Ketamine Alters Functional Gamma and Theta Resting-State Connectivity in Healthy Humans: Implications for Schizophrenia Treatment Targeting the Glutamate System

Disturbed functional connectivity is assumed to cause neurocognitive deficits in patients suffering from schizophrenia. A Glutamate N-methyl-D-aspartate receptor (NMDAR) dysfunction has been suggested as a possible mechanism underlying altered connectivity in schizophrenia, especially in the gamma- and theta-frequency range. The present study aimed to investigate the effects of the NMDAR-antagonist ketamine on resting-state power, functional connectivity, and schizophrenia-like psychopathological changes in healthy volunteers. In a placebo-controlled crossover design, 25 healthy subjects were recorded using resting-state 64-channel-electroencephalography (EEG) (eyes closed). The imaginary coherence-based Multivariate Interaction Measure (MIM) was used to measure gamma and theta connectivity across 80 cortical regions. The network-based statistic was applied to identify involved networks under ketamine. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). Ketamine caused an increase in all PANSS (p < 0.001) as well as 5D-ASC scores (p < 0.01). Significant increases in resting-state gamma and theta power were observed under ketamine compared to placebo (p < 0.05). The source-space analysis revealed two distinct networks with an increased mean functional gamma- or theta-band connectivity during the ketamine session. The gamma-network consisted of midline regions, the cuneus, the precuneus, and the bilateral posterior cingulate cortices, while the theta-band network involved the Heschl gyrus, midline regions, the insula, and the middle cingulate cortex. The current source density (CSD) within the gamma-band correlated negatively with the PANSS negative symptom score, and the activity within the gamma-band network correlated negatively with the subjective changed meaning of percepts subscale of the 5D-ASC. These results are in line with resting-state patterns seen in people who have schizophrenia and argue for a crucial role of the glutamate system in mediating dysfunctional gamma- and theta-band-connectivity in schizophrenia. Resting-state networks could serve as biomarkers for the response to glutamatergic drugs or drug development efforts within the glutamate system

From Shortage to Surge : A Developmental Switch in Hippocampal-Prefrontal Coupling in a Gene-Environment Model of Neuropsychiatric Disorders

Cognitive deficits represent a major burden of neuropsychiatric disorders and result in part from abnormal communication within hippocampal-prefrontal circuits. While it has been hypothesized that this network dysfunction arises during development, long before the first clinical symptoms, experimental evidence is still missing. Here, we show that pre-juvenile mice mimicking genetic and environmental risk factors of disease (dual-hit GE mice) have poorer recognition memory that correlates with augmented coupling by synchrony and stronger directed interactions between prefrontal cortex and hippocampus. The network dysfunction emerges already during neonatal development, yet it initially consists in a diminished hippocampal theta drive and consequently, a weaker and disorganized entrainment of local prefrontal circuits in discontinuous oscillatory activity in dual-hit GE mice when compared with controls. Thus, impaired maturation of functional communication within hippocampal-prefrontal networks switching from hypo- to hyper-coupling may represent a mechanism underlying the pathophysiology of cognitive deficits in neuropsychiatric disorders.Peer reviewe

Hallucinations in Hearing Impairment:How Informed Are Clinicians?

Background and Hypothesis: Patients with hearing impairment (HI) may experience hearing sounds without external sources, ranging from random meaningless noises (tinnitus) to music and other auditory hallucinations (AHs) with meaningful qualities. To ensure appropriate assessment and management, clinicians need to be aware of these phenomena. However, sensory impairment studies have shown that such clinical awareness is low.Study Design: An online survey was conducted investigating awareness of AHs among clinicians and their opinions about these hallucinations.Study Results: In total, 125 clinicians (68.8% audiologists; 18.4% Ear-Nose-Throat [ENT] specialists) across 10 countries participated in the survey. The majority (96.8%) was at least slightly aware of AHs in HI. About 69.6% of participants reported encountering patients with AHs less than once every 6 months in their clinic. Awareness was significantly associated with clinicians’ belief that patients feel anxious about their hallucinations (β = .018, t(118) = 2.47, P < .01), their belief that clinicians should be more aware of these hallucinations (β =.018, t(118) = 2.60, P < .01), and with confidence of clinicians in their skills to assess them (β = .017, t(118) = 2.63, P < .01). Clinicians felt underequipped to treat AHs (Median = 31; U = 1838; PFDRadj < .01).Conclusions: Awareness of AHs among the surveyed clinicians was high. Yet, the low frequency of encounters with hallucinating patients and their belief in music as the most commonly perceived sound suggest unreported cases. Clinicians in this study expressed a lack of confidence regarding the assessment and treatment of AHs and welcome more information

Aims and structure of the German Research Consortium BipoLife for the study of bipolar disorder

Background: Bipolar disorder is a severe and heterogeneous mental disorder. Despite great advances in neuroscience over the past decades, the precise causative mechanisms at the transmitter, cellular or network level have so far not been unraveled. As a result, individual treatment decisions cannot be tailor-made and the uncertain prognosis is based on clinical characteristics alone. Although a subpopulation of patients have an excellent response to pharmacological monotherapy, other subpopulations have been less well served by the medical system and therefore require more focused attention. In particular individuals at high risk of bipolar disorder, young patients in the early stages of bipolar disorder, patients with an unstable highly relapsing course and patients with acute suicidal ideation have been identified as those in need. Structure: A research consortium of ten universities across Germany has therefore implemented a 4 year research agenda including three randomized controlled trials, one epidemiological trial and one cross-sectional trial to address these areas of unmet needs. The topics under investigation will be the improvement of early recognition, specific psychotherapy, and smartphones as an aid for early episode detection and biomarkers of lithium response. A subset of patients will be investigated utilizing neuroimaging (fMRI), neurophysiology (EEG), and biomaterials (genomics, transcriptomics). Conclusions: This article aims to outline the rationale, design, and methods of these individual studies

Aims and structure of the German Research Consortium BipoLife for the study of bipolar disorder

Background: Bipolar disorder is a severe and heterogeneous mental disorder. Despite great advances in neuroscience over the past decades, the precise causative mechanisms at the transmitter, cellular or network level have so far not been unraveled. As a result, individual treatment decisions cannot be tailor-made and the uncertain prognosis is based on clinical characteristics alone. Although a subpopulation of patients have an excellent response to pharmacological monotherapy, other subpopulations have been less well served by the medical system and therefore require more focused attention. In particular individuals at high risk of bipolar disorder, young patients in the early stages of bipolar disorder, patients with an unstable highly relapsing course and patients with acute suicidal ideation have been identified as those in need. Structure: A research consortium of ten universities across Germany has therefore implemented a 4 year research agenda including three randomized controlled trials, one epidemiological trial and one cross-sectional trial to address these areas of unmet needs. The topics under investigation will be the improvement of early recognition, specific psychotherapy, and smartphones as an aid for early episode detection and biomarkers of lithium response. A subset of patients will be investigated utilizing neuroimaging (fMRI), neurophysiology (EEG), and biomaterials (genomics, transcriptomics). Conclusions: This article aims to outline the rationale, design, and methods of these individual studies

Auditory verbal hallucinations and the interhemispheric auditory pathway in chronic schizophrenia

Objectives—The interhemispheric auditory pathway has been shown to play a crucial role in the processing of acoustic stimuli, and alterations of structural and functional connectivity between bilateral auditory areas are likely relevant to the pathogenesis of auditory verbal hallucinations (AVHs). The aim of this study was to examine this pathway in patients with chronic schizophrenia regarding their lifetime history of AVHs. Methods—DTI scans were acquired from 33 healthy controls (HC), 24 schizophrenia patients with a history of AVHs (LT-AVH) and 9 schizophrenia patients without any lifetime hallucinations (N-LT-AVH). The interhemispheric auditory fibre bundles were extracted using streamline tractography. Subsequently, diffusivity indices, namely Fractional Anisotropy (FA), Trace, Mode, Axial and Radial Diffusivity, were calculated.Results—FA was decreased over the entire pathway in LT-AVH compared with N-LT-AVH. Moreover, LT-AVH displayed decreased FA and Mode as well as increased Radial Diffusivity in the midsagittal section of the fibre tract. Conclusions—These findings indicate complex microstructural changes in the interhemispheric auditory pathway of schizophrenia patients with a history of AVHs. Alterations appear to be absent in patients who have never hallucinated

Interaction of language, auditory and memory brain networks in auditory verbal hallucinations

Auditory verbal hallucinations (AVH) occur in psychotic disorders, but also as a symptom of other conditions and even in healthy people. Several current theories on the origin of AVH converge, with neuroimaging studies suggesting that the language, auditory and memory/limbic networks are of particular relevance. However, reconciliation of these theories with experimental evidence is missing. We review 50 studies investigating functional (EEG and fMRI) and anatomic (diffusion tensor imaging) connectivity in these networks, and explore the evidence supporting abnormal connectivity in these networks associated with AVH. We distinguish between functional connectivity during an actual hallucination experience (symptom capture) and functional connectivity during either the resting state or a task comparing individuals who hallucinate with those who do not (symptom association studies). Symptom capture studies clearly reveal a pattern of increased coupling among the auditory, language and striatal regions. Anatomical and symptom association functional studies suggest that the interhemispheric connectivity between posterior auditory regions may depend on the phase of illness, with increases in non-psychotic individuals and first episode patients and decreases in chronic patients. Leading hypotheses involving concepts as unstable memories, source monitoring, top-down attention, and hybrid models of hallucinations are supported in part by the published connectivity data, although several caveats and inconsistencies remain. Specifically, possible changes in fronto-temporal connectivity are still under debate. Precise hypotheses concerning the directionality of connections deduced from current theoretical approaches should be tested using experimental approaches that allow for discrimination of competing hypotheses

Transcranial alternating current stimulation (tACS): from basic mechanisms towards first applications in psychiatry

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