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Decreased mismatch negativity (MMN) is a proposed biomarker for psychotic disorders. However, the magnitude of the effect appears to be attenuated in first-episode populations. Furthermore, how mismatch negativity amplitudes are related to brain connectivity in this population is unclear. In this study, we used high-density EEG to record duration-deviant MMN from 22 patients with first-episode psychosis (FEP) and 23 age-matched controls (HC). Consistent with past work, we found decreased MMN amplitude in FEP over a large area of the frontal scalp. We also found decreased latency over the occipital scalp. MMN amplitude was negatively correlated with antipsychotic dose. We used Granger causality to investigate directional connectivity between frontal, midline, left, and right scalp during MMN and found reduced connectivity in FEP compared to HC and following deviant stimuli compared to standard stimuli. FEP participants with smaller decreases in connectivity from standard to deviant stimuli had worse disorganization symptoms. On the other hand, connectivity from the front of the scalp following deviant stimuli was relatively preserved in FEP compared to controls. Our results suggest that a relative imbalance of bottom-up and top-down perceptual processing is present in the early stages of psychotic disorders.

Although a substantial number of studies suggests some clinical benefit concerning negative symptoms in schizophrenia through the modulation of NMDA-receptor function, none of these approaches achieved clinical approval. Given the large body of evidence concerning glutamatergic dysfunction in a subgroup of patients, biomarkers to identify those with a relevant clinical benefit through glutamatergic modulation are urgently needed. A similar reduction of the early auditory evoked gamma-band response (aeGBR) as found in schizophrenia patients can be observed in healthy subjects following the application of an NMDA-receptor antagonist in the ketamine-model, which addresses the excitation / inhibition (E/I) imbalance of the disease. Moreover, this oscillatory change can be related to the emergence of negative symptoms. Accordingly, this study investigated whether glycine-related increases of the aeGBR, through NMDA-receptor co-agonism, accompany an improvement concerning negative symptoms in the ketamine-model. The impact of subanesthetic ketamine doses and the pretreatment with glycine was examined in twenty-four healthy male participants while performing a cognitively demanding aeGBR paradigm with 64-channel electroencephalography. Negative Symptoms were assessed through the PANSS. S-Ketamine alone caused a reduction of the aeGBR amplitude associated with more pronounced negative symptoms compared to placebo. Pretreatment with glycine attenuated both, the ketamine-induced alterations of the aeGBR amplitude and the increased PANSS negative scores in glycine-responders, classified based on relative aeGBR increase. Thus, we propose that the aeGBR represents a possible biomarker for negative symptoms in schizophrenia related to insufficient glutamatergic neurotransmission. This would allow to identify patients with negative symptoms, who might benefit from glutamatergic treatment.

Reports linking a 'jumping-to-conclusions' bias to delusions have led to growing interest in the neurobiological correlates of probabilistic reasoning. Several brain areas have been implicated in probabilistic reasoning; however, findings are difficult to integrate into a coherent account. The present study aimed to provide additional evidence by investigating, for the first time, effective connectivity among brain areas involved in different stages of evidence gathering. We investigated evidence gathering in 25 healthy individuals using fMRI and a new paradigm (Box Task) designed such as to minimize the effects of cognitive effort and reward processing. Decisions to collect more evidence ('draws') were contrasted to decisions to reach a final choice ('conclusions') with respect to BOLD activity. Psychophysiological interaction analysis was used to investigate effective connectivity. Conclusion events were associated with extensive brain activations in widely distributed brain areas associated with the task-positive network. In contrast, draw events were characterized by higher activation in areas assumed to be part of the task-negative network. Effective connectivity between the two networks decreased during draws and increased during conclusion events. Our findings indicate that probabilistic reasoning may depend on the balance between the task-positive and task-negative network, and that shifts in connectivity between the two may be crucial for evidence gathering. Thus, abnormal connectivity between the two systems may significantly contribute to the jumping-to-conclusions bias.

Background Reduced amplitude of the event related P300 potential is a prominent finding in schizophrenia patients and a promising endophenotype for genetic research. As yet, little is known on common genetic risk factors for P300 amplitude reduction and the clinical manifestation of schizophrenia. Recently, the Psychiatric Genomics Consortium (PGC2) identified 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance. We used data from 269 normal subjects with both electrophysiological and genotype data to explore the possible relevance of these schizophrenia index SNPs on the P300 amplitude. Methods The sample comprised 269 unrelated healthy volunteers of German descent from the general population of Munich, Germany. Subjects with neuropsychiatric disorders were excluded. Evoked potentials were recorded using an auditory oddball paradigm with 80% non-target stimuli (540 tones, 500 Hz) and 20% target stimuli (135 tones, 1000 Hz) presented binaurally through headphones in a pseudo randomized order. The P300 amplitude was detected semiautomatically as the most positive value in the timeframe 250–500ms post-stimulus with a visual control afterwards at the electrode position Fz. The sample was genotyped on different platforms following established quality control and imputation protocols. After excluding two SNPs with insufficient quality of imputation, 126 genome-wide significant schizophrenia index SNPs from PGC2 could be evaluated for association with P300 amplitude by linear regression. Results There were 12 associations significant on the p=0.05 level (chr5_140143664_I, rs6002655, rs12887734, rs11191419, rs75059851, rs7907645, rs7432375, rs12421382, rs36068923, rs6065094, chr10_104957618_I, rs6670165). None of the associations survived Bonferroni correction for 126 comparisons. When employing the exact binomial test the number of significant associations observed exceeded chance expectation (p=0,024). Only one half of the associations showed effects in the expected direction (lower P300 amplitude associated with schizophrenia risk allele or amplitude associated with protective allele). Discussion Although we found an overrepresentation of significant associations of schizophrenia index SNPs with event related P300 amplitudes we were unable to establish the connection for any specific locus with sufficient statistical power. The pattern of observed effects was not supportive of a specific role of PGC2 schizophrenia risk alleles in P300 amplitude in normal subjects.

Converging evidence suggests that frontostriatal abnormalities underlie OCD symptoms. The event-related potential P300 is generated along a widely distributed network involving several of the areas implicated in OCD. P300 abnormalities reported in patients with OCD suggest increased activity in these areas. The aim of the present study was to investigate this assumption in unmedicated patients with OCD, and to assess the effects of OCD treatment on P300 brain activity patterns. Seventy-one unmedicated patients with a DSM-IV diagnosis of OCD and 71 age- and gender-matched healthy control subjects participated in the study. The P300 was obtained through 32-channel EEG during an auditory oddball paradigm. Forty-three patients underwent a second EEG assessment after treatment with sertraline and behavioural therapy. Low-resolution electromagnetic tomography (LORETA) was used to localize the sources of brain electrical activity. Results: Increased P300-related activity was observed predominantly in the left orbitofrontal cortex, but also in left prefrontal, parietal and temporal areas, in patients compared to controls at baseline. After treatment, reduction of left middle frontal cortex hyperactivity was observed in patients. Conclusions: Findings of increased activity in frontoparietal areas in patients are consistent with several previous studies. Importantly, OCD treatment led to reduction of hyperactivity in the left middle frontal cortex, an area associated with context processing and uncertainty that might be important for the emergence of OCD symptoms. Thus, the present study is the first to show an association between P300 abnormalities and activity in brain regions postulated to be involved in the pathophysiology of OCD.

The regulation of emotion by cognitive reappraisal has attracted a lot of attention over the last decade. Studies using functional magnetic resonance imaging (fMRI) revealed a wide-spread network of multiple prefrontal and sub-cortical brain regions involved in the successful decrease of negative emotions. However, less is known about the temporal dynamics and the physiological mechanisms underlying these regulation processes. Synchronization of neural oscillations in specific frequency bands plays a key-role in the long-range interaction of different brain regions and oscillatory coupling in the theta frequency range was recently identified to play an important role in the interaction of prefrontal structures, the amygdala and the hippocampus in animal models. Accordingly, we investigated the role of prefrontal theta oscillations during the cognitive reappraisal of aversive pictures in humans. We hypothesized an increase in frontal theta oscillations during emotion regulation and a relationship between frontal theta power and the subjective success of emotion regulation. EEG from 30 healthy participants was recorded while they were asked to passively watch or reappraise the content of pictures with negative content. As expected, we found a significant increase in frequencies around 4Hz at electrode Fz during the regulation condition 'decrease' compared to the 'maintain' condition (p=.006) as well as for the regulation condition 'increase' compared to the 'maintain' condition (p=.017). Additionally, the strength of theta power was positively correlated with the regulation success as reported by the participants (r=0.463, p

Executive dysfunctions (regarding behavioural inhibition, decision making, flexibility or voluntary selection) rank among the core symptoms of attention deficit/hyperactivity disorder. Several studies demonstrated functional variations in patients with ADHD especially during response inhibition and flexibility. However, information about functional correlates of other aspects of executive functions such as voluntary selection processes is limited. A group of thirty adult patients with attention deficit/hyperactivity disorder (ADHD) and 30 healthy controls, matched for age and education, participated in the present study. Electrophysiological responses (event-related potentials, gamma oscillations) and behavioural data were acquired during the voluntary selection between various response alternatives. ADHD patients demonstrated increased responses in the gamma frequency band especially in frontal and fronto-central brain areas during voluntary response selection processes compared to healthy subjects. In addition, the error rate was increased in patients. Given that gamma-band responses have been related to GABAergic and glutamatergic responses these results may indicate accordant dysfunction in patients with ADHD.

Background There is growing evidence of abnormalities of high-frequency oscillations in the gamma-range of the electroencephalography in schizophrenia. The generation of neural activity in the gamma-band was shown to be critically related to a glutamatergic and GABAergic microcircuit which is also known to be involved in the pathophysiology of schizophrenia. Recently, a reduction of the early auditory evoked gamma-band response (eGBR) in schizophrenic patients was reported. In order to investigate the possible applicability of this neurophysiological marker as an intermediate phenotype for schizophrenia, this is the main question of our investigation: Is the early eGBR decreased regarding evoked power and phase locking in first-degree relatives of patients with schizophrenia? Methods We investigated the early eGBR in 17 unaffected first-degree relatives of patients with schizophrenia and in age-, gender- and education-matched groups of schizophrenic patients and healthy controls using an auditory reaction task. Results First-degree relatives of patients with schizophrenia and schizophrenic patients showed a significant reduction of evoked power and phase locking of the early eGBR compared to healthy controls. Conclusion This study shows significantly reduced evoked power and phase locking of the early auditory eGBR in first-degree relatives of patients with schizophrenia pointing to the applicability of this marker as a heritable intermediate phenotype for schizophrenia. The findings are in line with the hypothesis of a disturbed GABAergic interneural modulation of pyramidal cells in schizophrenia and findings of different schizophrenia risk genes associated with transmission at glutamatergic and GABAergic synapses.

Rationale There is evidence that the anti-glycation enzyme glyoxalase-1 (GLO1) may play a role in anxiety-related behaviour. However, discordant findings between GLO1 expression and anxiety-related behaviour have been observed in animal models. Because no data are available on the relation between GLO1 mRNA expression and human anxiety so far, we investigated the expression of GLO1 mRNA in peripheral blood cells in relation to cholecystokinin-tetrapeptide (CCK-4) induced panic anxiety in healthy subjects as an established model of human anxiety in healthy volunteers. Methods Twenty-three healthy subjects underwent challenge with CCK-4. GLO1 mRNA expression was assessed by quantitative real-time polymerase chain reaction prior to CCK-4 injection. Baseline anxiety was assessed with the State-Trait-Anxiety-Inventory (STAI) and panic response was measured with the Panic Symptom Scale (PSS). Results CCK-4 elicited a marked anxiety response accompanied by a significant increase in heart rate. GLO1 mRNA expression did not correlate with state or trait anxiety nor with severity of CCK-4 induced anxiety. Conclusions The lack of correlation between GLO1 mRNA expression and CCK-4 induced panic severity suggests that GLO1 is not involved into the acute panic response to CCK-4 in healthy volunteers. Therefore, further studies are needed to clarify the involvement of GLO1 in anxiety disorders at baseline and in anxiety challenge paradigms to resolve the apparent contradictions of preclinical studies concerning the relationship between GLO1 expression and anxiety.

Voluntary selection between response alternatives belongs to cognitive abilities controlling and regulating goal-directed behaviour. Voluntary selection processes are associated with increased neural activity, especially in medial and lateral frontal brain regions as well as the inferior parietal gyrus. However, the precise function of each brain region as well as the spatiotemporal characteristic of the brain regions involved is not yet clear. The aim of the present study was to disentangle distinct aspects of voluntary selection and their underlying neural processes. Hence, event-related potentials (ERPs) and functional MRI data were acquired simultaneously. Brain regions modulated by the task-induced amplitude variation of ERPs (N2, P3) were identified. The results showed N2-related hemodynamic responses, especially in medial and lateral frontal brain regions. Among other things, medial frontal brain regions are related to conflict monitoring, control of voluntary action and decision making. By contrast, the P3-amplitude proved to be predominantly related to increased BOLD responses in the temporo-parietal junction and lateral frontal brain regions. These brain regions are thought to play a decisive role in an attentional network involved in detecting auditory and visual stimuli. Overall, the results of the study indicated a whole network of brain regions to be associated with voluntary selection processes. In addition, at least some frontal brain regions seemed to be involved at an earlier stage than temporo-parietal regions, probably indicating a top-down process.

Different EEG-vigilance stages from full alertness to sleep onset can be separated during rest. Also fMRI research recently focused on the resting condition and identified several resting state networks. In order to deepen the understanding of different levels of global brain function from relaxed wakefulness to sleep onset the association between EEG-vigilance stages and BOLD signals was analysed. EEG-vigilance stages were attributed to consecutive 3-sec-EEG-segments by an algorithm using topographic and spectral information. Results of the classification were validated by analysing the heart rates during the different brain states. Vigilance stages served as regressors for the analysis of the simultaneously acquired fMRI data. Additionally resting state networks were derived from the fMRI data using independent component analysis (ICA). Also vigilance associated brain activity revealed by EEG-based standardized low resolution tomography (sLORETA) was compared to the results of the fMRI analysis. Results showed increased BOLD signal in the occipital cortex, the anterior cingulate cortex, the frontal cortex, the parietal cortices and the temporal cortices and decreasing BOLD signals in the thalamus and the frontal cortex for declining vigilance stages (A2, A3, B1, B2/B3) in comparison to the high vigilance stage A1. Resting state networks revealed a spatial overlap with the vigilance stage associated BOLD maps in conjunction analyses. sLORETA showed increased neuroelectric alpha activity at the occipital cortex comparable to occipital BOLD signal decreases when comparing stage A with stage B. Different EEG-vigilance stages during rest are associated with pronounced differences of BOLD signals in several brain areas which partly correspond to the resting state networks. For cognitive fMRI-research it therefore seems important to pay attention to vigilance switches in order to separate vigilance associated BOLD signal changes from those specifically related to cognition.

Rationale Experimental panic induction with cholecystokinin-tetrapeptide (CCK-4) has been established as a model to study the pathophysiology of panic disorder. In line with the serotonin (5-HT)-hypothesis of panic disorder it has been suggested that the panicogenic effects of CCK-4 are mediated in part through the 5-HT system. The analysis of the loudness dependency of the auditory evoked potentials (LDAEP) is a valid non-invasive indicator of central serotonergic activity. Methods We investigated the correlation between LDAEP and behavioral, cardiovascular and neuroendocrine panic responses to CCK-4 in 77 healthy volunteers and explored whether differences in LDAEP paralleled subjective panic severity. Behavioral panic responses were measured with the panic symptom scale (PSS). Heart rate and ACTH/cortisol plasma concentrations were assessed concomitantly. Results LDAEP did not differ between panickers and nonpanickers. Furthermore, LDAEP did not correlate with the behavioral panic response. However, a significant positive correlation between LDAEP and CCK-4 induced HPA-axis activation, which was uniform in panickers and nonpanickers, could be detected. Conclusions The psychological effects of CCK-4 rather are mediated by neurotransmitters others than the endogenous 5-HT system. However, the extent of the neuroendocrine activation related to the CCK-4 panic provocation was correlated with the LDAEP, thereby suggesting that central 5-HT mechanisms are involved in the HPA-axis activation during this challenge paradigm.

Alcohol-dependence is often associated with comorbid psychiatric symptoms. However, the results concerning the influence of these symptoms on cognitive functioning in alcoholism are still inconsistent. The aim of this study was to determine performance monitoring in healthy volunteers and alcohol-dependent patients, and to assess the influence of trait anxiety on these processes. Sixteen healthy volunteers and 16 detoxified alcohol-dependent patients completed an auditory go/nogo paradigm. Functional magnetic resonance imaging, event-related potentials and behavioral data were acquired simultaneously. The patients were classified by median split based on level of self-rated trait anxiety (state-trait anxiety inventory; STAI). The results showed no significant differences regarding inhibition-associated electrophysiological and behavioral responses between alcohol-dependent patients with high-trait anxiety scores and alcohol-addicts with low-STAI scores. However, the functional MRI data revealed elevated activations during the response inhibition task especially in the middle frontal gyrus (BA 6/9), the superior frontal gyrus (BA 6/8/9) and the right inferior frontal gyrus, as well as temporo-parietal brain regions in patients with high-trait anxiety compared to non-anxious alcohol-addicts. Patients and healthy controls showed comparable results with regard to neural and behavioral responses. These results suggest that inhibitory control capacities of alcohol-dependent patients are not consistent: alcohol-addicts with high-trait anxiety ratings showed elevated neural responses compared to patients without any comorbid psychiatric symptoms. This may indicate that comorbid psychiatric symptoms need to be considered when assessing brain responses in alcohol-dependent patients.

Two promising approaches have been introduced for the prediction of treatment response in major depression: one concept is based on the activity in the rostral anterior cingulate cortex (rACC). Subjects with higher metabolic rates respond better to sleep deprivation or antidepressive medication. Another approach is the investigation of the loudness dependence of the auditory evoked potential (LDAEP). Here, a high LDAEP is supposed to reflect low central serotonergic activity. We present the first study comparing both approaches in the same group of patients.Patients with major depression (n=20) were investigated using both resting EEG and LDAEP before treatment with either citalopram or reboxetine.We found significant differences between responders and non-responders in the rACC in the theta-frequency range (6.5-8 Hz, p0.05). In the subgroup of patients, treated with citalopram we found higher LDAEP-values in responders versus non-responders (p0.05) and a significant correlation between pre-treatment-LDAEP and improvement in the Hamilton score after treatment (r=0.71, p0.05).In combining both methods a prediction whether a patient with major depression might be at risk for non-response to a standard therapy as well as a suggestion for a pharmacological approach of choice seems to be possible.

High frequency oscillations in the 40 Hz (gamma-band)-range are involved in the synchronization of brain regions, e.g., in cognitive functions. It has been suggested that the auditory evoked gamma-band response (GBR) is affected by attention and apart from auditory cortex activity a frontal or anterior cingulate cortex (ACC) generator could be involved. It was the aim of the present study to address three questions: (1) is there a neural generator of the early evoked GBR in the dorsal (d)ACC? (2) Are there different activation patterns in the dACC and the auditory cortex areas in response to task difficulty? (3) Is it possible to detect an influence of early ACC-gamma-band activity (GBR timeframe) to later auditory information processing (N1 timeframe)? In the present EEG/ERP-study we have investigated 30 healthy subjects using six auditory reaction tasks with increasing difficulty and mental effort demands. In the MANOVA analysis we found a significant main effect of task difficulty on both the GBR amplitude (F=7.75; p

The function of the anterior cingulate cortex (ACC) has been discussed in the last years in the context of conflict monitoring and error detection. In addition, ACC activity has been described in the context of "conscious effort". Recent neurophysiological and neuroimaging studies have described a negative correlation between ACC activity and reaction times in simple or choice reaction time experiments. One suggested explanation for this finding has been that there is a relationship between effort and ACC activity. The present ERP-LORETA study of healthy volunteers (n=35) was intended to directly investigate this relationship. In this experiment, three conditions were investigated: condition I was a choice reaction task with the instruction to stay relaxed during the task (relaxed condition), condition II was the same choice reaction task with the instruction to press the respective button as fast and correct as possible (effort condition). Condition III was just listening to the tones without button press (control condition). Subjects had to score directly after each experimental run on a visual analogue scale the amount of effort they have actually spent. The subjects showed significantly shorter reaction times during the high effort condition in comparison to the relaxed condition, as well as increased N1 amplitudes and increased ACC activity. In a subgroup analysis, this effect was present only in subjects who were (according to their self-ratings) following the instructions closely. These results provide direct evidence for a close relationship between conscious effort and ACC activity and suggest the usefulness of the applied effort-self-rating.