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The current study examined the presence of abnormalities in cortical grey-matter (GM) in a sample of clinical high-risk (CHR) participants and examined relationships with psychosocial functioning and neurocognition. CHR-participants (n = 114), participants who did not fulfil CHR-criteria (CHR-negative) (n = 39) as well as a group of healthy controls (HC) (n = 49) were recruited. CHR-status was assessed using the Comprehensive Assessment of At-Risk Mental State (CAARMS) and the Schizophrenia Proneness Interview, Adult Version (SPI-A). The Brief Assessment of Cognition in Schizophrenia Battery (BACS) as well as tests for emotion recognition, working memory and attention were administered. In addition, role and social functioning as well as premorbid adjustment were assessed. No significant differences in GM-thickness and intensity were observed in CHR-participants compared to CHR-negative and HC. Circumscribed abnormalities in GM-intensity were found in the visual and frontal cortex of CHR-participants. Moreover, small-to-moderate correlations were observed between GM-intensity and neuropsychological deficits in the CHR-group. The current data suggest that CHR-participants may not show comprehensive abnormalities in GM. We discuss the implications of these findings for the pathophysiological theories of early stage-psychosis as well as methodological issues and the impact of different recruitment strategies., Competing Interests: Declaration of competing interest P.J.U. has received research support from Lilly and Lundbeck. S.M.L. has received lecture fees from Janssen, Otsuka and Sunovion. The remaining authors report no biomedical financial interests or potential conflicts of interest. The following are the supplementary data related to this article. Supplementary data to this article can be found online at https://doi.org/10.1016/j.schres.2019.08.034., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cognitive dysfunctions represent a core feature of schizophrenia and a predictor for clinical outcomes. One possible mechanism for cognitive impairments could involve an impairment in the experience-dependent modifications of cortical networks. Methods: To address this issue, we employed magnetoencephalography (MEG) during a visual priming paradigm in a sample of chronic patients with schizophrenia ( n = 14), and in a group of healthy controls ( n = 14). We obtained MEG-recordings during the presentation of visual stimuli that were presented three times either consecutively or with intervening stimuli. MEG-data were analyzed for event-related fields as well as spectral power in the 1-200 Hz range to examine repetition suppression and repetition enhancement. We defined regions of interest in occipital and thalamic regions and obtained virtual-channel data. Results: Behavioral priming did not differ between groups. However, patients with schizophrenia showed prominently reduced oscillatory response to novel stimuli in the gamma-frequency band as well as significantly reduced repetition suppression of gamma-band activity and reduced repetition enhancement of beta-band power in occipital cortex to both consecutive repetitions as well as repetitions with intervening stimuli. Moreover, schizophrenia patients were characterized by a significant deficit in suppression of the C1m component in occipital cortex and thalamus as well as of the late positive component (LPC) in occipital cortex. Conclusions: These data provide novel evidence for impaired repetition suppression in cortical and subcortical circuits in schizophrenia. Although behavioral priming was preserved, patients with schizophrenia showed deficits in repetition suppression as well as repetition enhancement in thalamic and occipital regions, suggesting that experience-dependent modification of neural circuits is impaired in the disorder., (Copyright © 2020 Sauer, Grent-'t-Jong, Wibral, Grube, Singer and Uhlhaas.)

Introduction: Alterations in autonomic functioning in individuals diagnosed with schizophrenia are well-documented. Yet, it is currently unclear whether these dysfunctions extend into the clinical high-risk state. Thus, we investigated resting heart rate (RHR) and heart rate variability (HRV) indices in individuals at clinical high-risk for psychosis (CHR-P). Methods: We recruited 117 CHR-P participants, 38 participants with affective disorders and substance abuse (CHR-N) as well as a group of 49 healthy controls. CHR-P status was assessed with the Comprehensive Assessment of At-Risk Mental States (CAARMS) and the Schizophrenia Proneness Instrument, Adult Version (SPI-A). We obtained 5 min, eyes-open resting-state MEG data, which was used for the extraction of cardiac field-related inter-beat-interval data and from which heart-rate and heart-rate variability measures were computed. Results: Compared to both CHR-N and healthy controls, CHR-P participants were characterized by an increased RHR, which was not explained by differences in psychopathological comorbidity and medication status. Increased RHR correlated with the presence of subthreshold psychotic symptoms and associated distress. No differences between groups were found for heart-rate variability measures, however. Furthermore, there was an association between motor-performance and psychophysiological measures. Conclusion: The current study provides evidence of alterations in autonomic functioning as disclosed by increased RHR in CHR-P participants. Future studies are needed to further evaluate this characteristic feature of CHR-P individuals and its potential predictive value for psychosis development., (Copyright © 2020 Kocsis, Gajwani, Gross, Gumley, Lawrie, Schwannauer, Schultze-Lutter, Grent-‘t-Jong and Uhlhaas.)

Sensory attenuation refers to the decreased intensity of a sensory percept when a sensation is self-generated compared with when it is externally triggered. However, the underlying brain regions and network interactions that give rise to this phenomenon remain to be determined. To address this issue, we recorded magnetoencephalographic (MEG) data from 35 healthy controls during an auditory task in which pure tones were either elicited through a button press or passively presented. We analyzed the auditory M100 at sensor- and source-level and identified movement-related magnetic fields (MRMFs). Regression analyses were used to further identify brain regions that contributed significantly to sensory attenuation, followed by a dynamic causal modeling (DCM) approach to explore network interactions between generators. Attenuation of the M100 was pronounced in right Heschl's gyrus (HES), superior temporal cortex (ST), thalamus, rolandic operculum (ROL), precuneus and inferior parietal cortex (IPL). Regression analyses showed that right postcentral gyrus (PoCG) and left precentral gyrus (PreCG) predicted M100 sensory attenuation. In addition, DCM results indicated that auditory sensory attenuation involved bi-directional information flow between thalamus, IPL, and auditory cortex. In summary, our data show that sensory attenuation is mediated by bottom-up and top-down information flow in a thalamocortical network, providing support for the role of predictive processing in sensory-motor system., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Importance: Psychotic disorders are characterized by impairments in neural oscillations, but the nature of the deficit, the trajectory across illness stages, and functional relevance remain unclear., Objectives: To examine whether changes in spectral power, phase locking, and functional connectivity in visual cortex are present during emerging psychosis and whether these abnormalities are associated with clinical outcomes., Design, Setting, and Participants: In this cross-sectional study, participants meeting clinical high-risk criteria for psychosis, participants with first-episode psychosis, participants with affective disorders and substance abuse, and a group of control participants were recruited. Participants underwent measurements with magnetoencephalography and magnetic resonance imaging. Data analysis was carried out between 2018 and 2019., Main Outcomes and Measures: Magnetoencephalographical activity was examined in the 1- to 90-Hz frequency range in combination with source reconstruction during a visual grating task. Event-related fields, power modulation, intertrial phase consistency, and connectivity measures in visual and frontal cortices were associated with neuropsychological scores, psychosocial functioning, and clinical symptoms as well as persistence of subthreshold psychotic symptoms at 12 months., Results: The study participants included those meeting clinical high-risk criteria for psychosis (n = 119; mean [SD] age, 22 [4.4] years; 32 men), 26 patients with first-episode psychosis (mean [SD] age, 24 [4.2] years; 16 men), 38 participants with affective disorders and substance abuse (mean [SD] age, 23 [4.7] years; 11 men), and 49 control participants (mean age [SD], 23 [3.6] years; 16 men). Clinical high-risk participants and patients with first-episode psychosis were characterized by reduced phase consistency of β/γ-band oscillations in visual cortex (d = 0.63/d = 0.93). Moreover, the first-episode psychosis group was also characterized by reduced occipital γ-band power (d = 1.14) and altered visual cortex connectivity (d = 0.74-0.84). Impaired fronto-occipital connectivity was present in both clinical high-risk participants (d = 0.54) and patients with first-episode psychosis (d = 0.84). Importantly, reductions in intertrial phase coherence predicted persistence of subthreshold psychosis in clinical high-risk participants (receiver operating characteristic area under curve = 0.728; 95% CI, 0.612-0.841; P = .001)., Conclusions and Relevance: High-frequency oscillations are impaired in the visual cortex during emerging psychosis and may be linked to behavioral and clinical impairments. Impaired phase consistency of γ-band oscillations was also associated with the persistence of subthreshold psychosis, suggesting that magnetoencephalographical measured neural oscillations could constitute a biomarker for clinical staging of emerging psychosis.

Cognitive deficits are a fundamental feature of schizophrenia for which currently no effective treatments exist. This paper examines the possibility to use transcranial direct current stimulation (tDCS) to target cognitive deficits in schizophrenia as evidence from studies in healthy participants suggests that tDCS may improve cognitive functions and associated neural processes. We carried out a systematic review with the following search terms: 'tDCS', 'electric brain stimulation', 'schizophrenia', 'cognitive', 'cognition' until March 2019. 659 records were identified initially, 612 of which were excluded after abstract screening. The remaining 47 articles were assessed for eligibility based on our criteria and 26 studies were excluded. In addition, we compared several variables, such as online vs. offline-stimulation protocols, stimulation type and intensity on mediating positive vs. negative study outcomes. The majority of studies (n = 21) identified significant behavioural and neural effects on a range of cognitive functions (versus n = 11 with null results), including working memory, attention and social cognition. However, we could not identify tDCS parameters (electrode montage, stimulation protocol, type and intensity) that clearly mediated effects on cognitive deficits. There is preliminary evidence for the possibility that tDCS may improve cognitive deficits in schizophrenia. We discuss the rationale and strength of evidence for using tDCS for targeting cognitive deficits in schizophrenia as well as methodological issues and potential mechanisms of action., Competing Interests: Declaration of competing interest P.J.U. has received research support from Lilly and Lundbeck. The remaining authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The current study examined the pattern of neurocognitive impairments in a community-recruited sample of clinical high-risk (CHR) participants and established relationships with psychosocial functioning., Methods: CHR-participants (n = 108), participants who did not fulfil CHR-criteria (CHR-negatives) (n = 42) as well as a group of healthy controls (HCs) (n = 55) were recruited. CHR-status was assessed using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and the Schizophrenia Proneness Instrument, Adult Version (SPI-A). The Brief Assessment of Cognition in Schizophrenia Battery (BACS) as well as tests for emotion recognition, working memory and attention were administered. In addition, role and social functioning as well as premorbid adjustment were assessed., Results: CHR-participants were significantly impaired on the Symbol-Coding and Token-Motor task and showed a reduction in total BACS-scores. Moreover, CHR-participants were characterised by prolonged response times (RTs) in emotion recognition as well as by reductions in both social and role functioning, GAF and premorbid adjustments compared with HCs. Neurocognitive impairments in emotion recognition accuracy, emotion recognition RT, processing speed and motor speed were associated with several aspects of functioning explaining between 4% and 12% of the variance., Conclusion: The current data obtained from a community sample of CHR-participants highlight the importance of dysfunctions in motor and processing speed and emotion recognition RT. Moreover, these deficits were found to be related to global, social and role functioning, suggesting that neurocognitive impairments are an important aspect of sub-threshold psychotic experiences and a possible target for therapeutic interventions.

Background: The first rate-limiting step for improving outcomes of psychosis through preventive interventions in people at clinical high risk for psychosis (CHR-P) is the ability to accurately detect individuals who are at risk for the development of this disorder. Currently, this detection power is sub-optimal. Methods: This is a conceptual and nonsystematic review of the literature, focusing on the work conducted by leading research teams in the field. The results will be structured in the following sections: understanding the CHR-P assessment, validity of the CHR-P as a universal risk state for psychosis, and improving the detection of at-risk individuals in secondary mental health care, in primary care, and in the community. Results: CHR-P instruments can provide adequate prognostic accuracy for the prediction of psychosis provided that they are employed in samples who have undergone risk enrichment during recruitment. This substantially limits their detection power in real-world settings. Furthermore, there is initial evidence that not all cases of psychosis onset are preceded by a CHR-P stage. A transdiagnostic individualized risk calculator could be used to automatically screen secondary mental health care medical notes to detect those at risk of psychosis and refer them to standard CHR-P assessment. Similar risk estimation tools for use in primary care are under development and promise to boost the detection of patients at risk in this setting. To improve the detection of young people who may be at risk of psychosis in the community, it is necessary to adopt digital and/or sequential screening approaches. These solutions are based on recent scientific evidence and have potential for implementation internationally. Conclusions: The best strategy to improve the detection of patients at risk for psychosis is to implement a clinical research program that integrates different but complementary detection approaches across community, primary, and secondary care. These solutions are based on recent scientific advancements in the development of risk estimation tools and e-health approaches and have the potential to be applied across different clinical settings., (Copyright © 2019 Fusar-Poli, Sullivan, Shah and Uhlhaas.)

E-mental health is an emerging area of research that has the potential to overcome some of the current barriers to progress in working with people at clinical high risk for psychosis (CHR-P). This article provides an overview of how e-mental health could be used in the detection, prediction, and treatment in the CHR-P population. Specifically, we evaluate e-detection, e-prediction, and e-therapeutics for this clinical population. E-mental health holds great promise to improve current management of CHR-P individuals., (©Thomas Reilly, Andrea Mechelli, Philip McGuire, Paolo Fusar-Poli, Peter J Uhlhaas. Originally published in JMIR Mental Health (http://mental.jmir.org), 03.10.2019.)

Background: Anomalies in visual and auditory perception represent an important aspect of the symptomatic manifestation of schizophrenia (ScZ). However, there are currently no instruments available that allow the assessment of the full range of auditory and visual abnormalities using a self-report measure., Methods: We developed the 85-item Audio-Visual Abnormalities Questionnaire (AVAQ) to assess abnormalities in auditory and visual processing. The AVAQ was validated in an online-sample of 355 healthy participants to establish the factorial structure, internal consistency and reliability of the instrument. In addition, participants completed the Autism-Spectrum Quotient (AQ) and the Schizotypal Personality Questionnaire (SPQ) to establish convergent validity regarding autistic and schizotypal traits., Results: High internal consistency was observed for the total AVAQ-scale (α = 0.99) as well as for the visual (α = 0.98), auditory (α = 0.96) and the audio-visual subscales (α = 0.83). Principal component analyses demonstrated one factor comprising 78 items. The AVAQ was positively correlated with the SPQ (r = 0.69, p < .001) as well as the AQ (r = 0.38, p < .001). Correlations with the SPQ were highest for unusual perceptual experiences (r = 0.72, p < .001) and lowest for social anxiety (r = 0.30, p < .001)., Conclusion: The AVAQ demonstrated excellent reliability, internal consistency and construct validity. Accordingly, the instrument could be useful for characterizing sensory dysfunctions across the schizophrenia spectrum that could guide interventions as well as aid the development of biomarkers., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Identification of participants at clinical high-risk (CHR) for the development of psychosis is an important objective of current preventive efforts in mental health research. However, the utility of using web-based screening approaches to detect CHR participants at the population level has not been investigated., Methods: We tested a web-based screening approach to identify CHR individuals. Potential participants were invited to a website via e-mail invitations, flyers, and invitation letters involving both the general population and mental health services. Two thousand two hundred seventy-nine participants completed the 16-item version of the prodromal questionnaire (PQ-16) and a 9-item questionnaire of perceptual and cognitive aberrations (PCA) for the assessment of basic symptoms (BS) online. 52.3% of participants met a priori cut-off criteria for the PQ and 73.6% for PCA items online. One thousand seven hundred eighty-seven participants were invited for a clinical interview and n = 356 interviews were conducted (response rate: 19.9%) using the Comprehensive Assessment of At-Risk Mental State (CAARMS) and the Schizophrenia Proneness Interview, Adult Version (SPI-A). n = 101 CHR participants and n = 8 first-episode psychosis (FEP) were detected. ROC curve analysis revealed good to moderate sensitivity and specificity for predicting CHR status based on online results for both UHR and BS criteria (sensitivity/specificity: PQ-16 = 82%/46%; PCA = 94%/12%). Selection of a subset of 10 items from both PQ-16 and PCA lead to an improved of specificity of 57% while only marginally affecting sensitivity (81%). CHR participants were characterized by similar levels of functioning and neurocognitive deficits as clinically identified CHR groups., Conclusion: These data provide evidence for the possibility to identify CHR participants through population-based web screening. This could be an important strategy for early intervention and diagnosis of psychotic disorders., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

The identification of biomarkers for the early diagnosis of schizophrenia that could inform novel treatment developments is an important objective of current research. This paper will summarize recent work that has investigated changes in oscillatory activity and event-related potentials with Electro/Magnetoencephalography (EEG/MEG) in participants at high-risk for the development of schizophrenia, highlighting disruptions in sensory and cognitive operations prior to the onset of the syndrome. Changes in EEG/MEG-data are consistent with evidence for alterations in Glutamatergic and GABAergic neurotransmission as disclosed by Magnetic Resonance Spectroscopy and brain stimulation, indicating changes in Excitation/Inhibition balance parameters prior to the onset of psychosis. Together these data emphasize the importance of research into neuronal dynamics as a crucial approach to establish functional relationships between impairments in neural circuits and emerging psychopathology that together could be fundamental for early intervention and the identification of novel treatments for emerging psychosis., (Copyright © 2017. Published by Elsevier Inc.)

We examined alterations in E/I-balance in schizophrenia (ScZ) through measurements of resting-state gamma-band activity in participants meeting clinical high-risk (CHR) criteria (n = 88), 21 first episode (FEP) patients and 34 chronic ScZ-patients. Furthermore, MRS-data were obtained in CHR-participants and matched controls. Magnetoencephalographic (MEG) resting-state activity was examined at source level and MEG-data were correlated with neuropsychological scores and clinical symptoms. CHR-participants were characterized by increased 64-90 Hz power. In contrast, FEP- and ScZ-patients showed aberrant spectral power at both low- and high gamma-band frequencies. MRS-data showed a shift in E/I-balance toward increased excitation in CHR-participants, which correlated with increased occipital gamma-band power. Finally, neuropsychological deficits and clinical symptoms in FEP and ScZ-patients were correlated with reduced gamma band-activity, while elevated psychotic symptoms in the CHR group showed the opposite relationship. The current study suggests that resting-state gamma-band power and altered Glx/GABA ratio indicate changes in E/I-balance parameters across illness stages in ScZ., Competing Interests: TG, JG, JG, MW, RG, AG, SL, MS, FS, TN, DK, FL, WS, PU No competing interests declared, (© 2018, Grent-'t-Jong et al.)

Emerging evidence supports the role of neural oscillations as a mechanism for predictive information processing across large-scale networks. However, the oscillatory signatures underlying auditory mismatch detection and information flow between brain regions remain unclear. To address this issue, we examined the contribution of oscillatory activity at theta/alpha-bands (4-8/8-13 Hz) and assessed directed connectivity in magnetoencephalographic data while 17 human participants were presented with sound sequences containing predictable repetitions and order manipulations that elicited prediction-error responses. We characterized the spectro-temporal properties of neural generators using a minimum-norm approach and assessed directed connectivity using Granger Causality analysis. Mismatching sequences elicited increased theta power and phase-locking in auditory, hippocampal and prefrontal cortices, suggesting that theta-band oscillations underlie prediction-error generation in cortical-subcortical networks. Furthermore, enhanced feedforward theta/alpha-band connectivity was observed in auditory-prefrontal networks during mismatching sequences, while increased feedback connectivity in the alpha-band was observed between hippocampus and auditory regions during predictable sounds. Our findings highlight the involvement of hippocampal theta/alpha-band oscillations towards auditory prediction-error generation and suggest a spectral dissociation between inter-areal feedforward vs. feedback signalling, thus providing novel insights into the oscillatory mechanisms underlying auditory predictive processing.

Hypofunction of the N-methyl-d-aspartate receptor (NMDAR) has been implicated as a possible mechanism underlying cognitive deficits and aberrant neuronal dynamics in schizophrenia. To test this hypothesis, we first administered a sub-anaesthetic dose of S-ketamine (0.006 mg/kg/min) or saline in a single-blind crossover design in 14 participants while magnetoencephalographic data were recorded during a visual task. In addition, magnetoencephalographic data were obtained in a sample of unmedicated first-episode psychosis patients (n = 10) and in patients with chronic schizophrenia (n = 16) to allow for comparisons of neuronal dynamics in clinical populations versus NMDAR hypofunctioning. Magnetoencephalographic data were analysed at source-level in the 1-90 Hz frequency range in occipital and thalamic regions of interest. In addition, directed functional connectivity analysis was performed using Granger causality and feedback and feedforward activity was investigated using a directed asymmetry index. Psychopathology was assessed with the Positive and Negative Syndrome Scale. Acute ketamine administration in healthy volunteers led to similar effects on cognition and psychopathology as observed in first-episode and chronic schizophrenia patients. However, the effects of ketamine on high-frequency oscillations and their connectivity profile were not consistent with these observations. Ketamine increased amplitude and frequency of gamma-power (63-80 Hz) in occipital regions and upregulated low frequency (5-28 Hz) activity. Moreover, ketamine disrupted feedforward and feedback signalling at high and low frequencies leading to hypo- and hyper-connectivity in thalamo-cortical networks. In contrast, first-episode and chronic schizophrenia patients showed a different pattern of magnetoencephalographic activity, characterized by decreased task-induced high-gamma band oscillations and predominantly increased feedforward/feedback-mediated Granger causality connectivity. Accordingly, the current data have implications for theories of cognitive dysfunctions and circuit impairments in the disorder, suggesting that acute NMDAR hypofunction does not recreate alterations in neural oscillations during visual processing observed in schizophrenia.

Patients with schizophrenia (ScZ) show pronounced dysfunctions in auditory perception but the underlying mechanisms as well as the localization of the deficit remain unclear. To examine these questions, the current study examined whether alterations in the neuromagnetic mismatch negativity (MMNm) in ScZ-patients could involve an impairment in sensory predictions in local sensory and higher auditory areas. Using a whole-head MEG-approach, we investigated the MMNm as well as P300m and N100m amplitudes during a hierarchical auditory novelty paradigm in 16 medicated ScZ-patients and 16 controls. In addition, responses to omitted sounds were investigated, allowing for a critical test of the predictive coding hypothesis. Source-localization was performed to identify the generators of the MMNm, omission responses as well as the P300m. Clinical symptoms were examined with the positive and negative syndrome scale. Event-related fields (ERFs) to standard sounds were intact in ScZ-patients. However, the ScZ-group showed a reduction in the amplitude of the MMNm during both local (within trials) and global (across trials) conditions as well as an absent P300m at the global level. Importantly, responses to sound omissions were reduced in ScZ-patients which overlapped both in latency and generators with the MMNm sources. Thus, our data suggest that auditory dysfunctions in ScZ involve impaired predictive processes that involve deficits in both automatic and conscious detection of auditory regularities. Hum Brain Mapp 38:5082-5093, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Mismatch negativity (MMN) is a neurophysiological measure of auditory novelty detection that could serve as a translational biomarker of psychiatric disorders, such as schizophrenia. However, the replicability of its magnetoencephalographic (MEG) counterpart (MMNm) has been insufficiently addressed. In the current study, test-retest reliability of the MMNm response to both duration and omission deviants was evaluated over two MEG sessions in 16 healthy adults. MMNm amplitudes and latencies were obtained at both sensor- and source-level using a cortically-constrained minimum-norm approach. Intraclass correlations (ICC) were derived to assess stability of MEG responses over time. In addition, signal-to-noise ratios (SNR) and within-subject statistics were obtained in order to determine MMNm detectability in individual participants. ICC revealed robust values at both sensor- and source-level for both duration and omission MMNm amplitudes (ICC = 0.81-0.90), in particular in the right hemisphere, while moderate to strong values were obtained for duration MMNm and omission MMNm peak latencies (ICC = 0.74-0.88). Duration MMNm was robustly identified in individual participants with high SNR, whereas omission MMNm responses were only observed in half of the participants. Our data indicate that MMNm to unexpected duration changes and omitted sounds are highly reproducible, providing support for the use of MEG-parameters in basic and clinical research., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)

The application of neuroimaging to provide mechanistic insights into circuit dysfunctions in major psychiatric conditions and the development of biomarkers are core challenges in current psychiatric research. We propose that recent technological and analytic advances in magnetoencephalography (MEG), a technique that allows measurement of neuronal events directly and noninvasively with millisecond resolution, provides novel opportunities to address these fundamental questions. Because of its potential in delineating normal and abnormal brain dynamics, we propose that MEG provides a crucial tool to advance our understanding of pathophysiological mechanisms of major neuropsychiatric conditions, such as schizophrenia, autism spectrum disorders, and the dementias. We summarize the mechanisms underlying the generation of MEG signals and the tools available to reconstruct generators and underlying networks using advanced source-reconstruction techniques. We then surveyed recent studies that have used MEG to examine aberrant rhythmic activity in neuropsychiatric disorders. This was followed by links with preclinical research that has highlighted possible neurobiological mechanisms, such as disturbances in excitation/inhibition parameters, that could account for measured changes in neural oscillations. Finally, we discuss challenges as well as novel methodological developments that could pave the way for widespread application of MEG in translational research with the aim of developing biomarkers for early detection and diagnosis.

The thalamus has recently received renewed interest in systems-neuroscience and schizophrenia (ScZ) research because of emerging evidence highlighting its important role in coordinating functional interactions in cortical-subcortical circuits. Moreover, higher cognitive functions, such as working memory and attention, have been related to thalamo-cortical interactions, providing a novel perspective for the understanding of the neural substrate of cognition. The current review will support this perspective by summarizing evidence on the crucial role of neural oscillations in facilitating thalamo-cortical (TC) interactions during normal brain functioning and their potential impairment in ScZ. Specifically, we will focus on the relationship between NMDA-R mediated (glutamatergic) neurotransmission in TC-interactions. To this end, we will first review the functional anatomy and neurotransmitters in thalamic circuits, followed by a review of the oscillatory signatures and cognitive processes supported by TC-circuits. In the second part of the paper, data from preclinical research as well as human studies will be summarized that have implicated TC-interactions as a crucial target for NMDA-receptor hypofunctioning. Finally, we will compare these neural signatures with current evidence from ScZ-research, suggesting a potential overlap between alterations in TC-circuits as the result of NMDA-R deficits and stage-specific alterations in large-scale networks in ScZ., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: The transition from adolescence to adulthood is associated with the emergence of psychosis and other mental health problems, highlighting the importance of this developmental period for the understanding of developing psychopathology and individual differences in risk and resilience. The Youth Mental Health Risk and Resilience Study (YouR-Study) aims to identify neurobiological mechanisms and predictors of psychosis-risk with a state-of-the-art neuroimaging approach (Magnetoencephalography, Magnetic Resonance Spectroscopy, Magnetic Resonance Imaging) in combination with core psychological processes, such as affect regulation and attachment, that have been implicated in the development and maintenance of severe mental health problems., Methods/design: One hundred participants meeting clinical high-risk criteria (CHR) for psychosis through the Comprehensive Assessment of At-Risk Mental State and Schizophrenia Proneness Instrument, Adult Version, in the age range from 16 to 35 years of age will be recruited. Mental-state monitoring up to a total of 2 years will be implemented to detect transition to psychosis. In addition, a sample of n = 40 help-seeking participants will be recruited who do not meet CHR-criteria, a group of n = 50 healthy control participants and a sample of n = 25 patients with first-episode psychosis. MEG-activity will be obtained during auditory and visual tasks to examine neural oscillations and event-related fields. In addition, we will obtain estimates of GABA and Glutamate levels through Magnetic Resonance Spectroscopy (MRS) to examine relationships between neural synchrony and excitatory-inhibition (E/I) balance parameters. Neuroimaging will be complemented by detailed neuropsychological assessments as well as psychological measures investigating the impact of childhood abuse, attachment experiences and affect regulation., Discussion: The YouR-study could potentially provide important insights into the neurobiological mechanisms that confer risk for psychosis as well as biomarkers for early diagnosis of severe mental health problems. Moreover, we expect novel data related to the contribution of affect regulation and attachment-processes in the development of mental health problems, leading to an integrative model of early stage psychosis and the factors underlying risk and resilience of emerging psychopathology.

Importance: The neurobiological mechanisms underlying circuit dysfunctions in schizophrenia remain poorly understood. The 40-Hz auditory steady-state response (ASSR) has been suggested as a potential biomarker for schizophrenia., Objectives: To provide a meta-analytical insight into the presence of 40-Hz ASSR impairments in patients with schizophrenia and to examine the effects of the participant group, stimulus parameters, and analysis and recording techniques., Data Sources: Searches were conducted in PubMed and reference lists of appropriate publications to identify relevant studies published from November 1999 to March 2016. Initial literature searches were performed with combinations of the following search terms: (1) auditory steady state response, (2) schizophrenia, (3) 40 Hz, (4) EEG, (5) MEG, and (6) steady state response., Study Selection: Original articles reporting 40-Hz ASSR data on patients with schizophrenia (chronic or first episode) compared with healthy controls using electroencephalographic (EEG) and magnetoencephalographic (MEG) recordings., Data Extraction and Synthesis: Hedges g effect sizes were calculated using sample sizes, P values, and/or Cohen d effect sizes from 20 studies. Effect size data were pooled using random-effects models. Publication bias was corrected for using funnel plots, the Egger regression test, and a trim and fill test. The contributions of study design parameters and participant characteristics were assessed using a mixed linear model approach and subsequent post hoc t tests. The present analysis was performed during the period from November 2015 to March 2016., Main Outcomes and Measures: Random model Hedges g effect sizes for auditory steady-state amplitude and phase-locking measures from sensor/electrode and sources-space responses in EEG and MEG studies., Results: Of the 20 studies analyzed (representing a total of 590 healthy controls and 606 patients with schizophrenia), 17 reported significant reductions in 40-Hz ASSR spectral power and/or phase locking in patients with schizophrenia compared with healthy controls (Hedges g effect: -0.58 [power] and -0.46 [phase]). Effect sizes from spectral power and phase-locking measures did not differ significantly (95% CI, -0.49 to 0.22; t = -0.80; P = .43). Stimulus characteristics and analysis methods were not associated with the findings of 40-Hz ASSR impairment in schizophrenia., Conclusions and Relevance: The 40-Hz ASSR spectral power and phase-locking deficits are robust in schizophrenia, which suggests that these measures could be useful probes for assessing circuit dysfunctions in the disorder. Moreover, these findings should motivate large-scale studies of the longitudinal expression in patients with schizophrenia and at-risk populations, to further validate the 40-Hz ASSR as a potential biomarker.

Background: Gamma-band oscillations are prominently impaired in schizophrenia, but the nature of the deficit and relationship to perceptual processes is unclear., Methods: 16 patients with chronic schizophrenia (ScZ) and 16 age-matched healthy controls completed a visual paradigm while magnetoencephalographic (MEG) data was recorded. Participants had to detect randomly occurring stimulus acceleration while viewing a concentric moving grating. MEG data were analyzed for spectral power (1-100Hz) at sensor- and source-level to examine the brain regions involved in aberrant rhythmic activity, and for contribution of differences in baseline activity towards the generation of low- and high-frequency power., Results: Our data show reduced gamma-band power at sensor level in schizophrenia patients during stimulus processing while alpha-band and baseline spectrum were intact. Differences in oscillatory activity correlated with reduced behavioral detection rates in the schizophrenia group and higher scores on the "Cognitive Factor" of the Positive and Negative Syndrome Scale. Source reconstruction revealed that extra-striate (fusiform/lingual gyrus), but not striate (cuneus), visual cortices contributed towards the reduced activity observed at sensor-level in ScZ patients. Importantly, differences in stimulus-related activity were not due to differences in baseline activity., Conclusions: Our findings highlight that MEG-measured high-frequency oscillations during visual processing can be robustly identified in ScZ. Our data further suggest impairments that involve dysfunctions in ventral stream processing and a failure to increase gamma-band activity in a task-context. Implications of these findings are discussed in the context of current theories of cortical-subcortical circuit dysfunctions and perceptual processing in ScZ., (Copyright © 2016 Elsevier B.V. All rights reserved.)

High frequency brain oscillations are associated with numerous cognitive and behavioral processes. Non-invasive measurements using electro-/magnetoencephalography (EEG/MEG) have revealed that high frequency neural signals are heritable and manifest changes with age as well as in neuropsychiatric illnesses. Despite the extensive use of EEG/MEG-measured neural oscillations in basic and clinical research, studies demonstrating test-retest reliability of power and frequency measures of neural signals remain scarce. Here, we evaluated the test-retest reliability of visually induced gamma (30-100Hz) oscillations derived from sensor and source signals acquired over two MEG sessions. The study required participants (N=13) to detect the randomly occurring stimulus acceleration while viewing a moving concentric grating. Sensor and source MEG measures of gamma-band activity yielded comparably strong reliability (average intraclass correlation, ICC=0.861). Peak stimulus-induced gamma frequency (53-72Hz) yielded the highest measures of stability (ICCsensor=0.940; ICCsource=0.966) followed by spectral signal change (ICCsensor=0.890; ICCsource=0.893) and peak frequency bandwidth (ICCsensor=0.856; ICCsource=0.622). Furthermore, source-reconstruction significantly improved signal-to-noise for spectral amplitude of gamma activity compared to sensor estimates. Our assessments highlight that both sensor and source derived estimates of visually induced gamma-band oscillations from MEG signals are characterized by high test-retest reliability, with source derived oscillatory measures conferring an improvement in the stability of peak-frequency estimates. Importantly, our finding of high test-retest reliability supports the feasibility of pharma-MEG studies and longitudinal aging or clinical studies., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

The graph theoretical analysis of structural magnetic resonance imaging (MRI) data has received a great deal of interest in recent years to characterize the organizational principles of brain networks and their alterations in psychiatric disorders, such as schizophrenia. However, the characterization of networks in clinical populations can be challenging, since the comparison of connectivity between groups is influenced by several factors, such as the overall number of connections and the structural abnormalities of the seed regions. To overcome these limitations, the current study employed the whole-brain analysis of connectional fingerprints in diffusion tensor imaging data obtained at 3 T of chronic schizophrenia patients (n = 16) and healthy, age-matched control participants (n = 17). Probabilistic tractography was performed to quantify the connectivity of 110 brain areas. The connectional fingerprint of a brain area represents the set of relative connection probabilities to all its target areas and is, hence, less affected by overall white and gray matter changes than absolute connectivity measures. After detecting brain regions with abnormal connectional fingerprints through similarity measures, we tested each of its relative connection probability between groups. We found altered connectional fingerprints in schizophrenia patients consistent with a dysconnectivity syndrome. While the medial frontal gyrus showed only reduced connectivity, the connectional fingerprints of the inferior frontal gyrus and the putamen mainly contained relatively increased connection probabilities to areas in the frontal, limbic, and subcortical areas. These findings are in line with previous studies that reported abnormalities in striatal-frontal circuits in the pathophysiology of schizophrenia, highlighting the potential utility of connectional fingerprints for the analysis of anatomical networks in the disorder.

In its initial formulation, the concept of basic symptoms (BSs) integrated findings on the early symptomatic course of schizophrenia and first in vivo evidence of accompanying brain aberrations. It argued that the subtle subclinical disturbances in mental processes described as BSs were the most direct self-experienced expression of the underlying neurobiological aberrations of the disease. Other characteristic symptoms of psychosis (e.g., delusions and hallucinations) were conceptualized as secondary phenomena, resulting from dysfunctional beliefs and suboptimal coping styles with emerging BSs and/or concomitant stressors. While BSs can occur in many mental disorders, in particular affective disorders, a subset of perceptive and cognitive BSs appear to be specific to psychosis and are currently employed in two alternative risk criteria. However, despite their clinical recognition in the early detection of psychosis, neurobiological research on the aetiopathology of psychosis with neuroimaging methods has only just begun to consider the neural correlate of BSs. This perspective paper reviews the emerging evidence of an association between BSs and aberrant brain activation, connectivity patterns, and metabolism, and outlines promising routes for the use of BSs in aetiopathological research on psychosis.

Stability of oscillatory signatures across magnetoencephalography (MEG) measurements is an important prerequisite for basic and clinical research that has been insufficiently addressed. Here, we evaluated the test-retest reliability of auditory steady-state responses (ASSRs) over two MEG sessions. The study required participants (N=13) to detect the rare occurrence of pure tones interspersed within a stream of 5 Hz or 40 Hz amplitude-modulated (AM) tones. Intraclass correlations (ICC; Shrout and Fleiss, 1979) were derived to assess stability of spectral power changes and the inter-trial phase coherence (ITPC) of task-elicited neural responses. ASSRs source activity was estimated using eLORETA beamforming from bilateral auditory cortex. ASSRs to 40 Hz AM stimuli evoked stronger power modulation and phase-locking than 5 Hz stimulation. Overall, spectral power and ITPC values at both sensor- and source-level showed robust ICC values. Notably, ITPC measures yielded higher ICCs (~0.86-0.96) between sessions compared to the assessment of spectral power change (~0.61-0.82). Our data indicate that spectral modulations and phase consistency of ASSRs in MEG data are highly reproducible, providing support for MEG-measured oscillatory parameters in basic and clinical research., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Hypofunctioning of the N-methyl-D-aspartate receptor (NMDA-R) has been prominently implicated in the pathophysiology of schizophrenia (ScZ). The current study tested the effects of ketamine, a dissociative anesthetic and NMDA-R antagonist, on resting-state activity recorded with magnetoencephalography (MEG) in healthy volunteers. In a single-blind cross-over design, each participant (n = 12) received, on 2 different sessions, a subanesthetic dose of S-ketamine (0.006 mg/Kg) and saline injection. MEG-data were analyzed at sensor- and source-level in the beta (13-30 Hz) and gamma (30-90 Hz) frequency ranges. In addition, connectivity analysis at source-level was performed using transfer entropy (TE). Ketamine increased gamma-power while beta-band activity was decreased. Specifically, elevated 30-90 Hz activity was pronounced in subcortical (thalamus and hippocampus) and cortical (frontal and temporal cortex) regions, whilst reductions in beta-band power were localized to the precuneus, cerebellum, anterior cingulate, temporal and visual cortex. TE analysis demonstrated increased information transfer in a thalamo-cortical network after ketamine administration. The findings are consistent with the pronounced dysregulation of high-frequency oscillations following the inhibition of NMDA-R in animal models of ScZ as well as with evidence from electroencephalogram-data in ScZ-patients and increased functional connectivity during early illness stages. Moreover, our data highlight the potential contribution of thalamo-cortical connectivity patterns towards ketamine-induced neuronal dysregulation, which may be relevant for the understanding of ScZ as a disorder of disinhibition of neural circuits., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A considerable body of work over the last 10 years combining noninvasive electrophysiology (electroencephalography/magnetoencephalography) in patient populations with preclinical research has contributed to the conceptualization of schizophrenia as a disorder associated with aberrant neural dynamics and disturbances in excitation/inhibition balance. This complements previous research that has largely focused on the identification of abnormalities in circumscribed brain regions and on disturbances of dopaminergic mechanisms as a cause of positive symptoms and executive deficits. In the current review, we provide an update on studies focusing on aberrant neural dynamics. First, we discuss the role of rhythmic activity in neural dynamics and in the coordination of distributed neuronal activity into organized neural states. This is followed by an overview on the current evidence for impaired neural oscillations and synchrony in schizophrenia and associated abnormalities in gamma-aminobutyric acidergic and glutamatergic neurotransmission. Finally, we discuss the distinction between fundamental symptoms, which are reflected in cognitive deficits, and psychotic, accessory symptoms, the latter likely constituting a compensatory response for aberrant neuronal dynamics., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Human brain maturation is characterized by the prolonged development of structural and functional properties of large-scale networks that extends into adulthood. However, it is not clearly understood which features change and which remain stable over time. Here, we examined structural connectivity based on diffusion tensor imaging (DTI) in 121 participants between 4 and 40 years of age. DTI data were analyzed for small-world parameters, modularity, and the number of fiber tracts at the level of streamlines. First, our findings showed that the number of fiber tracts, small-world topology, and modular organization remained largely stable despite a substantial overall decrease in the number of streamlines with age. Second, this decrease mainly affected fiber tracts that had a large number of streamlines, were short, within modules and within hemispheres; such connections were affected significantly more often than would be expected given their number of occurrences in the network. Third, streamline loss occurred earlier in females than in males. In summary, our findings suggest that core properties of structural brain connectivity, such as the small-world and modular organization, remain stable during brain maturation by focusing streamline loss to specific types of fiber tracts., (© The Author 2013. Published by Oxford University Press.)

Neural oscillations have received recently a great deal of interest in schizophrenia research because of the possibility to integrate findings from non-invasive electro/magnetoencephalographical recordings with pre-clinical research, which could potentially lead to the identification of pathophysiological mechanisms and novel treatment targets. In the current paper, we review the potential as well as the challenges of this approach by summarizing findings on alterations in rhythmic activity from both animal models and human data which have implicated dysfunctional neural oscillations in the explanation of cognitive deficits and certain clinical symptoms of schizophrenia. Specifically, we will focus on findings that have examined neural oscillations during 1) perceptual processing, 2) working memory and executive processes and 3) spontaneous activity. The importance of the development of paradigms suitable for human and animal models is discussed as well as the search for mechanistic explanation for oscillatory dysfunctions., (© The Author(s) 2015.)

Schizophrenia is characterized by dysfunctions in neural circuits that can be investigated with electrophysiological methods, such as EEG and MEG. In the present human study, we examined event-related fields (ERFs), in a sample of medication-naive, first-episode schizophrenia (FE-ScZ) patients (n = 14) and healthy control participants (n = 17) during perception of Mooney faces to investigate the integrity of neuromagnetic responses and their experience-dependent modification. ERF responses were analyzed for M100, M170, and M250 components at the sensor and source levels. In addition, we analyzed peak latency and adaptation effects due to stimulus repetition. FE-ScZ patients were characterized by significantly impaired sensory processing, as indicated by a reduced discrimination index (A'). At the sensor level, M100 and M170 responses in FE-ScZ were within the normal range, whereas the M250 response was impaired. However, source localization revealed widespread elevated activity for M100 and M170 in FE-ScZ and delayed peak latencies for the M100 and M250 responses. In addition, M170 source activity in FE-ScZ was not modulated by stimulus repetitions. The present findings suggest that neural circuits in FE-ScZ may be characterized by a disturbed balance between excitation and inhibition that could lead to a failure to gate information flow and abnormal spreading of activity, which is compatible with dysfunctional glutamatergic neurotransmission.

Evidence from anatomical and functional imaging studies have highlighted major modifications of cortical circuits during adolescence. These include reductions of gray matter (GM), increases in the myelination of cortico-cortical connections and changes in the architecture of large-scale cortical networks. It is currently unclear, however, how the ongoing developmental processes impact upon the folding of the cerebral cortex and how changes in gyrification relate to maturation of GM/WM-volume, thickness and surface area. In the current study, we acquired high-resolution (3 Tesla) magnetic resonance imaging (MRI) data from 79 healthy subjects (34 males and 45 females) between the ages of 12 and 23 years and performed whole brain analysis of cortical folding patterns with the gyrification index (GI). In addition to GI-values, we obtained estimates of cortical thickness, surface area, GM and white matter (WM) volume which permitted correlations with changes in gyrification. Our data show pronounced and widespread reductions in GI-values during adolescence in several cortical regions which include precentral, temporal and frontal areas. Decreases in gyrification overlap only partially with changes in the thickness, volume and surface of GM and were characterized overall by a linear developmental trajectory. Our data suggest that the observed reductions in GI-values represent an additional, important modification of the cerebral cortex during late brain maturation which may be related to cognitive development.

Neural oscillations at different frequencies have recently been related to a wide range of basic and higher cognitive processes. One possible role of oscillatory activity is to assure the maintenance of information in working memory (WM). Here we review the possibility that rhythmic activity at theta, alpha, and gamma frequencies serve distinct functional roles during WM maintenance. Specifically, we propose that gamma-band oscillations are generically involved in the maintenance of WM information. By contrast, alpha-band activity reflects the active inhibition of task-irrelevant information, whereas theta-band oscillations underlie the organization of sequentially ordered WM items. Finally, we address the role of cross-frequency coupling (CFC) in enabling alpha-gamma and theta-gamma codes for distinct WM information., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Recent findings have implicated thalamic alpha oscillations in the phasic modulation of cortical activity. However, the precise relationship between thalamic alpha oscillations and neocortical activity remains unclear. Here we show in a large sample of healthy human participants (n = 45) using spatial filtering techniques and measures of phase amplitude coupling that the amplitude of gamma-band activity in posterior medial parietal cortex is modulated by the phase of thalamic alpha oscillations during eyes-closed resting-state recordings. In addition, our findings show that gamma-band activity in visual cortex was not modulated by thalamic alpha oscillations but coupled to the phase of strong cortical alpha activity. To overcome the limitations of electromagnetic source localization we estimated conduction delays using transfer entropy and found nonspurious information transfer from thalamus to cortex. The present findings provide novel evidence for magneto-encephalography-measured phase coupling between cortical gamma-band activity and thalamic alpha oscillations, which highlight the role of phasic inhibition in the coordination of cortical activity.

Introduction: High-frequency oscillations are important for sensory processing and dysfunctions in the amplitude and synchrony of beta- and gamma-band oscillations have been demonstrated in schizophrenia (ScZ). However, the presence of aberrant high-frequency oscillations in first-episode (FE), medication-naive patients during sensory processing is unclear., Methods: Magnetoencephalographic (MEG) data were recorded from 15 never-medicated, FE-ScZ patients and 20 matched healthy controls during the perception of Mooney faces. MEG data were analysed for spectral power and single-sensor phase-locking in the beta (13-25Hz) and gamma- (25-140Hz) frequency range., Results: FE-ScZ patients were characterized by significantly impaired sensory processing as indicated by a reduced discrimination index (A'). Impaired behavioural performance in ScZ-patients was accompanied by decreased spectral power in the high- (60-120Hz) gamma-band range. In contrast, oscillations in the lower (25-60Hz) gamma-band were largely intact and beta-band oscillations were increased. Analysis of cross-frequency coupling showed a reduced correlation between 60 and 120Hz amplitude values and beta-band power in FE-ScZ-patients relative to controls., Discussion: Our findings show that impaired sensory processing in medication-naive, FE-schizophrenia is related to a dysregulation of neural oscillations which involves both an impairment in the generation of high gamma-band activity as well as a failure to downregulate task-irrelevant beta-band activity. Because of the interrelationship of these dysfunctions and the role of inhibitory networks in the shaping of high-frequency activity, aberrant neural oscillations in FE-schizophrenia may be linked to dysfunctions in the excitation-inhibition (E/I)-balance., (© 2013.)

Visual information is fundamental to how we understand our environment, make predictions, and interact with others. Recent research has underscored the importance of visuo-perceptual dysfunctions for cognitive deficits and pathophysiological processes in schizophrenia. In the current paper, we review evidence for the relevance of high frequency (beta/gamma) oscillations towards visuo-perceptual dysfunctions in schizophrenia. In the first part of the paper, we examine the relationship between beta/gamma band oscillations and visual processing during normal brain functioning. We then summarize EEG/MEG-studies which demonstrate reduced amplitude and synchrony of high-frequency activity during visual stimulation in schizophrenia. In the final part of the paper, we identify neurobiological correlates as well as offer perspectives for future research to stimulate further inquiry into the role of high-frequency oscillations in visual processing impairments in the disorder.

Neural oscillations at low- and high-frequency ranges are a fundamental feature of large-scale networks. Recent evidence has indicated that schizophrenia is associated with abnormal amplitude and synchrony of oscillatory activity, in particular, at high (beta/gamma) frequencies. These abnormalities are observed during task-related and spontaneous neuronal activity which may be important for understanding the pathophysiology of the syndrome. In this paper, we shall review the current evidence for impaired beta/gamma-band oscillations and their involvement in cognitive functions and certain symptoms of the disorder. In the first part, we will provide an update on neural oscillations during normal brain functions and discuss underlying mechanisms. This will be followed by a review of studies that have examined high-frequency oscillatory activity in schizophrenia and discuss evidence that relates abnormalities of oscillatory activity to disturbed excitatory/inhibitory (E/I) balance. Finally, we shall identify critical issues for future research in this area.

Background: Adolescence is the phase of life between late childhood and adulthood. Typically, adolescents seek diversion, new experiences, and strong emotions, sometimes putting their health at serious risk. In Germany, for example, 62% of all deaths among persons aged 15 to 20 are due to traumatic injuries. Neuroscientific explanations have been proposed for typical adolescent behavior; with these explanations in mind, one can derive appropriate ways of dealing with adolescents., Method: We selectively review pertinent articles retrieved from the PubMed database about the structural and functional development of the brain in adolescence., Results: New findings in developmental psychology and neuroscience reveal that a fundamental reorganization of the brain takes place in adolescence. In postnatal brain development, the maximum density of gray matter is reached first in the primary sensorimotor cortex, and the prefrontal cortex matures last. Subcortical brain areas, especially the limbic system and the reward system, develop earlier, so that there is an imbalance during adolescence between the more mature subcortical areas and less mature prefrontal areas. This may account for typical adolescent behavior patterns, including risk-taking., Conclusion: The high plasticity of the adolescent brain permits environmental influences to exert particularly strong effects on cortical circuitry. While this makes intellectual and emotional development possible, it also opens the door to potentially harmful influences.

Schizophrenia remains a daunting challenge for efforts aimed at identifying fundamental pathophysiological processes and to develop evidence-based effective treatments and interventions. One reason for the lack of progress lies in the fact that the pathophysiology of schizophrenia has been predominantly conceived in terms of circumscribed alterations in cellular and anatomical variables. In the current review, it is proposed that this approach needs to be complemented by a focus on the neuronal dynamics in large-scale networks which is compatible with the notion of dysconnectivity, highlighting the involvement of both reduced and increased interactions in extended cortical circuits in schizophrenia. Neural synchrony is one candidate mechanisms for achieving functional connectivity in large-scale networks and has been found to be impaired in schizophrenia. Importantly, alterations in the synchronization of neural oscillations can be related to dysfunctions in the excitation-inhibition (E/I)-balance and developmental modifications with important implications for translational research., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Current theories of the pathophysiology of schizophrenia have focused on abnormal temporal coordination of neural activity. Oscillations in the gamma-band range (>25 Hz) are of particular interest as they establish synchronization with great precision in local cortical networks. However, the contribution of high gamma (>60 Hz) oscillations toward the pathophysiology is less established. To address this issue, we recorded magnetoencephalographic (MEG) data from 16 medicated patients with chronic schizophrenia and 16 controls during the perception of Mooney faces. MEG data were analysed in the 25-150 Hz frequency range. Patients showed elevated reaction times and reduced detection rates during the perception of upright Mooney faces while responses to inverted stimuli were intact. Impaired processing of Mooney faces in schizophrenia patients was accompanied by a pronounced reduction in spectral power between 60-120 Hz (effect size: d = 1.26) which was correlated with disorganized symptoms (r = -0.72). Our findings demonstrate that deficits in high gamma-band oscillations as measured by MEG are a sensitive marker for aberrant cortical functioning in schizophrenia, suggesting an important aspect of the pathophysiology of the disorder.

Cognitive deficits are a core dysfunction in schizophrenia. In this issue of Neuron, Parnaudeau et al. (2013) investigated synchronization in thalamocortical pathways in an animal model to address the disconnection between brain regions as a mechanism for working memory impairments in the disorder., (Copyright © 2013 Elsevier Inc. All rights reserved.)

In recent years, numerous studies have tested the relevance of neural oscillations in neuropsychiatric conditions, highlighting the potential role of changes in temporal coordination as a pathophysiological mechanism in brain disorders. In the current review, we provide an update on this hypothesis because of the growing evidence that temporal coordination is essential for the context and goal-dependent, dynamic formation of large-scale cortical networks. We shall focus on issues that we consider particularly promising for a translational research program aimed at furthering our understanding of the origins of neuropsychiatric disorders and the development of effective therapies. We will focus on schizophrenia and autism spectrum disorders (ASDs) to highlight important issues and challenges for the implementation of such an approach. Specifically, we will argue that deficits in temporal coordination lead to a disruption of functional large-scale networks, which in turn can account for several specific dysfunctions associated with these disorders., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Previous studies in electrophysiology have provided consistent evidence for a relationship between neural oscillations in different frequency bands and the maintenance of information in working memory (WM). While the amplitude and cross-frequency coupling of neural oscillations have been shown to be modulated by the number of items retained during WM, interareal phase synchronization has been associated with the integration of distributed activity during WM maintenance. Together, these findings provided important insights into the oscillatory dynamics of cortical networks during WM. However, little is known about the cortical regions and frequencies that underlie the specific maintenance of behaviorally relevant information in WM. In the current study, we addressed this question with magnetoencephalography and a delayed match-to-sample task involving distractors in 25 human participants. Using spectral analysis and beamforming, we found a WM load-related increase in the gamma band (60-80 Hz) that was localized to the right intraparietal lobule and left Brodmann area 9 (BA9). WM-load related changes were also detected at alpha frequencies (10-14 Hz) in Brodmann area 6, but did not covary with the number of relevant WM-items. Finally, we decoded gamma-band source activity with a linear discriminant analysis and found that gamma-band activity in left BA9 predicted the number of target items maintained in WM. While the present data show that WM maintenance involves activity in the alpha and gamma band, our results highlight the specific contribution of gamma band delay activity in prefrontal cortex for the maintenance of behaviorally relevant items.

Current theories of the pathophysiology of autism spectrum disorders (ASD) have focused on abnormal temporal coordination of neural activity in cortical circuits as a core impairment of the disorder. In the current study, we examined the possibility that gamma-band activity may be crucially involved in aberrant brain functioning in ASD. Magneto-encephalographic (MEG) data were recorded from 13 adult human participants with ASD and 16 controls during the presentation of Mooney faces. MEG data were analyzed in the 25-150 Hz frequency range and a beamforming approach was used to identify the sources of spectral power. Participants with ASD showed elevated reaction times and reduced detection rates during the perception of upright Mooney faces, while responses to inverted stimuli were in the normal range. Impaired perceptual organization in the ASD group was accompanied by a reduction in both the amplitude and phase locking of gamma-band activity. A beamforming approach identified distinct networks during perceptual organization in controls and participants with ASD. In controls, perceptual organization of Mooney faces involved increased 60-120 Hz activity in a frontoparietal network, while in the ASD group stronger activation was found in visual regions. These findings highlight the contribution of impaired gamma-band activity toward complex visual processing in ASD, suggesting atypical modulation of high-frequency power in frontoposterior networks.

Deep brain stimulation (DBS) has successfully advanced our treatment options for putative therapy-resistant neuropsychiatric diseases. Building on this strong foundation, more and more mental disorders in the stadium of therapy-resistance are considered as possible indications for DBS. Especially, schizophrenia with its associated severe and difficult to treat symptoms is gaining attention. This attention demands critical questions regarding the assumed mechanisms of DBS and its possible influence on the supposed pathophysiology of schizophrenia. Here, we synoptically compare current approaches and theories of DBS and discuss the feasibility of DBS in schizophrenia as well as the transferability from other psychiatric disorders successfully treated with DBS. For this we consider recent advances in animal models of schizophrenic symptoms, results regarding the influence of DBS on dopaminergic transmission as well as data concerning neural oscillation and synchronisation. In conclusion, the use of DBS for some symptoms of schizophrenia seems to be a promising approach, but the lack of a comprehensive theory of the mechanisms of DBS as well as its impact on schizophrenia might hinder the use of DBS for schizophrenia at this point in time., (© Georg Thieme Verlag KG Stuttgart · New York.)

Human brain networks can be characterized at different temporal or spatial scales given by the age of the subject or the spatial resolution of the neuroimaging method. Integration of data across scales can only be successful if the combined networks show a similar architecture. One way to compare networks is to look at spatial features, based on fiber length, and topological features of individual nodes where outlier nodes form single node motifs whose frequency yields a fingerprint of the network. Here, we observe how characteristic single node motifs change over age (12-23 years) and network size (414, 813, and 1615 nodes) for diffusion tensor imaging structural connectivity in healthy human subjects. First, we find the number and diversity of motifs in a network to be strongly correlated. Second, comparing different scales, the number and diversity of motifs varied across the temporal (subject age) and spatial (network resolution) scale: certain motifs might only occur at one spatial scale or for a certain age range. Third, regions of interest which show one motif at a lower resolution may show a range of motifs at a higher resolution which may or may not include the original motif at the lower resolution. Therefore, both the type and localization of motifs differ for different spatial resolutions. Our results also indicate that spatial resolution has a higher effect on topological measures whereas spatial measures, based on fiber lengths, remain more comparable between resolutions. Therefore, spatial resolution is crucial when comparing characteristic node fingerprints given by topological and spatial network features. As node motifs are based on topological and spatial properties of brain connectivity networks, these conclusions are also relevant to other studies using connectome analysis.