NMDA Receptor Hypofunction Leads to Generalized and Persistent Aberrant γ Oscillations Independent of Hyperlocomotion and the State of Consciousness

Hakami, Tahir; Jones, Nigel C.; Tolmacheva, E.A.; Gaudias, Julien; Chaumont, Jospeh; Salzberg, Michael; O’Brien, Terence J.; Pinault, Didier

doi:10.1371/journal.pone.0006755

Cited by 207 publications

(269 citation statements)

References 72 publications

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“…This finding is also in accordance with previous results in cortical slices where NMDA blockers suppress the lower frequencies (53). At the same time, we found that NMDA-receptor blockers enhanced γ-oscillations, in accordance with previous results obtained with the systemic application of NMDA antagonists in rodents (78) and with local application in the visual cortex of monkeys (79).…”

Section: Discussionsupporting

confidence: 93%

Alpha and gamma oscillations characterize feedback and feedforward processing in monkey visual cortex

Kerkoerle

Self

Dagnino

et al. 2014

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

850

138

776

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This Feature Article is part of a series identified by the Editorial Board as reporting findings of exceptional significance.Edited by Terrence J. Sejnowski, Salk Institute for Biological Studies, La Jolla, CA, and approved August 8, 2014 (received for review February 22, 2014) Cognitive functions rely on the coordinated activity of neurons in many brain regions, but the interactions between cortical areas are not yet well understood. Here we investigated whether lowfrequency (α) and high-frequency (γ) oscillations characterize different directions of information flow in monkey visual cortex. We recorded from all layers of the primary visual cortex (V1) and found that γ-waves are initiated in input layer 4 and propagate to the deep and superficial layers of cortex, whereas α-waves propagate in the opposite direction. Simultaneous recordings from V1 and downstream area V4 confirmed that γ-and α-waves propagate in the feedforward and feedback direction, respectively. Microstimulation in V1 elicited γ-oscillations in V4, whereas microstimulation in V4 elicited α-oscillations in V1, thus providing causal evidence for the opposite propagation of these rhythms. Furthermore, blocking NMDA receptors, thought to be involved in feedback processing, suppressed α while boosting γ. These results provide new insights into the relation between brain rhythms and cognition.neuronal synchronization | attention | perceptual organization | phase coherence | Granger causality A reas of the visual cortex are arranged hierarchically, with low-level areas representing simple features and higher areas representing the more complex aspects of the visual world (1, 2). Neurons in many visual areas are coactive during the perception of a visual stimulus and it is difficult to disentangle the influences of lower areas onto higher areas from the effects that go in the opposite direction (3). Studies of visual cognition could benefit enormously from markers of cortical activity that distinguish between feedforward and feedback effects. One such putative marker is cortical oscillatory activity, because oscillations of different frequencies have been proposed to propagate either in feedforward or in the feedback direction (4, 5), but experimental evidence for this view is sparse (6).Low-frequency rhythms, like the α-rhythm-which is particularly pronounced in the visual cortex-have been proposed to characterize spontaneous activity (7,8) as the α-rhythm increases when the subject closes the eyes (9). More recent observations have also implicated α-oscillations in the active suppression of irrelevant, unattended information (10, 11). In contrast, the high-frequency γ-rhythm increases if visual stimuli are presented, and in particular if they are task-relevant (12, 13). One influential hypothesis has been that γ-oscillations play a role in feature binding (14), but later studies cast doubt on this proposal (15,16). A more recent hypothesis holds that γ-oscillations facilitate the communication between cortical areas (17), but both evidence in fa...

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Section: Discussionsupporting

confidence: 93%

Alpha and gamma oscillations characterize feedback and feedforward processing in monkey visual cortex

Kerkoerle

Self

Dagnino

et al. 2014

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

850

138

776

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“…9 The emergence and recovery processes were characterized by increased high gamma activity and coherence. Similar increases in high gamma power and coherence have been reported after subanaesthetic doses of ketamine in rats [29][30][31] and humans. 32 In addition, subanaesthetic ketamine in rats induces hyperlocomotion, [29][30][31] which has been attributed to increases in power and coherence in higher gamma frequencies in the basal ganglia motor circuit.…”

Section: Discussionsupporting

confidence: 79%

Electroencephalographic coherence and cortical acetylcholine during ketamine-induced unconsciousness

Pal

Hambrecht-Wiedbusch

Silverstein

et al. 2015

British Journal of Anaesthesia

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Background: There is limited understanding of cortical neurochemistry and cortical connectivity during ketamine anaesthesia. We conducted a systematic study to investigate the effects of ketamine on cortical acetylcholine (ACh) and electroencephalographic coherence. Methods: Male Sprague-Dawley rats (n=11) were implanted with electrodes to record electroencephalogram (EEG) from frontal, parietal, and occipital cortices, and with a microdialysis guide cannula for simultaneous measurement of ACh concentrations in prefrontal cortex before, during, and after ketamine anaesthesia. Coherence and power spectral density computed from the EEG, and ACh concentrations, were compared between conscious and unconscious states. Loss of righting reflex was used as a surrogate for unconsciousness. Results: Ketamine-induced unconsciousness was associated with a global reduction of power (P=0.02) in higher gamma bandwidths (>65 Hz), a global reduction of coherence (P≤0.01) across a broad frequency range (0.5-250 Hz), and a significant increase in ACh concentrations (P=0.01) in the prefrontal cortex. Compared with the unconscious state, recovery of righting reflex was marked by a further increase in ACh concentrations (P=0.0007), global increases in power in theta (4-10 Hz; P=0.03) and low gamma frequencies (25-55 Hz; P=0.0001), and increase in power (P≤0.01) and coherence (P≤0.002) in higher gamma frequencies (65-250 Hz). Acetylcholine concentrations, coherence, and spectral properties returned to baseline levels after a prolonged recovery period. Conclusions: Ketamine-induced unconsciousness is characterized by suppression of high-frequency gamma activity and a breakdown of cortical coherence, despite increased cholinergic tone in the cortex.

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“…The resulting hyperglutamatergic state is believed to mediate the enhanced field gamma activity by stimulating kainate and AMPA receptor-mediated activation of the cortical interneuron-pyramidal cell network (McNally et al, 2011;Roopun et al, 2008). Indeed, a robust increase in field gamma oscillations is one of the most consistent findings in response to systemic treatment with NMDA antagonists (Hakami et al, 2009;Kocsis, 2012;Sebban et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…To understand whether the induced gamma is a mere reflection of the elevation in baseline gamma activity that NMDA antagonists are well known to engender (Hakami et al, 2009;Kocsis, 2012;Sebban et al, 2002), we compared induced power through duration of train stimulation with the total gamma band power at the beginning of each epoch when there was no auditory stimulation. We found a highly significant positive correlation (Pearson's r) and no statistical difference between the two measures (paired t-test; data not shown) under all treatment conditions, suggesting that induced power in our paradigm was merely reflecting the gamma power present in the signal.…”

Section: Induced Powermentioning

confidence: 99%

40 Hz Auditory Steady-State Response Is a Pharmacodynamic Biomarker for Cortical NMDA Receptors

Sivarao

Chen

Senapati

et al. 2016

Neuropsychopharmacol

108

106

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Schizophrenia patients exhibit dysfunctional gamma oscillations in response to simple auditory stimuli or more complex cognitive tasks, a phenomenon explained by reduced NMDA transmission within inhibitory/excitatory cortical networks. Indeed, a simple steady-state auditory click stimulation paradigm at gamma frequency (~40 Hz) has been reproducibly shown to reduce entrainment as measured by electroencephalography (EEG) in patients. However, some investigators have reported increased phase locking factor (PLF) and power in response to 40 Hz auditory stimulus in patients. Interestingly, preclinical literature also reflects this contradiction. We investigated whether a graded deficiency in NMDA transmission can account for such disparate findings by administering subanesthetic ketamine (1-30 mg/kg, i.v.) or vehicle to conscious rats (n = 12) and testing their EEG entrainment to 40 Hz click stimuli at various time points (~7-62 min after treatment). In separate cohorts, we examined in vivo NMDA channel occupancy and tissue exposure to contextualize ketamine effects. We report a robust inverse relationship between PLF and NMDA occupancy 7 min after dosing. Moreover, ketamine could produce inhibition or disinhibition of the 40 Hz response in a temporally dynamic manner. These results provide for the first time empirical data to understand how cortical NMDA transmission deficit may lead to opposite modulation of the auditory steady-state response (ASSR). Importantly, our findings posit that 40 Hz ASSR is a pharmacodynamic biomarker for cortical NMDA function that is also robustly translatable. Besides schizophrenia, such a functional biomarker may be of value to neuropsychiatric disorders like bipolar and autism spectrum where 40 Hz ASSR deficits have been documented.

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NMDA Receptor Hypofunction Leads to Generalized and Persistent Aberrant γ Oscillations Independent of Hyperlocomotion and the State of Consciousness

Cited by 207 publications

References 72 publications

Alpha and gamma oscillations characterize feedback and feedforward processing in monkey visual cortex

Alpha and gamma oscillations characterize feedback and feedforward processing in monkey visual cortex

Electroencephalographic coherence and cortical acetylcholine during ketamine-induced unconsciousness

40 Hz Auditory Steady-State Response Is a Pharmacodynamic Biomarker for Cortical NMDA Receptors

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