Acute ketamine dysregulates task-related gamma-band oscillations in thalamo-cortical circuits in schizophrenia

Grent-‘t-Jong, Tineke; Rivolta, Davide; Groß, Joachim; Gajwani, Ruchika; Lawrie, Stephen M.; Schwannauer, Matthias; Heidegger, Tonio; Wibral, Michael; Singer, Wolf; Sauer, Andreas; Scheller, Bertram; Uhlhaas, Peter J.

doi:10.1093/brain/awy175

Cited by 51 publications

(42 citation statements)

References 86 publications

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“…Secondly, we localized the most consistent differences to the thalamus. While localization of thalamic generators from MEG data remains challenging, we would like to note that reconstruction of MEG time-courses in the thalamus has been consistently demonstrated by our (38,39) and other groups (40). Moreover, our analyses revealed that there were no differences in neighboring structures, such as putamen, pallidum and caudate nucleus, suggesting that signal-leakage, for example, did not contribute to our observations.…”

Section: Strengths and Limitationssupporting

confidence: 69%

40 Hz Auditory Steady-State Responses Predict Transition to Psychosis in Clinical-High-Risk Participants: A MEG Study

Grent-‘t-Jong

Gajwani

Groß

et al. 2020

Preprint

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Objective: To examine whether 40-Hz Auditory Steady-State Responses (ASSR) in participants at clinical high-risk for psychosis predict clinical outcomes. Method: In this study, magnetoencephalography (MEG) data were collected during a 40-Hz ASSR paradigm in 116 participants meeting clinical high-risk (CHR-P) for psychosis criteria, a clinical control group characterized by affective disorders and/or substance abuse (CHR-N: n=38), 32 first-episode psychosis patients (FEP, 14 antipsychotic-naive), and 49 healthy controls. We examined 40-Hz-ASSR- source-activity in bilateral Heschl's gyrus, superior temporal gyrus, Rolandic operculum, and the thalamus. Group differences in ASSR amplitudes were tested and correlated with neuropsychological scores, psychosocial functioning, and clinical symptoms. Linear discriminant analyses was used to assess whether 40-Hz-ASSR predicts transition to psychosis and persistence of APS. Results: Compared to controls, 40-Hz-ASSR responses in CHR-Ps were impaired in right Rolandic operculum (d=0.41) and right thalamus (d=0.43), particularly in those with combined UHR/BS symptoms and CHR-Ps who transitioned to psychosis (n=11). FEP-patients showed significant impairments in the right thalamus (d=0.58), while the CHR-N group was unaffected. Importantly, right thalamus 40-Hz-ASSRs predicted transition to psychosis (transitioned [n=11] vs non-transitioned [n=105]); classification accuracy 73.3%, AUC=0.827), whereas this was not the case for persistent APS (Persistent [n=41] vs non-Persistent [n=37]; classification accuracy 56.4%). Conclusions: The current study indicates that MEG-recorded 40-Hz-ASSRs constitute a potential biomarker for predicting transition to psychosis in CHR-P participants.

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Section: Strengths and Limitationssupporting

confidence: 69%

40 Hz Auditory Steady-State Responses Predict Transition to Psychosis in Clinical-High-Risk Participants: A MEG Study

Grent-‘t-Jong

Gajwani

Groß

et al. 2020

Preprint

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“…Our findings clarify how low-dose ketamine triggers its rapid action within the neocortex. Acute sub-anesthetic ketamine administration in healthy volunteers induces schizophrenia-like symptoms and neurocognitive deficits while impacting thalamo-cortical processing distinct from the disease state [53]. At clinically relevant low-dose, we found that cortical response enhancement is borne by 2A subunit-containing NMDA receptors localized to a subset of PV-positive, fast-spiking interneurons.…”

Section: Discussionmentioning

confidence: 98%

NMDA 2A receptors in parvalbumin cells mediate sex-specific rapid ketamine response on cortical activity

et al. 2019

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Ketamine has emerged as a widespread treatment for a variety of psychiatric disorders when used at sub-anesthetic doses, but the neural mechanisms underlying its acute action remain unclear. Here, we identified NMDA receptors containing the 2A subunit (GluN2A) on parvalbumin (PV)-expressing inhibitory interneurons as a pivotal target of low-dose ketamine. Genetically deleting GluN2A receptors globally or selectively from PV interneurons abolished the rapid enhancement of visual cortical responses and gamma-band oscillations by ketamine. Moreover, during the follicular phase of the estrous cycle in female mice, the ketamine response was transiently attenuated along with a concomitant decrease of grin2A mRNA expression within PV interneurons. Thus, GluN2A receptors on PV interneurons mediate the immediate actions of low-dose ketamine treatment, and fluctuations in receptor expression across the estrous cycle may underlie sex-differences in drug efficacy.

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“…Results from human studies reveal that an antidepressant dose of ketamine induces an acute enhancement of the power (amplitude) of qEEG oscillations within the 30-to 80-Hz gamma range in the parietal (88), cingulate (88), and cerebral (89) as well as general cortical brain areas (90). Increases in cortical gamma power have been ascribed to a mechanism related to the psychotomimetic actions of ketamine (91)(92)(93), putatively via NMDAR inhibition-mediated modulation of interneuron activity (94). Similar to ketamine, (2R,6R)-HNK administration increases high-frequency cortical gamma qEEG oscillations in mice (15), but unlike ketamine, this metabolite does not exert behavioral changes in the prepulse inhibition task at doses up to 375 mg/kg, indicative of a lack of psychosis potential (15) and relevant NMDAR inhibition (26)(27)(28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

( 2R,6R )-hydroxynorketamine exerts mGlu ₂ receptor-dependent antidepressant actions

Zanos

Highland

Stewart

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

116

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Currently approved antidepressant drugs often take months to take full effect, and ∼30% of depressed patients remain treatment resistant. In contrast, ketamine, when administered as a single subanesthetic dose, exerts rapid and sustained antidepressant actions. Preclinical studies indicate that the ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a rapid-acting antidepressant drug candidate with limited dissociation properties and abuse potential. We assessed the role of group II metabotropic glutamate receptor subtypes 2 (mGlu 2 ) and 3 (mGlu 3 ) in the antidepressant-relevant actions of (2R,6R)-HNK using behavioral, genetic, and pharmacological approaches as well as cortical quantitative EEG (qEEG) measurements in mice. Both ketamine and (2R,6R)-HNK prevented mGlu 2/3 receptor agonist (LY379268)induced body temperature increases in mice lacking the Grm3, but not Grm2, gene. This action was not replicated by NMDA receptor antagonists or a chemical variant of ketamine that limits metabolism to (2R,6R)-HNK. The antidepressant-relevant behavioral effects and 30-to 80-Hz qEEG oscillation (gamma-range) increases resultant from (2R,6R)-HNK administration were prevented by pretreatment with an mGlu 2/3 receptor agonist and absent in mice lacking the Grm2, but not Grm3 −/− , gene. Combined subeffective doses of the mGlu 2/3 receptor antagonist LY341495 and (2R,6R)-HNK exerted synergistic increases on gamma oscillations and antidepressant-relevant behavioral actions. These findings highlight that (2R,6R)-HNK exerts antidepressant-relevant actions via a mechanism converging with mGlu 2 receptor signaling and suggest enhanced cortical gamma oscillations as a marker of target engagement relevant to antidepressant efficacy. Moreover, these results support the use of (2R,6R)-HNK and inhibitors of mGlu 2 receptor function in clinical trials for treatment-resistant depression either alone or in combination. ketamine | hydroxynorketamine | antidepressant | mGlu 2 receptor |

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Acute ketamine dysregulates task-related gamma-band oscillations in thalamo-cortical circuits in schizophrenia

Cited by 51 publications

References 86 publications

40 Hz Auditory Steady-State Responses Predict Transition to Psychosis in Clinical-High-Risk Participants: A MEG Study

40 Hz Auditory Steady-State Responses Predict Transition to Psychosis in Clinical-High-Risk Participants: A MEG Study

NMDA 2A receptors in parvalbumin cells mediate sex-specific rapid ketamine response on cortical activity

( 2R,6R )-hydroxynorketamine exerts mGlu ₂ receptor-dependent antidepressant actions

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Acute ketamine dysregulates task-related gamma-band oscillations in thalamo-cortical circuits in schizophrenia

Cited by 51 publications

References 86 publications

40 Hz Auditory Steady-State Responses Predict Transition to Psychosis in Clinical-High-Risk Participants: A MEG Study

40 Hz Auditory Steady-State Responses Predict Transition to Psychosis in Clinical-High-Risk Participants: A MEG Study

NMDA 2A receptors in parvalbumin cells mediate sex-specific rapid ketamine response on cortical activity

( 2R,6R )-hydroxynorketamine exerts mGlu 2 receptor-dependent antidepressant actions

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( 2R,6R )-hydroxynorketamine exerts mGlu ₂ receptor-dependent antidepressant actions