Transcranial direct current stimulation (tDCS): a novel therapeutic treatment

Dr Donel Martin School of Psychiatry, UNSW

. Leading tertiary referral clinic for brain stimulation treatment in Australia Sydney . Conducted first RCT of rTMS Neurostimulation in Australia in 1997

Centre . Conducted first RCT of tDCS in (SyNC) Australia in 2007

. Training courses on rTMS and tDCS since 2014

Transcranial Direct Current Stimulation (tDCS)

Anode (+ve)

Cathode (-ve) tDCS = small unidirectional current (1-2mA) Clinical translation potential of tDCS

‘Home-supervised’ tDCS ‘DIY’ tDCS tDCS: Lasting effects after stimulation

13 min

9 min 7 min 11 min 5 min

Nitsche & Paulus (2001) tDCS: Applications (-2013)

Bikson et al., 2016 Why tDCS for depression? control network

Fitzgerald et al., 2010

Rayner et al., 2016 tDCS: Antidepressant effects (Brunoni et al., 2016)

Active Sham OR CI NNT Response 34% 19% 2.44 1.38-4.32 7 Remission 23.1% 12.7% 2.38 1.22-4.64 9 tDCS: Effects on learning

Reis et al., 2009 tDCS enhances rehabilitation after stroke

Overall positive effect of tDCS + training compared to sham tDCS + training

Positive effects found for subacute and chronic phases

Kang et al., 2016 Transcranial direct current stimulation

 tDCS causes lasting modifications in neuronal excitability

 Promising antidepressant effects, though modest

 Can improve learning when applied during concurrent training/rehabilitation

 Excellent translation potential

However…

 “Current evidence does not allow making any recommendation of Level A (definite efficacy) for any indication…” Lefaucheur et al., 2017. Evidence-based guidelines

 Large inter-individual variability in outcomes after tDCS (e.g., depression)

 Need to first optimise/individualise tDCS “dose” Acknowledgments Sydney Neurostimulation Centre (SyNC), Black Dog Institute Angelo Alonzo Nicholas Chand Veronica Galvez Ortiz Stevan Nikolin Vanessa Dong Giselle Lo Ada Wong Lucy McGuirk Divya Kumar Kevin Yeung Shani Lauf Colleen Loo Seeking Volunteers:

Clinical trial in older adults (60-85) with Mild Memory Problems

CONTACT: Donel Martin Ph: (02) 9382 8353 [email protected]

Transcranial Magnetic Stimulation (TMS) a real alternative for Major Depression Disorder

Dr Jason Pace What is Transcranial Magnetic Stimulation ?

TMS technology was invented in 1985. Consists of a coil which is placed on a persons head and applies a pulsating magnetic energy to the cerebral cortex This subsequently induces electrical activity in the brain. rTMS is when TMS is delivered in a repeated sequence of pulsing magnetic energy that is applied for the treatment.

While is comes from the school of brain stimulation, unlike ECT treatment, TMS does not involve inducing seizures and is administered to patients in an outpatient setting while fully awake and does not cause any cognitive impairment. What does rTMS treatment involve?

An initial planning session to creates a customised treatment plan for the patient.

Subsequent sessions last about 40 minutes. rTMS needs to be given at least 3 times a week.

Treatment for acute depression requires 30 sessions.

TMS can be given while patient are still taking medication.

rTMS tolerability Typically patient experience some discomfort in the scalp locally over the treatment area. This may cause a mild headache post treatment.

Despite some discomfort, patients rates rTMS as a very well tolerable and acceptable procedure. Studies show very few drop outs and clinically compliance is excellent.

No systemic side effects.

Very low risk of seizure.

Who is a good candidate for rTMS ?

TGA guidelines recommends - Treatment Resistant Depressive disorder

Consider prior to ECT

Consider if tolerating medication has been a problems

Unipolar or Bipolar Depression

Over 18 years and not pregnant is limited

TMS for TRD is equally effective in patient >65yr. (Conelea et al Journal of Affective Disorders, Aug 2017)

Effectiveness of TMS

 Carpenter et al.(Depress Anxiety 2012) in a multisite naturalistic study involving 307 patient from 42 clinics demonstrated 58% response rate and 37% remission rates, with the average patient receiving 28 treatment sessions.

 Antidepressant effect of TMS is independent of medication, a meta-analysis of 54 sham-controlled studies published between 1997–2013 (Kedzior et al, Neuropsychiatr Dis Treat. 2014).

 Over 15 meta-analyses of TMS for depression, including more recent randomised control studies all consistently show statistically significant efficacy. ( Perera et al, Brain Stimulation 9 (2016)

 TGA approved 2007, FDA approved 2008, RANZCP guidelines endorsed 2013, NICE indorsed 2016.

Long Term Benefits of TMS

Multisite, naturalistic observational study, shows improvement in depressive symptoms following a course of rTMS, was maintained over the 12 month period for both responders and remitters. (Dunner , Sackeim, Carpenter et al J Clin Psychiatry 2014).

Philip et al (Brain Stimulation 2016) showed that 70% of patients having benefited from TMS remained well 12 months. More importantly 70% of patient that relapsed, responded as well and quicker to a retreatment with TMS. This suggests TMS can be potentially useful in maintenances treatment. Sydney TMS

Started in December 2015

Treated 130 patients

Offices in Castle Hill & St Leonards

Accepting referrals for GPs and Psychiatrists for TRD patients only over 18yrs.

Our Observation

Mean age of 45.09 , Range 18-90 yrs

Sex 59% male , 41% female.

All Patients met diagnosis of Treatment resistant Major Depressive Disorder ( failed two adequate trails of medications)

Average number of TMS sessions - 28

In addition to clinical observations we also conduct baseline and repeated HAM-D and MADRS ( every 10 sessions) mean HAM-D pre treatment score 16.13 (SD=7.32) mean MADRS pre treatment score 26.15 (SD=10.75). Outcomes so far.

Analyses using SPSS was performed on data from 54 patients who completed at least 20 sessions. The level of statistical significance was set at p .05

Response – was defined as a 50% reduction in scores

Remission -was defined as HAMD (total score ≤7) and MADRS (total score ≤9)

Response or Remission 50% Response rate 41% Remission rates 28%

These results reached statistically significance even with only 54 patient.

Where to next for TMS treatment ?

 “Theta Burst “a new ultra high frequently TMS that is looking promising and reduces treatment times to 10 minutes so could reduce costs of treatment.

 More evidence is emerging regards safety of offering patients sessions in shorter intervals, eg 2-3 sessions daily safely.

 Other Conditions ;

 OCD - Kumar et al , Neuropsychiatry (London) (2016)

 Addictions- Gorelick et al Ann N Y Acad Sci. 2014 Oct

 Schizophrenia – Cochrane Review 2015- some evidence in reducing auditory hallucinations but generally quality of research is poor.

 Others…ADHD, Tourettes, Austism… very early work only

Take Home…….

TMS is NOT an experimental treatment, it is a Real treatment option and with over 20 years of research and international governing body endorsement,

TRD = should consider TMS rather than ongoing medication trial and certainly prior to ECT

TMS is not only good in acute treatment but maybe most useful as maintenance treatment for patient with chronic depression

Patient tolerability and acceptance of TMS is excellent.

PSYCHIATRY

PERMINDER SACHDEV CENTRE FOR HEALTHY BRAIN AGEING (CHeBA) UNIVERSITY OF NEW SOUTH WALES & NEUROPSYCHIATRIC INSTITUTE THE PRINCE of WALES HOSPITAL SYDNEY • Psychiatric disorders are often chronic and difficult to treat Treatment Resistant Depression (TRD) Lack of adequate clinical response after 2 well-delivered treatments First treatment: 50% respond (35% remit)1 Second treatment: 20-25% respond (10-15% remit)2,3 Thus, over 20% of depressed patients have TRD

About 10% of OCD is severe and disabling and resistant to treatment

1 Depression Guideline Panel. Vol. 1. 1993. 2 Fava M, et al. Psychiatr Clin North Am. 2003;26:457-494. 3 Rush AJ, Ryan ND. Current and emerging therapeutics for depression. In: Davis KL, et al (eds). 2002:1081-1095. How do we improve the treatment of psychiatric disorders?

• Better use of existing treatments • New drugs • New psychological treatments • Neuromodulation – TMS – tDCS – VNS – DBS Neural circuits underlie all behaviour A ‘connectogram’ for an example healthy adult female subject

The outermost ring shows the various brain regions arranged by lobe. The set of five rings (from the outside inward) reflect grey matter volume, area, thickness, curvature, and connectivity density. The lines inside of the circle represent the computed degrees of connectivity between segmented brain regions using diffusion tractography, with colour representing the relative fractional anisotropy of the connection.

1 5 O C T O B E R 2 0 1 5 | VO L 5 2 6 | N AT U R E | 3 7 7 The DeLong “Box” Models of Basal Ganglia Circuitry and Their Use in Guiding Deep-Brain Stimulation (DBS).

N Engl J Med 2012;367: 1529-38. Functional networks in the intrinsic activity of the brain.

Ann. N.Y. Acad. Sci. 1394 (2017) 31–54 C 2016 PSYCHOSURGERY

Surgical planning of deep brain stimulation of the antero-medial globus pallidus interna in a patient with Tourette Syndrome MECHANISMS

(1) Depolarization blockade: stimulation-induced alterations in the activation of voltage-gated currents that block neural output near the stimulating electrode (Beurrier et al., 2001)

(2) Synaptic inhibition: indirect inhibition of neuronal output by activation of axon terminals that make synaptic connections with neurons near the stimulating electrode (Dostrovsky et al., 2000)

(3) Synaptic depression: synaptic transmission failure of the efferent output of stimulated neurons as a result of transmitter depletion (Urbano et al., 2002)

(4) Network disruption: stimulation-induced disruption of pathologic network (Montgomery & Baker, 2000). PET scans before and after DBS DBS for psychiatric disorders

Tourette’s syndrome Thalamus (intralaminar nuclei) Globus pallidus internus Globus pallidus externus

Obsessive–compulsive disorder Internal capsule (anterior limb) Nucleus accumbens Subthalamic nucleus Inferior thalamic peduncle Caudate nucleus

Depression Subcallosal cingulate gyrus Internal capsule (anterior limb) Nucleus accumbens Inferior thalamic peduncle Lateral habenula

Aggressiveness Hypothalamus Drug addiction Nucleus accumbens Alzheimer’s disease Hypothalamus/fornix Minimally conscious states Thalamus (intralaminar nuclei) Obesity Hypothalamus Anorexia nervosa Subcallosal cingulate gyrus Autism Amygdala Location of various targets for ablation or DBS for psychiatric disorders. CGT, cingulotomy; CPT, capsulotomy; HAB, habenula; ITP, inferior thalamic peduncle; SCC, subcallosal cingulate; SCT, subcaudate tractotomy; VC/VS, ventral capsule/ventral striatum. Note that the current VC/VS target is more posterior and inferior to the classic CPT target (Greenberg et al. 2010); the VC/VS and NAcc targets span a very similar area (Greenberg et al. 2010, Schlaepfer et al. 2008); the SCC target is more medial and anterior to the classic SCT target; the classic CGT target is in the dorsal anterior cingulate (not rostral or subcallosal) Tourette Syndrome Double-blind clinical trial of thalamic stimulation in patients with Tourette Syndrome

Ackerman et al, Brain 2011: 134; 832–844

Centromedian nucleus - substantia periventricular - nucleus ventralis- oralis internus crosspoint in the thalamus Globus pallidus DBS

Martinez-Fernandez et al, 2011

Posterolateral GPi

Anteromedial GPi Patient characteristics

No. Age Sex Duration of Severity No. of drugs OCD Major Attentional Other Illness tried before Depression problems (Years) DBS 1 26 M 16 Severe 4 Y Y N Nil 2 18 F 14 Very severe 6 Y Y Y Severe self-injurious behavior, coprolalia

3 34 F 27 Severe 4 Y Y N Nil 4 25 F 15 Severe 5 Y N N Mild intellectual disability

5 33 M 24 Severe 31 Y Y N Anxiety dystonia

6 27 M 18 Severe 62 Y Y Y Anxiety 7 22 M 17 Severe 3 N N N Nil 8 30 M 20 Severe 4 N N N Nil 9 27 M 20 Severe 4 Y Y N OCD depression 10 38 M 33 Severe 6 Y N N Nil 11 50 M 45 Severe 3 Y N N Anxiety Change in Total Yale Global Tic Severity Score

100

90 84.45 80

70

60

50 45 42.55 40

30

20

10

0 TYGTSS Pre DBS TYGTSS 1 month post DBS TYGTSS final follow up DBS for TS

N = 11 1 Month 3 Months Wilcoxon paired Comparisons Mean SD Mean SD 3 months v BL Z (p)

M 22.36 (2.063) 10.91 (7.217) -2.803 (.002)

V 18.00 (4.960) 10.00 (6.856) -2.809 (.002)

TTSS 41.27 (6.857) 22.00 (14.450) -2.803 (.002)

TYGTSS 84.45 (13.619) 45.00 (24.572) -2.805 (.002)

YBOCS 15.82 (13.068) 6.82 (8.784) -2.371 (.016)

HDRS 16.45 (7.607) 6.55 (4.927) -2.848 (.002)

GAF 47.27 (15.551) 74.55 (15.725) -2.820 (.002)

GTS-QOL 39.09 (21.659) 73.18 15.045) -2.943 (.001) Updated series (N=17)

Friedman BL 1 month 3 months Final test

Mean Mean Mean Mean Χ2 (SD) (SD) (SD) (SD) (d.f.=3) 10.62 M 21.53 11.13 11.41 21.7*

V 17.59 10.33 8.62 9.18 25.2* TTSS 39.71 22.27 19.92 20.88 23.8* TYGTSS 81.76 46.47 42.62 39.12 26.0* YBOCS 13.88 6.80 5.54 5.35 17.1* 15.6* HDRS 15.35 6.60 5.31 8.24

GAF 50.00 76.00 74.62 73.53 24.9* GTS_QOL 40.88 72.67 75.38 66.76 30.0* * p<0.001

DEPRESSION Depression – open label studies

Author N Target Results Jimenez 2005 1 Inf thal remission peduncle Lozano 2008 20 Subcallosal 11/20 had >50% reduction 1 yr cing Malone 2009 15 VC/VS 6/15 in remission 1yr Bewernick 2010 10 NAc 5/10 with >50% reduction 1 yr Holtzheimer 17 Subcallosal 10/17 in remission 2 yrs 2012 cing Lozano 2012 21 Subcallosal 6/21 with >50% reduction 1 yr cing Puigdemont 8 Subcallosal 4/8 in remission at 1 yr 2012 cing Schlaepfer 2013 7 MFB 6/7 had >50% reduction 3-6 m Torres 1 Subcallosal remission cing Outcome during the 16-week blinded-treatment phase. MADRS, Montgomery–Åsberg Depression Rating Scale.

Darin D. Dougherty, et al. A Randomized Sham-Controlled Trial of Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Chronic Treatment-Resistant Depression. Biological Psychiatry, Volume 78, Issue 4, 2015, 240–248

The results of this first randomized controlled study of DBS for the treatment of TRD did not demonstrate a significant difference in response rates between the active and control groups at the end of the 16-week controlled phase. However, a range of 20% to 26.7% of patients did achieve response at any time during the open-label continuation phase

Long-term follow-up data. Top graph represents data as a continuous variable. Bottom graph represents data as a categorical variable. N=25 (32% men); mean age 53.2 (8.4) years. Mean HAM-D-17 scores decreased from 22.2 (20.3-24.1) at baseline to 15.9 (12.3-19.5) (P = .001)in the optimization phase (51.6 weeks); 10 patients (40%) were classified as responders and 15 (60%) as nonresponders. 16 patients entered the randomized 12-wk crossover phase. During active DBS, patients scored significantly lower on the HAM-D-17 scale (13.6 [95% CI, 9.8-17.4]) than during sham DBS (23.1 [95% CI, 20.6-25.6]) (P < .001). Bergfeld IO et al. JAMA Psychiatry May 2016 Volume 73, Number 5 Obsessive Compulsive Disorders (OCD) Nuttin et al. Long-term Electrical Capsular Stimulation in Patients with Obsessive-Compulsive Disorder. Neurosurgery 2003; 521263-1274. Bar graphs showing the effects of capsular stimulation on psychiatrist-rated Y-BOCS, CGS, and CGI scores. Y-BOCS (A) and CGS (B) scores of Patients 1, 2, 3, and 4 are shown at presurgical baseline (BASELINE), in the stimulator-on condition(ON), and in the stimulator-off condition (OFF) of the crossover design, after 6 months of continuous stimulation, after the end of the crossover design phase (CS), and the patients’ most recent scores in the stimulator-on condition (RECENT) (i.e., after 24 months in the trial for Patient 2 and after 21 months in the trial for Patient 3). Patient 3 refused to have the electrode switched off. Just before changing the electrode because of dead battery, a Y-BOCS score was obtained. C, CGI ratings with reference to presurgical baseline levels of the same patients. Recent data for Patient 1 are after capsulotomy. Y- BOCS score definitions: 0–7, subclinical; 8–15, mild; 16–23, moderate; 24–31, severe; 32–40, extremely severe. CGS score definitions: 0, no illness; 1, minimal; 2, mild; 3, moderate; 4, moderate;-severe; 5, severe; 6, very severe. CGI score definitions: 1, much worse; 2, minimally worse; 3, no change; 4, minimally improved; 5, much improved; 6, very much improved. From: Nuttin: Neurosurgery, Volume 52(6).June 2003.1263-1274

Average Global Assessment of Functioning scores over time. Mean YBOCS scores pretreatment and at each point.

DBS of the ventral internal capsule/ventral striatum for OCD: worldwide experience

Greenberg B, et al. Molecular Psychiatry (2010) 15, 64–79 NAc DBS for OCD (N=16)

Denys et al. Arch Gen Psychiatry. 2010;67(10):1061-1068

Change in absolute Y-BOCS, HAM-A,and HAM-D scores across the study (84 weeks). A, Change in the open phase (32 weeks). B, Summed increases (weeks 32-34) and decreases (weeks 34-36) during the crossover phase. C, Changes in the maintenance phase (weeks 36-84).

In the open phase, the mean (SD) Y-BOCS score decreased by 46%, from 33.7 (3.6) at baseline to 18.0 (11.4) after 8 months (P.001). Nine of 16 patients were responders, with a mean (SD) Y-BOCS score decrease of 23.7 (7.0), or 72%. In the double-blind, sham-controlled phase (n=14), the mean (SD) Y-BOCS score difference between active and sham stimulation was 8.3 (2.3), or 25% (P=.004). Depression and anxiety decreased significantly. Except for mild forgetfulness and word-finding problems, no permanent adverse events were reported. Comparison between baseline scores of the DBS group and a Dutch norm population in WHOQOL-BREF before and after DBS. WHOQOL-BREF, WHO Quality of Life Scale Brief Version—Range: domain scores 4–20, higher scores indicate better quality of life brief version;

Pieter Ooms et al. J Neurol Neurosurg Psychiatry 2014;85:153-158 Adverse events

Surgery related: – Wound infection – Haemorrhage Device related: – Breakage of leads – Feeling of leads, neurostimulator – Feeling of electric current around stimulator Stimulation related: – Psychiatric – Physical RANZCP Position Statement

 DBS is a well-established procedure for the treatment of advanced movement disorders, such as Parkinson’s disease, tremor and dystonia. It has also been used in the control of the movement disorder associated with severe and medically intractable Tourette syndrome.

 Current research and clinical trials into the use of DBS to treat psychiatric disorders such as OCD, depression, substance use disorders, and anorexia are slowly occurring worldwide. It has been approved by the Food and Drug Administration for OCD treatment in the US but is still considered an experimental treatment for this disorder in most countries.

 Whilst further research and clinical trials are required to develop a substantial body of evidence to support efficacy and safety of DBS to treat psychiatric disorders, there is evidence to suggest that it may play a role in the treatment of a select group of patients with severe / treatment resistant psychiatric disorders in the future.

 Its use in psychiatric disorders should be considered experimental at this time and only be applied in the context of appropriately developed and human research and ethics committee approved clinical studies. Avoiding the errors of Psychosurgery

• Use only in severely disabled individuals • Obtain full informed consent • Further knowledge of mechanisms • Use double blind controlled investigations when possible to evaluate outcome • Supported by interdisciplinary teams • To help restore (but not augment) normal function • Follow up every patient diligently and report results in scientific journals

QEEG & Neurofeedback

A/Prof Roger Gurr Western Sydney University headspace Youth Early Psychosis Program Objective Measures of Brain Functioning

• Functional Molecular Resonance Imaging – fMRI • Amplitude of radio waves re-emitted by hydrogen protons of the brain located in a strong magnetic field. Functional MRI records vascular reactions of the brain tissue in response to tasks. • Positron Emission Tomography – PET • A nuclear medicine functional imaging technique that is used to observe metabolic processes in the body. • Electroencephalography – EEG • Recording on the scalp the electrical potentials created by brain activity. • Event Related Potentials – ERP • Brain electrical activity generated by structured tasks, traits vs current state. • Comparison database for age group and ERP method.

What is EEG?

Electroencephalography... EEG is often used to diagnose ... is a process used to image the brain while at seizures or check for changes in rest or is performing a cognitive task. consciousness

EEG can also be used:

in the clinical assessment of clients to guide therapeutic interventions

as an outcome measure – to evaluate

efficacy of therapy

CLINICAL WORK: EEG for Assessment and Outcomes Measurement 4 How do we record EEG

Electroencephalography is a simple, painless and completely safe procedure. The brain electrical activity is recorded by multiple sensors placed on the scalp.

The sensors are attached to the amplifier that enhances the electrical signals captured on the surface of the scalp. This signal is further analysed by a specially designed computer program.

5 CLINICAL WORK: EEG for Assessment and Outcomes Measurement The EEG reflects brain states

Brain waves arise from synchronised activation of many neurons. This is how different areas of the brain communicate with each other and how the brain communicates with the rest of the body.

Slower brain waves (Delta, Theta and Alpha) indicate lower level of activity, idling or sleep

Faster brain waves (Beta, High Beta, Gamma) indicate high level of activity

An EEG reading indicates which parts of the brain are functioning properly and which are not.

CLINICAL WORK: EEG for Assessment and Outcomes Measurement 6 EEG at STARTTS: in Assessment

EEG is used at STARTTS for assessment of clients

To discern possible causes of problems (such as headaches, memory loss or attentional difficulties)

To determine which therapeutic interventions may be appropriate with complex cases

To determine if neurofeedback is an appropriate intervention, and to guide the intervention

CLINICAL WORK: EEG for Assessment and Outcomes Measurement 7 Case examples – EEG in Assessment

Case 2: Use of EEG to investigate the possible cause of memory difficulties in a client presenting with PTSD symptoms in order to make a decision about appropriate intervention (38 y.o. male)

Faster alpha brain-wave activity is suggestive of the sympathetic nervous system overarousal frequently seen in PTSD. Poor working memory could be a result of a high level of arousal, rather than specific brain dysfunction. Deep relaxation exercises could be recommended.

CLINICAL WORK: EEG for Assessment and Outcomes Measurement 8 EEG at STARTTS: to guide neurofeedback treatment

EEG can help in guiding 1 EEG recording eyes closed neurofeedback treatment

Through EEG testing and clinical assessment we determine the most appropriate neurofeedback 2 Maps of spectral display treatment protocol.

Changes in EEG over the course of neurofeedback treatment help us revise the changes and help us plan further treatment.

CLINICAL WORK: EEG for Assessment and Outcomes Measurement 9 EEG at STARTTS: as an Outcomes Measure

1 Maps of asymmetry of EEG power EEG is a resource for evaluating the spectra before the treatment effectiveness of therapy

Brainwave activity can be shown graphically as Brain Mapping. Maps of asymmetry of EEG power Mapping shows activity recorded 2 spectra after treatment through separate electrodes to

provide a detailed picture.

In this example, changes in brainwave activity after therapeutic Brain mapping shows normalisation of the intervention can be observed. left pre-frontal cortex functioning after 20 CBT sessions

CLINICAL WORK: EEG for Assessment and Outcomes Measurement 10 Go NoGo

Why EEG Neurofeedback

• Interacts directly with behaviour of the cortex and functional networks, bypassing consciously held agendas • Utilises the principles by which the brain learns: engage, reward, repeat and reinforce • Drives plastic change • Easy to participate • Lasting change Neurofeedback Games

Growing Evidence Base

• Post traumatic stress disorder • Controlled studies • Measurement of change correlates with subjective improvement • Developmental Trauma Disorder • Clinical evidence – hard to do controlled trials • ADHD sub groups • Problems of grouping 7 disparate disorders with similar symptoms • Autism Spectrum Disorders • Obsessive Compulsive Disorder • Epilepsy • ? Auditory Verbal Hallucinations • ? Schizophrenia - corollary discharges

Inspiring reading:

Neurofeedback in the Treatment of Developmental Trauma Calming the Fear-Driven Brain

Sebern Fisher, WW. Norton & Co, 2014

Contact: [email protected]