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

Abstract

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.

Acute Phencyclidine Alters Neural Oscillations Evoked by Tones in the Auditory Cortex of Rats

“…The suppression of high frequency gamma activity by PCP in the present study is similar to several other studies of auditory ERPs in rodents with NMDAr function impaired through genetic manipulations [25] and other NMDAr antagonists, such as MK-801 [30], ketamine [14], and PCP [28]. In contrast, relatively low dose ketamine administration in humans [27] and mice [26] failed to suppress auditory evoked gamma activity.…”

“…Hall et al (2011) used a twin design and found that auditory gamma-band power and phase locking to standard tones in an auditory oddball paradigm were heritable responses associated with schizophrenia: both patients with schizophrenia and their non-psychotic co-twins showed reduced gamma power [3]. The pathophysiological mechanisms responsible for deficits in auditory gamma-band activity in schizophrenia have focused on the role of the parvalbumin-positive gamma-amino butyric acid (GABA) receptor and to N -methyl-d-aspartate receptor (NMDAr) [4,12–14]. Both in vitro and in vivo evidence suggest that excitatory principal neurons, parvalbumin inhibitory interneurons, subtype A of the gamma-amino butyric acid receptor family (GABA A ), and NMDAr modulate neural synchrony in the gamma frequency range [15–18].…”

“…One factor that may account for differences among studies is the dose of the NMDAr antagonist or degree of genetically manipulated receptor hypofunction. With auditory steady state responses (ASSRs), for example, high levels of NMDAr blockade may be required to reduce gamma synchrony [14,28]. Secondly, subchronic or chronic administration using either multiple single doses or continuous delivery of NMDAr antagonists may have quite different physiological effects [29].…”

MEG and EEG demonstrate similar test-retest reliability of the 40 Hz auditory steady-state response

“…This is an important finding, given the increasing use of the ASSR as a biomarker in investigations of neuropsychiatric disorders (O’Donnell et al, 2013; Sivarao et al, 2016; Thune et al, 2016). Consistent with our previous findings with EEG data (McFadden et al, 2014), we found the ASSR to be reliable across two sessions, spaced approximately one week apart.…”

“…Much evidence suggests that ASSR abnormalities reflect dysfunctional gamma-aminobutyric acid (GABA) neurotransmission, leading to inefficiencies in brain inhibitory function (Brenner et al, 2009; Kwon et al, 1999; Lewis et al, 2005; O’Donnell et al, 2013; Vohs et al, 2010). However, there is also evidence suggesting that the ASSR involves glutamatergic dysfunction (Brenner et al, 2009; Kwon et al, 1999; Leishman et al, 2015; O’Donnell et al, 2013; Plourde et al, 1997; Sivarao et al, 2013; Sivarao, 2015; Sivarao et al, 2016; Vohs et al, 2012), particularly supported by emerging evidence that the 40 Hz ASSR may be more sensitive to N -methyl-D-aspartate (NMDA) receptor antagonism than to GABA-A receptor antagonism (Sullivan et al, 2015). With this growing body of evidence, the ASSR demonstrates strong potential as a biomarker in clinical studies of neuropsychiatric disorders (O’Donnell et al, 2013; Sivarao, 2015; Thune et al, 2016).…”