A Cinch for the Brain

Our bodies, our behavior and even our brains are anything but symmetrical. And this seems to be an important factor in the seamless functioning of our thought, speech and motor faculties. Researchers at the Max Planck Institute for Psycholinguistics in Nijmegen are currently searching for genetic clues to this phenomenon. They want to decode the fundamental molecular biological mechanisms that contribute to asymmetry in the brain, and to identify possible causes for neurological disorders.

TEXT STEFANIE REINBERGER

t first glance, the human ture. It’s divided into two halves, both A strong left: Rafael Nadal, for body appears to be com- of which are equal in size and whose many years the world’s number pletely symmetrical: two furrows and bulges follow a similar pat- one men’s player, is right-handed but holds the arms, two legs, two eyes, tern. But the functional centers are ex- racket in his left most of two ears. Even features tremely unevenly distributed. The right the time. Researchers are likeA the nose and mouth appear to be and left hemispheres specialize in dif- studying how the brains of left- evenly positioned in both halves of ferent cognitive functions. They essen- and right-handed people differ. the face in most people. On closer in- tially divide up the work between them, spection, though, we see that one leg possibly to expand the total range of is longer than the other, one hand is tasks performed. stronger, or maybe the left ear is posi- “Lateralization is a very distinct phe- tioned lower than the right one. This nomenon in language,” explains Clyde becomes even clearer when we take a Francks, Research Group Leader in the look inside the body: the heart beats Language and Genetics Department at on the left-hand side; the liver and the Max Planck Institute for Psycholin- gallbladder, in contrast, are located in guistics in Nijmegen, in the Nether- the right half of the body. The right lands. “Speech is processed predomi- kidney usually sits slightly lower than nantly in the left half of the brain in the left one, which is generally some- most people.” Only in less than 1 per- what bigger and heavier. cent of the population are the main cen- The external appearance of the ters of speech processing in the right brain would also lead us to believe that half – a phenomenon that occurs almost it is a completely symmetrical struc- exclusively in left-handed people. >

34 MaxPlanckResearch 3 | 16 Photo: Issei Kato/Reuters 3 | MaxPlanckResearch 16MaxPlanckResearch FOCUS_Symmetry 35 the brain are already very apparent the brainarealreadyvery differences betweenthetwo halvesof This issuggestedbythefact thatthe netics playanimportant role here. largely unclear. likelythatge It isvery in itsfunction,contrast, arestill in thebrainand lead totheasymmetry oping organism. nents arearrangedinthenewlydevel- determines how the individual compo- asymmetric structureofthemolecules development,the es ofembryonic the anatomy. Evenintheearlieststag- combined, isprimarilyresponsiblefor which also determines how proteins are asymmetric structureofaminoacids, ly ofthebody,” hepointsout.The seems todeveloplargelyindependent- Francks. “Inthebrain, however, it – isabasicbiologicalprinciple,”says structure andinthebrainbehavior “Lateralization –bothinthebody 36 MaxPlanckResearch 3 MaxPlanckResearch The cause and the mechanisms that The causeandthemechanismsthat » few people whose brain is specialized mirror-inversely to the majority of people. of majority the specializedmirror-inverselyisto brain whose people few the in only not and – person to person from differently expressed isLateralization | 16 - edness attheWellcome Trust Centre searching forgenesunderlyinghand- years now. A zoologist, he has been the lateralization of the brain for many Clyde Franckshasbeenfascinated by LEFT- GENE DISCOVERY OFAN INITIAL vor asanadult. indicator of which hand they will fa- they prefertosuckisahighlyaccurate es are15weeksold,thethumbthat quently thantheleft.Oncefetus- babies movetherightarmmorefre shows that85percent ofthegrowing human fetuses, an ultrasound scan ioral principle. Even in ten-week-old the moststrikingasymmetricbehav and thatsimultaneouslyconstitutes related tolateralizationinthebrain, is handedness–aneffectthatalso early in development. A case in point - - The subject of “asymmetry in the brain The subject of “asymmetry ment, herecruitedhisformer colleague. the newLanguageandGenetics Depart for Psycholinguisticsin2010 tosetup Fisher joinedtheMax Planck Institute speech andlanguage,in2001. When gene FOXP2,whichplaysakeyrolein He haddiscoveredthewidelyknown however, was focusedonothertopics. stitute forPsycholinguistics.Fisher, rently aDirectorattheMaxPlanckIn- while with Simon E. Fisher, who is cur- paternal line. edness and is passed down through the linked tothetendencytowardleft-hand brane neuronal1),whichmaybe RTM1 (leucine-richrepeattransmem- ofagenecalledLR of thediscovery member. In2007,hepublisheddetails dent andlaterasanacademicstaff since 2002, initially as a doctoral stu- for HumanGeneticsinOxford,UK, In Oxford,Francksworkedfora - - -

Photo: Frank Vinken Photo: Frank Vinken

Graphic: PLOS ONE, 2014 (1848–1905) justa few years later, in by German neurologist Carl Wernicke guage, Wernicke’s area, was discovered mar. Anotherimportant centeroflan- cessing ofsentencestructure andgram speech productionaswell inthepro- considered toplayanimportantrolein Broca’s areaafterhim,whichisnow of themaincentersspeech,named display thesedeficits. affecting therighthemisphere,didnot posite sideofthebrain,however, thus whose injurieswerelocatedontheop pressing themselvesverbally. Patients they werenolongercapableofex stand whatwasbeingsaidto them, but those affected were still able to under- left half of the brain was destroyed, nomenon: if a particular area in the had stumbledacrossastrangephe ed asymmetricallyacrossthebrain.He for languageandspeecharedistribut- that theimportantfunctionalcenters ready discoveredintheearly1860s with ClydeFrancks. Planck InstituteinNijmegentogether and behavior” thus arrived at the Max almost exclusively in left-handed people. left-handed in exclusively almost itself manifests hemisphere cerebral right the in processing language increased of phenomenon rare Thepeople. left-handed around to applies same The one. right the in than hemisphere cerebral left the in more language process people right-handed of percent imaging (MRI) show that more than than more that show (MRI) imaging Right cerebralhemispheres.two the of functionalities various the and ness interested in the links between handed are Researchers left-handedness. influence that genes for looking is she doctorate, her Clyde Francks’ research group. As part of Left The Frenchmanhaddiscoveredone French physician had al- Tulya Kavaklioglu is a member of Studies using magnetic resonance 80 percentof 90

- - - - - based onbloodcirculation orsugarme- to depict the active regions of the brain functional imaging,whichcanbeused More recentscientificstudiesbasedon AND WOMEN DIFFERENCES BETWEENMEN in mostpeople. Wernicke regionislocatedontheleft sion –andjustlikeBroca’s area,the important roleinlanguagecomprehen- 1874. Thisregionofthebrainplaysan left alsodifferintermsof howpro cessing islocatedprincipally onthe people whosecenteroflanguage pro- the majorityofpeople.The brainsof brain isspecializedmirror-inversely to and not only inthe few people whose differently frompersonto– in thelefthemisphere. the righthemisphere–albeitlessthan report languageandspeechactivityin from oneanother. Researchers thusalso often eveninregionsthatarefarapart cessing are distributedacross the brain, areas for language and language pro tabolism, haveshownthattherelevant L Moreover, lateralization isexpressed % of study participants study of % 50 - - analyzed imagesofbrainscans ofmore gate it again himself. The two scientists lupe, hethereforedecided to investi er withdoctoralstudentTulio Guada- differences betweenthesexes. Togeth- past, hesuspectedthatthere were slight had includedintheirstudy. of thebrainthatDutchresearchers sexes intheregionsandfunctions differences whatsoeverbetweenthe than women, they did not identify any men aremorefrequentlyleft-handed brain. Theyconcludedthat,although certain regionsandfunctionsofthe handedness andthelateralizationof tists analyzeddatafrom13studieson carried outameta-analysis.Thescien- ical CenterUtrechtintheNetherlands of researchers fromtheUniversity Med question. In2008,forexample,ateam differentanswerstothegender very tween menandwomen? how does it affect the differences be- dividual’s cognitivefunctions?And brain. Buthowdoesthisaffectanin- even affectjustindividualareasofthe is.Thismay nounced theasymmetry 80 Previous research findings provided Francks wasn’t convinced.Asinthe 3 | MaxPlanckResearch 16MaxPlanckResearch FOCUS_Symmetry R 37 - - FOCUS_Symmetry

Below Gender-specific differences are found in the asymmetry of the , an area that is located in both cerebral hemispheres: left-right asymmetry is generally less pronounced in women than in men. Men with less-pronounced left-right asymmetry often experience reading difficulties. Right The molecular biology lab at the Max Planck Institute for Psycholinguistics offers researchers the opportunity to study at cellular level the effect of certain genes on the development of the brain.

Distribution of planum temporale asymmetry by gender

12

10 Women Men 8

6 Thickness 4

2

0 0.00 0.05 0.10 0.15 0.20 0.25 Asymmetry index

than 2,300 healthy men and women. of the brain and can be up to five times lateralized than in men. Now, it can’t In this study, they were able to access bigger there than its equivalent on the be concluded from this result that data that research groups in various in- right-hand side. Researchers also see a women are therefore the weaker read- stitutions in the Netherlands had been connection between a lack of left-right ers. “That is not the case,” emphasizes collecting since 2007 as part of the asymmetry in the planum temporale Francks. “But men in whom the left- Brain Imaging Genetics Study, as well and . Those affected by this dis- right asymmetry of the planum tem- as data from a long-term German study order have difficulty reading and un- porale is less pronounced have a great- on health. It is only through collabora- derstanding words even though their er tendency to be dyslexic.” tive research endeavors like this that it intelligence, eyesight and hearing have Francks was not satisfied with a pure is even possible to generate such a large developed normally. survey – ultimately, his work is con- group of subjects – and thus obtain a cerned primarily with decoding the data quantity whose final analysis is SURPRISING LINK TO SEX mechanisms of lateralization. Therefore, truly statistically meaningful. HORMONES in the next step, he and Guadalupe an- In their study, Francks and Guada- alyzed the genetic data that he had on lupe concentrated on the planum tem- Francks and his colleague measured his subjects. The researchers concentrat- porale, a region of the brain that their the planum temporale using very ex- ed on searching for so-called single nu- colleagues in Utrecht already had in act methods to determine the volume cleotide polymorphisms (SNPs). These their sights. The planum temporale sits of areas of the brain. When the re- are not mutations, but rather gene vari- on both sides of the brain in the tem- searchers had finally analyzed the ations that occur with a certain frequen- poral lobe and plays a role in the pro- available data, it was clear that there is cy in the population and in which only cessing of language and music, but it indeed a difference between men and a single base pair is modified in the also has an influence on absolute pitch. women – at least in the planum tem- DNA strand. In around 90 percent of the population, porale. Francks’ studies showed that The results were interesting: in con-

it is more pronounced on the left side this region in the female brain is less junction with the manifestation of left- Graphic: Max Planck Institute for Psycholinguistics

38 MaxPlanckResearch 3 | 16 Graphic: Max Planck Institute for Psycholinguistics

Photo: Frank Vinken seems, atfirstglance,almost simple: Francks andhisteamin Nijmegen puzzle infutureresearch projects. tic ability. Francks wantstosolvethis ultimately playinreadingand linguis- still unclear what role steroid hormones both menandwomen.However, itis alization of the planum temporale in appears tohaveaneffectonthelater- ing ofthesteroidhormonesactually male sexhormones.Andthefunction- things, inthesynthesisofmaleandfe- roid hormones,namely, amongother are involvedinthemetabolismofste- ly highnumberofSNPsingenesthat rale, theresearchers foundaparticular- intheplanumtempo right asymmetry Much oftheworkdoneby Clyde » that determines handedness or . brain or handedness determines that variationsingle gene no is there that sure very be can We - sphere inmostpeople,buttheir shape nounced intheleftcerebral hemi convolutions morestrongly pro- comprehension. Notonlyare Heschl’s cortex andisimportantfor language auditory spheres; ithousestheprimary temporal lobeinbothcerebralhemi This region ofthe brain is locatedin the chl’s convolutions,astheyareknown. when theresearchers examinedHes stack. Thiswasrevealed,forexample, proverbial search foraneedleinhay- causes of the lateralization is akin to the Thesearchstraightforward. forgenetic this asymmetry. Butit’s notquitethat gene variationsexistthatcanexplain region inthebrainandcheckwhether they chooseaprominent,asymmetric - - - Nevertheless, despitestudyingthedata to acertainextent,mustbeinherited. viduals –anatomicalpeculiaritiesthat, also variesconsiderablybetweenindi- members ofaPakistanifamily thatin- analyzed thegeneticmaterial of17 year, theNijmegen-basedresearchers for othergeneshandedness. Justlast Equally sobering is the current search COMPLEX ANDMULTIFACETED GENETIC INFLUENCESARE tion ofHeschl’s convolutions. ly inconjunctionwiththemanifesta- any genevariationsthatoccurunique- Max Planckresearchers couldn’t detect of more than 3,000 test subjects, the 3

| MaxPlanckResearch 16MaxPlanckResearch 39 FOCUS_Symmetry

Heschl’s convolutions

Left For scientists, the brain is much more than simply gray matter. The folds and indentations in the form a specific pattern. Individual functions can be allocated to specific sections: the primary auditory cortex, for instance, is located in the Heschl’s convolutions. Right Handedness manifests itself at a very early stage. Based on the preferred thumb, hand preference can be clearly determined, not only in babies, but even in 15-week-old embryos.

cluded a remarkably high number of ual weight: here, too, a myriad of SNPs gene, in other words how frequently it left-handed individuals. “These are re- and other forms of modifications in is transcribed. ally the best conditions for detecting the genome influence the phenotype All of this clearly shows that anyone genetic material for the phenomenon,” – the observable physical characteris- searching for genetic causes for asym- An initiative of the Robert Bosch Stiftung in cooperation with says Tulya Kavaklioglu, the doctoral tics. In addition, at least height and metry in the brain and behavior needs Expert Database of Outstanding Spektrum der Wissenschaft and Nature Publishing Group student entrusted with this topic in weight are also shaped by environ- not only stamina but, most important- Francks’ team. “Still, we found abso- mental influences, a phenomenon ly, a large number of test subjects. This Female Academics lutely nothing.” that could also play a part in the later- is the only way that slight effects can Frustrating for the doctoral student, alization of the brain. be detected. To this end, large research yet an important finding for this area networks have been established in re- AcademiaNet is a unique service for research facilities, of research. The apparent failure under- DISRUPTED ASYMMETRY COULD cent years. These include the interna- scores how complex and multifaceted CAUSE DISORDERS tional consortium ENIGMA (Enhanc- journalists and conference organisers searching for outstanding the genetic influences must be that ul- ing Neuro Imaging Genetics through female academics with boardroom experience and management timately lead to a certain region of the Added to this are so-called epigenetic Meta-Analysis), whose objective is to skills on top of their excellent qualifications. brain being more strongly lateralized in mechanisms, DNA modifications that pool data from imaging procedures and some people than in others, or to cer- affect whether and to what extent a cer- genetic studies in order to gain a better AcademiaNet, the European expert database of tain individuals preferring the left hand tain gene or a certain variation even has understanding of the brain and its outstanding female academics, offers: over the right hand. any impact. In 2014, Francks’ team de- functioning in very large groups of sub- “We can be very sure that there is tected such an effect in the LRRTM1 jects. Clyde Francks heads up the Later- :: Over 2.100 profiles of highly qualified female no single gene variation that deter- gene. This is the gene that Francks as- alization group in this network. researchers of all disciplines and fields – nominated by over mines handedness or brain asymme- sociated with the propensity for At this point, the question may well try,” emphasizes Francks. Instead, a left-handedness during his time in Ox- be asked: Why are the Nijmegen re- 48 renowned partner organisations in 18 countries number of variations in the genome ford – at least when there is hypermeth- searchers even making such a major ef- seem to ultimately lead to the anatom- ylation of LRRTM1, that is, when it fort to detect a few fine genetic traces :: Customised search options according to discipline and area ical manifestation that researchers see contains too few methyl groups com- that make tiny contributions to the in- of expertise in their brain scans or simply in their pared to a “healthy” variant. This in- dividual brain anatomy? Is it important subjects’ preferred hand. This is simi- volves small chemical appendages on to know why Heschl’s convolutions are :: Current news about »Women in Science«

lar to body size, eye color and individ- the DNA that affect the activity of a manifested in a particular way in one Graphic: Max Planck Institute for Psycholinguistics; photo: shutterstock www.academia-net.org 40 MaxPlanckResearch 3 | 16 person and slightly differently in an- other? And what is the use of knowing about genes that help determine TO THE POINT

whether we prefer to use our right or l The two halves of the perform different tasks, but the asymmetry left hand for certain activities? varies in each individual.

“We are interested in understanding l There is no clear link between right- and left-handedness and the distribution the fundamental genetic and molecu- of other functions in the human brain. Thus, in terms of language processing, lar biological principles that lead to lat- the brain structure of left-handed people is, in most cases, similar to that of eralization of the brain,” says Francks. right-handed people. Disorders such as also l Certain brain asymmetries manifest themselves differently in men and women. appear to be linked to insufficient cere- l The search for the genetic causes of right- and left-handedness and of deviations bral lateralization. And deviations in in brain symmetry has proved to be difficult. the asymmetry of certain structures deep inside the cerebrum evidently play a role in hyperactivity in children. GLOSSARY “If we understand the mechanisms of Lateralization: A basic biological principle whereby the human body, despite its symmetri- how the asymmetry occurs, we can cal appearance, exhibits anatomical and functional differences between the right and left then move on to investigating at what halves. Lateralization of the brain is most apparent in language processing. point something goes wrong if the lat- Single Nucleotide Polymorphism (SNP): A variation of an individual base pair in a DNA eralization is damaged,” says Francks. strand. SNPs are inherited and hereditary genetic variants – in contrast to mutations, which And that would be an important first generally indicate a new modification. step in one day helping people affected by the phenomenon.

An initiative of the Robert Bosch Stiftung in cooperation with Expert Database of Outstanding Spektrum der Wissenschaft and Nature Publishing Group Female Academics

AcademiaNet is a unique service for research facilities, journalists and conference organisers searching for outstanding female academics with boardroom experience and management skills on top of their excellent qualifications.

AcademiaNet, the European expert database of outstanding female academics, offers:

:: Over 2.100 profiles of highly qualified female researchers of all disciplines and fields – nominated by over 48 renowned partner organisations in 18 countries

:: Customised search options according to discipline and area of expertise

:: Current news about »Women in Science« Graphic: Max Planck Institute for Psycholinguistics; photo: shutterstock www.academia-net.org