Impaired Potentiation of Theta Oscillations During a Visual Cortical Plasticity Paradigm in Individuals With Schizophrenia

Abstract

Long-term potentiation (LTP) is a form of experience-dependent synaptic plasticity mediated by glutamatergic transmission at N-methyl-D-aspartate receptors (NMDARs). Impaired neuroplasticity has been implicated in the pathophysiology of schizophrenia, possibly due to underlying NMDAR hypofunction. Analogous to the high frequency electrical stimulation used to induce LTP in vitro and in vivo in animal models, repeated high frequency presentation of a visual stimulus in humans in vivo has been shown to induce enduring LTP-like neuroplastic changes in electroencephalography (EEG)-based visual evoked potentials (VEPs) elicited by the stimulus. Using this LTP-like visual plasticity paradigm, we previously showed that visual high-frequency stimulation (VHFS) induced sustained changes in VEP amplitudes in healthy controls, but not in patients with schizophrenia. Here, we extend this prior work by re-analyzing the EEG data underlying the VEPs, focusing on neuroplastic changes in stimulus-evoked EEG oscillatory activity following VHFS. EEG data were recorded from 19 patients with schizophrenia and 21 healthy controls during the visual plasticity paradigm. Event-related EEG oscillations (total power, intertrial phase coherence; ITC) elicited by a standard black and white checkerboard stimulus (~0.83 Hz, several 2-min blocks) were assessed before and after exposure to VHFS with the same stimulus (~8.9 Hz, 2 min). A cluster-based permutation testing approach was applied to time-frequency data to examine LTP-like plasticity effects following VHFS. VHFS enhanced theta band total power and ITC in healthy controls but not in patients with schizophrenia. The magnitude and phase synchrony of theta oscillations in response to a visual stimulus were enhanced for at least 22 min following VHFS, a frequency domain manifestation of LTP-like visual cortical plasticity. These theta oscillation changes are deficient in patients with schizophrenia, consistent with hypothesized NMDA receptor dysfunction.

Abnormal synaptic plasticity and impaired cognition in schizophrenia

“…Evidence has shown altered LTP-like plasticity in SCZ compared to healthy subjects[ 61 , 62 ]. Furthermore, NMDAR antagonists (phencyclidine, MK801, and ketamine) can induce SCZ-like symptoms in healthy individuals[ 63 , 64 ].…”

Sensory Tetanization to Induce LTP-Like Plasticity: A Review and Reassessment of the Approach

“…Studies of aging find that older adults exhibit more modest changes in ERP amplitude after tetanization than younger adults (Abuleil et al, 2019; de Gobbi Porto et al, 2015; Spriggs et al, 2017). Studies of patients diagnosed with schizophrenia (Çavuş et al, 2012; D’Souza et al, 2018; Forsyth et al, 2017; Hamilton et al, 2020; Jahshan et al, 2017; Mears & Spencer, 2012; Valstad et al, 2021; but see Wynn et al, 2019), bipolar disorder (Elvsåshagen et al, 2012; Valstad et al, 2021; Zak et al, 2018), and depression (Normann et al, 2007; Sumner, McMillan, et al, 2020) have also found that these patient populations exhibit more modest changes in response amplitudes after tetanization compared to healthy controls, while adults with autism spectrum disorder can exhibit more pronounced response amplitude increases (Wilson et al, 2017). The broad interdisciplinary use of sensory tetanization to study plasticity and how plasticity changes across different experimental groups demonstrates the potential value of this in vivo approach.…”

Memory Disorders Related to Hippocampal Function: The Interest of 5-HT4Rs Targeting

“…Additionally, recent technical developments using repetitive Transcranial Magnetic Stimulation (rTMS) and ElectroEncephaloGraphy (EEG), has enabled the non-invasive investigation of LTP in human cortical tissue [ 43 , 128 ]. Thus, a decrease in LTP-like plasticity was observed in various conditions, including aging [ 129 ], MDD [ 130 , 131 ], SCZ [ 132 , 133 ] and AD [ 134 ] ( Figure 2 ). Although based on a cortical readout, the conclusions drawn are overall consistent with those coming from the deep electrophysiological recordings, conducted in different animal models.…”