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In bipolar disorder (BD), the alternation of extreme mood states indicates deficits in emotion processing, accompanied by aberrant neural function of the emotion network. The present study investigated the effects of an emotion-centered psychotherapeutic intervention on amygdala responsivity and connectivity during emotional face processing in BD.

In bipolar disorder, impaired affective theory of mind (aToM) performance and aberrant neural activation in the ToM brain network partly explain social functioning impairments. However, it is not yet known whether psychotherapy of bipolar disorder influences neuroimaging markers of aToM.

Abnormal gamma-band oscillations (GBO) have been frequently associated with the pathophysiology of schizophrenia. GBO are modulated by glutamate, a neurotransmitter, which is continuously discussed to shape the complex symptom spectrum in schizophrenia. The current study examined the effects of ketamine, a glutamate N-methyl-d-aspartate receptor (NMDAR) antagonist, on the auditory-evoked gamma-band response (aeGBR) and psychopathological outcomes in healthy volunteers to investigate neuronal mechanisms of psychotic behavior. In a placebo-controlled, randomized crossover design, the aeGBR power, phase-locking factor (PLF) during a choice reaction task, the Positive and Negative Syndrome Scale (PANSS) and the Altered State of Consciousness (5D-ASC) Rating Scale were assessed in 25 healthy subjects. Ketamine was applied in a subanaesthetic dose. Low-resolution brain electromagnetic tomography was used for EEG source localization. Significant reductions of the aeGBR power and PLF were identified under ketamine administration compared to placebo (p< 0.01). Source-space analysis of aeGBR generators revealed significantly reduced current source density (CSD) within the anterior cingulate cortex during ketamine administration. Ketamine induced an increase in all PANSS (p< 0.001) as well as 5D-ASC scores (p< 0.01) and increased response times (p< 0.001) and error rates (p< 0.01). Only negative symptoms were significantly associated with an aeGBR power decrease (p= 0.033) as revealed by multiple linear regression. These findings argue for a substantial role of the glutamate system in the mediation of dysfunctional gamma band responses and negative symptomatology of schizophrenia and are compatible with the NMDAR hypofunction hypothesis of schizophrenia.

Auditory verbal hallucinations (AVH) are a common positive symptom of schizophrenia. Excitatory-to-inhibitory (E/I) imbalance related to disturbed N-methyl-d-aspartate receptor (NMDAR) functioning has been suggested as a possible mechanism underlying altered connectivity and AVH in schizophrenia. The current study examined the effects of ketamine, a NMDAR antagonist, on glutamate-related mechanisms underlying interhemispheric gamma-band connectivity, conscious auditory perception during dichotic listening (DL), and the emergence of auditory verbal distortions and hallucinations (AVD/AVH) in healthy volunteers. In a single-blind, pseudo-randomized, placebo-controlled crossover design, nineteen male, right-handed volunteers were measured using 64 channel electroencephalography (EEG). Psychopathology was assessed with the PANSS interview and the 5D-ASC questionnaire, including a subscale to detect auditory alterations with regard to AVD/AVH (AUA-AVD/AVH). Interhemispheric connectivity analysis was performed using eLORETA source estimation and lagged phase synchronization (LPS) in the gamma-band range (30–100 Hz). Ketamine induced positive symptoms such as hallucinations in a subgroup of healthy subjects. In addition, interhemispheric gamma-band connectivity was found to be altered under ketamine compared to placebo, and subjects with AUA-AVD/AVH under ketamine showed significantly higher interhemispheric gamma-band connectivity than subjects without AUA-AVD/AVH. These findings demonstrate a relationship between NMDAR functioning, interhemispheric connectivity in the gamma-band frequency range between bilateral auditory cortices and the emergence of AVD/AVH in healthy subjects. The result is in accordance with the interhemispheric miscommunication hypothesis of AVH and argues for a possible role of glutamate in AVH in schizophrenia.

Background: The observation that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists such as ketamine transiently induce schizophrenia-like positive, negative and cognitive symptoms has led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. NMDAR hypofunction can explain many schizophrenia symptoms directly due to excitatory-to-inhibitory (E/I) imbalance, but also dopaminergic dysfunction itself. However, so far no new drug targeting the NMDAR has been successfully approved. In the search for possible biomarkers it is interesting that ketamine-induced psychopathological changes in healthy participants were accompanied by altered electro-(EEG), magnetoencephalographic (MEG) and functional magnetic resonance imaging (fMRI) signals. Methods: We systematically searched PubMed/Medline and Web of Knowledge databases (January 2006 to July 2017) to identify EEG/MEG and fMRI studies of the ketamine model of schizophrenia with human subjects. The search strategy identified 209 citations of which 46 articles met specified eligibility criteria. Results: In EEG/MEG studies, ketamine induced changes of event-related potentials, such as the P300 potential and the mismatch negativity, similar to alterations observed in schizophrenia patients. In fMRI studies, alterations of activation were observed in different brain regions, most prominently within the anterior cingulate cortex and limbic structures as well as task-relevant brain regions. These alterations were accompanied by changes in functional connectivity, indicating a balance shift of the underlying brain networks. Pharmacological treatments did alter ketamine-induced changes in EEG/MEG and fMRI studies to different extents. Conclusion: This review highlights the potential applicability of the ketamine model for schizophrenia drug development by offering the possibility to assess the effect of pharmacological agents on schizophrenia- like symptoms and to find relevant neurophysiological and neuroimaging biomarkers.

Progress in the understanding of normal and disturbed brain function is critically dependent on the methodological approach that is applied. Both electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) are extremely efficient methods for the assessment of human brain function. The specific appeal of the combination is related to the fact that both methods are complementary in terms of basic aspects: EEG is a direct measurement of neural mass activity and provides high temporal resolution. FMRI is an indirect measurement of neural activity and based on hemodynamic changes, and offers high spatial resolution. Both methods are very sensitive to changes of synaptic activity, suggesting that with simultaneous EEG and fMRI the same neural events can be characterized with both high temporal and spatial resolution. Since neural oscillations that can be assessed with EEG are a key mechanism for multi-site communication in the brain, EEG-fMRI can offer new insights into the connectivity mechanisms of brain networks.

Introduction:Despite the progress in antipsychotic treatment, modern antipsychotic medication is still associated with side effects, reduced compliance, drug discontinuation and insufficient effects on negative and cognitive symptoms. Sertindoleis an antipsychotic compound, with high affinity for dopamine D2, serotonin 5-HT2A, 5-HT2Cand α1-adrenergic receptors, which has been reintroduced in the market after extended re-evaluation of its safety and risk–benefit profile.Areas covered:Sertindole's pharmacological profile, pharmacokinetics, neuophysiological properties, efficacy on positive, negative and cognitive symptoms and safety issues are covered in this article, based on a literature review from 1990 to 2012.Expert opinion:Based on five double-blind, randomized, placebo-, haloperidol- or risperidone-controlled studies in patients with schizophrenia, sertindole shows a comparable efficacy with haloperidol and risperidone on positive symptoms, while the effect on negative symptoms seems to be superior. Sertindole is generally well tolerated, but is associated with a dose-related QTc interval prolongation (22 ms). Risk factors for drug-induced arrhythmia, such as cardiac diseases, congenital long QT syndrome, prolongated QTc at baseline, etc. and drug interactions should be considered before prescribing sertindole. To minimize cardiovascular risk, regular ECG recording is required. Sertindole can be an important second-line option for the treatment of schizophrenia for patients intolerant to at least one other antipsychotic. Further comparison with other SGAs and investigations on subgroups (e.g., children, elderly, first-episode, treatment-refractory patients, etc.) are still needed for a precise understanding of the therapeutic benefits and its role in schizophrenia therapy.

Over the last few years, neuroimaging techniques have contributed greatly to the identification of the structural and functional neuroanatomy of anxiety disorders. The amygdala seems to be a crucial structure for fear and anxiety, and has consistently been found to be activated in anxiety-provoking situations. Apart from the amygdala, the insula and anterior cinguiate cortex seem to be critical, and all three have been referred to as the “fear network.” In the present article, we review the main findings from three major lines of research. First, we examine human models of anxiety disorders, including fear conditioning studies and investigations of experimentally induced panic attacks. Then we turn to research in patients with anxiety disorders and take a dose look at post-traumatic stress disorder and obsessive-compulsive disorder. Finally, we review neuroimaging studies investigating neural correlates of successful treatment of anxiety, focusing on exposure-based therapy and several pharmacological treatment options, as well as combinations of both.

The terminal autoreceptor 5HT1B is centrally involved in the regulation of the brain serotonergic system and in several psychiatric disorders including depression, addiction, and obsessivecompulsive disorder. The loudness dependence of the auditory evoked N1P2component LDAEP; primary auditory cortex is currently considered as one of bestvalidated indicators of serotonergic neurotransmission, especially for synaptically released serotonin. Since the 5HT1B receptor is involved in the release of serotonin at terminal endings of cortical neurons, this study addressed the question whether single nucleotide polymorphism SNP in the gene coding for this receptor HTR1B are related to LDAEP of the primary auditory cortex tangential dipole investigating a communitybased sample of 127 healthy subjects randomly selected from the general population. In this carefully recruited sample, a GG haplotype rs1213368rs6296 and the respective Galleles were found to be related to a strong LDAEP response of the left tangential dipole, indicating low serotonergic activity. Apart from the fact that this is the first study which relates HTR1B SNPs to a measure of serotonergic function, it can be speculated that LDAEP may reflect parts of the release mechanism of serotonin at cortical synapses, although the lateralized finding cannot be entirely explained. Carriers of the Galleles may be characterized by a particularly strong feedback inhibition of serotonin release at cortical terminals in the primary auditory cortex, possibly mediated by higher sensitivity of 5HT1B receptors associated with low serotonergic activity. © 2007 WileyLiss, Inc.

Neurophysiological findings such as reduced amplitudes of the P300 potential in patients with schizophrenia are among the most robust findings in biological psychiatry. An enormous literature with findings of abnormal central processing in psychiatric diseases has been acquired during the last decades. However, the benefit of this research has been limited in part due to the unresolved problem of precise and correct localization of the underlying neural generators. The difficulty of correct localization is due to the fact that different constellations of cortical neuroelectric generators can produce identical EEG activity. Therefore, even concerning several major event related potentials no generally accepted knowledge about their cerebral generation exists. While correct localization can easily be obtained by imaging methods based on hemodynamic changes such as functional magnetic resonance imaging (fMRI), these techniques can not distinguish between different aspects of neural activity such as oscillation modes or stages of information processing that are only some milliseconds apart. Accordingly, the integration of simultaneous measurements of EEG and fMRI has become a methodological key issue today. EEG-fMRI may prove to be crucial in providing much deeper understanding of brain activity over the next decades. This review summarizes the basic physiology, methodological issues and interesting applications in psychiatry.

Anxiety disorders are highly prevalent in patients with alcohol use disorder. The purpose of the present study was to examine the neural correlates of behavioral inhibition in alcohol-dependent patients (ICD-10: F 10.2), and in healthy controls and to determine the influence of anxiety on these processes. Therefore, behavioral responses (reaction times; error rates) and event-related potentials of 16 patients with alcohol dependence syndrome and 16 age-and gender-matched healthy controls were recorded while the participants performed an auditory go/no-go task. The patient group was stratified according to their self-rated trait anxiety (STAI) with scores above and below median. We hypothesized that patients suffering from alcohol dependence would show reduced no-go P3 amplitudes involved in response inhibition compared to healthy subjects. In patients with alcoholism and high trait anxiety the decline of no-go P3 amplitudes was expected to be less distinct.The estimation of effect size based on the reaction times of patients with high and low anxiety ratings revealed a cohen's d of 0.61 indicating a small effect. High trait anxiety ratings were also associated with slightly enhanced no-go P3 amplitudes in central brain regions (Mean no-go P3 amplitude at Cz: 10.43 µV) compared to patients with low anxiety scores (Mean 8.98 µV). The effect size (cohen's d) revealed a small effect. Using the Mann-Whitney-U-test for independent samples of the comparison of high- and low-anxious patients, however, did not reveal any significant differences concerning no-go P3 amplitudes. Patients with alcohol use disorder and healthy controls did not differ significantly with regard to reaction time, error rate and no-go P3 amplitudes.This study suggests that no-go P3 amplitudes in patients with alcohol use disorder might be affected to some degree by habitual anxiety. The results emphasize the importance of monitoring trait anxiety in studies regarding cognitive functions in subjects with alcohol use disorder.

During the last 10 years the knowledge about rostral anterior cingulate cortex (ACC) activity in major depression has substantially increased. Several groups have independently described a relationship between resting activity in this area and response to antidepressant treatment.We have recently confirmed a relationship between resting activity of rostral ACC activity and response in a group of 20 patients with major depression using resting theta activity. In this earlier study regions of interest (ROI) were defined in order to establish regional specificity. Differences between responders and nonresponders were only found in the ACC-ROI, but not in the posterior cingulate region. We have now reanalyzed our data using a whole brain voxelwise approach, in order not to miss any other relevant functional differences. In addition to major differences between responders and nonresponders in the rostral ACC, we have identified a nearby region in the midline orbito-frontal region.

Brain monoaminergic neurotransmission is involved in the pathophysiology of various psychiatric disorders including depression. Reliable indicators of central monoaminergic activity might be helpful to specifically identify and differentiate dysfunctions in individual patients in order to selectively adjust medication and predict clinical response.In patients with depression, predictors of treatment response to serotonergic versus non-serotonergic (e.g., noradrenergic) antidepressants could be of considerable clinical relevance by avoiding unfavorable factors such as a prolonged duration of the disorder, risk of suicidality and therapy-resistance. Consequently, these tools might help to decrease direct and indirect costs of treatment.The loudness dependence of the N1/P2 component of auditory evoked potentials (LD) has been proposed as a noninvasive neurophysiological indicator of central serotonergic function. This review focuses on recent studies providing evidence for the validity of LD as an indirect serotonergic marker and highlights data on the clinical application in terms of prediction of treatment response in patients with depression.

Electrophysiological assessments of psychiatric disorders have produced a number of promising, highly replicable findings and thus carry the potential of becoming clinically utilizable in the diagnostic or prognostic evaluation of psychopathological conditions. The procedures involved are rather complex technically and the interpretation of the findings require a combined neurophysiological and clinical expertise. On the other hand, electrophysiological techniques are in general non-invasive and relatively inexpensive, and neurophysiology laboratories are widely available in the clinical setting.Among these techniques, event-related potentials (ERPs) are of major interest in psychiatry, particularly since these tools can indicate cortical neuronal dysfunctions, which play a major role in various neuropsychiatric disorders.

Event related potentials (ERP) are important clinical and research instruments in neuropsychiatry, particularly due to their strategic role for the investigation of brain function. These techniques are often underutilized in the evaluation of neurological and psychiatric disorders, but nevertheless they can be most useful and highly effective in the diagnostic workup of a wide range of neuropsychiatric disorders as well as in monitoring the course of the disorders and the prediction of treatment responses.ERP are noninvasive instruments that directly reflect cortical neuronal activity. Cortical neuronal dysfunction plays a major role in variable neuropsychiatric disorders, and a change in cortical activity under medication might reflect treatment response and could be useful for monitoring drug effects.ERP are the only methods with a sufficiently high time resolution for the analysis of the dynamic patterns of neuronal brain activity, e.g., synchronization and desynchronization, oscillations, coherence, gamma band activity, latency of event related activity, etc., which are crucial for a deeper understanding of functional (neurophysiological) correlates of cognitive, emotional and behavioral disturbances in neuropsychiatric patients.Methodological advances have further improved and strengthened the position of ERP concerning research and clinical application. The usefulness and applicability of ERP in determining and monitoring clinico-pharmacological effects will be summarized mainly by focussing on the auditory evoked P300 and the N1/P2 component of auditory evoked potentials. Owing to important recent developments in the field of brain functional diagnostics the combination of neurophysiological techniques and functional magnetic resonance imaging (fMRI) will be included.

There is good evidence from neuroanatomic postmortem and functional imaging studies that dysfunction of the anterior cingulate cortex plays a prominent role in the pathophysiology of schizophrenia. So far, no electrophysiological localization study has been performed to investigate this deficit. We investigated 18 drug-free schizophrenic patients and 25 normal subjects with an auditory choice reaction task and measured event-related activity with 19 electrodes. Estimation of the current source density distribution in Talairach space was performed with low-resolution electromagnetic tomography (LORETA). In normals, we could differentiate between an early event-related potential peak of the N1 (90–100 ms) and a later N1 peak (120–130 ms). Subsequent current-density LORETA analysis in Talairach space showed increased activity in the auditory cortex area during the first N1 peak and increased activity in the anterior cingulate gyrus during the second N1 peak. No activation difference was observed in the auditory cortex between normals and patients with schizophrenia. However, schizophrenics showed significantly less anterior cingulate gyrus activation and slowed reaction times. Our results confirm previous findings of an electrical source in the anterior cingulate and an anterior cingulate dysfunction in schizophrenics. Our data also suggest that anterior cingulate function in schizophrenics is disturbed at a relatively early time point in the information-processing stream (100–140 ms poststimulus).