Stephan Bender

Intra-individual reaction time variability in schizophrenia, depression and borderline personality disorder

Intra-individual reaction time variability (IIV) in neuropsychological task performance reflects short term fluctuations in performance. Increased IIV has been reported in patients with schizophrenia and could be related to a deficient neural timing mechanism, but the role of IIV in adult patients with other psychiatric disorders has not been established. Therefore, we compared IIV measures obtained in a Go/Nogo task from patients with schizophrenia, major depression and borderline personality disorder. IIV was increased for patients with schizophrenia. When correcting for differences in mean reaction time, depressive and borderline patients also showed increased IIV. Importantly, all groups showed a strong association between IIV and accuracy of task performance. This suggests that increased IIV might be a sensitive marker for the efficiency of top-down attentional control in all diagnostic groups. Aside from these similarities, the complete results including measures of IIV, mean reaction time and accuracy show differential patterns for patients with schizophrenia compared to those with borderline personality disorder or depression. These results are discussed with respect to common versus disorder-specific neural mechanisms underlying increased IIV.

Annual Research Review: Reaction time variability in ADHD and autism spectrum disorders: measurement and mechanisms of a proposed trans-diagnostic phenotype

BACKGROUND Intraindividual variability in reaction time (RT) has received extensive discussion as an indicator of cognitive performance, a putative intermediate phenotype of many clinical disorders, and a possible trans-diagnostic phenotype that may elucidate shared risk factors for mechanisms of psychiatric illnesses. SCOPE AND METHODOLOGY Using the examples of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD), we discuss RT variability. We first present a new meta-analysis of RT variability in ASD with and without comorbid ADHD. We then discuss potential mechanisms that may account for RT variability and statistical models that disentangle the cognitive processes affecting RTs. We then report a second meta-analysis comparing ADHD and non-ADHD children on diffusion model parameters. We consider how findings inform the search for neural correlates of RT variability. FINDINGS Results suggest that RT variability is increased in ASD only when children with comorbid ADHD are included in the sample. Furthermore, RT variability in ADHD is explained by moderate to large increases (d = 0.63-0.99) in the ex-Gaussian parameter τ and the diffusion parameter drift rate, as well as by smaller differences (d = 0.32) in the diffusion parameter of nondecision time. The former may suggest problems in state regulation or arousal and difficulty detecting signal from noise, whereas the latter may reflect contributions from deficits in motor organization or output. The neuroimaging literature converges with this multicomponent interpretation and also highlights the role of top-down control circuits. CONCLUSION We underscore the importance of considering the interactions between top-down control, state regulation (e.g., arousal), and motor preparation when interpreting RT variability and conclude that decomposition of the RT signal provides superior interpretive power and suggests mechanisms convergent with those implicated using other cognitive paradigms. We conclude with specific recommendations for the field for next steps in the study of RT variability in neurodevelopmental disorders.

Electroencephalographic response to transcranial magnetic stimulation in children: Evidence for giant inhibitory potentials

The electroencephalographic response to transcranial magnetic stimulation (TMS) recently has been established as a direct parameter of motor cortex excitability. Its N100 component was suggested to reflect an inhibitory response. We investigated influences of cerebral maturation on TMS‐evoked N100 in 6‐ to 10‐year‐old healthy children. We used a forewarned reaction time (contingent negative variation) task to test the effects of response preparation and sensory attention on N100 amplitude. Single‐pulse TMS of motor cortex at 105% motor threshold intensity evoked N100 amplitudes of more than 100μV in resting children (visible in single trials), which correlated negatively with age and positively with absolute stimulation intensity. During late contingent negative variation, which involves preactivation of the cortical structures necessary for a fast response, N100 amplitude was significantly reduced. We conclude that (1) N100 amplitude reduction during late contingent negative variation provides further evidence that TMS‐evoked N100 reflects inhibitory processes, (2) response preparation and attention modulate N100, and (3) TMS‐evoked N100 undergoes maturational changes and could serve to test cortical integrity and inhibitory function in children. Parallels between the inhibitory N100 after TMS (provoking massive synchronous excitation) and the inhibitory wave component of epileptic spike wave complexes are suggested. Ann Neurol 2005

Emotional and Behavioural Problems in Children and Adolescents with Primary Headache

Psychiatric co-morbidity is an important risk factor for chronification of primary headache into adulthood. The aim of this study was to investigate the extent and clinical relevance of emotional and behavioural problems in children and adolescents with primary headache. Children and adolescents (n = 128) with primary headache (International Headache Society, codes 1.1, 1.2, 2.1) and 83 matched controls aged 6-18 years were examined by standardized dimensional psychomet-rical tests (Child Behaviour Checklist, Depression Inventory for Children and Adolescents, Anxiety Questionnaire for Pupils). Children and adolescents with primary headache suffer more often from internalizing problems (depression, anxiety, somatization) than healthy controls. The detected emotional and behavioural problems are clinically relevant and require particular therapy in every third child suffering from headache. Two out of three children and adolescents with primary headache do not show clinically relevant psychopathology and may benefit from minimal therapeutic intervention. One of three examined headache patients needs additional psychiatric therapy.

How do children prepare to react? Imaging maturation of motor preparation and stimulus anticipation by late contingent negative variation.

Both the motor system and the frontal executive control system show a late maturation in humans which continues into school-age and even adolescence. We investigated the maturation of preparation processes towards a fast motor reaction in 74 healthy right-handed children aged 6 to 18 years and analyzed the topography of the late component of contingent negative variation (lCNV) in a 64-electrode high density sensor array. While adolescents from about 12 years on showed a bilaterally distributed centro-parietal maximum like adults do, younger children almost completely missed the negativity over the left central area contralaterally to the side of the anticipated movement. The reason, as revealed by current source density, was that only adolescents showed significant evoked activity of the left pre-/primary motor and supplementary/cingulate motor areas, while in contrast both age groups displayed significant current sinks over the right (ipsilateral) centro-temporal area and right posterior parietal cortex. Spatio-temporal source analysis confirmed that negativity over the right posterior parietal area could not be explained by a projection via volume conduction from frontal areas involved in motor preparation but represented an independent component with a different maturational course most likely related to sensory attention. Significant event-related desynchronization of alpha-power over the contralateral sensorimotor cortex was found in the younger age group, indicating that also 6- to 11-year-old children were engaged in motor preparation. Thus, the missing current sink over the contalateral sensorimotor cortex during late CNV in 6- to 11-year-old children might reflect the immaturity of a specific subcomponent of the motor preparation system which is related to evoked (late CNV) but not induced activity (alpha-ERD).

Butterbur root extract and music therapy in the prevention of childhood migraine: an explorative study.

Background: Migraine is very common in school‐aged children, but despite a number of pharmacological and non‐pharmacological options for prophylaxis, randomized controlled evidence in children is small. Evidence‐based prophylactic drugs may have considerable side effects.

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.

Which perspectives can endophenotypes and biological markers offer in the early recognition of schizophrenia

SummaryThe early recognition of schizophrenia seems crucial; various studies relate a longer duration-of-untreated-psychosis to a worse prognosis. We give an overview over common psychopathological early recognition instruments (BSABS, CAARMS, SIPS, IRAOS, ERIraos). However, many clinical symptoms of prodromal schizophrenia stages are not sufficiently specific. Thus we review recent contributions of neuroimaging and electrophysiological as well as genetic studies: which new diagnostic perspectives offer endophenotypes (such as P300, P50 sensory gating, MMN, smooth pursuit eye movements; indicating a specific genetic vulnerability) together with a better understanding of schizophrenic pathophysiology (state-dependent biological markers, e.g. aggravated motor neurological soft signs during psychosis) in prodromal schizophrenia when still ambiguous clinical symptoms are present. Several examples (e.g. from COMT polymorphisms to working memory deficits) illustrate more specific underlying neuronal mechanisms behind behavioural symptoms. This way, a characteristic pattern of disturbed cerebral maturation might be distinguished in order to complement clinical instruments of early schizophrenia detection.

Frontal lobe involvement in the processing of meaningful auditory stimuli develops during childhood and adolescence

Auditory event-related N1b reflects attention-related processing in bilateral temporal auditory cortex. Frontal contributions indicating an orienting reaction have been suggested. We analyzed the maturation of frontal contributions to the auditory event-related potential following the warning stimulus in a contingent negative variation (CNV) task by high-resolution current source density mapping and spatio-temporal source analysis in 80 healthy subjects and 121 primary headache patients (migraine with/without aura, tension type headache) from 6 to 18 years; as increased orienting responses and disturbed maturation have been described in migraineurs. A selective local increase of N1b with age occurred at mid-frontocentral leads. This increase could not be explained sufficiently by overlapping bilateral temporal sources but pointed towards additional frontal activation over the supplementary motor area (SMA) in adolescents which was absent in children. A second frontal N1 component peaked about 50 ms later, showed an earlier maturation and has been suggested to reflect early response selection processes in the anterior cingulate. Primary headache patients showed the same component structure and developmental trajectory as healthy subjects without significant influences of differential diagnosis. We conclude that: (1) Brain maturation crucially influences N1b. (2) Two frontal lobe N1 components can be dissociated in their maturational trajectory. (3) Early SMA activation could be elicited by rare auditory stimuli from about 12 years on, allowing fast sensory-motor coupling without previous categorical stimulus classification. (4) Primary headache patients did not differ in their maturation of frontal or temporal contributions to N1b when elicited by moderately loud short tone bursts.

On the Temporal Characteristics of Performance Variability in Attention Deficit Hyperactivity Disorder (ADHD)

Increased intra-subject variability of reaction times (ISV-RT) is one of the most consistent findings in attention-deficit/hyperactivity disorder (ADHD). Although the nature of this phenomenon is still unclear, it has been hypothesised to reflect interference from the Default Mode Network (DMN). So far, ISV-RT has been operationally defined either as a frequency spectrum of the underlying RT time series, or as a measure of dispersion of the RT scores distribution. Here, we use a novel RT analysis framework to link these hitherto unconnected facets of ISV-RT by determining the sensitivity of different measures of RT dispersion to the frequency content of the underlying RT time series. N=27 patients with ADHD and N=26 healthy controls performed several visual N-back tasks. Different measures of RT dispersion were repeatedly modelled after individual frequency bands of the underlying RT time series had been either extracted or suppressed using frequency-domain filtering. We found that the intra-subject standard deviation of RT preserves the “1/f noise” characteristic typical of human RT data. Furthermore and most importantly, we found that the ex-Gaussian parameter τ is rather exclusively sensitive to frequencies below 0.025 Hz in the underlying RT time series and that the particularly slow RTs, which nourish τ, occur regularly as part of an quasi-periodic, ultra-slow RT fluctuation. Overall, our results are compatible with the idea that ISV-RT is modulated by an endogenous, slowly fluctuating process that may reflect DMN interference.