Andreas J. Fallgatter

Three-dimensional tomography of event-related potentials during response inhibition: evidence for phasic frontal lobe activation

OBJECTIVES Spatial analysis of the evoked brain electrical fields during a cued continuous performance test (CPT) revealed an extremely robust anteriorization of the positivity of a P300 microstate in the NoGo compared to the Go condition (NoGo-anteriorization in a previous study). To allow a neuroanatomical interpretation the NoGo-anteriorization was investigated with a new three-dimensional source tomography method (LORETA) was applied. METHODS The CPT contains subsets of stimuli requiring the execution (Go) or the inhibition (NoGo) of a cued motor response which can be considered as mutual control conditions for the event-related potential (ERP) study of inhibitory brain functions 21-channel ERPs were obtained from 10 healthy subjects during a cued CPT, and analyzed with LORETA. RESULTS Topographic analyses revealed significantly different scalp distributions between the Go and the NoGo conditions in both P100 and P300 microstates, indicating that already at an early stage different neural assemblies are activated. LORETA disclosed a significant hyperactivity located in the right frontal lobe during the NoGo condition in the P300 microstate. CONCLUSIONS The results indicate that right frontal sources are responsible for the NoGo-anteriorization of the scalp P300 which is consistent with animal and human lesion studies of inhibitory brain functions. Furthermore, it demonstrates that frontal activation is confined to a brief microstate and time-locked to phasic inhibitory motor control. This adds important functional and chronometric specificity to findings of frontal activation obtained with PET and Near-Infrared-Spectroscopy studies during the cued CPT, and suggests that these metabolic results are not due to general task demands.

Neural Hyporesponsiveness and Hyperresponsiveness During Immediate and Delayed Reward Processing in Adult Attention-Deficit/Hyperactivity Disorder

BACKGROUND Dysfunctional reward processing, accompanied by a limited ability to tolerate reward delays, has been proposed as an important feature in attention-deficit/hyperactivity disorder (ADHD). METHODS Using functional magnetic resonance imaging (fMRI), brain activation in adult patients with ADHD (n=14) and healthy control subjects (n=12) was examined during a series of choices between two monetary reward options that varied by delay to delivery. RESULTS Compared with healthy control subjects, hyporesponsiveness of the ventral-striatal reward system was replicated in patients with ADHD and was evident for both immediate and delayed rewards. In contrast, delayed rewards evoked hyperactivation in dorsal caudate nucleus and amygdala of ADHD patients. In both structures, neural activity toward delayed rewards was significantly correlated with self-rated ADHD symptom severity. CONCLUSIONS The finding of ventral-striatal hyporesponsiveness during immediate and delayed reward processing in patients with ADHD further strengthens the concept of a diminished neural processing of rewards in ADHD. Hyperactivation during delayed reward processing, gradually increasing along the ventral-to-dorsal extension of the caudate nucleus, and especially the concomitant hyperactivation of the amygdala are in accordance with predictions of the delay aversion hypothesis.

Consensus paper of the WFSBP Task Force on Biological Markers: biological markers in depression.

Biological markers for depression are of great interest to aid in elucidating the causes of major depression. We assess currently available biological markers to query their validity for aiding in the diagnosis of major depression. We specifically focus on neurotrophic factors, serotonergic markers, biochemical markers, immunological markers, neuroimaging, neurophysiological findings, and neuropsychological markers. We delineate the most robust biological markers of major depression. These include decreased platelet imipramine binding, decreased 5-HT1A receptor expression, increase of soluble interleukin-2 receptor and interleukin-6 in serum, decreased brain-derived neurotrophic factor in serum, hypocholesterolemia, low blood folate levels, and impaired suppression of the dexamethasone suppression test. To date, however, none of these markers are sufficiently specific to contribute to the diagnosis of major depression. Thus, with regard to new diagnostic manuals such as DSM-V and ICD-11 which are currently assessing whether biological markers may be included in diagnostic criteria, no biological markers for major depression are currently available for inclusion in the diagnostic criteria.

Model-based analysis of rapid event-related functional near-infrared spectroscopy (NIRS) data: A parametric validation study

To validate the usefulness of a model-based analysis approach according to the general linear model (GLM) for functional near-infrared spectroscopy (fNIRS) data, a rapid event-related paradigm with an unpredictable stimulus sequence was applied to 15 healthy subjects. A parametric design was chosen wherein four differently graded contrasts of a flickering checkerboard were presented, allowing directed hypotheses about the rank order of the evoked hemodynamic response amplitudes. The results indicate the validity of amplitude estimation by three main findings (a) the GLM approach for fNIRS data is capable to identify human brain activation in the visual cortex with inter-stimulus intervals of 4-9 s (6.5 s average) whereas in non-visual areas no systematic activation was detectable; (b) the different contrast level intensities lead to the hypothesized rank order of the GLM amplitude parameters: visual cortex activation evoked by highest contrast>moderate contrast>lowest contrast>no stimulation; (c) analysis of null-events (no stimulation) did not produce any significant activation in the visual cortex or in other brain areas. We conclude that a model-based GLM approach delivers valid fNIRS amplitude estimations and enables the analysis of rapid event-related fNIRS data series, which is highly relevant in particular for cognitive fNIRS studies.

The NoGo-anteriorization as a neurophysiological standard-index for cognitive response control.

Event related potentials (ERPs) during the Go- and the NoGo-condition of the Continuous Performance Test (CPT) were applied to investigate the neurophysiological basis of cognitive response control. These conditions of the test represent the execution and the inhibition of an anticipated motor response. In a previous study, the comprehensive spatial analysis of the ERPs allowed to define a parameter which robustly reflected the anteriorization of the positive P300 field area during the NoGo- compared to the Go-condition (NoGo-anteriorisation, NGA). The result was found consistently in all investigated subjects. The present study replicated the finding in 27 healthy subjects without any exception. Moreover, the latencies were longer and the amplitudes showed a trend to be higher in the NoGo- compared to the Go-ERP. This is interpreted as a sign of higher processing demands in the NoGo-condition. In conclusion, the ability of the NGA to express reliably the differences of brain activity leading to execution or suppression of a prepared motor response qualifies this parameter as a topographical standard-index for cognitive response control.

A neuronal nitric oxide synthase (NOS-I) haplotype associated with schizophrenia modifies prefrontal cortex function

Nitric oxide (NO) is a gaseous neurotransmitter thought to play important roles in several behavioral domains. On a neurobiological level, NO acts as the second messenger of the N-methyl-D-aspartate receptor and interacts with both the dopaminergic as well as the serotonergic system. Thus, NO is a promising candidate molecule in the pathogenesis of endogenous psychoses and a potential target in their treatment. Furthermore, the chromosomal locus of the gene for the NO-producing enzyme NOS-I, 12q24.2, represents a major linkage hot spot for schizophrenic and bipolar disorder. To investigate whether the gene encoding NOS-I (NOS1) conveys to the genetic risk for those diseases, five NOS1 polymorphisms as well as a NOS1 mini-haplotype, consisting of two functional polymorphisms located in the transcriptional control region of NOS1, were examined in 195 chronic schizophrenic, 72 bipolar-I patients and 286 controls. Single-marker association analysis showed that the exon 1c promoter polymorphism was linked to schizophrenia (SCZ), whereas synonymous coding region polymorphisms were not associated with disease. Long promoter alleles of the repeat polymorphism were associated with less severe psychopathology. Analysis of the mini-haplotype also revealed a significant association with SCZ. Mutational screening did not detect novel exonic polymorphisms in patients, suggesting that regulatory rather than coding variants convey the genetic risk on psychosis. Finally, promoter polymorphisms impacted on prefrontal functioning as assessed by neuropsychological testing and electrophysiological parameters elicited by a Go-Nogo paradigm in 48 patients (continuous performance test). Collectively these findings suggest that regulatory polymorphisms of NOS1 contribute to the genetic risk for SCZ, and modulate prefrontal brain functioning.

Altered response control and anterior cingulate function in attention-deficit/hyperactivity disorder boys

OBJECTIVE To investigate mechanisms and structures underlying prefrontal response control and inhibition in boys suffering from attention-deficit/hyperactivity disorder (ADHD). METHOD Sixteen boys with ADHD and 19 healthy controls were investigated electrophysiologically during performance of a visual Go-Nogo task (Continuous Performance Test, CPT). An electrophysiological source localization method was employed to further analyze the data. RESULTS The ADHD boys showed a significantly diminished central Nogo-P3, due to a lack of Nogo-related frontalization of the positive brain electrical field in this group. This two-dimensional effect was associated with a significantly reduced activation of the anterior cingulate cortex (ACC) in the ADHD boys in the Nogo condition of the CPT. Both groups did not significantly differ regarding the amplitude of the Nogo-N2. CONCLUSIONS The results indicate deficits in prefrontal response control in unmedicated ADHD boys that do not seem to be specifically inhibitory in nature. A supposed dysfunction of the ACC in ADHD was confirmed.

A robust assessment of the NoGo-anteriorisation of P300 microstates in a cued Continuous Performance Test.

SummaryThe Continuous Performance Test (CPT) is successfully applied in clinical routine to evaluate attentional performance. The aim of the present study was to investigate the features of the ERPs related to the conditions of a cued CPT, in particular the Go-and the NoGo-condition demanding either the execution or the inhibition of a prepared motor response. For that purpose, 21-channel-ERPs of ten healthy subjects elicited by the Go, NoGo, primer and distractor cues were analyzed with reference-independent methods. The P300 microstates were identified by means of a data-driven segmentation of the ERPs based on the individual peaks of the Global Field Power (GFP). The topographical assessment of the P300 fields yielded an extraordinarily robust result consisting of a more anterior location of the positive centroid in the NoGo compared to the Go condition in every single subject. In conclusion, this result is an impressive validation of the applied reference-independent spatial analysis which reveals the rapid changes of the brain electrical field configurations related to the execution/inhibition paradigm within the cued CPT. Because of the stability of the NoGo anteriorisation we propose to use this parameter as a topographical standard index, analogous to the amplitude effect between oddball targets and nontargets which defines the classical P300.

Functional near-infrared spectroscopy: A long-term reliable tool for measuring brain activity during verbal fluency

The present study investigated the short- and long-term retest reliability of brain activity measured with functional near-infrared spectroscopy (fNIRS) during verbal fluency, the most published cognitive task within fNIRS literature. We examined 15 healthy right handed subjects in a block design task with retest intervals of three weeks and one year. Performance was constant over time. Amplitude of brain activation, as indicated by increases of oxygenated (O(2)Hb) and total (totHb) and decreases of deoxygenated haemoglobin (HHb), was reduced at session two and reversed at the third session for the fluency related region of interest (ROI). Small decreases for session two and three were found outside the ROI. These changes in amplitude may contribute to variability of reproducibility as measured with intraclass correlation coefficients (ICCs) within the ROI. Acceptable reliability for all chromophores and comparisons was reached for the mean of repeated measures at cluster level. Spatial (size and localisation), temporal and whole probe set activity was completely acceptable without exception. Retest reliability was not satisfactory at single subject and single channel level. Amplitude decreases over time outside the ROI suggest higher physiological or arousal effects for session one. Amplitude recovery in the ROI in session three argues for a psychological effect. Overall our findings indicate that fNIRS analyses at single subject and single channel level should be interpreted cautiously, while group and cluster analyses have sufficient test retest reliability.

Reduced lateral prefrontal activation in adult patients with attention-deficit/hyperactivity disorder (ADHD) during a working memory task: a functional near-infrared spectroscopy (fNIRS) study.

Near-infrared spectroscopy (NIRS) is an optical imaging method, which allows non-invasive in vivo measurements of changes in the concentration of oxygenated (O2Hb) and deoxygenated (HHb) haemoglobin in cortical tissue. For the present study, we examined 13 adult ADHD patients and 13 age- and gender-matched healthy controls by means of multi-channel NIRS (Optical Topography; ETG-100, Hitachi Medical Co., Japan) during performance of a working memory (n-back) paradigm. Compared to the healthy control group, ADHD patients showed reduced task-related increases in the concentration of O2Hb in NIRS channels located over the ventro-lateral prefrontal cortex, indicating reduced activation during performance of the n-back task in this part of the brain. This finding was particularly apparent for the task condition with high working memory load (2-back), and was accompanied by a statistical trend towards an increased number of omission errors in the patient group. The data confirm previous findings of working memory deficits and prefrontal cortex dysfunction in patients suffering from ADHD, and are discussed in the light of imaging findings and theoretical models of working memory function.