Theta-phase gamma-amplitude coupling as a neurophysiological marker in neuroleptic-naïve schizophrenia

Won, Geun Hui; Kim, Jun Won; Choi, Tae Young; Lee, Young Sik; Min, Kyung Joon; Seol, Ki Ho

doi:10.1016/j.psychres.2017.12.021

Cited by 32 publications

(29 citation statements)

References 46 publications

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“…We found a deficit in the phaseamplitude coupling between theta and slow-gamma oscillations in the CA1 area of Cacna1c +/rats, manifested specifically during the exploration of a novel environment, indicating an impaired coupling between CA1 neurons and excitatory input from area CA3 (52). Alterations in theta-gamma PAC across brain regions has been recently reported in animal models of psychosis 17 (23,62) and in schizophrenic patients (63,64), and therefore may reflect a broader spectrum of network deficits in psychoses. Taken together these results show that low dosage of Cacna1c impairs both plasticity and network activation in the hippocampus in a manner likely to contribute to the observed deficits in contextual learning and latent inhibition seen in Cacna1c +/rats.…”

Section: Discussionsupporting

confidence: 56%

“…*p <0.05 determined by two-way repeated measures ANOVA followed by Tukey adjustment of p-values for contrasts. 64 intra-burst, top to bottom) versus spine distance from soma. APCaTs evoked with bursts of two to five APs are significantly smaller in spines located beyond 150 µm from soma, in Cacna1c +/compared to Cacna1c +/+ neurons.…”

Section: Intra-hippocampal Infusionmentioning

confidence: 99%

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Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by mutation of the psychiatric risk gene Cacna1c

Tigaret

Lin

Morrell

et al. 2020

Preprint

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One Sentence Summary: Neurotrophin receptor activation reveals that BDNF mimetic drugs have therapeutic potential to ameliorate genetic risk for psychiatric disorders.Abstract: Genetic variation in CACNA1C, which encodes the alpha-1 subunit of CaV1.2 L-type voltage-gated calcium channels, is strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. To translate genetics to neurobiological mechanisms and rational therapeutic targets, we investigated the impact of altered Cacna1c dosage on rat cognitive, synaptic and circuit phenotypes implicated by patient studies. We show that rats hemizygous for Cacna1c harbor marked impairments in learning to disregard non-salient stimuli, a behavioral change previously associated with psychosis. This behavioral deficit is accompanied by dys-coordinated network oscillations during learning, pathway-selective disruption of hippocampal synaptic plasticity, attenuated Ca 2+ signaling in dendritic spines and decreased signaling through the Extracellular-signal Regulated Kinase (ERK) pathway. Activation of the ERK pathway by a small molecule agonist of TrkB/TrkC neurotrophin receptors rescued both behavioral and synaptic plasticity deficits in Cacna1c +/rats. These results map a route through which genetic variation in CACNA1C can disrupt experience-dependent synaptic signaling and circuit activity, culminating in cognitive alterations associated with psychiatric disorders. Our findings highlight targeted activation of neurotrophin signaling pathways with BDNF mimetic drugs as a novel, genetically informed therapeutic approach for rescuing behavioral abnormalities in psychiatric disorder.

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Section: Discussionsupporting

confidence: 56%

Section: Intra-hippocampal Infusionmentioning

confidence: 99%

Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by mutation of the psychiatric risk gene Cacna1c

Tigaret

Lin

Morrell

et al. 2020

Preprint

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“…Enhanced theta band synchronization, however, may not be specifically attributed to OCD because such a spectrum of synchronization has also been described in patients with dystonia, Tourette syndrome, and psychiatric disorders such as schizophrenia and attention deficit/hyperactivity disorder (Maling et al, 2012; Alam et al, 2015; Kim et al, 2016; Kohl et al, 2016; Neumann et al, 2017, 2018; Won et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Neurobiological Mechanisms of Metacognitive Therapy – An Experimental Paradigm

et al. 2019

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Introduction The neurobiological mechanisms underlying the clinical effects of psychotherapy are scarcely understood. In particular, the modifying effects of psychotherapy on neuronal activity are largely unknown. We here present data from an innovative experimental paradigm using the example of a patient with treatment resistant obsessive-compulsive disorder (trOCD) who underwent implantation of bilateral electrodes for deep brain stimulation (DBS). The aim of the paradigm was to examine the short term effect of metacognitive therapy (MCT) on neuronal local field potentials (LFP) before and after 5 MCT sessions. Methods DBS electrodes were implanted bilaterally with stereotactic guidance in the bed nucleus of the stria terminalis/ internal capsule (BNST/IC). The period between implantation of the electrodes and the pacemaker was used for the experimental paradigm. DBS electrodes were externalized via extension cables, yielding the opportunity to record LFP directly from the BNST/IC. The experimental paradigm was designed as follows: (a) baseline recording of LFP from the BNST/IC, (b) application of 5 MCT sessions over 3 days, (c) post-MCT recording from the BNST/IC. The Obsessive-Compulsive Disorder- scale (OCD-S) was used to evaluate OCD symptoms. Results OCD symptoms decreased after MCT. These reductions were accompanied by a decrease of the relative power of theta band activity, while alpha, beta, and gamma band activity was significantly increased after MCT. Further, analysis of BNST/IC LFP and frontal cortex EEG coherence showed that MCT decreased theta frequency band synchronization. Discussion Implantation of DBS electrodes for treating psychiatric disorders offers the opportunity to gather data from neuronal circuits, and to compare effects of therapeutic interventions. Here, we demonstrate direct effects of MCT on neuronal oscillatory behavior, which may give possible cues for the neurobiological changes associated with psychotherapy.

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“…Treatment with NMDAR antagonists, such as ketamine, phencyclidine and MK801, induces SWM deficits (Beraki et al, 2009; Castane et al, 2015; Enomoto and Floresco, 2009; Verma and Moghaddam, 1996) and tends to reduce hippocampal theta oscillations, while enhancing PFC and hippocampal delta-, gamma- and high-frequency oscillations (130–180 Hz; Hinman et al, 2013; Hunt and Kasicki, 2013; Kjaerby et al, 2017; Korotkova et al, 2010; Lazarewicz et al, 2010; Moran et al, 2015; Sapkota et al, 2016). Acute and chronic ketamine treatment in rodents also alters the coupling of hippocampal theta phase with gamma- and high-frequency oscillation power (Caixeta et al, 2013; Michaels et al, 2018), reminiscent of the global and fronto-temporal frequency coupling alterations reported in patients with schizophrenia (Allen et al, 2011; Sun et al, 2013; Won et al, 2017). While the effects of NMDAR antagonists on long-range hippocampal-PFC synchrony are less clear (Lee et al, 2017), reports have shown that sub-anaesthetic doses of ketamine increase hippocampal-PFC functional connectivity measured using functional magnetic resonance imaging (fMRI) in rats (Gass et al, 2014) and humans (Grimm et al, 2015).…”

Section: Disordered Hippocampal-pfc Communication and Swm In Models Fmentioning

confidence: 99%

The dynamics of disordered dialogue: Prefrontal, hippocampal and thalamic miscommunication underlying working memory deficits in schizophrenia

Kupferschmidt

Gordon

2018

Brain and Neuroscience Advances

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The prefrontal cortex is central to the orchestrated brain network communication that gives rise to working memory and other cognitive functions. Accordingly, working memory deficits in schizophrenia are increasingly thought to derive from prefrontal cortex dysfunction coupled with broader network disconnectivity. How the prefrontal cortex dynamically communicates with its distal network partners to support working memory and how this communication is disrupted in individuals with schizophrenia remain unclear. Here we review recent evidence that prefrontal cortex communication with the hippocampus and thalamus is essential for normal spatial working memory, and that miscommunication between these structures underlies spatial working memory deficits in schizophrenia. We focus on studies using normal rodents and rodent models designed to probe schizophrenia-related pathology to assess the dynamics of neural interaction between these brain regions. We also highlight recent preclinical work parsing roles for long-range prefrontal cortex connections with the hippocampus and thalamus in normal and disordered spatial working memory. Finally, we discuss how emerging rodent endophenotypes of hippocampal- and thalamo-prefrontal cortex dynamics in spatial working memory could translate into richer understanding of the neural bases of cognitive function and dysfunction in humans.

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Theta-phase gamma-amplitude coupling as a neurophysiological marker in neuroleptic-naïve schizophrenia

Cited by 32 publications

References 46 publications

Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by mutation of the psychiatric risk gene Cacna1c

Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by mutation of the psychiatric risk gene Cacna1c

Neurobiological Mechanisms of Metacognitive Therapy – An Experimental Paradigm

The dynamics of disordered dialogue: Prefrontal, hippocampal and thalamic miscommunication underlying working memory deficits in schizophrenia

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