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Single-Dose Memantine Improves Cortical Oscillatory Response Dynamics in Patients with Schizophrenia.

ABSTRACT: Aberrant gamma-band (30-80?Hz) oscillations may underlie cognitive deficits in schizophrenia (SZ). Gamma oscillations and their regulation by NMDA receptors can be studied via their evoked power (?EP) and phase locking (?PL) in response to auditory steady-state stimulation; these auditory steady-state responses (ASSRs) may be biomarkers for target engagement and early therapeutic effects. We previously reported that memantine, an NMDA receptor antagonist, enhanced two biomarkers of early auditory information processing: prepulse inhibition and mismatch negativity (MMN) in SZ patients and healthy subjects (HS). Here, we describe memantine effects on ?EP and ?PL in those subjects. SZ patients (n=18) and HS (n=14) received memantine 20?mg (p.o.) and placebo over 2 test days in a double-blind, randomized, counterbalanced, cross-over design. The ASSR paradigm (1?ms, 85?dB clicks in 250-0.5?s trains at a frequency of 40?Hz; 0.5?s inter-train interval) was used to assess ?EP and ?PL. SZ patients had reduced ?EP and ?PL; memantine enhanced ?EP and ?PL (p<0.025 and 0.002, respectively) in both SZ and HS. In patients, significant correlations between age and memantine effects were detected for ?EP and ?PL: greater memantine sensitivity on ?EP and ?PL were present in younger SZ patients, similar to our reported findings with MMN. Memantine acutely normalized cortical oscillatory dynamics associated with NMDA receptor dysfunction in SZ patients. Ongoing studies will clarify whether these acute changes predict beneficial clinical, neurocognitive and functional outcomes. These data support the use of gamma-band ASSR as a translational end point in pro-cognitive drug discovery and early-phase clinical trials.

SUBMITTER: Light GA

PROVIDER: S-EPMC5686499 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Single-Dose Memantine Improves Cortical Oscillatory Response Dynamics in Patients with Schizophrenia.

Light Gregory A GA Zhang Wen W Joshi Yash B YB Bhakta Savita S Talledo Jo A JA Swerdlow Neal R NR

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20170420 13

Aberrant gamma-band (30-80 Hz) oscillations may underlie cognitive deficits in schizophrenia (SZ). Gamma oscillations and their regulation by NMDA receptors can be studied via their evoked power (γEP) and phase locking (γPL) in response to auditory steady-state stimulation; these auditory steady-state responses (ASSRs) may be biomarkers for target engagement and early therapeutic effects. We previously reported that memantine, an NMDA receptor antagonist, enhanced two biomarkers of early auditor ...[more]

PMID: 28425497

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Project description:The distribution of pathology in frontotemporal dementia is anatomically selective, to distinct cortical regions and with differential neurodegeneration across the cortical layers. The cytoarchitecture and connectivity of cortical laminae preferentially supports frequency-specific oscillations and hierarchical information transfer between brain regions. We therefore predicted that in frontotemporal dementia, core functional deficits such as disinhibition would be associated with differences in the frequency spectrum and altered cross-frequency coupling between frontal cortical regions. We examined this hypothesis using a 'Go-NoGo' response inhibition paradigm with 18 patients with behavioural variant frontotemporal dementia and 20 healthy aged-matched controls during magnetoencephalography. During Go and NoGo trials, beta desynchronization was severely attenuated in patients. Beta power was associated with increased impulsivity, as measured by the Cambridge Behavioural Inventory, a carer-based questionnaire of changes in everyday behaviour. To quantify the changes in cross-frequency coupling in the frontal lobe, we used dynamic causal modelling to test a family of hierarchical casual models, which included the inferior frontal gyrus, pre-supplementary motor area (preSMA) and primary motor cortex. This analysis revealed evidence for cross-frequency coupling in a fully connected network in both groups. However, in the patient group, we identified a significant loss of reciprocal connectivity of the inferior frontal gyrus, particularly for interactions in the gamma band and for theta to alpha coupling. Importantly, although prefrontal coupling was diminished, gamma connectivity between preSMA and motor cortex was enhanced in patients. We propose that the disruption of behavioural control arises from reduced frequency-specific connectivity of the prefrontal cortex, together with a hyper-synchronous reorganization of connectivity among preSMA and motor regions. These results are supported by preclinical evidence of the selectivity of frontotemporal lobar degeneration on oscillatory dynamics, and provide a clinically relevant yet precise neurophysiological signature of behavioural control as a potential pharmacological target for early phase experimental medicines studies.

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Single-Dose Memantine Improves Cortical Oscillatory Response Dynamics in Patients with Schizophrenia.

Publications

Single-Dose Memantine Improves Cortical Oscillatory Response Dynamics in Patients with Schizophrenia.

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