open ventricular in cases of obstructive hydrocephalus. An opening is made drainage can be done, the ventricular tap is used in infants and on the floor of the third ventricle (more precisely, the tuber sometimes VP or ventriculoatrial (VA) shunts are performed.1

Figure 3. Ventriculoatrial (VA) shunting (on the left) and most commonly performed, ventriculoperitoneal (VP) shunting (on the right). Source: Where do cerebral shunts drain cerebrospinal fluid (CSF) to, and what happens to CSF once drained? - Quora. https://www.quora.com/Where-do-cerebral-shunts-drain-cerebrospinal-fluid-CSF-to-and-what-happens-to-CSF-once-drained. Published May 12, 2014. Accessed August 4, 2017. gyrus | vol. 4 | no. 3 – 4 | july – december 2017 358 sleep disorders

Neurosurgery Junaković A. Pediatric hydrocephalus: causes, symptoms and treatment modalities. pp. 355 – 360

Rarely, some medications can be used to treat hydrocephalus CSF SHUNTS and to delay surgical treatment. It is used in premature infants in cases of posthemorrhagic hydrocephalus, but it is never con- Hydrocephalus is still a very common condition treated sidered as a long-term therapy in the chronic phase of hydro- by pediatric neurosurgeons and many advances have been cephalus. Diuretics can decrease the production of CSF by the made in shunt and adjuvant technology. Krystal L. Tomei has choroid plexus, such as acetazolamide (carboanhydrase inhib- reported that neurosurgeons have an array of valve options itor) and furosemide (loop diuretic). Isosorbide can increase that facilitate improved customization of CSF diversion, CSF reabsorption, but its effectiveness is still questionable.1 depending on the patient’s needs. Today, neurosurgeons have both fixed-pressure and programmable valves available. Fixed-pressure valves may include antisiphon components HYDROCEPHALUS IN CLINICAL AND to prevent overdrainage. On the other hand, programmable GENETIC SYNDROMES valves that are adjustable by magnets and safe for MRI up to 3 Tesla are also available. Both types of valves have several Many clinical and genetic syndromes are accompanied advantages and disadvantages, as Krystal L. Tomei reports. by hydrocephalus. Tully and Dobyns report that the vast Programmable valves may be beneficial in younger patients, majority of patients with neural tube defects present with while fixed-pressure valves can be used in patients where hydrocephalus. Intracranial arachnoid cysts are also a cause MRI is necessary. Siphon-guard options that are available of hydrocephalus where those simple cysts obstruct CSF help to prevent overdrainage, but cannot be used in patients outflow. Progressive hydrocephalus can also occur due to with low pressure hydrocephalus. Nonprogrammable valves skeletal dysplasias and FGFR – associated craniosynostosis have a 5-year survival rate in children which is higher than syndromes because mutations in FGFR genes cause cranial programmable ones. In addition to that, programmable changes which can lead to the obstruction of CSF outflow valves may have a higher intrinsic failure rate. One of the and reduction of CSF absorption. FGFR mutation can also earliest programmable valves is the Codman-Medos-Hakim enlarge the brain itself. Mutations in the RAS pathway (also valve which is used in neonates. However, there are also called RASopathies) can lead to multifactorial hydrocephalus. studies that support the use of programmable valves where One of the RASopathies called Costello syndrome is defined it is determined that programmable valves carry a reduced by cerebellar overgrowth and structural heart disease which risk of proximal failure and prevention of the formation can lead to increased venous pressure and that may create a of the ependymal adhesions along the proximal catheter. pressure gradient that impedes absorption of CSF into the In adult patients, there is lower risk for revision when using systemic circulation. Some additional syndromes that are programmable valves than fixed-pressure valves, while there associated with hydrocephalus are Gorlin syndrome, primary is no significant difference in pediatric population.14 ciliary dyskinesia, and mucopolysaccharidoses.13

REFERENCES:

1. Nelson SL. Hydrocephalus. http://emedicine.medscape.com/article/1135286-overview. Accessed August 4, 2017. 2. Venkataramana NK. Hydrocephalus Indian scenario – A review. J Pediatr Neurosci. 2011;6(3):11. doi:10.4103/1817-1745.85704. 3. Ivančević Ž, ed. MSD priručnik dijagnostike i terapije. 18th ed. Split: Placebo; 2010. 4. Jamshidi A, Glidewell C, Murnick J, Magge S, Reilly BK. Resolution of bilateral sensorineural hearing loss following ventriculoperitoneal shunt and literature review. Int J Pediatr Otorhinolaryngol. 2017;100:141-144. doi:10.1016/j.ijporl.2017.06.034. 5. Morais BA, Cardeal DD, Ribeiro e Ribeiro R, et al. Hydrocephalus: a rare initial manifestation of sporadic intramedullary hemangioblastoma. Childs Nerv Syst. 2017;33(8):1399-1403. doi:10.1007/s00381-017-3415-0. 6. Oxford Medical Dictionary – Mobile Application. 7. CT scan vs. MRI. http://www.diffen.com/difference/CT_Scan_vs_MRI. Accessed August 4, 2017. 8. Beuriat PA, Puget S, Cinalli G, et al. Hydrocephalus treatment in children: long-term outcome in 975 consecutive patients. J Neurosurg Pediatr. 2017;20(1):10-18. doi: 10.3171/2017.2.PEDS16491. 9. Hoshide R, Calayag M, Meltzer H, Levy M, Gonda D. Robot-Assisted Endoscopic Third Ventriculostomy. Neurosurgery. 2016;63(CN suppl 1):204. doi:10.1227/01.neu.0000489841.88045.a3. 10. Complications of ETV and ETV/CPC. http://www.hydroassoc.org/complications-of-etv-and-etvcpc/. Accessed August 4, 2017. 11. Bowes AL, King-Robson J, Dawes WJ, James G, Aquilina K. Neuroendoscopic surgery in children: does age at intervention influence safety and efficacy? A single-center experience. J Neurosurg Pediatr. 2017;20(4):324-328. doi:10.3171/2017.4.PEDS16488. 12. Nishiyama K, Yoshimura J, Fujii Y. Limitations of Neuroendoscopic Treatment for Pediatric Hydrocephalus and Consider- ations from Future Perspectives. Neurol Med Chir (Tokyo). 2015;55(8):611-616. doi:10.2176/nmc.ra.2014-0433. 13. Tully HM, Dobyns WB. Infantile hydrocephalus: A review of epidemiology, classification and causes. Eur J Med Genet. 2014;57(8):359-368. doi:10.1016/j.ejmg.2014.06.002. 14. Tomei KL. The Evolution of Cerebrospinal Fluid Shunts: Advances in Technology and Technique. Pediatr Neurosurg. 2017;52(6):369-380. doi:10.1159/000477174.

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Neurosurgery Junaković A. Pediatric hydrocephalus: causes, symptoms and treatment modalities. pp. 355 – 360

PEDIJATRIJSKI HIDROCEFALUS: UZROCI, SIMPTOMI I MODALITETI LIJEČENJA

Sažetak

Hidrocefalus se može definirati kao nagomilavanje cerebrospinalne tekućine u moždanim komorama. Može se podijeliti na opstruktivni i komunicirajući hidrocefalus ili se etiološki klasificirati u kongen- italni i stečeni. Pacijent se uglavnom prezentira s makrocefalijom, povećanom iritabilnosti, glavobol- jom, znakom zalazećeg sunca, spastičnošću donjih udova, pozitivnim Macewen znakom te znakovima povećanja intrakranijalnog tlaka poput papiledema. Najčešći uzroci kongenitalnog hidrocefalusa su određene malformacije moždanoga debla kao akveduktalna stenoza, Dandy-Walker malformacija, Arnold-Chiari malformacija tip 1 i 2, ageneza foramena Monroi. Česti razlozi za razvoj opstruktiv- nog hidrocefalusa su tumori mozga (medulobastom), intraventrikularno krvarenje i subarahnoidalno krvarenje. Općenito, hidrocefalus se može razviti zbog opstrukcije protoka cerebrospinalne tekućine, njezine povećane proizvodnje, ili pak slabe reapsorpcije. CT i MR su dobro poznate slikovne tehnike koje se koriste za dijagnosticiranje hidrocefalusa, uključujući i ultrazvuk kroz prednju fontanelu i rijetko korištenu cerebralnu angiografiju. Ponekad, ako se sumnja na X-vezani hidrocefalus, radi se genetičko testiranje, a EEG se koristi samo u slučaju epileptičnih napadaja. Većina pacijenata se liječi kirurškim putem. Lijekovi, poput diuretika acetazolamida i furosemida, koriste se samo kako bi malo odgodili operaciju. Najčešće izvođena operacija je izvođenje „šanta“ čija je svrha stvaranje komunik- acije između moždanih komora i neke tjelesne šupljine za drenažu kao što su pleura, peritoneum ili desna pretklijetka. Najčešće izvođeni su ventrikuloperitonelani (VP) i ventrikuloatrijski (VA) šant. Alternativa šantu je endoskopska ventrikulostomija treće komore, čija je glavna prednost u odnosu na šant smanjeni rizik od infekcija.

Ključne riječi: cerebrospinalni likvor, endoskopska ventrikulostomija, intrakranijalni tlak, neurokirurgija, pedijatrijski hidrocefalus, ventrikuloatrijski šant, ventrikuloperitonealni šant

Received September 2, 2017. Accepted October 24, 2017.

gyrus | vol. 4 | no. 3 – 4 | july – december 2017 360 sleep disorders

Erratum Dekanić A. Erratum to: Research on factors that control the activation of spinal cord endogenous stem cells. p. 361 ERRATUM TO: RESEARCH ON FACTORS THAT CONTROL THE ACTIVATION OF SPINAL CORD ENDOGENOUS STEM CELLS

Ana Dekanić 0000-0002-5487-3611 Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia E-mail: [email protected]

Erratum to:

Dekanić A, Mladinić M. Research on factors that control the activation of spinal cord endogenous stem cells. Gyrus.2015;3(suppl 2):53. Available at: http://gyrus.hiim.hr/images/suplement2/neuro2015_Part28.pdf.

The full list of authors was not included in the original article. Andrea Nistri should be listed as the second author.

The full and complete list of authors in the original article should be as following:

Ana Dekanić1,2, Andrea Nistri2, Miranda Mladinić1,2 1 University of Rijeka, Department of Biotechnology, Rijeka, Croatia 2 International School for Advanced Studies, Trieste, Italy

Received September 6, 2017. Accepted September 20, 2017.

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Human fetal midbrain slide, 20 postconceptional weeks (PCW), Golgi staining. Blood vessels and radial glial cells’ processes are visible. This image is property of Zagreb Neuroembriological Collection, Croatian Institute for Brain Research, University of Zagreb School of Medicine. For details see Kostović et al. 1991; Judaš et al. 2011.

gyrus | vol. 4 | no. 3 – 4 | july – december 2017 362 sleep disorders keyword and author index

KEYWORD INDEX

299 activation-synthesis hypothesis 329 neuronal theory 304 affect 355 neurosurgery 315 alcohol 355 pediatric hydrocephalus 339 antiepileptics 319 perception 348 bright light therapy (BLT) 304 periodicity 329 calcitonin gene-related peptide (CGRP) 339 pregnancy 311 cardiovascular system 278 primitive reflex integration 278 cerebral palsy 323 prion 355 cerebrospinal fluid (CSF) 323 prion disease 304 circadian clocks 343 progesterone 348 circadian rhythm 299 psychoanalytic theory 304 circaseptan 311 quality of life 315 clinical approach 315 quetiapine 343 cognition 299 REM 311 cognitive disorders 348 seasonal affective disorder 319 cognitive neuroscience 304 seasonal mood disorder 339 complications 339 seizure 323 Creutzfeldt-Jakob disease 311 sleep deprivation 319 crossmodal transfer 311 sleep disorders 348 depressive disorder 315 sleepwalking 299 dreaming 315 slow wave activity (SWA) 311 endocrine system 343 spatial memory 355 endoscopic ventriculostomy 278 strength training 335,339 epilepsy 293 synapses 343 estradiol 319 synesthesia 355 intracranial pressure 278 Therasuit® 293 learning 323 transmissible spongiform encephalopathies 335 major depressive disorder (MDD) 335 trigeminal nerve 293 memory 335 trigeminal nerve stimulation (TNS) 299 memory consolidation 329 vascular theory 293 memory disorders 355 ventriculoatrial shunt 329 migraine 355 ventriculoperitoneal shunt 329 migraine aura 343 working memory 319 multisensory integration 315 zolpidem 323 neurodegeneration 293 neurogenesis AUTHOR INDEX

291 Bardak, Ana 278 Batelić Dragić, Rašeljka 267, 275 Prpić, Nikola 287 Ćusek, Luka 348 Radić, Jana 361 Dekanić, Ana 265 Škoro, Matea 315 Dragičević, Dora 293 Smoljo, Tomislav 264 Friganović, Krešimir 286, 339 Starčević, Ivana 289 Hohšteter, Bea 249, 269 Tomić, Barbara 274, 335 Horvat Velić, Emina 265 Topić, Iva 288 Ivek, Ida 299 Vukić, Vana 355 Junaković, Alisa 323 Zelić, Dora Franka 291 Kovačević, Stjepan 271 Kraljević, Ana 271 Lončar, Sara 269 Mlinarić, Ivan 304 Mutak, Augustin 311 Nedić, Elizabeth 343 Novak, Anamarija 319 Paulik, Andrea 329 Popović, Josipa

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acknowledgement to the reviewers

ACKNOWLEDGEMENT TO THE REVIEWERS ZAHVALA RECENZENTIMA

The Editorial Board of Gyrus Journal would like to thank the reviewers for their efforts and constructive suggestions for improvement of our authors’ manuscripts. The reviewers contributed their time and expertise for the creation of the following issues:

Urednički savjet časopisa Gyrus zahvaljuje recenzentima na njihovom trudu i konstruktivnim prijedlozima za poboljšanje radova naših autora. Svoje vrijeme i stručnost utkali su u stvaranje sljedećih brojeva časopisa:

Gyrus Vol. 3, No. 4 Marina Boban, MD, PhD, Assistant Professor Tina Dušek, MD, PhD, Assistant Professor Sanja Hajnšek, MD, PhD, Professor Helena Šarac, MD, PhD

Gyrus Vol. 4, No. 1 Raphael Béné, MD Maja Cepanec, PhD, Assistant Professor Srećko Gajović, MD, PhD, Professor Rudolf Gregurek, MD, PhD, Professor Ivana Hromatko, PhD, Assistant Professor Svjetlana Kalanj-Bognar, MD, PhD, Professor Marcel Marjanović Kavanagh, MD Monika Mudrovčić, MD Željka Petelin Gadže, MD, PhD, Assistant Professor Mateja Strinović, MD Božidar Nikša Tarabić, MA

Gyrus Vol. 4, No. 2 Fadi Almahariq, MD Raphael Béné, MD Krsto Dawidowsky, MD, PhD, Assistant Professor Vinka Knezović, MD Darko Orešković, MD Nives Pećina-Šlaus, PhD, Professor Maja Rogić Vidaković, PhD Dora Sedmak, MD Marina Šagud, MD, PhD, Assistant Professor

Gyrus Vol. 4, No. 3-4 Domagoj Džaja, MD, PhD Ivana Hromatko, PhD, Assistant Professor Dragutin Ivanec, PhD, Professor Vinka Knezović, MD Darija Mahović Lakušić, MD, PhD, Associate Professor Alma Mihaljević-Peleš, MD, PhD, Professor Dinka Pavičić Baldani, MD, PhD, Associate Professor Željka Petelin Gadže, MD, PhD, Associate Professor Marina Raguž, MD Goran Sedmak, MD, PhD, Assistant Professor Marina Šagud, MD, PhD, Assistant Professor Meri Tadinac, PhD, Professor Marko Zorić, MD gyrus | vol. 4 | no. 3 – 4 | july – december 2017 VII sleep disorders guide for authors

GUIDE FOR AUTHORS

Do you find yourself enjoying Gyrus and wanting to contribute, but aren’t sure how to go about it or where to even begin? Are you uncertain about details of the article format? Confused about or the publishing process? This is the place to resolve any such quandaries!

Several types of articles are published in Gyrus. The journal can be divided into two distinct parts. first part

First part of Gyrus has a structure, layout and writing style intended for a broader audience.

The articles are shorter and of a more flexible structure, the pages are brighter and livelier. But don’t let this fun-loving appearance fool you – this is still hardcore neuroscience, only presented in a more approachable format.

If this is your first time contributing to Gyrus and you just want to get the feel of it, the right choice for you might be theEditor’s Choice section. Editor’s Choice consists of shorter texts which summarize an interesting neuroscientific study and present it in an entertaining manner to a broader audience. It can be a study you yourself have read about and found interesting, or you can choose from a list of works the Editorial Board has suggested as subjects for this section. A more detailed guide on writing for Editor’s Choice can be found at our website (http://gyrus.hiim.hr/).

First part also contains Infographics. If you have an idea how to visually present information related to neuroscience, even if you don’t know how to execute it yourself, please feel free to contact us! Our graphic team would be more than happy to help.

Additionally, we also have regular sections such as Case Report (presenting a noteworthy clinical case), Book or Movie Review (a brief analysis of a neuroscience-related book or movie; think of it as an opportunity to recommend it to others or to bring attention to its shortcomings). If you have an idea for one of these, please feel free to let us know!

On a similar note, if you happened to participate in a noteworthy, neuroscience-related event (a lecture/workshop/congress/ campaign), we would be very happy if you could write a short report, contact us and share your experiences with others through our News & Education section. second part

The second part of Gyrus has the characteristics of a true academic journal. Its structure is rigidly defined; all the articles follow the same rules and format which includes an abstract, references and keywords. The scholarly articles published in Gyrus are exclusively review articles. Review articles are a type of paper where multiple scientific works concerning a certain subject are condensed into a single text to offer a unified, summarized view of the current knowledge on the subject matter. This is highly practical – you allow a reader looking to learn about a certain topic to gain the information and insight contained in dozens of papers just by reading your one article!

If you like the sound of that, but aren’t entirely sure how to pull of such an endeavor, fear not! We’ve prepared a short online how-to guide that we hope you’ll find useful (available from http://gyrus.hiim.hr/).

You’ll notice that the second part of Gyrus is divided into sections. There are four regular sections: Fundamental Neuroscience; Neurology; Psychiatry and Psychology; and Neurosurgery. Each issue also has an Issue Topic section – several articles dedicated to a single, narrower subject (such as “Pituitary Gland”).

At our writer’s room meeting, as well as Gyrus’ website, you’ll be able to see topics suggested by Gyrus editors. If you have a topic idea of your own, feel free to contact us at [email protected] with your suggestions. Fresh new ideas are always welcome at Gyrus!

VIII july – december 2017 | gyrus | vol. 4 | no. 3 – 4 sleep disorders guide for authors guide for authors

What exactly should your paper look like?

First of all, it should be written in English! English is the language of the academic and business world, as well as the language in which most of the literature you will be reading is written. Honing your English writing skills is always a good idea!

The minimum recommended length for a paper is 1500 words. The font should be Times New Roman, size 12, with double spacing.

The form of review articles doesn’t dictate a rigid subdivision into sections, but for layout purposes, we recommend that your article has a defined Introduction and Conclusion.

Each paper should have an Abstract in both English and Croatian (Cro. Sažetak). In case you don’t speak Croatian fluently, help will be provided regarding the translation. The length of the Abstract should be 200–300 words. The purpose of the Abstract is to sum up the main ideas and conclusion of your work. What it actually does is quickly and easily give a potential reader an idea about the bottom line of your article and whether it holds any information relevant to their interests.

You are also going to need 5–7 keywords in English and Croatian (Cro. ključne riječi). They should be listed alphabetically, below the Abstract. The keywords have to be from MeSH vocabulary thesaurus which can be found at https://www.ncbi.nlm.nih.gov/mesh.

Another crucial part of writing a review article is, of course, the references. To produce a review article in Gyrus, you should read and cite a minimum of 5 and ideally about a dozen papers. As for the citation style, Gyrus uses the American Medical Association (AMA) rules. You can visit their website for details about how exactly to cite an article, a book, a poster etc., but to sum up – the citation number goes at the end of the sentence where the content is referenced, after the full stop, in superscript; while the citations themselves are listed after the body of the article in order of their appearance in the text. The easiest way to organize your references is using a program such as Mendeley®, which you can download for free.

It’s advisable that you supplement your article with figures and/or tables which will liven things up a bit and make it easier for the reader to comprehend and digest your text. The figures and tables should be attached separately when sending the submission email, in JPEG format, numbered, with their intended placement in the text clearly marked and a short description written at the end of the document. We’ll merge everything into the final text during layout. If a part of your text refers to a figure or table, you should put “(Figure 1)” or “(Table 1)” at the end of last relevant sentence to indicate so.

It’s also advisable that you obtain these figures and tables legally! That means either using figures that are public domain (Google Image Search lets you filter images by license) or asking the author for permission. Furthermore, you can use ClinicalKey multimedia search engine at https://www.clinicalkey.com/ (you’ll have to login or register to have free access). It’s very helpful if you also provide the link to the figure source when you submit your article, in case we need the figure in its original format. There is also, of course, the option of creating your own illustrations, graphs, or tables! If you have an idea for an illustration, but don’t know how to execute it yourself, you can ask our graphic team for help.

The final version of your article should be submitted at [email protected]. You’ll be notified as soon as we receive it. The article is then forwarded to the editor you were assigned (by then, you will have probably heard from him or her; part of their role is to help you along with the writing process, give you advice and answer your questions). Their main job is to help you polish your paper to perfection. In the process, they will probably suggest some minor or major alterations to your text or point out possible errors so they can be corrected before publishing.

We won’t lie – writing a review article and getting it published is a rather time-consuming process. But don’t let it discour- age you! You can always count on the help of Gyrus’ editors if you encounter any difficulties.

gyrus | vol. 4 | no. 3 – 4 | july – december 2017 IX sleep disorders

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Would you like to write? Are you interested in the process of creating an issue of the journal? Would you like to learn how to write a good scholarly article? We invite all the interested students to join our editorial staff. Contact us and we’ll be happy to respond. Send your applications directly to our Editor-in-Chief: [email protected] Photographers needed! We invite all the students interested in the field of photography to contribute in creating our journal and seize this opportunity to implement their passion into our scholarly journal. Proofreaders for Croatian and English needed! We invite all young people who have a fair good command of English and/or Croatian grammar to join our ranks and contribute to the process of editing and correcting the mistakes that find their way into the presented articles. A certificate for the contribution will be presented to our most trusted and hard-working proofreaders.

join the ranks of student society for neuroscience

Are you interested in certain areas that carry the “neuro-” prefix? Are you curious to find out more about how our brain works? Do neuroscience, neurology, psychiatry, psychology or even neurosurgery sound interesting to you? Would you like to become a member of one of the most active student groups at the University of Zagreb? If you answered positively on most of the aforementioned questions, we happily suggest that you join the student society for neuroscience. Join by sending your name, your institution’s/faculty’s name and your year of study, on our email: [email protected] We’ll respond promptly!

X july – december 2017 | gyrus | vol. 4 | no. 3 – 4 sleep disorders timeline

XII july – december 2017 | gyrus | vol. 4 | no. 3 – 4