Cortical inhibition in attention deficit hyperactivity disorder: new insights from the electroencephalographic response to transcranial magnetic stimulation.

Attention deficit hyperactivity disorder is one of the most frequent neuropsychiatric disorders in childhood. Transcranial magnetic stimulation studies based on muscle responses (motor-evoked potentials) suggested that reduced motor inhibition contributes to hyperactivity, a core symptom of the disease. Here we employed the N100 component of the electroencephalographic response to transcranial magnetic stimulation as a novel marker for a direct assessment of cortical inhibitory processes, which has not been examined in attention deficit hyperactivity disorder so far. We further investigated to what extent affected children were able to regulate motor cortical inhibition, and whether effects of age on the electroencephalographic response to transcranial magnetic stimulation were compatible with either a delay in brain maturation or a qualitatively different development. N100 amplitude evoked by transcranial magnetic stimulation and its age-dependent development were assessed in 20 children with attention deficit hyperactivity disorder and 19 healthy control children (8-14 years) by 64-channel electroencephalography. Amplitude and latency of the N100 component were compared at rest, during response preparation in a forewarned motor reaction time task and during movement execution. The amplitude of the N100 component at rest was significantly lower and its latency tended to be shorter in children with attention deficit hyperactivity disorder. Only in controls, N100 amplitude to transcranial magnetic stimulation was reduced by response preparation. During movement execution, N100 amplitude decreased while motor evoked potential amplitudes showed facilitation, indicating that the electroencephalographic response to transcranial magnetic stimulation provides further information on cortical excitability independent of motor evoked potential amplitudes and spinal influences. Children with attention deficit hyperactivity disorder showed a smaller N100 amplitude reduction during movement execution compared with control children. The N100 amplitude evoked by transcranial magnetic stimulation decreased with increasing age in both groups. The N100 reduction in children with attention deficit hyperactivity disorder at all ages suggests a qualitative difference rather than delayed development of cortical inhibition in this disease. Findings further suggest that top-down control of motor cortical inhibition is reduced in children with attention deficit hyperactivity disorder. We conclude that evoked potentials in response to transcranial magnetic stimulation are a promising new marker of cortical inhibition in attention deficit hyperactivity disorder during childhood.

[1]  S. Bender,et al.  The topography of the scalp-recorded visual N700 , 2008, Clinical Neurophysiology.

[2]  R. Benecke,et al.  Restoration of Disturbed Intracortical Motor Inhibition and Facilitation in Attention Deficit Hyperactivity Disorder Children by Methylphenidate , 2007, Biological Psychiatry.

[3]  Joseph Biederman,et al.  Attention-Deficit/Hyperactivity Disorder: A Selective Overview , 2005, Biological Psychiatry.

[4]  Jyrki P. Mäkelä,et al.  Reproducibility of TMS—Evoked EEG responses , 2009, Human brain mapping.

[5]  M. Döpfner,et al.  Diagnostik-System für psychische Störungen im Kindes- und Jugendalter nach ICD-10 und DSM-IV (DISYPS-KJ) , 2000 .

[6]  H. Heinrich,et al.  Children with comorbid attention‐deficit‐hyperactivity disorder and tic disorder: Evidence for additive inhibitory deficits within the motor system , 2001, Annals of neurology.

[7]  J. Bartko,et al.  Cortical correlates of neuromotor development in healthy children , 2003, Clinical Neurophysiology.

[8]  Stephan Bender,et al.  Frontal lobe involvement in the processing of meaningful auditory stimuli develops during childhood and adolescence , 2006, NeuroImage.

[9]  M. Webster,et al.  Prefrontal GABA(A) receptor alpha-subunit expression in normal postnatal human development and schizophrenia. , 2010, Journal of psychiatric research.

[10]  Risto J. Ilmoniemi,et al.  Methodology for Combined TMS and EEG , 2009, Brain Topography.

[11]  J Zhang,et al.  Should transcranial magnetic stimulation research in children be considered minimal risk? , 2004, Clinical Neurophysiology.

[12]  Stephan Bender,et al.  How do children prepare to react? Imaging maturation of motor preparation and stimulus anticipation by late contingent negative variation , 2005, NeuroImage.

[13]  T. Paus,et al.  Synchronization of neuronal activity in the human primary motor cortex by transcranial magnetic stimulation: an EEG study. , 2001, Journal of neurophysiology.

[14]  Aristea S Galanopoulou,et al.  GABAA Receptors in Normal Development and Seizures: Friends or Foes? , 2008, Current neuropharmacology.

[15]  M. Denckla,et al.  Anomalies of motor development in hyperactive boys , 1978, Annals of neurology.

[16]  Synnöve Carlson,et al.  Electrophysiological correlates of short-latency afferent inhibition: a combined EEG and TMS study , 2009, Experimental Brain Research.

[17]  E Donchin,et al.  A new method for off-line removal of ocular artifact. , 1983, Electroencephalography and clinical neurophysiology.

[18]  Vladimir Litvak,et al.  Artifact correction and source analysis of early electroencephalographic responses evoked by transcranial magnetic stimulation over primary motor cortex , 2007, NeuroImage.

[19]  Eric M. Wassermann,et al.  Transcranial Magnetic Stimulation-Evoked Cortical Inhibition: A Consistent Marker of Attention-Deficit/Hyperactivity Disorder Scores in Tourette Syndrome , 2005, Biological Psychiatry.

[20]  Alan C. Evans,et al.  Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation , 2007, Proceedings of the National Academy of Sciences.

[21]  Terence W. Picton,et al.  Ocular artifacts in recording EEGs and event-related potentials II: Source dipoles and source components , 2005, Brain Topography.

[22]  M. Kinsbourne MINIMAL BRAIN DYSFUNCTION AS A NEURODEVELOPMENTAL LAG , 1973, Annals of the New York Academy of Sciences.

[23]  M. Garvey,et al.  Quantifying excessive mirror overflow in children with attention-deficit/hyperactivity disorder , 2011, Neurology.

[24]  A. Carlsson,et al.  Suppression of ethanol-induced locomotor stimulation by GABA-like drugs , 1976, Naunyn-Schmiedeberg's Archives of Pharmacology.

[25]  Seppo Kähkönen,et al.  The novelty value of the combined use of electroencephalography and transcranial magnetic stimulation for neuroscience research , 2006, Brain Research Reviews.

[26]  Jan K Buitelaar,et al.  Internal and external validity of Attention-Deficit Hyperactivity Disorder in a population-based sample of adults , 2004, Psychological Medicine.

[27]  B. Rockstroh Slow cortical potentials and behavior , 1989 .

[28]  U. Ravens-Sieberer,et al.  Psychometric properties of two ADHD questionnaires: comparing the Conners’ scale and the FBB-HKS in the general population of German children and adolescents – results of the BELLA study , 2008, European Child & Adolescent Psychiatry.

[29]  M. Onofrj,et al.  Age-related changes of evoked potentials , 1997, Neurophysiologie Clinique/Clinical Neurophysiology.

[30]  C. Miniussi,et al.  Transcranial magnetic stimulation and cortical evoked potentials: A TMS/EEG co-registration study , 2006, Clinical Neurophysiology.

[31]  D. Gilbert Motor cortex inhibitory function in Tourette syndrome, attention deficit disorder, and obsessive compulsive disorder: studies using transcranial magnetic stimulation. , 2006, Advances in neurology.

[32]  P. Ambrosini,et al.  Videotape reliability of the third revised edition of the K-SADS. , 1989, Journal of the American Academy of Child and Adolescent Psychiatry.

[33]  B. Bettler,et al.  Expression of gamma-aminobutyric acid B receptor subunits in hypothalamus of male and female developing rats. , 2005, Brain research. Developmental brain research.

[34]  P. Rossini,et al.  Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. , 1994, Electroencephalography and clinical neurophysiology.

[35]  J C Rothwell,et al.  Comparison of descending volleys evoked by transcranial magnetic and electric stimulation in conscious humans. , 1998, Electroencephalography and clinical neurophysiology.

[36]  Miyabi Tanaka,et al.  Magnetic stimulation of motor cortex in children: maturity of corticospinal pathway and problem of clinical application , 1997, Brain and Development.

[37]  E. Bullmore,et al.  Functional frontalisation with age: mapping neurodevelopmental trajectories with fMRI , 2000, Neuroscience & Biobehavioral Reviews.

[38]  J G Semmler,et al.  Hemispheric differences in motor cortex excitability during a simple index finger abduction task in humans. , 1998, Journal of neurophysiology.

[39]  N. Makris,et al.  Structural Brain Imaging of Attention-Deficit/Hyperactivity Disorder , 2005, Biological Psychiatry.

[40]  Martin Eimer,et al.  The neural signature of phosphene perception , 2010, Human brain mapping.

[41]  R. J. Ilmoniemi,et al.  Bilateral changes in excitability of sensorimotor cortices during unilateral movement: Combined electroencephalographic and transcranial magnetic stimulation study , 2008, Neuroscience.

[42]  Thomas Kammer,et al.  Electroencephalographic response to transcranial magnetic stimulation in children: Evidence for giant inhibitory potentials , 2005, Annals of neurology.

[43]  P. Fitzgerald,et al.  Long-Interval Cortical Inhibition from the Dorsolateral Prefrontal Cortex: a TMS–EEG Study , 2008, Neuropsychopharmacology.

[44]  F. Matsuo,et al.  Electrical phenomena associated with movements of the eyelid. , 1975, Electroencephalography and clinical neurophysiology.

[45]  Vincenzo Romei,et al.  Handedness is mainly associated with an asymmetry of corticospinal excitability and not of transcallosal inhibition , 2004, Clinical Neurophysiology.

[46]  Wim J. Riedel,et al.  Contingent negative variation as a dopaminergic biomarker: evidence from dose-related effects of methylphenidate , 2011, Psychopharmacology.

[47]  M. Garvey,et al.  Transcranial magnetic stimulation in children. , 2004, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[48]  B. Bettler,et al.  Developmental Changes of Agonist Affinity at GABABR1 Receptor Variants in Rat Brain , 1998, Molecular and Cellular Neuroscience.

[49]  M. Fillmore,et al.  Tolerance to the impairing effects of alcohol on the inhibition and activation of behavior , 2010, Psychopharmacology.

[50]  Christoph Klein,et al.  Intra-Subject Variability in Attention-Deficit Hyperactivity Disorder , 2006, Biological Psychiatry.

[51]  M. Bonnard,et al.  Prior intention can locally tune inhibitory processes in the primary motor cortex: direct evidence from combined TMS‐EEG , 2009, The European journal of neuroscience.

[52]  F. Glocker,et al.  Maturation of inhibitory and excitatory motor cortex pathways in children , 2009, Brain and Development.

[53]  R. Ilmoniemi,et al.  Modulation of electroencephalographic responses to transcranial magnetic stimulation: evidence for changes in cortical excitability related to movement , 2003, The European journal of neuroscience.

[54]  Otavio G. Lins,et al.  Ocular artifacts in recording EEGs and event related potentials. , 1993 .

[55]  R. Hari,et al.  Magnetic fields produced by eye blinking. , 1985, Electroencephalography and clinical neurophysiology.

[56]  Stewart H. Mostofsky,et al.  Overflow Movements Predict Impaired Response Inhibition in Children with ADHD , 2003, Perceptual and motor skills.

[57]  F. Glocker,et al.  Low level of intracortical inhibition in children shown by transcranial magnetic stimulation. , 2004, Neuropediatrics.

[58]  Seppo Kähkönen,et al.  Effects of alcohol on TMS-evoked N100 responses , 2007, Journal of Neuroscience Methods.

[59]  H. Heinrich,et al.  [Transcranial magnetic stimulation in child and adolescent psychiatry: excitability of the motor system in tic disorders and/or attention deficit hyperactivity disorders]. , 2001, Zeitschrift fur Kinder- und Jugendpsychiatrie und Psychotherapie.

[60]  R. Shepherd,et al.  Maturation of the cortical auditory evoked potential in infants and young children , 2006, Hearing Research.

[61]  K. Chiappa,et al.  Variability of motor potentials evoked by transcranial magnetic stimulation. , 1993, Electroencephalography and clinical neurophysiology.

[62]  C. Brunia,et al.  A spatio-temporal dipole model of the readiness potential in humans. I. Finger movement. , 1994, Electroencephalography and clinical neurophysiology.

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

[64]  R. Barry,et al.  Age-related changes in child and adolescent event-related potential component morphology, amplitude and latency to standard and target stimuli in an auditory oddball task. , 1996, International journal of psychophysiology : official journal of the International Organization of Psychophysiology.

[65]  S. Faraone,et al.  Age-dependent decline of symptoms of attention deficit hyperactivity disorder: impact of remission definition and symptom type. , 2000, The American journal of psychiatry.

[66]  J. Sergeant The cognitive-energetic model: an empirical approach to Attention-Deficit Hyperactivity Disorder , 2000, Neuroscience & Biobehavioral Reviews.

[67]  C. Barkmann,et al.  The German version of the Centre for Epidemiological Studies Depression Scale for Children: psychometric evaluation in a population-based survey of 7 to 17 years old children and adolescents – results of the BELLA study , 2008, European Child & Adolescent Psychiatry.

[68]  Joseph Biederman,et al.  Attention-deficit/hyperactivity disorder: diagnosis, lifespan, comorbidities, and neurobiology. , 2007, Journal of pediatric psychology.

[69]  P. Berg,et al.  The correction of ocular artifacts: a topographic perspective , 2000, Clinical Neurophysiology.

[70]  H. Heinrich,et al.  Deficient intracortical inhibition in drug-naive children with attention-deficit hyperactivity disorder is enhanced by methylphenidate , 2000, Neuroscience Letters.

[71]  Seppo Kähkönen,et al.  The effect of stimulus intensity on brain responses evoked by transcranial magnetic stimulation , 2004, Human brain mapping.

[72]  P. Mazzone,et al.  The effect on corticospinal volleys of reversing the direction of current induced in the motor cortex by transcranial magnetic stimulation , 2001, Experimental Brain Research.

[73]  W. Paulus,et al.  Motor system excitability in healthy children: developmental aspects from transcranial magnetic stimulation. , 1999, Electroencephalography and clinical neurophysiology. Supplement.

[74]  S. Herpertz,et al.  Intracortical motor inhibition and facilitation in adults with attention deficit/hyperactivity disorder , 2008, Journal of Neural Transmission.