Brain Stimulation for Emotion Regulation in Adolescents With Psychiatric Disorders: Study Protocol for a Clinical-Transdiagnostical, Randomized, Triple-Blinded and Sham-Controlled Neurotherapeutic Trial

Background Anxiety, conduct and depressive disorders represent three highly prevalent psychiatric conditions in adolescents. A shared underpinning of these disorders is a shortcoming in emotion regulation, connected to the functioning of the ventromedial prefrontal cortex. Thus, an intervention able to target the suggested neural correlate seems to be highly desirable, aiming to hinder a maladaptive development of emotion regulation abilities and chronification of associated psychiatric disorders. As transcranial direct current stimulation (tDCS) was repeatedly demonstrated as a safe and non-invasive method to modulate specific brain activity, research is in demand to evaluate neurotherapeutic applications in adolescents with psychiatric disorders. Method This transdiagnostic, randomized, triple-blind and sham-controlled clinical neurostimulation trial primary aims to investigate if emotion regulation abilities are increased after tDCS in adolescents with psychiatric disorders. Secondly, disorder-specific changes in the anxiety, depression or conduct disorder will be investigated, as well as changes in quality of life, and cognitive and emotional functioning after tDCS intervention. We will include 108 adolescents with psychiatric disorders, displaying a substantial deficit in emotion regulation. Of these, one third each has to be primarily diagnosed with a depressive, anxiety or conduct disorder, respectively. Participants will be randomized to the experimental group (n = 54) receiving real anodal tDCS, or to the control group (n = 54) receiving sham tDCS. Brain stimulation will be applied for 20 min on five consecutive days twice targeting the ventromedial prefrontal cortex (vmPFC). Changes in emotion regulation, together with changes in disorder-specific clinical symptoms will be recorded by multi-informant psychological ratings. To inspect changes in behavior and gaze, computerized tasks and an eye tracker system will be used. Changes in brain responses to emotional and cognitive stimuli will be examined with three functional magnetic resonance imaging (fMRI) paradigms. In addition, a resting state MRI will be acquired to investigate possible changes in brain connectivity. Discussion By investigating “emotion regulation” as transdiagnostic treatment target, this project is oriented toward the Research Domain Criteria framework with a dimensional view on mental illness. The study aims at investigating the potential of tDCS as non-invasive intervention for depressive, anxiety and conduct disorders in adolescents and broadening the scientific foundation for its clinical application. Clinical Trial Registration The study is ongoing and has been registered in the German Registry of Clinical Trials (DRKS-ID: DRKS00025601X) on the 28.06.2021.

[1]  Alexander Opitz,et al.  Determinants of the electric field during transcranial direct current stimulation , 2015, NeuroImage.

[2]  T. Hendler,et al.  Modulating Emotional Experience Using Electrical Stimulation of the Medial‐Prefrontal Cortex: A Preliminary tDCS‐fMRI Study , 2019, Neuromodulation : journal of the International Neuromodulation Society.

[3]  P. Ciechanski,et al.  Modeling Transcranial Direct-Current Stimulation-Induced Electric Fields in Children and Adults , 2018, Front. Hum. Neurosci..

[4]  N. J. Davis.  Transcranial stimulation of the developing brain: a plea for extreme caution , 2014, Front. Hum. Neurosci..

[5]  V. Arolt,et al.  Of ‘Disgrace’ and ‘Pain’ – Corticolimbic Interaction Patterns for Disorder-Relevant and Emotional Words in Social Phobia , 2014, PloS one.

[6]  O. Piguet,et al.  Transcranial direct current stimulation (tDCS) over vmPFC modulates interactions between reward and emotion in delay discounting , 2019, Scientific Reports.

[7]  N. Heinrichs,et al.  Die Eltern-Kurzversion des Fragebogens zur Erhebung der Emotionsregulation bei Kindern und Jugendlichen (FEEL-KJ) , 2018 .

[8]  M. Craske,et al.  Positive and Negative Emotion Regulation in Adolescence: Links to Anxiety and Depression , 2019, Brain sciences.

[9]  P. Auquier,et al.  KIDSCREEN-52 quality-of-life measure for children and adolescents , 2005, Expert review of pharmacoeconomics & outcomes research.

[10]  Z. Daskalakis,et al.  Transcranial Direct Current Stimulation: Considerations for Research in Adolescent Depression , 2017, Front. Psychiatry.

[11]  Lehana Thabane,et al.  Treating child and adolescent anxiety effectively: Overview of systematic reviews. , 2015, Clinical psychology review.

[12]  S. Lisanby,et al.  The Dynamic Duo: Combining noninvasive brain stimulation with cognitive interventions , 2019, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[13]  M. Nitsche,et al.  Physiology of Transcranial Direct Current Stimulation , 2018, The journal of ECT.

[14]  B. J. Casey,et al.  Baseline brain function in the preadolescents of the ABCD Study , 2021, Nature Neuroscience.

[15]  A. Grob,et al.  FEEL-KJ : Fragebogen zur Erhebung der Emotionsregulation bei Kindern und Jugendlichen , 2006 .

[16]  E. Leibenluft,et al.  Abnormal ventromedial prefrontal cortex function in children with psychopathic traits during reversal learning. , 2008, Archives of general psychiatry.

[17]  K. Shadan,et al.  Available online: , 2012 .

[18]  Natalie C. Ebner,et al.  FACES—A database of facial expressions in young, middle-aged, and older women and men: Development and validation , 2010, Behavior research methods.

[19]  J. Thorne,et al.  Transcranial direct current stimulation of the prefrontal cortex modulates working memory performance: combined behavioural and electrophysiological evidence , 2011, BMC Neuroscience.

[20]  Christina F. Chick,et al.  Identification of Common Neural Circuit Disruptions in Emotional Processing Across Psychiatric Disorders. , 2020, The American journal of psychiatry.

[21]  Lourdes Rey,et al.  In pursuit of job satisfaction and happiness: Testing the interactive contribution of emotion-regulation ability and workplace social support. , 2018, Scandinavian journal of psychology.

[22]  D. De Ridder,et al.  Changing Brain Networks Through Non-invasive Neuromodulation , 2018, Front. Hum. Neurosci..

[23]  Á. Pascual-Leone,et al.  Transcranial Magnetic and Direct Current Stimulation in Children , 2017, Current Neurology and Neuroscience Reports.

[24]  P. Staiger,et al.  Emotion regulation as a transdiagnostic treatment construct across anxiety, depression, substance, eating and borderline personality disorders: A systematic review. , 2017, Clinical psychology review.

[25]  Katherine E. Prater,et al.  Failure of anterior cingulate activation and connectivity with the amygdala during implicit regulation of emotional processing in generalized anxiety disorder. , 2010, The American journal of psychiatry.

[26]  Lesley K. Fellows,et al.  Ventromedial Frontal Lobe Plays a Critical Role in Facial Emotion Recognition , 2008, Journal of Cognitive Neuroscience.

[27]  P. Frick,et al.  Inventory of Callous–Unemotional Traits , 2017 .

[28]  Thomas Dierks,et al.  The development and evaluation of a computer-based program to test and to teach the recognition of facial affect , 2002, International journal of circumpolar health.

[29]  Y. Wang.  Transcranial direct current stimulation for the treatment of major depressive disorder: A meta-analysis of randomized controlled trials , 2019, Psychiatry Research.

[30]  T. Hendler,et al.  Attenuating anger and aggression with neuromodulation of the vmPFC: A simultaneous tDCS-fMRI study , 2018, Cortex.

[31]  Lena Sarp,et al.  The fade-in – Short stimulation – Fade out approach to sham tDCS – Reliable at 1 mA for naïve and experienced subjects, but not investigators , 2012, Brain Stimulation.

[32]  E. Santarnecchi,et al.  tDCS targeting the Ventromedial Prefrontal Cortex reduces reactive aggression and modulates electrophysiological responses in a forensic population. , 2021, Biological psychiatry. Cognitive neuroscience and neuroimaging.

[33]  G. Hartwigsen,et al.  Effects of single-session transcranial direct current stimulation on reactive response inhibition , 2021, Neuroscience & Biobehavioral Reviews.

[34]  Joseph E LeDoux,et al.  Extinction Learning in Humans Role of the Amygdala and vmPFC , 2004, Neuron.

[35]  C. Loo,et al.  Noninvasive brain stimulation in psychiatric disorders: a primer , 2018, Revista brasileira de psiquiatria.

[36]  M. Nitsche,et al.  Studying and modifying brain function with non-invasive brain stimulation , 2018, Nature Neuroscience.

[37]  E. Dubow,et al.  Continuity of aggression from childhood to early adulthood as a predictor of life outcomes: implications for the adolescent-limited and life-course-persistent models. , 2009, Aggressive behavior.

[38]  Aaron D. J. Frost,et al.  A Measure of Cognitive and Affective Empathy in Children Using Parent Ratings , 2008, Child psychiatry and human development.

[39]  S. Shimojo,et al.  Noninvasive remote activation of the ventral midbrain by transcranial direct current stimulation of prefrontal cortex , 2013, Translational Psychiatry.

[40]  P. Riva,et al.  Modulation of negative emotions through anodal tDCS over the right ventrolateral prefrontal cortex , 2018, Neuropsychologia.

[41]  M. Bajbouj,et al.  Transcranial Direct Current Stimulation Enhances Cognitive Control During Emotion Regulation , 2014, Brain Stimulation.

[42]  A. Carvalho,et al.  Repetitive Transcranial Magnetic Stimulation for the Acute Treatment of Major Depressive Episodes: A Systematic Review With Network Meta-analysis , 2017, JAMA psychiatry.

[43]  Joshua M. Carlson,et al.  VENTROMEDIAL PREFRONTAL CORTEX REACTIVITY IS ALTERED IN GENERALIZED ANXIETY DISORDER DURING FEAR GENERALIZATION , 2013, Depression and anxiety.

[44]  M. Nitsche,et al.  Pharmacological Modulation of Cortical Excitability Shifts Induced by Transcranial Direct Current Stimulation in Humans , 2003, The Journal of physiology.

[45]  Michael A. Nitsche,et al.  Non-invasive brain stimulation for the treatment of brain diseases in childhood and adolescence: state of the art, current limits and future challenges , 2013, Front. Syst. Neurosci..

[46]  F. Taremian,et al.  Transcranial Direct Current Stimulation on Opium Craving, Depression, and Anxiety: A Preliminary Study. , 2019, The journal of ECT.

[47]  R. Cohen Kadosh,et al.  Brain stimulation for treatment and enhancement in children: an ethical analysis , 2014, Front. Hum. Neurosci..

[48]  Mark W. Woolrich,et al.  Resting-state fMRI in the Human Connectome Project , 2013, NeuroImage.

[49]  Adam J. Woods,et al.  Dosage Considerations for Transcranial Direct Current Stimulation in Children: A Computational Modeling Study , 2013, PloS one.

[50]  L. J. Martinussen,et al.  Inhibition of emotions in healthy aging: age‐related differences in brain network connectivity , 2021, Brain and behavior.

[51]  Katie A McLaughlin,et al.  Emotion regulation deficits in generalized anxiety disorder, social anxiety disorder, and their co-occurrence. , 2009, Journal of anxiety disorders.

[52]  B. Abler,et al.  Emotion Regulation Questionnaire – Eine deutschsprachige Fassung des ERQ von Gross und John , 2009 .

[53]  Heather L. Urry,et al.  Failure to Regulate: Counterproductive Recruitment of Top-Down Prefrontal-Subcortical Circuitry in Major Depression , 2007, The Journal of Neuroscience.

[54]  M. Koenigs,et al.  The Multifaceted Role of the Ventromedial Prefrontal Cortex in Emotion, Decision Making, Social Cognition, and Psychopathology , 2017, Biological Psychiatry.

[55]  A. Brunoni,et al.  Transcranial direct current stimulation for the treatment of generalized anxiety disorder: A randomized clinical trial. , 2019, Journal of affective disorders.

[56]  J. Carlin,et al.  The prognosis of common mental disorders in adolescents: a 14-year prospective cohort study , 2014, The Lancet.

[57]  A. Etkin,et al.  Common abnormalities and disorder-specific compensation during implicit regulation of emotional processing in generalized anxiety and major depressive disorders. , 2011, The American journal of psychiatry.

[58]  L. Poustka,et al.  Repeated Sessions of Transcranial Direct Current Stimulation on Adolescents With Autism Spectrum Disorder: Study Protocol for a Randomized, Double-Blind, and Sham-Controlled Clinical Trial , 2021, Frontiers in Psychiatry.

[59]  R. C. Oldfield.  The assessment and analysis of handedness: the Edinburgh inventory. , 1971, Neuropsychologia.

[60]  Heidi Johansen-Berg,et al.  Polarity-specific effects of motor transcranial direct current stimulation on fMRI resting state networks☆ , 2014, NeuroImage.

[61]  W. Kirchner.  Age differences in short-term retention of rapidly changing information. , 1958, Journal of experimental psychology.

[62]  S. Calkins,et al.  The role of emotion regulation in children's early academic success. , 2007 .

[63]  Susmita Halder,et al.  Cognitive Behavior Therapy for Children and Adolescents: Challenges and Gaps in Practice , 2019, Indian journal of psychological medicine.

[64]  M. Garvey,et al.  The National Institute of Mental Health Research Domain Criteria and Clinical Research in Child and Adolescent Psychiatry. , 2016, Journal of the American Academy of Child and Adolescent Psychiatry.

[65]  M. Nitsche,et al.  A systematic review on the therapeutic effectiveness of non-invasive brain stimulation for the treatment of anxiety disorders , 2019, Neuroscience & Biobehavioral Reviews.

[66]  J. Treasure,et al.  Mental health problems in Austrian adolescents: a nationwide, two-stage epidemiological study applying DSM-5 criteria , 2017, European Child & Adolescent Psychiatry.

[67]  F. Zappasodi,et al.  Local and remote effects of transcranial direct current stimulation on the electrical activity of the motor cortical network , 2014, Human brain mapping.

[68]  Daniel Lundqvist,et al.  The EU-Emotion Stimulus Set: A validation study , 2016, Behavior research methods.

[69]  H. Damasio,et al.  Characterization of the decision-making deficit of patients with ventromedial prefrontal cortex lesions. , 2000, Brain : a journal of neurology.

[70]  Sarah H. Lisanby,et al.  Fundamentals of transcranial electric and magnetic stimulation dose: Definition, selection, and reporting practices , 2012, Brain Stimulation.

[71]  Joseph M. Orr,et al.  The Organization of Right Prefrontal Networks Reveals Common Mechanisms of Inhibitory Regulation Across Cognitive, Emotional, and Motor Processes. , 2016, Cerebral cortex.

[72]  F. Schreiber,et al.  Erfassung der Emotionsregulation bei Jugendlichen anhand des „Affective Style Questionnaire – Youth (ASQ-Y)“ , 2019, Diagnostica.

[73]  Maite Garaigordobil,et al.  Child and Adolescent Depression: A Review of Theories, Evaluation Instruments, Prevention Programs, and Treatments , 2019, Front. Psychol..

[74]  M. B. Nielsen,et al.  Emotion Regulation in Current and Remitted Depression: A Systematic Review and Meta-Analysis , 2018, Front. Psychol..

[75]  Yuyou Chen,et al.  Modulating the Activity of the VMPFC With tDCS Alters the Social Framing Effect , 2021, Frontiers in Behavioral Neuroscience.

[76]  Abhishek Datta,et al.  State-of-art neuroanatomical target analysis of high-definition and conventional tDCS montages used for migraine and pain control , 2015, Front. Neuroanat..

[77]  I. Benseñor,et al.  Efficacy and Safety of Transcranial Direct Current Stimulation as an Add-on Treatment for Bipolar Depression: A Randomized Clinical Trial , 2017, JAMA psychiatry.

[78]  Arno Villringer,et al.  Dynamic modulation of intrinsic functional connectivity by transcranial direct current stimulation. , 2012, Journal of neurophysiology.

[79]  M. Koenigs,et al.  Ventromedial Prefrontal Cortex Is Critical for the Regulation of Amygdala Activity in Humans , 2015, Biological Psychiatry.

[80]  D. Wechsler.  Wechsler Adult Intelligence Scale , 2021, Encyclopedia of Evolutionary Psychological Science.

[81]  F. Fregni,et al.  Safety and acceptability of transcranial direct current stimulation for the acute treatment of major depressive episodes: Analysis of individual patient data. , 2017, Journal of affective disorders.

[82]  Wayne M Glines,et al.  Epidemiology of mental disorders in children and adolescents , 2009, Dialogues in clinical neuroscience.

[83]  P. Ekman,et al.  Constants across cultures in the face and emotion. , 1971, Journal of personality and social psychology.

[84]  M. Nitsche,et al.  Evaluation of Sham Transcranial Direct Current Stimulation for Randomized, Placebo-Controlled Clinical Trials , 2013, Brain Stimulation.

[85]  Jacqueline K. Harris,et al.  Reduced accuracy accompanied by reduced neural activity during the performance of an emotional conflict task by unmedicated patients with major depression: A CAN-BIND fMRI study. , 2019, Journal of affective disorders.

[86]  Hang Ye,et al.  Modulating the Activity of vmPFC Regulates Informational Social Conformity: A tDCS Study , 2020, Frontiers in Psychology.

[87]  G. Salum,et al.  Annual research review: A meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. , 2015, Journal of child psychology and psychiatry, and allied disciplines.

[88]  L. Parra,et al.  Inter-Individual Variation during Transcranial Direct Current Stimulation and Normalization of Dose Using MRI-Derived Computational Models , 2012, Front. Psychiatry.

[89]  C. Urgesi,et al.  Non-invasive Brain Stimulation for the Rehabilitation of Children and Adolescents With Neurodevelopmental Disorders: A Systematic Review , 2019, Front. Psychol..

[90]  M. Bikson,et al.  Evidence-Based Guidelines and Secondary Meta-Analysis for the Use of Transcranial Direct Current Stimulation in Neurological and Psychiatric Disorders , 2020, The international journal of neuropsychopharmacology.

[91]  D Cicchetti,et al.  Emotion regulation among school-age children: the development and validation of a new criterion Q-sort scale. , 1997, Developmental psychology.

[92]  Amanda S Morris,et al.  Assessing callous-unemotional traits in adolescent offenders: validation of the Inventory of Callous-Unemotional Traits. , 2008, International journal of law and psychiatry.

[93]  T. In-Albon,et al.  Überprüfung der Gütekriterien der deutschen Version der Difficulties in Emotion Regulation Scale in einer klinischen und einer Schülerstichprobe Jugendlicher , 2018, Zeitschrift für Klinische Psychologie und Psychotherapie.

[94]  Martin A. Lindquist,et al.  Response variability of different anodal transcranial direct current stimulation intensities across multiple sessions , 2017, Brain Stimulation.

[95]  C. Krishnan,et al.  Safety of Noninvasive Brain Stimulation in Children and Adolescents , 2015, Brain Stimulation.

[96]  Megan A. Boudewyn,et al.  Transcranial direct current stimulation: a roadmap for research, from mechanism of action to clinical implementation , 2019, Molecular Psychiatry.

[97]  M. Herrmann,et al.  Augmentation of Fear Extinction by Transcranial Direct Current Stimulation (tDCS) , 2018, Front. Behav. Neurosci..

[98]  N. Koutsouleris,et al.  Transcranial direct current stimulation in children and adolescents: a comprehensive review , 2016, Journal of Neural Transmission.

[99]  Brent G. Nelson,et al.  Low-Intensity Transcranial Current Stimulation in Psychiatry. , 2017, The American journal of psychiatry.

[100]  J. Mattingley,et al.  Understanding the minds of others: A neuroimaging meta-analysis , 2016, Neuroscience & Biobehavioral Reviews.

[101]  R. Adolphs,et al.  Damage to the prefrontal cortex increases utilitarian moral judgements , 2007, Nature.

[102]  G. Stams,et al.  UvA-DARE ( Digital Academic Repository ) Measuring Empathy in a German Youth Prison : A Validation of the German Version of the Basic Empathy Scale ( BES ) in a Sample of Incarcerated Juvenile Offenders , 2017 .

[103]  C. Panari,et al.  Emotion Regulation and Employability: The Mediational Role of Ambition and a Protean Career among Unemployed People , 2020, Sustainability.

[104]  S. Rossi,et al.  Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines , 2017, Clinical Neurophysiology.

[105]  Colleen K. Loo,et al.  Inter- and Intra-individual Variability in Response to Transcranial Direct Current Stimulation (tDCS) at Varying Current Intensities , 2015, Brain Stimulation.

[106]  C. Spielberger,et al.  Manual for the State-Trait Anxiety Inventory , 1970 .

[107]  Hartwig R. Siebner,et al.  Combining non-invasive transcranial brain stimulation with neuroimaging and electrophysiology: Current approaches and future perspectives , 2016, NeuroImage.

[108]  Brenda K. Bryant,et al.  An Index of Empathy for Children and Adolescents. , 1982 .

[109]  Mukesh Dhamala,et al.  Reduced Medial Prefrontal-Subcortical Connectivity in Dysphoria: Granger Causality Analyses of Rapid Functional Magnetic Resonance Imaging , 2015, Brain Connect..

[110]  A. Brunoni,et al.  Transcranial Direct Current Stimulation in Child and Adolescent Psychiatry. , 2016, Journal of child and adolescent psychopharmacology.

[111]  Tamara Vanderwal,et al.  Inscapes: A movie paradigm to improve compliance in functional magnetic resonance imaging , 2015, NeuroImage.

[112]  D. Tranel,et al.  Acquired Personality Disturbances Associated With Bilateral Damage to the Ventromedial Prefrontal Region , 2000, Developmental neuropsychology.

[113]  James J Gross,et al.  Emotion regulation and psychopathology. , 2015, Annual review of clinical psychology.

[114]  Frank Padberg,et al.  Transcranial direct current stimulation for acute major depressive episodes: Meta-analysis of individual patient data , 2016, British Journal of Psychiatry.

[115]  M. Koenigs,et al.  Ventromedial prefrontal cortex mediates visual attention during facial emotion recognition. , 2014, Brain : a journal of neurology.