Dissociation and Brain Rhythms: Pitfalls and Promises

Recently, Vesuna et al. proposed a novel circuit mechanism underlying dissociative states using optogenetics and pharmacology in mice in combination with intracranial recordings and electrical stimulation in an epilepsy patient. Specifically, the authors identified a posteromedial cortical delta-rhythm that underlies states of dissociation. In the following, we would like to critically review these findings in the context of the human literature on dissociation as well as highlight the challenges in translational neuroscience to link complex behavioral phenotypes in psychiatric syndromes to circumscribed circuit mechanisms

Towards a neurodynamical understanding of the prodrome in schizophrenia

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 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

40 Hz auditory steady state responses in schizophrenia: towards a mechanistic biomarker for circuit dysfunctions and early detection and diagnosis

There is converging evidence that 40 Hz Auditory Steady State Responses (ASSRs) are robustly impaired in schizophrenia and could constitute a potential biomarker for characterizing circuit dysfunctions as well as enable early detection and diagnosis. In the current paper, we provide an overview of the mechanisms involved in 40 Hz ASSRs, drawing on computational, physiological and pharmacological data with a focus on parameters modulating the balance between excitation/inhibition. We will then summarize findings from electro- and magnetoencephalographical studies in clinical high-risk for psychosis participants, first-episode psychosis and schizophrenia patients to identify the pattern of deficits across illness-stages, the relationship with clinical variables and prognostic potential. Finally, data on genetics and developmental modifications will be reviewed, highlighting the importance of late modifications of 40 Hz ASSRs during adolescence which are closely related to the underlying changes in gamma-aminobutyric acid interneurons. Together, our review suggests that 40 Hz ASSRs may constitute an informative electrophysiological approach to characterize circuit dysfunctions in psychosis that could be relevant for the development of mechanistic biomarkers

Thalamo-cortical communication, glutamatergic neurotransmission and neural oscillations:a unique window into the origins of ScZ?

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

Impairment in predictive processes during auditory mismatch negativity in ScZ: evidence from event-related fields

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

Investigating cortico-subcortical circuits during auditory sensory attenuation: a combined magnetoencephalographic and dynamic causal modelling study

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

Altered autonomic function in individuals at clinical high risk for psychosis

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

Association of Magnetoencephalographically Measured High-Frequency Oscillations in Visual Cortex With Circuit Dysfunctions in Local and Large-scale Networks During Emerging Psychosis

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

Thalamo-cortical circuits during sensory attenuation in emerging psychosis: a combined magnetoencephalography and dynamic causal modelling study

Evidence suggests that schizophrenia (ScZ) involves impairments in sensory attenuation. It is currently unclear, however, whether such deficits are present during early-stage psychosis as well as the underlying network and the potential as a biomarker. To address these questions, Magnetoencephalography (MEG) was used in combination with computational modeling to examine M100 responses that involved a "passive" condition during which tones were binaurally presented, while in an "active" condition participants were asked to generate a tone via a button press. MEG data were obtained from 109 clinical high-risk for psychosis (CHR-P) participants, 23 people with a first-episode psychosis (FEP), and 48 healthy controls (HC). M100 responses at sensor and source level in the left and right thalamus (THA), Heschl's gyrus (HES), superior temporal gyrus (STG) and right inferior parietal cortex (IPL) were examined and dynamic causal modeling (DCM) was performed. Furthermore, the relationship between sensory attenuation and persistence of attenuated psychotic symptoms (APS) and transition to psychosis was investigated in CHR-P participants. Sensory attenuation was impaired in left HES, left STG and left THA in FEP patients, while in the CHR-P group deficits were observed only in right HES. DCM results revealed that CHR-P participants showed reduced top-down modulation from the right IPL to the right HES. Importantly, deficits in sensory attenuation did not predict clinical outcomes in the CHR-P group. Our results show that early-stage psychosis involves impaired sensory attenuation in auditory and thalamic regions but may not predict clinical outcomes in CHR-P participants

Oscillatory neural signatures of visual perception across developmental stages in individuals with 22q11.2 deletion syndrome

Background: Numerous behavioral studies have highlighted the contribution of visual perceptual deficits to the nonverbal cognitive profile of individuals with 22q11.2 deletion syndrome. However, the neurobiological processes underlying these widespread behavioral alterations are yet to be fully understood. Thus, in this paper, we investigated the role of neural oscillations toward visuoperceptual deficits to elucidate the neurobiology of sensory impairments in deletion carriers. Methods: We acquired 125 high-density electroencephalography recordings during a visual grating task in a group of 62 deletion carriers and 63 control subjects. Stimulus-elicited oscillatory responses were analyzed with 1) time-frequency analysis using wavelets decomposition at sensor and source level, 2) intertrial phase coherence, and 3) Granger causality connectivity in source space. Additional analyses examined the development of neural oscillations across age bins. Results: Deletion carriers had decreased theta-band (4–8 Hz) and gamma-band (58–68 Hz) spectral power compared with control subjects in response to the visual stimuli, with an absence of age-related increase of theta- and gamma-band responses. Moreover, adult deletion carriers had decreased gamma- and theta-band responses but increased alpha/beta desynchronization (10–25 Hz) that correlated with behavioral performance. Granger causality estimates reflected an increased frontal-occipital connectivity in the beta range (22–40 Hz). Conclusions: Deletion carriers exhibited decreased theta- and gamma-band responses to visual stimuli, while alpha/beta desynchronization was preserved. Overall, the lack of age-related changes in deletion carriers implicates developmental impairments in circuit mechanisms underlying neural oscillations. The dissociation between the maturation of theta/gamma- and alpha/beta-band responses may indicate a selective impairment in supragranular cortical layers, leading to compensatory top-down connectivity