Influence of NOS1AP Risk Variants on the Corrected QT (QTc) Interval in the Pharmacotherapy of Schizophrenia.

INTRODUCTION: The variants of the gene for nitric oxide synthase 1 adaptor protein (NOS1AP) are associated with schizophrenia and cardiovascular deficits involving corrected QT (QTc) interval prolongation. Here, we investigated a possible pharmacogenetic effect of antipsychotic treatment on QTc length in interaction with two NOS1AP variants (rs12143842 and rs10494366) whose minor alleles are associated with increased QTc interval length. METHODS: We conducted a retrospective analysis of electrocardiographic (ECG) and genotype data of 239 patients diagnosed with schizophrenia. We converted antipsychotics dosage to chlorpromazine equivalents and defined daily doses. We analysed the effects of the minor (i. e. rs12143842-CT/TT and rs10494366-GT/GG) and major (i. e. rs12143842-CC and rs10494366-TT) allele genotypes to QTc interval for female and male participants separately. RESULTS: As expected, rs12143842 and rs10494366 exhibit strong linkage disequilibrium. Both polymorphisms had no direct effect on antipsychotic use or QTc interval. However, there was a continuous increase in QTc interval with increasing antipsychotic dosage in males. For both variants, positive correlation of QTc length with antipsychotic dosage was found in homozygous male carriers of the major alleles (i. e. rs12143842-CC and rs10494366-TT), but not in minor allele carriers. There was no significant interaction between antipsychotic dosage and QTc interval for either genotype in female patients. CONCLUSIONS: In this study, a significant interaction was found between both NOS1AP variants, rs12143842 and rs10494366, and antipsychotic treatment on the QTc interval in a sex-dependent manner. Our findings might be relevant for adequate antipsychotic treatment in rs12143842 and rs10494366 major allele carriers.

Test-retest reliability of prepulse inhibition (PPI) and PPI correlation with working memory.

OBJECTIVE: Sensorimotor gating is experimentally operationalized by the prepulse inhibition (PPI) of the startle response (SR). Previous studies suggest high test-retest reliability of PPI and potential correlation with working memory (WM). Here, we aimed to validate and extend the test-retest reliability of PPI in healthy humans and its correlation with WM performance. METHODS: We applied an acoustic startle PPI paradigm with four different prepulse intensities (64, 68, 72 and 76 dB) and two different WM tasks [n-back, change detection task (CDT)] in a group of 26 healthy adults (final sample size n = 23). To assess test-retest reliability, we performed all tests on two separate days ~27 days (range: 21-32 days) apart. RESULTS: We were able to confirm high test-retest reliability of the PPI with a mean intraclass correlation (ICC) of > 0.80 and significant positive correlation of PPI with n-back but not with CDT performance. Detailed analysis showed that PPI across all prepulse intensities significantly correlated with both the 2-back and 0-back conditions, suggesting regulation by cross-conditional processes (e.g. attention). However, when removing the 0-back component from the 2-back data, we found a specific and significant correlation with WM for the 76-dB PPI condition. CONCLUSION: With the present study, we were able to confirm the high test-retest reliability of the PPI in humans and could validate and expand on its correlation with WM performance.

Reliable and efficient recording of the error-related negativity with a speeded Eriksen Flanker Task.

OBJECTIVE: There is accumulating evidence that the error-related negativity (ERN), an event-related potential elicited after erroneous actions, is altered in different psychiatric disorders and may help to guide treatment options. Thus, the ERN is a promising candidate as a psychiatric biomarker. Basic methodological requirements for a biomarker are that their measurements are standardised and reliable. The aim of the present study was to establish ERN acquisition in a reliable, time-efficient and patient-friendly way for use in clinical practice. METHODS: Healthy subjects performed a speeded Eriksen Flanker Task that increases the number of errors. In a test-retest design (N = 14) with two sessions separated by 28 days we assessed the reliability of the ERN. To ensure external validity, we aimed to replicate previously reported correlation patterns of ERN amplitude with (A) number of errors and (B) negative affect. In order to optimise the clinical use of the task, we determined to which extent the task can be shortened while keeping reliability >0.80. RESULTS: We found excellent reliability of the ERN (intraclass correlation coefficients = 0.806-0.947) and replicated ERN correlation patterns. The task can be halved to a patient-friendly length of 200 trials (recorded in 8 min) keeping reliability >0.80. CONCLUSIONS: The modified task provides reliable and efficient recording of the ERN, facilitating its use as a psychiatric biomarker.

The impact of enhancing perceived self-efficacy in torture survivors.

BACKGROUND: Perceived self-efficacy (SE) is an important factor underlying psychological well-being. Refugees suffer many experiences that can compromise SE. This study tested the impact of enhancing perceived SE on coping with trauma reminders and distress tolerance in tortured refugees. METHODS: Torture survivors (N = 40) were administered a positive SE induction in which they retrieved mastery-related autobiographical memories, or a non-SE (NSE) induction, and then viewed trauma-related images. Participants rated their distress following presentation of each image. Participants then completed a frustration-inducing mirror-tracing task to index distress tolerance. RESULTS: Participants in the SE condition reported less distress and negative affect, and improved coping in relation to viewing the trauma-related images than those in the NSE condition. The SE induction also led to greater persistence with the mirror-tracing task than the NSE induction. CONCLUSIONS: These findings provide initial evidence that promoting SE in tortured refugees can assist with managing distress from trauma reminders, and promoting greater distress tolerance. Enhancing perceived SE in tortured refugees may increase their capacity to tolerate distress during therapy, and may be a useful means to improve treatment response.

Evidence for a Sex-Dependent MAOA× Childhood Stress Interaction in the Neural Circuitry of Aggression.

Converging evidence emphasizes the role of an interaction between monoamine oxidase A (MAOA) genotype, environmental adversity, and sex in the pathophysiology of aggression. The present study aimed to clarify the impact of this interaction on neural activity in aggression-related brain systems. Functional magnetic resonance imaging was performed in 125 healthy adults from a high-risk community sample followed since birth. DNA was genotyped for the MAOA-VNTR (variable number of tandem repeats). Exposure to childhood life stress (CLS) between the ages of 4 and 11 years was assessed using a standardized parent interview, aggression by the Youth/Young Adult Self-Report between the ages of 15 and 25 years, and the VIRA-R (Vragenlijst Instrumentele En Reactieve Agressie) at the age of 15 years. Significant interactions were obtained between MAOA genotype, CLS, and sex relating to amygdala, hippocampus, and anterior cingulate cortex (ACC) response, respectively. Activity in the amygdala and hippocampus during emotional face-matching increased with the level of CLS in male MAOA-L, while decreasing in male MAOA-H, with the reverse pattern present in females. Findings in the opposite direction in the ACC during a flanker NoGo task suggested that increased emotional activity coincided with decreased inhibitory control. Moreover, increasing amygdala activity was associated with higher Y(A)SR aggression in male MAOA-L and female MAOA-H carriers. Likewise, a significant association between amygdala activity and reactive aggression was detected in female MAOA-H carriers. The results point to a moderating role of sex in the MAOA× CLS interaction for intermediate phenotypes of emotional and inhibitory processing, suggesting a possible mechanism in conferring susceptibility to violence-related disorders.

Interaction between COMT Val(158)Met polymorphism and childhood adversity affects reward processing in adulthood.

BACKGROUND: Accumulating evidence suggests that altered dopamine transmission may increase the risk of mental disorders such as ADHD, schizophrenia or depression, possibly mediated by reward system dysfunction. This study aimed to clarify the impact of the COMT Val(158)Met polymorphism in interaction with environmental variation (G×E) on neuronal activity during reward processing. METHODS: 168 healthy young adults from a prospective study conducted over 25years participated in a monetary incentive delay task measured with simultaneous EEG-fMRI. DNA was genotyped for COMT, and childhood family adversity (CFA) up to age 11 was assessed by a standardized parent interview. RESULTS: At reward delivery, a G×E revealed that fMRI activation for win vs. no-win trials in reward-related regions increased with the level of CFA in Met homozygotes as compared to Val/Met heterozygotes and Val homozygotes, who showed no significant effect. During the anticipation of monetary vs. verbal rewards, activation decreased with the level of CFA, which was also observed for EEG, in which the CNV declined with the level of CFA. CONCLUSIONS: These results identify convergent genetic and environmental effects on reward processing in a prospective study. Moreover, G×E effects during reward delivery suggest that stress during childhood is associated with higher reward sensitivity and reduced efficiency in processing rewarding stimuli in genetically at-risk individuals. Together with previous evidence, these results begin to define a specific system mediating interacting effects of early environmental and genetic risk factors, which may be targeted by early intervention and prevention.

Delay discounting and response disinhibition under acute experimental stress in women with borderline personality disorder and adult attention deficit hyperactivity disorder.

BACKGROUND: Impulsivity is a core feature of borderline personality disorder (BPD) and attention deficit hyperactivity disorder (ADHD). In BPD, impulsive behavior primarily occurs under acute stress; impulse control deficits under non-stress conditions may be partly related to co-morbid ADHD. We aimed to investigate whether acute experimental stress has an impact on self-reported impulsivity, response inhibition (action withholding, action cancelation) and delay discounting in BPD compared to ADHD. METHOD: Thirty female BPD patients, 28 female ADHD patients (excluding patients with co-morbid BPD and ADHD), and 30 female healthy controls (HC) completed self-reports and behavioral measures of impulsivity (IMT, assessing action withholding; GoStop, measuring action cancelation, Delay Discounting Task) under baseline conditions and after an experimental stress induction (Mannheim Multicomponent Stress Test). RESULTS: Both patient groups reported higher impulsivity than HC, ADHD reported higher trait impulsivity than BPD. On the IMT, ADHD showed significant action-withholding deficits under both conditions, while BPD performed significantly worse than HC under stress. In BPD but not ADHD and HC, action-withholding deficits (IMT) were significantly increased under stress compared to baseline, while no group/stress effects were found for action cancelation (GoStop). Delay discounting was significantly more pronounced in BPD than in HC (no stress effect was found). CONCLUSIONS: In BPD, behavioral deficits in action withholding (but not in action cancelation) appear to be influenced by acute experimental stress. Delay discounting seems to be a general feature of BPD, independent of co-morbid ADHD and acute stress, possibly underlying typical expressions of behavioral impulsivity in the disorder.

Application of high-frequency repetitive transcranial magnetic stimulation to the DLPFC alters human prefrontal-hippocampal functional interaction.

Neural plasticity is crucial for understanding the experience-dependent reorganization of brain regulatory circuits and the pathophysiology of schizophrenia. An important circuit-level feature derived from functional magnetic resonance imaging (fMRI) is prefrontal-hippocampal seeded connectivity during working memory, the best established intermediate connectivity phenotype of schizophrenia risk to date. The phenotype is a promising marker for the effects of plasticity-enhancing interventions, such as high-frequency repetitive transcranial magnetic stimulation (rTMS), and can be studied in healthy volunteers in the absence of illness-related confounds, but the relationship to brain plasticity is unexplored. We recruited 39 healthy volunteers to investigate the effects of 5 Hz rTMS on prefrontal-hippocampal coupling during working memory and rest. In a randomized and sham-controlled experiment, neuronavigation-guided rTMS was applied to the right dorsolateral prefrontal cortex (DLPFC), and fMRI and functional connectivity analyses [seeded connectivity and psychophysiological interaction (PPI)] were used as readouts. Moreover, the test-retest reliability of working-memory related connectivity markers was evaluated. rTMS provoked a significant decrease in seeded functional connectivity of the right DLPFC and left hippocampus during working memory that proved to be relatively time-invariant and robust. PPI analyses provided evidence for a nominal effect of rTMS and poor test-retest reliability. No effects on n-back-related activation and DLPFC-hippocampus resting-state connectivity were observed. These data provide the first in vivo evidence for the effects of plasticity induction on human prefrontal-hippocampal network dynamics, offer insights into the biological mechanisms of a well established intermediate phenotype linked to schizophrenia, and underscores the importance of the choice of outcome measures in test-retest designs.

Simultaneous EEG and fMRI reveals a causally connected subcortical-cortical network during reward anticipation.

Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) have been used to study the neural correlates of reward anticipation, but the interrelation of EEG and fMRI measures remains unknown. The goal of the present study was to investigate this relationship in response to a well established reward anticipation paradigm using simultaneous EEG-fMRI recording in healthy human subjects. Analysis of causal interactions between the thalamus (THAL), ventral-striatum (VS), and supplementary motor area (SMA), using both mediator analysis and dynamic causal modeling, revealed that (1) THAL fMRI blood oxygenation level-dependent (BOLD) activity is mediating intermodal correlations between the EEG contingent negative variation (CNV) signal and the fMRI BOLD signal in SMA and VS, (2) the underlying causal connectivity network consists of top-down regulation from SMA to VS and SMA to THAL along with an excitatory information flow through a THAL→VS→SMA route during reward anticipation, and (3) the EEG CNV signal is best predicted by a combination of THAL fMRI BOLD response and strength of top-down regulation from SMA to VS and SMA to THAL. Collectively, these findings represent a likely neurobiological mechanism mapping a primarily subcortical process, i.e., reward anticipation, onto a cortical signature.

Occipital and orbitofrontal hemodynamics during naturally paced reading: an fNIRS study.

Humans typically read at incredibly fast rates, because they predict likely occurring words from a given context. Here, we used functional near-infrared spectroscopy (fNIRS) to track the ultra-rapid hemodynamic responses of words presented every 280 ms in a naturally paced sentence context. We found a lower occipital deoxygenation to unpredictable than to predictable words. The greater hemodynamic responses to unexpected words suggest that the visual features of expected words have been pre-activated previous to stimulus presentation. Second, we tested opposing theoretical proposals about the role of the medial orbitofrontal cortex (OFC): Either OFC may respond to the breach of expectation; or OFC is activated when the present stimulus matches the prediction. A significant interaction between word frequency and predictability indicated OFC responses to breaches of expectation for low- but not for high-frequency words: OFC is sensitive to both, bottom-up processing as mediated by word frequency, as well as top-down predictions. Particularly, when a rare word is unpredictable, OFC becomes active. Finally, we discuss how a high temporal resolution can help future studies to disentangle the hemodynamic responses of single trials in such an ultra-rapid event succession as naturally paced reading.

Test-retest reliability of fMRI-based graph theoretical properties during working memory, emotion processing, and resting state.

The investigation of the brain connectome with functional magnetic resonance imaging (fMRI) and graph theory analyses has recently gained much popularity, but little is known about the robustness of these properties, in particular those derived from active fMRI tasks. Here, we studied the test-retest reliability of brain graphs calculated from 26 healthy participants with three established fMRI experiments (n-back working memory, emotional face-matching, resting state) and two parcellation schemes for node definition (AAL atlas, functional atlas proposed by Power et al.). We compared the intra-class correlation coefficients (ICCs) of five different data processing strategies and demonstrated a superior reliability of task-regression methods with condition-specific regressors. The between-task comparison revealed significantly higher ICCs for resting state relative to the active tasks, and a superiority of the n-back task relative to the face-matching task for global and local network properties. While the mean ICCs were typically lower for the active tasks, overall fair to good reliabilities were detected for global and local connectivity properties, and for the n-back task with both atlases, smallworldness. For all three tasks and atlases, low mean ICCs were seen for the local network properties. However, node-specific good reliabilities were detected for node degree in regions known to be critical for the challenged functions (resting-state: default-mode network nodes, n-back: fronto-parietal nodes, face-matching: limbic nodes). Between-atlas comparison demonstrated significantly higher reliabilities for the functional parcellations for global and local network properties. Our findings can inform the choice of processing strategies, brain atlases and outcome properties for fMRI studies using active tasks, graph theory methods, and within-subject designs, in particular future pharmaco-fMRI studies.

Amygdala habituation: a reliable fMRI phenotype.

Amygdala function is of high interest for cognitive, social and psychiatric neuroscience, emphasizing the need for reliable assessments in humans. Previous work has indicated unsatisfactorily low within-subject reliability of amygdala activation fMRI measures. Based on basic science evidence for strong habituation of amygdala response to repeated stimuli, we investigated whether a quantification of habituation provides additional information beyond the usual estimate of the overall mean activity. We assessed the within-subject reliability of amygdala habituation measures during a facial emotion matching paradigm in 25 healthy subjects. We extracted the amygdala signal decrement across the course of the fMRI run for the two test-retest measurement sessions and compared reliability estimates with previous findings based on mean response amplitude. Retest-reliability of the session-wise amygdala habituation was significantly higher than the evoked amygdala mean amplitude (intraclass correlation coefficients (ICC)=0.53 vs. 0.16). To test the task-specificity of this finding, we compared the retest-reliability of amygdala habituation across two different tasks. Significant amygdala response decrement was also seen in a cognitive task (n-back working memory) that did not per se activate the amygdala, but was totally unreliable in that context (ICC~0.0), arguing for task-specificity. Together the results show that emotion-dependent amygdala habituation is a robust and considerably more reliable index than the mean amplitude, and provides a robust potential endpoint for within-subject designs including pharmaco-fMRI studies.

Sequential inhibitory control processes assessed through simultaneous EEG-fMRI.

Inhibitory response control has been extensively investigated in both electrophysiological (ERP) and hemodynamic (fMRI) studies. However, very few multimodal results address the coupling of these inhibition markers. In fMRI, response inhibition has been most consistently linked to activation of the anterior insula and inferior frontal cortex (IFC), often also the anterior cingulate cortex (ACC). ERP work has established increased N2 and P3 amplitudes during NoGo compared to Go conditions in most studies. Previous simultaneous EEG-fMRI imaging reported association of the N2/P3 complex with activation of areas like the anterior midcingulate cortex (aMCC) and anterior insula. In this study we investigated inhibitory control in 23 healthy young adults (mean age=24.7, n=17 for EEG during fMRI) using a combined Flanker/NoGo task during simultaneous EEG and fMRI recording. Separate fMRI and ERP analysis yielded higher activation in the anterior insula, IFG and ACC as well as increased N2 and P3 amplitudes during NoGo trials in accordance with the literature. Combined analysis modelling sequential N2 and P3 effects through joint parametric modulation revealed correlation of higher N2 amplitude with deactivation in parts of the default mode network (DMN) and the cingulate motor area (CMA) as well as correlation of higher central P3 amplitude with activation of the left anterior insula, IFG and posterior cingulate. The EEG-fMRI results resolve the localizations of these sequential activations. They suggest a general role for allocation of attentional resources and motor inhibition for N2 and link memory recollection and internal reflection to P3 amplitude, in addition to previously described response inhibition as reflected by the anterior insula.

Prefrontal correlates of approach preferences for alcohol stimuli in alcohol dependence.

An approach bias for alcohol stimuli (i.e. faster approach than avoidance reactions) might facilitate relapses in alcohol dependence. Neurobiological models suggest hypersensitivity in the reward system [inter alia nucleus accumbens and orbitofrontal cortex (OFC)] to cause pathologically enhanced approach impulses towards alcohol stimuli. At the same time, in alcohol dependence, these structures are only insufficiently controlled by a hypoactive dorsolateral prefrontal cortex (DLPFC). The present study investigated the cortical aspects of this model with functional near-infrared spectroscopy in 21 alcohol-dependent in-patients and 21 healthy controls (HC; comparable in age, gender and education) during performance of the Approach-Avoidance Task (AAT) for the first time. Complementing previous findings, in reaction times (RTs), patients showed stronger approach preferences for alcohol than non-alcohol stimuli. For non-alcohol stimuli, patients even displayed avoidance preferences. The reversed pattern was found in HC. Group differences in activity of the OFC were identical to those in RTs, revealing patients to assign higher subjective value to approaching alcohol stimuli. In both groups, regulatory activity in the right DLPFC was stronger during avoiding than approaching alcohol pictures. Probable awareness of the behavioural hypotheses due to explicit task instructions and patients' deficient prefrontal function might account for this equally aligned pattern. Results are discussed with regard to recent findings revealing a reduced behavioural approach bias and risk for relapse by applying a retraining version of the AAT. Functional measurements might serve as a method for monitoring the corresponding neurobiological changes and-possibly-predicting the success of such a training.

Genetic interaction of PICALM and APOE is associated with brain atrophy and cognitive impairment in Alzheimer's disease.

BACKGROUND: Evidence has emerged indicating that the ε4 allele of APOE and PICALM interact in conferring risk of Alzheimer's disease (AD). The biologic basis of this interaction is unclear, but it is likely to have phenotypic relevance and contribute to the structural and clinical heterogeneity of AD. METHODS: The aim of this study was to investigate interaction effects of the APOE ε4 allele and the alleles at the single-nucleotide polymorphism rs3851179 located in the PICALM locus. We analyzed brain volumes and cognitive phenotypes of 165 patients with early AD dementia. RESULTS: There was a synergistic adverse effect of homozygosity for the PICALM risk allele G in rs3851179 and APOE ε4 on volume in prefrontal and performance on the Trail Making Test A, which is sensitive to processing speed and working memory function. CONCLUSIONS: The data suggest a neural mechanism for APOE-PICALM interactions in patients with manifest AD and indicate that the PICALM genotype modulates both brain atrophy and cognitive performance in APOE ε4 carriers.

Self-report assessment of Positive Appraisal Style (PAS): Development of a process-focused and a content-focused questionnaire for use in mental health and resilience research.

Positive Appraisal Style Theory of Resilience posits that a person's general style of evaluating stressors plays a central role in mental health and resilience. Specifically, a tendency to appraise stressors positively (positive appraisal style; PAS) is theorized to be protective of mental health and thus a key resilience factor. To this date no measures of PAS exist. Here, we present two scales that measure perceived positive appraisal style, one focusing on cognitive processes that lead to positive appraisals in stressful situations (PASS-process), and the other focusing on the appraisal contents (PASS-content). For PASS-process, the items of the existing questionnaires Brief COPE and CERQ-short were analyzed in exploratory and confirmatory factor analyses (EFA, CFA) in independent samples (N = 1157 and N = 1704). The resulting 10-item questionnaire was internally consistent (α = .78, 95% CI [.86, .87]) and showed good convergent and discriminant validity in comparisons with self-report measures of trait optimism, neuroticism, urgency, and spontaneity. For PASS-content, a newly generated item pool of 29 items across stressor appraisal content dimensions (probability, magnitude, and coping potential) were subjected to EFA and CFA in two independent samples (N = 1174 and N = 1611). The resulting 14-item scale showed good internal consistency (α = .87, 95% CI [.86, .87]), as well as good convergent and discriminant validity within the nomological network. The two scales are a new and reliable way to assess self-perceived positive appraisal style in large-scale studies, which could offer key insights into mechanisms of resilience.

Variability of (functional) hemodynamics as measured with simultaneous fNIRS and fMRI during intertemporal choice.

Neural processing inferred from hemodynamic responses measured with functional near infrared spectroscopy (fNIRS) may be confounded with individual anatomical or systemic physiological sources of variance. This may hamper the validity of fNIRS signal interpretations and associations between individual traits and brain activation, such as the link between impulsivity-related personality traits and decreased prefrontal cognitive control during reward-based decision making. Hemodynamic responses elicited by an intertemporal choice reward task in 20 healthy subjects were investigated for multimodal correlations of simultaneous fNIRS-fMRI and for an impact of anatomy and scalp fMRI signal fluctuations on fNIRS signals. Moreover, correlations of prefrontal activation with trait "sensitivity to reward" (SR) were investigated for differences between methods. While showing substantial individual variability, temporal fNIRS-fMRI correlations increased with the activation, which both methods consistently detected within right inferior/middle frontal gyrus. Here, up to 41% of fNIRS channel activation variance was explained by individual gray matter volume simulated to be reached by near-infrared light, and up to 20% by scalp-cortex distance. Extracranial fMRI and fNIRS time series showed significant temporal correlations in the temple region. SR was negatively correlated with fMRI but not fNIRS activation elicited by immediate rewards of choice within right inferior/middle frontal gyrus. Higher SR increased the correlation between extracranial fMRI and fNIRS signals and decreased fNIRS-fMRI correlations. Task-related fNIRS signals might be impacted by regionally and individually weighted sources of anatomical and systemic physiological error variance. Trait-activation correlations might be affected or biased by systemic physiological responses, which should be accounted for in future fNIRS studies of interindividual differences.

A novel approach to probabilistic biomarker-based classification using functional near-infrared spectroscopy.

Pattern recognition approaches to the analysis of neuroimaging data have brought new applications such as the classification of patients and healthy controls within reach. In our view, the reliance on expensive neuroimaging techniques which are not well tolerated by many patient groups and the inability of most current biomarker algorithms to accommodate information about prior class frequencies (such as a disorder's prevalence in the general population) are key factors limiting practical application. To overcome both limitations, we propose a probabilistic pattern recognition approach based on cheap and easy-to-use multi-channel near-infrared spectroscopy (fNIRS) measurements. We show the validity of our method by applying it to data from healthy controls (n = 14) enabling differentiation between the conditions of a visual checkerboard task. Second, we show that high-accuracy single subject classification of patients with schizophrenia (n = 40) and healthy controls (n = 40) is possible based on temporal patterns of fNIRS data measured during a working memory task. For classification, we integrate spatial and temporal information at each channel to estimate overall classification accuracy. This yields an overall accuracy of 76% which is comparable to the highest ever achieved in biomarker-based classification of patients with schizophrenia. In summary, the proposed algorithm in combination with fNIRS measurements enables the analysis of sub-second, multivariate temporal patterns of BOLD responses and high-accuracy predictions based on low-cost, easy-to-use fNIRS patterns. In addition, our approach can easily compensate for variable class priors, which is highly advantageous in making predictions in a wide range of clinical neuroimaging applications.

Genetic variation in MAOA modulates prefrontal cortical regulation of approach-avoidance reactions.

BACKGROUND: Regulation of automatic approach and avoidance behavior requires affective and cognitive control, which are both influenced by a genetic variation in the gene encoding Monoamine Oxidase A (termed MAOA-uVNTR). METHODS: The current study investigated MAOA genotype as a moderator of prefrontal cortical activation measured with functional near-infrared spectroscopy (fNIRS) in 37 healthy young adults during performance of the approach-avoidance task with positive and negative pictures. RESULTS: Carriers of the low- compared to the high-expressing genetic variant (MAOA-L vs. MAOA-H) showed increasing regulatory activity in the right dorsolateral prefrontal cortex (DLPFC) during incompatible conditions (approach negative, avoid positive). This might have been a compensatory mechanism for stronger emotional reactions as shown in previous studies and might have prevented any influence of incompatibility on behavior. In contrast, fewer errors but also lower activity in the right DLPFC during processing of negative compared to positive stimuli indicated MAOA-H carriers to have used other regulatory areas. This resulted in slower reaction times in incompatible conditions, but--in line with the known better cognitive regulation efficiency--allowed them to perform incompatible reactions without activating the DLPFC as the highest control instance. Carriers of one low- and one high-expressing allele lay as an intermediate group between the reactions of the low- and high-expressing groups. CONCLUSIONS: The relatively small sample size and restriction to fNIRS for assessment of cortical activity limit our findings. Nevertheless, these first results suggest monoam-inergic mechanisms to contribute to interindividual differences in the two basic behavioral principles of approach and avoidance and their neuronal correlates.