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Transcranial alternating current stimulation (tACS) is a unique form of non-invasive brain stimulation. Sinusoidal alternating electric currents are delivered to the scalp to affect mostly cortical neurons. tACS is supposed to modulate brain function and, in turn, cognitive processes by entraining brain oscillations and inducing long-term synaptic plasticity. Therefore, tACS has been investigated in cognitive neuroscience, but only recently, it has been also introduced in psychiatric clinical trials. This review describes current concepts and first findings of applying tACS as a potential therapeutic tool in the field of psychiatry. The current understanding of its mechanisms of action is explained, bridging cellular neuronal activity and the brain network mechanism. Revisiting the relevance of altered brain oscillations found in six major psychiatric disorders, putative targets for the management of mental disorders using tACS are discussed. A systematic literature search on PubMed was conducted to report findings of the clinical studies applying tACS in patients with psychiatric conditions. In conclusion, the initial results may support the feasibility of tACS in clinical psychiatric populations without serious adverse events. Moreover, these results showed the ability of tACS to reset disturbed brain oscillations, and thus to improve behavioural outcomes. In addition to its potential therapeutic role, the reactivity of the brain circuits to tACS could serve as a possible tool to determine the diagnosis, classification or prognosis of psychiatric disorders. Future double-blind randomised controlled trials are necessary to answer currently unresolved questions. They may aim to detect response predictors and control for various confounding factors.

Auditory verbal hallucinations (AVH) are hallmark symptoms of schizophrenia and have been linked to abnormal activation, connectivity and integration within the auditory, language, and memory brain networks. The interhemispheric miscommunication theory of AVH is based on a steadily growing number of studies using a variety of modalities (EEG, fMRI, DTI) reporting that both altered integrity of the interhemispheric auditory pathways and disturbed functional gamma-band synchrony between right and left auditory cortices significantly contribute to abnormal auditory processing and the emergence of AVH. Moreover, initial studies using pharmacological EEG and 1 H MR spectroscopy provided first insights into the underlying neurochemistry of AVH. It has been suggested that the observed interhemispheric gamma-band alterations might be mediated by an excitatory-to-inhibitory (E/I) imbalance due to dysfunction of N-methyl-d-aspartate receptor (NMDAR). In support, a potential NMDAR hypofunction is proposed to be compensated by increased levels of glutamate in prefrontal and auditory brain areas. In this mini-review paper, we used the levels of explanation approach and present how interhemispheric brain connectivity (brain-imaging level) corresponds to auditory perception (cognitive level), and eventually how these parameters are related to changes in neurotransmission (cellular level) and to the occurrence of AVH (clinical level). To the best of our knowledge, this is the first overview that overcomes traditional boundaries and presents converging evidence from different levels of knowledge that validate and support each other, and particularly point toward the role of an interhemispheric miscommunication in AVH., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

Background: Reasoning biases such as the jumping-to-conclusions bias (JTC) are thought to contribute to delusions. Interventions targeting these biases such as metacognitive training (MCT) may improve delusions. So far, it is not clear whether JTC depends on dopaminergic reward areas that constitute the main action locus of antipsychotic drugs, or on additional cortical areas. The present study aimed to investigate fMRI activation and functional connectivity patterns underlying JTC, and their changes following MCT, in patients with delusions., Methods: Participants were 25 healthy individuals and 26 patients with current delusions who were either medication-free or on stable medication without sufficient response. We assessed (1) BOLD activity in the task-positive (TPN), task-negative (TNN), and subcortical reward network (RN); (2) Psychophysiological interactions (PPI) of peak activation areas., Results: Presence of JTC (irrespective of group) was associated with lower RN activity during conclusion events, and with increased effective connectivity between TPN and TNN during draw events. Following MCT, changes were observed in TPN activity and in effective connectivity of inferior parietal cortex (part of the TPN) with all three target networks., Conclusion: JTC is associated not only with reward system areas that constitute the main target of antipsychotic drugs, but also with cortical areas, particularly of the TPN.

We propose a new method for the localization of nonlinear cross-frequency coupling in EEG and MEG data analysis, based on the estimation of bicoherences at the source level. While for the analysis of rhythmic brain activity, source directions are commonly chosen to maximize power, we suggest to maximize bicoherence instead. The resulting nonlinear cost function can be minimized effectively using a gradient approach. We argue, that bicoherence is also a generally useful tool to analyze phase-amplitude coupling (PAC), by deriving formal relations between PAC and bispectra. This is illustrated in simulated and empirical LFP data. The localization method is applied to EEG resting state data, where the most prominent bicoherence signatures originate from the occipital alpha rhythm and the mu rhythm. While the latter is hardly visible using power analysis, we observe clear bicoherence peaks in the high alpha range of sensorymotor areas. We additionally apply our method to resting-state data of subjects with schizophrenia and healthy controls and observe significant bicoherence differences in motor areas which could not be found from analyzing power differences., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Aberrant salience mainly is attributed to excessive dopaminergic processing in the ventral striatum. Increased gamma power during sensory processing of physical salience has been shown to be associated with positive trait schizotypy. In the present study, this is assessed in patients with schizophrenia., Methods: The early evoked visual gamma-band response (GBR) at 40 Hz was assessed for a schizophrenia patient group (N = 22) and a matched healthy control group (N = 22) applying EEG time-frequency analysis. The GBR was assessed for two conditions within a visual detection paradigm: a target with or without a physically salient distracter and evaluated in relation to the PANSS., Results: A 2 × 2 ANOVA revealed a significant main effect of condition and a trend interaction of group and condition for the GBR, with highest power for schizophrenia patients in the physically salient distracter condition. Moreover, evoked GBR power in this condition was correlated with positive (r = 0.664; P = 0.001**) and disorganised (r = 0.618; P = 0.002**) schizophrenia symptoms., Conclusions: Evoked GBR power during processing of physical salience in schizophrenia was associated with positive symptoms. We suggest that abnormal processing of physically salient stimuli might be involved in the pathophysiological genesis of positive symptoms.

Background: Targeting the N -methyl-D-aspartate receptor (NMDAR) is a major translational approach for treating negative symptoms of schizophrenia. Ketamine comprehensively produces schizophrenia-like symptoms, such as positive, cognitive and negative symptoms in healthy volunteers. The amplitude of the mismatch negativity (MMN) is known to be significantly reduced not only in patients with schizophrenia, but also in healthy controls receiving ketamine. Accordingly, it was the aim of the present study to investigate whether changes of MMN amplitudes during ketamine administration are associated with the emergence of schizophrenia-like negative symptoms in healthy volunteers., Methods: We examined the impact of ketamine during an MMN paradigm with 64-channel electroencephalography (EEG) and assessed the psychopathological status using the Positive and Negative Syndrome Scale (PANSS) in healthy male volunteers using a single-blind, randomized, placebo-controlled crossover design. Low-resolution brain electromagnetic tomography was used for source localization., Results: Twenty-four men were included in our analysis. Significant reductions of MMN amplitudes and an increase in all PANSS scores were identified under the ketamine condition. Smaller MMN amplitudes were specifically associated with more pronounced negative symptoms. Source analysis of MMN generators indicated a significantly reduced current source density (CSD) under the ketamine condition in the primary auditory cortex, the posterior cingulate and the middle frontal gyrus., Limitations: The sample included only men within a tight age range of 20-32 years., Conclusion: The MMN might represent a biomarker for negative symptoms in schizophrenia related to an insufficient NMDAR system and could be used to identify patients with schizophrenia with negative symptoms due to NMDAR dysfunction.

Objectives: Abnormalities of oscillatory gamma activity are supposed to reflect a core pathophysiological mechanism underlying cognitive disturbances in schizophrenia. The auditory evoked gamma-band response (aeGBR) is known to be reduced across all stages of the disease. The present study aimed to elucidate alterations of an aeGBR-specific network mediated by gamma oscillations in the high-risk state of psychosis (HRP) by means of functional magnetic resonance imaging (fMRI) informed by electroencephalography (EEG)., Methods: EEG and fMRI were simultaneously recorded from 27 HRP individuals and 26 healthy controls (HC) during performance of a cognitively demanding auditory reaction task. We used single trial coupling of the aeGBR with the corresponding blood oxygen level depending response (EEG-informed fMRI)., Results: A gamma-band-specific network was significantly lower active in HRP subjects compared with HC (random effects analysis, P < .01, Bonferroni-corrected for multiple comparisons) accompanied by a worse task performance. This network involved the bilateral auditory cortices, the thalamus and frontal brain regions including the anterior cingulate cortex, as well as the bilateral dorsolateral prefrontal cortex., Conclusions: For the first time we report a reduced activation of an aeGBR-specific network in HRP subjects brought forward by EEG-informed fMRI. Because the HRP reflects the clinical risk for conversion to psychotic disorders including schizophrenia and the aeGBR has repeatedly been shown to be altered in patients with schizophrenia the results of our study point towards a potential applicability of aeGBR disturbances as a marker for the prediction of transition of HRP subjects to schizophrenia., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

The beneficial effects of placebo treatments on fear and anxiety (placebo anxiolysis) are well known from clinical practice, and there is strong evidence indicating a contribution of treatment expectations to the efficacy of anxiolytic drugs. Although clinically highly relevant, the neural mechanisms underlying placebo anxiolysis are poorly understood. In two studies in humans, we tested whether the administration of an inactive treatment along with verbal suggestions of anxiolysis can attenuate experimentally induced states of phasic fear and/or sustained anxiety. Phasic fear is the response to a well defined threat and includes attentional focusing on the source of threat and concomitant phasic increases of autonomic arousal, whereas in sustained states of anxiety potential and unclear danger requires vigilant scanning of the environment and elevated tonic arousal levels. Our placebo manipulation consistently reduced vigilance measured in terms of undifferentiated reactivity to salient cues (indexed by subjective ratings, skin conductance responses and EEG event-related potentials) and tonic arousal [indexed by cue-unrelated skin conductance levels and enhanced EEG alpha (8-12 Hz) activity], indicating a downregulation of sustained anxiety rather than phasic fear. We also observed a placebo-dependent sustained increase of frontal midline EEG theta (4-7 Hz) power and frontoposterior theta coupling, suggesting the recruitment of frontally based cognitive control functions. Our results thus support the crucial role of treatment expectations in placebo anxiolysis and provide insight into the underlying neural mechanisms., (Copyright © 2015 the authors 0270-6474/15/357365-09$15.00/0.)

Background: Disturbed functional connectivity is assumed to underlie neurocognitive deficits in patients with schizophrenia. As neurocognitive deficits are already present in the high-risk state, identification of the neural networks involved in this core feature of schizophrenia is essential to our understanding of the disorder. Resting-state studies enable such investigations, while at the same time avoiding the known confounder of impaired task performance in patients. The aim of the present study was to investigate EEG resting-state connectivity in high-risk individuals (HR) compared to first episode patients with schizophrenia (SZ) and to healthy controls (HC), and its association with cognitive deficits., Methods: 64-channel resting-state EEG recordings (eyes closed) were obtained for 28 HR, 19 stable SZ, and 23 HC, matched for age, education, and parental education. The imaginary coherence-based multivariate interaction measure (MIM) was used as a measure of connectivity across 80 cortical regions and six frequency bands. Mean connectivity at each region was compared across groups using the non-parametric randomization approach. Additionally, the network-based statistic was applied to identify affected networks in patients., Results: SZ displayed increased theta-band resting-state MIM connectivity across midline, sensorimotor, orbitofrontal regions and the left temporoparietal junction. HR displayed intermediate theta-band connectivity patterns that did not differ from either SZ or HC. Mean theta-band connectivity within the above network partially mediated verbal memory deficits in SZ and HR., Conclusions: Aberrant theta-band connectivity may represent a trait characteristic of schizophrenia associated with neurocognitive deficits. As such, it might constitute a promising target for novel treatment applications., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Over the last decade, there has been growing interest in aberrant salience as a precursor of positive symptoms in schizophrenia. The present study investigates the neurophysiology of attentional capture by salient stimuli in the visual modality. Evoked oscillatory activity in the gamma frequency range (40 Hz) was assessed during visual processing of physically salient distracters and evaluated in relation to schizotypy and its positive, negative and disorganized dimension. The early evoked visual gamma-band response (GBR) was assessed for 24 healthy participants using EEG time-frequency analysis. Physical salience was constituted by colored stimuli diverting from an ongoing baseline condition. schizotypal personality traits were measured by the schizotypal personality questionnaire (SPQ; Raine in Schizophr Bull 17:555-564, 1991). The early evoked visual GBR was significantly pronounced in the physically salient distracter condition. GBR signal power was significantly correlated with positive schizotypal personality traits (r = 0.588; p = 0.024*). Our results indicate that the early evoked GBR in visual processing of physically salient distracters is associated with schizotypy. These findings refer to the phenomenology of aberrant salience by bridging the gap to neurophysiological research on early sensory selection and attentional capture in the schizophrenia spectrum.

CNTNAP2 is a gene on chromosome 7 that has shown associations with autism and schizophrenia, and there is evidence that it plays an important role for neuronal synchronization and brain connectivity. In this study, we assessed the relationship between Diffusion Tensor Imaging (DTI), a putative marker of anatomical brain connectivity, and multiple single nucleotide polymorphisms (SNPs) spread out over this large gene. 81 healthy controls and 44 patients with schizophrenia (all Caucasian) underwent DTI and genotyping of 31 SNPs within CNTNAP2. We employed Tract-based Spatial Statistics (TBSS) for inter-subject brain registration and computed average diffusivity values for six major white matter tracts. Analyses of Covariance (ANCOVAs) were computed to test for possible associations with genotypes. The strongest association, which survived rigorous Bonferroni correction, was between rs2710126 genotype and Fractional Anisotropy (FA) in the uncinate fasciculus (p = .00003). This anatomical location is particularly interesting given the enriched fronto-temporal expression of CNTNAP2 in the developing brain. For this SNP, no phenotype association has been reported before. There were several further genotype-DTI associations that were nominally significant but did not survive Bonferroni correction, including an association between axial diffusivity in the dorsal cingulum bundle and a region in intron 13 (represented by rs2710102, rs759178, rs2538991), which has previously been reported to be associated with anterior-posterior functional connectivity. We present new evidence about the effects of CNTNAP2 on brain connectivity, whose disruption has been hypothesized to be central to schizophrenia pathophysiology., (© 2013 Published by Elsevier Ltd.)

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.

Event-related potential (ERP) studies in the visual domain often report an emotion-evoked early posterior negativity (EPN). Studies in the auditory domain have recently shown a similar component. Little source localization has been done on the visual EPN, and no source localization has been done on the auditory EPN. The aim of the current study was to identify the neural generators of the auditory EPN using EEG-fMRI single-trial coupling. Data were recorded from 19 subjects who completed three auditory choice reaction tasks: (1) a control task using neutral tones; (2) a prosodic emotion task involving the categorization of syllables; and (3) a semantic emotion task involving the categorization of words. The waveforms of the emotion tasks diverged from the neutral task over parietal scalp during a very early time window (132-156 ms) and later during a more traditional EPN time window (252-392 ms). In the EEG-fMRI analyses, the variance of the voltage in the earlier time window was correlated with activity in the medial prefrontal cortex, but only in the word task. In the EEG-fMRI analyses of the traditional EPN time window both emotional tasks covaried with activity in the left superior parietal lobule. Our results support previous parietal cortex source localization findings for the visual EPN, and suggest enhanced selective attention to emotional stimuli during the EPN time window., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Deficits in executive functions, e.g. voluntary selection, are considered central to the attention-deficit/hyperactivity disorder (ADHD). The aim of this simultaneous EEG/fMRI study was to examine associated neural correlates in ADHD patients. Patients with ADHD and healthy subjects performed an adapted go/nogo task including a voluntary selection condition allowing participants to freely decide, whether to press the response button. Electrophysiologically, response inhibition and voluntary selection led to fronto-central responses. The fMRI data revealed increased medial/lateral frontal and parietal activity during the voluntary selection task. Frontal brain responses were reduced in ADHD patients compared to controls during free responses, whereas parietal brain functions seemed to be unaffected. These results may indicate that selection processes are related to dysfunctions, predominantly in frontal brain regions in ADHD patients.

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., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Studies of schizophrenia with functional MRI have shown hyper- and hypoactivations in various brain regions including the prefrontal cortex. Functional anomalies have also been reported in first-degree relatives of schizophrenic patients. The aim of this study was to examine working memory related brain functions in healthy subjects, schizophrenic patients and unaffected relatives and to determine the influence of psychopathology on these processes. A parametric n-back working memory task and functional MRI were used to examine 61 patients with schizophrenia, 11 nonpsychotic relatives of schizophrenic patients and a comparison group of 61 healthy subjects. The results indicated increased as well as decreased brain functions in schizophrenic patients compared to the control group depending on the task difficulty and the performance: during the attention task (0-back), which served as control condition, behavioral responses of patients and healthy subjects hardly differed but BOLD responses were considerably enhanced in schizophrenic patients. With increasing task difficulty differences between groups in BOLD responses diminished whereas behavioral deficits of patients increased. The examination of attention-independent working memory-functions (2- vs. 0-back) produced hypoactivations in patients, especially in frontal, temporal and subcortical brain regions. Furthermore, positive symptoms were associated with parietal dysfunctions. Behavioral performance and neural responses of unaffected relatives of schizophrenic patients were intermediate between schizophrenic patients and controls indicating slight brain dysfunctions. In addition, compensatory strategies were demonstrated. These findings suggest that the genetic risk for schizophrenia is accompanied by neural inefficiency which is associated with cognitive deficits, especially in difficult tasks.

Interhemispheric coherence derived from electroencephalogram (EEG) recordings is a measure of functional interhemispheric connectivity. Diffusion tensor imaging (DTI) determines the integrity of subcortical fiber tracts. We studied the pattern of subcortical fiber tracts underlying interhemispheric coherence and its alteration in 16 subjects with amnestic mild cognitive impairment (MCI), an at risk syndrome for Alzheimer's disease, and 20 cognitively healthy elderly control subjects using resting state EEG and high resolution DTI at 3 T. We used a multivariate network approach based on principal component analysis to determine effects of coherence on the regional pattern of diffusivity. Temporo-parietal coherence in the alpha band was significantly correlated with diffusivity in predominantly posterior white matter tracts including posterior corpus callosum, parietal, temporal and occipital lobe white matter, thalamus, midbrain, pons, and cerebellum, both in MCI subjects and controls (P < 0.05). In MCI subjects, frontal coherence in the alpha band was significantly correlated with a predominately frontal pattern of diffusivity including fiber tracts of the anterior corpus callosum, frontal lobe white matter, thalamus, pons, and cerebellum (P < 0.05). The study provides a methodology to access specific networks of subcortical fiber tracts subserving the maintenance of interhemispheric resting state coherence in the human brain., (Copyright 2009 Wiley-Liss, Inc)

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.

Experimental panic induction with cholecystokinin tetrapeptide (CCK-4) is considered as a suitable model to investigate the pathophysiology of panic attacks. While only a few studies investigated the brain activation patterns following CCK-4, no data are available on the putative involvement of the amygdala in the CCK-4 elicited anxiety response. We studied the functional correlates of CCK-4-induced anxiety in healthy volunteers by means of functional magnetic resonance imaging (fMRI) and region of interest (ROI) analysis of the amygdala. Sixteen healthy volunteers underwent challenge with CCK-4 compared with placebo in a single-blind design. Functional brain activation patterns were determined for the CCK-4-challenge, the placebo response and anticipatory anxiety (AA). CCK-4-induced anxiety was accompanied by a strong and robust activation (random effects analysis, P < 0.00001, uncorrected for multiple testing) in the ventral anterior cingulate cortex (ACC), middle and superior frontal gyrus, precuneus, middle and superior temporal gyrus, occipital lobe, sublobar areas, cerebellum, and brainstem. In contrast, random effects group analysis for placebo and AA using the same level of significance generated no significant results. Using a more liberal level of significance, activations could be observed in some brain regions such as the dorsal part of the ACC during AA (random effects analysis, P < 0.005). Overall functional responses did not differ between panickers and nonpanickers. Only 5 of 11 subjects showed strong amygdala activation. However, ROI analysis pointed towards higher scores in fear items in these subjects. In conclusion, while overall brain activation patterns are not related to the subjective anxiety response to CCK-4, amygdala activation may be involved in the subjective perception of CCK-4-induced fear.

There is increasing evidence that obsessive-compulsive disorder (OCD) is associated with a dysfunction of cortico-striato-thalamo-cortical neuronal circuits. In order to examine treatment-related changes in neuronal processes, a drug-naive female patient with OCD (subtype: washing/contamination fear) and an age- and gender-matched healthy control were repeatedly tested using functional magnetic resonance imaging (MRI) during the presentation of a symptom provocation task. Patient-specific visual stimuli of symptom provoking situations were compared with disgust provoking and neutral pictures. FMRI scanning was conducted at the beginning, during and upon completion of an inpatient treatment. During the treatment period of more than eight weeks (combined behavioural and systemic couple therapy) the patient filled out a therapy process questionnaire (TPQ) which was administered daily. Results show a phase transition-like change characterized by a sudden reduction of clinical symptoms as assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) in the middle of the treatment period. Before the discontinuous symptom reduction occurred, the dynamic complexity of the TPQ-time series increased which might be indicative for a critical instability of the system. The fMRI results at the beginning of the treatment suggest strong activities in various brain regions, especially in the anterior cingulate cortex. The results of the second and third acquisition revealed comparably smaller OCD-related neuronal responses. The results may indicate that important clinical changes are taking place during the psychotherapy process which correspond to changing patterns of brain activation as well as to critical instabilities and phase-transition like phenomena in the time-series of the patient's daily self-report data.

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.

The following review is focusing on results of functional neuroimaging. After some introductory remarks on the phenomenology, epidemiology, and psychotherapy approaches of obsessive-compulsive disorders (OCD) the most important OCD-related brain regions are presented. Obviously, not only the prominent cortico-striato-thalamo-cortical feedback loops are involved, as functional brain imaging studies tell us, but also other regions as the inferior parietal lobe, the anterior and posterior cingulate gyrus, insula, amygdala, cerebellum, and others. Subclassifications using factor-analysis methods support the hypothesis, that most important subtypes ("washing/contamination fear", "obsessions/checking", "symmetry/ordering", "hoarding") involve different, but partially overlapping brain areas. Stimulation paradigms in fMRI-research are commonly based on symptom provocation by visual or tactile stimuli, or on action-monitoring and error-monitoring tasks. Deficits in action-monitoring and planning are discussed to be one of the basic dysfunctions of OCD. Finally, results of psychotherapeutic induced variations of brain activations in OCD are presented.

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.

An important reason for the interest in P300 event-related potentials are findings in patients with psychiatric disorders like schizophrenia or alcoholism in which attenuations of the P300 amplitude are common findings. The P300 wave has been suggested to be a promising endophenotype for genetic research since attenuations of the amplitude and latency can be observed not only in patients but also in relatives. In parallel, the search for genes involved in the pathogenesis of psychiatric disorders has revealed for both, schizophrenia and alcoholism an association with a DRD3 Ser9Gly polymorphism in a number of studies. In the present study, we have investigated 124 unrelated healthy subjects of German descent and have found diminished parietal and increased frontal P300 amplitudes in Gly9 homozygotes in comparison to Ser9 carriers. This finding suggests a possible role of the DRD3 receptor gene in the interindividual variation of P300 amplitudes. Further studies should address the direct role of the DRD3 Ser9Gly polymorphism in attenuated P300 amplitudes in psychiatric disorders like schizophrenia or alcoholism.

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.

Serotonin and dopamine transporter (SERT, DAT) availabilities have prospectively been investigated using [123I]beta-CIT and single photon emission computed tomography in subjects with obsessive-compulsive disorder under treatment with the selective serotonin reuptake inhibitor citalopram. SERT availability decreased by a mean 36.5%, whereas DAT availability increased by about 40%. The data point at a citalopram induced modulation of both serotonergic and dopaminergic activity and support the notion of functional interactions of monoaminergic systems in the human brain.

fMRI and EEG are complimentary methods for the analysis of brain activity since each method has its strength where the other one has limits: The spatial resolution is thus in the range of millimeters with fMRI and the time resolution is in the range of milliseconds with EEG. For a comprehensive understanding of brain activity in target detection, nine healthy subjects (age 24.2 +/- 2.9) were investigated with simultaneous EEG (27 electrodes) and fMRI using an auditory oddball paradigm. As a first step, event-related potentials, measured inside the scanner, have been compared with the potentials recorded in a directly preceding session in front of the scanner. Attenuated amplitudes were found inside the scanner for the earlier N1/P2 component but not for the late P300 component. Second, an independent analysis of the localizations of the fMRI activations and the current source density as revealed by low resolution electromagnetic tomography (LORETA) has been done. Concordant activations were found in most regions, including the temporoparietal junction (TPJ), the supplementary motor area (SMA)/anterior cingulate cortex (ACC), the insula, and the middle frontal gyrus, with a mean Euclidean distance of 16.0 +/- 6.6 mm between the BOLD centers of gravity and the LORETA-maxima. Finally, a time-course analysis based on the current source density maxima was done. It revealed different time-course patterns in the left and right hemisphere with earlier activations in frontal and parietal regions in the right hemisphere. The results suggest that the combination of EEG and fMRI permits an improved understanding of the spatiotemporal dynamics of brain activity.

Background: Individuals with bipolar disorder are commonly correctly diagnosed a decade after symptom onset. Machine learning techniques may aid in early recognition and reduce the disease burden. As both individuals at risk and those with a manifest disease display structural brain markers, structural magnetic resonance imaging may provide relevant classification features. Methods: Following a pre-registered protocol, we trained linear support vector machine (SVM) to classify individuals according to their estimated risk for bipolar disorder using regional cortical thickness of help-seeking individuals from seven study sites (N = 276). We estimated the risk using three state-of-the-art assessment instruments (BPSS-P, BARS, EPI bipolar). Results: For BPSS-P, SVM achieved a fair performance of Cohen's κ of 0.235 (95% CI 0.11–0.361) and a balanced accuracy of 63.1% (95% CI 55.9–70.3) in the 10-fold cross-validation. In the leave-one-site-out cross-validation, the model performed with a Cohen's κ of 0.128 (95% CI −0.069 to 0.325) and a balanced accuracy of 56.2% (95% CI 44.6–67.8). BARS and EPI bipolar could not be predicted. In post hoc analyses, regional surface area, subcortical volumes as well as hyperparameter optimization did not improve the performance. Conclusions: Individuals at risk for bipolar disorder, as assessed by BPSS-P, display brain structural alterations that can be detected using machine learning. The achieved performance is comparable to previous studies which attempted to classify patients with manifest disease and healthy controls. Unlike previous studies of bipolar risk, our multicenter design permitted a leave-one-site-out cross-validation. Whole-brain cortical thickness seems to be superior to other structural brain features. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia has long been suggested to represent a disorder with prominent neural dysconnectivity. Gamma-band oscillations are highly relevant in this context, due both to their proposed involvement in neuronal synchronization and to their association with neurotransmitter systems relevant for schizophrenia. Several task-related studies have confirmed reduced power and synchronization of gamma-band oscillations in schizophrenia, but it has been suggested that these findings might not apply to the resting state. The present study aimed to investigate resting-state gamma-band connectivity in patients with schizophrenia. Methods: Sixtyfour channel resting-state electroencephalography (eyes closed) was recorded in 22 patients with first-episode schizophrenia and 22 healthy controls matched for age and gender. Orthogonalized power envelope correlation was used as a measure of connectivity across 80 cortical regions at 40 Hz. Mean connectivity at each region was compared across groups using the nonparametric randomization approach. Additionally, the network-based statistic was applied to identify affected networks in patients. Results: Patients displayed increased mean functional gamma-band connectivity compared to controls in the left rolandic operculum. Network-based analyses indicated increased connectivity in patients within a strongly lateralized network consisting mainly of left inferior frontal/ orbitofrontal, lateral and medial temporal, and inferior parietal areas. Within this network, gamma-band connectivity was higher in patients with low positive and disorganization symptom levels. Conclusions: The present study provides a link between resting-state gamma-band connectivity and the core symptoms of schizophrenia. The observed findings are different than those reported by task-related studies, suggesting that resting-state studies might reveal new aspects in the pathophysiology of schizophrenia. [ABSTRACT FROM AUTHOR]

Background: The study of individuals at clinical high risk (CHR) for psychosis provides an important opportunity for unraveling pathological mechanisms underlying schizophrenia and related disorders. A small number of diffusion tensor magnetic resonance imaging (DTI) studies in CHR samples have yielded anatomically inconsistent results. The present study is the first to apply tract-based spatial statistics (TBSS) to perform a whole-brain DTI analysis in CHR subjects. Methods: A total of 28 individuals meeting CHR criteria and 34 healthy controls underwent DTI. TBSS was used for a group comparison of fractional anisotropy (FA), as well as axial, radial, and mean diffusivity (AD, RD, and MD). Conversion to psychosis was monitored during a mean follow-up period of 12.3 months. Results: The rate of conversion to psychosis was relatively low (4%). TBSS revealed increased MD in several clusters in the right hemisphere, most notably in the superior longitudinal fasciculus (SLF), posterior corona radiata, and corpus callosum (splenium and body). Increased RD was restricted to a smaller area in the posterior parietal lobe. Conclusion: We present further evidence that white matter microstructure is abnormal in CHR individuals, even in a sample in which the vast majority do not transition to psychosis over the following year. In accord with previous studies on CHR individuals and patients with early-onset schizophrenia, our findings suggest an important pathological role for the parietal lobe and especially the SLF. The latter is known to undergo particularly dynamic microstructural changes during adolescence and early adulthood, a critical phase for the development of psychotic illness. [ABSTRACT FROM PUBLISHER]

Background Recent studies using an advanced diffusion model, Free Water Imaging (FWI), have demonstrated that fractional anisotropy (FA) reductions in schizophrenia (SZ) patients were mostly associated with increases in extracellular free-water (FW) in the early stages of the illness, while patients with chronic SZ predominantly showed decreases in FA of the tissue (FAt). Conversely, a study comparing patients with chronic bipolar disorder (BP) and healthy individuals (HC) reported that FW was increased in BP subjects suggesting a different trajectory compared to the one found in SZ patients. The present study is the first to investigate WM properties in adolescent-onset SZ and BP together. Utilizing conventional diffusion tensor imaging and FWI, we aim to identify imaging biomarkers that could help differentiate the biological nature of these two disorders. Methods Forty-eight (20F/28M) SZ patients (mean age: 16.28), 15 (7F/8M) BP patients (mean age: 15.52) and 35 (18F/17M) HCs (mean age: 15.65) were included in the study. The mean duration of psychosis (DOP) was 0.97 years in BP subjects and 1.84 years in SZ subjects. All participants underwent diffusion MRI scanning (1.5 T Siemens Magnetom Sonata, 60 gradient directions with b = 1000 m/s2 and 5 images with b = 0 m/s2). Each scan was repeated three times to increase the signal-to-noise ratio and was subsequently corrected for motion and eddy currents before getting averaged. FA, FAt and FW maps were calculated and then skeletonized using Tract-Based Spatial Statistics (TBSS). Voxel-wise, non-parametric statistics were conducted with 5000 permutations and threshold-free cluster enhancement controlling for age, sex and motion. Statistical maps were family-wise error corrected at a significance level of p < 0.05. Results Significant ANOVA effects were explained by pairwise post-hoc t-tests revealing the expected global FA decrease in SZ and BP subjects comparing to HCs. Further, lower FA restricted to the corpus callosum was found in BP comparing to SZ individuals. Applying FWI, BP subjects had both spatially limited decreased FAt and widespread increased FW comparing with HCs, while SZ subjects had extensively decreased FAt but not increased FW. Comparing between the BP and SZ groups, there was no difference in FAt, but significantly higher FW in BP in most regions of the WM skeleton. Discussion Our results are in line with previous studies suggesting a perturbation of WM health in individuals suffering from BP and SZ. The use of FWI in the present study allows for the further clarification of the biological nature of FA reductions: while SZ patients showed only reductions in FAt compared to HCs, the BP group also had marked increases in FW both compared to HCs and the SZ group. These increases in FW spatially overlapped with FA decreases, suggesting that an extra-cellular pathology is driving the observed FA reductions. The present alterations of WM properties in adolescent-onset BP are similar to those previously described in chronic BP and indicate that FW increases might be a biomarker of BP disorder. Interestingly, the adolescent SZ group, unlike recent-onset or first episode adult SZ cohorts, show no FW alterations, but instead FAt reductions similar to those previously reported in chronic SZ subjects. This could be explained by the longer illness duration, or different disease trajectories between adult and adolescent-onset psychosis. Taken together, we show differential patterns of WM aberrations in adolescent-onset SZ and BP, which lend support to the presence of distinct pathologies underlying the neurobiological development and manifestation of these disorders. [ABSTRACT FROM AUTHOR]