Do NMDA-R Antagonists Re-Create Patterns of Spontaneous Gamma-Band Activity in Schizophrenia? A Systematic Review and Perspective

This systematic review (2021) compared gamma-band oscillations elicited by NMDA-receptor agonists such as ketamine to neural oscillations observed in patients with schizophrenia. Whereas NMDAR agonists consistently upregulate gamma-band power, connectivity parameters of schizophrenia were inconsistent by comparison and thus incongruent with the hypothesis that their pathophysiological signatures are caused by NMDA-R hypofunction.

Abstract

“Introduction: NMDA-R hypofunctioninig is a core pathophysiological mechanism in schizophrenia. However, it is unclear whether the physiological changes observed following NMDA-R antagonist administration are consistent with gamma-band alterations in schizophrenia.

Methods: This systematic review examined the effects of NMDA-R antagonists on the amplitude of spontaneous gamma-band activity and functional connectivity obtained from preclinical (n = 24) and human (n = 9) studies and compared these data to resting-state EEG/MEG-measurements in schizophrenia patients (n = 27).

Results: Overall, the majority of preclinical and human studies observed increased gamma-band power following acute administration of NMDA-R antagonists. However, the direction of gamma-band power alterations in schizophrenia were inconsistent, which involved upregulation (n = 10), decreases (n = 7), and no changes (n = 8) in spectral power. Five out of 6 preclinical studies observed increased connectivity, while in healthy controls receiving Ketamine and in schizophrenia patients the direction of connectivity results was also inconsistent.

Discussion: Accordingly, the effects of NMDA-R hypofunctioning on gamma-band oscillations are different than pathophysiological signatures observed in schizophrenia. The implications of these findings for current E/I balance models of schizophrenia are discussed.”

Authors: Bianca Bianciardi & Peter J. Uhlhaas

Summary

This systematic review examined the effects of NMDA-R antagonists on spontaneous gamma-band activity and functional connectivity in preclinical models of schizophrenia and healthy controls. The results were inconsistent, with some studies reporting increases and others reporting decreases in gamma-band power and connectivity.

1. Introduction

Despite more than a hundred years of research, the pathophysiological processes underpinning the circuit dysfunctions that give rise to the symptomatic manifestation of schizophrenia remain to be determined. Hypofunctioning of the N-methyl-d-aspartate receptor (NMDA-R) has been considered a key process in the pathophysiology of schizophrenia.

Studies with NMDA-R antagonists in healthy volunteers showed that the symptoms of ScZ could be transiently evoked, and that alterations in resting-state activity induced by acute Ketamine administration resemble those observed in ScZ.

Evidence from non-invasive neuroimaging and post-mortem tissue suggests that the excitatory drive onto interneurons is disturbed in ScZ, and that Copy Number Variants substantially increase susceptibility to ScZ are enriched for NMDA-Rs.

Animal models of ScZ have been shown to have circuit dysfunctions and cognitive deficits, which may be explained by a shift in the balance between Excitation/Inhibition (E/I-Balance) across cortical and subcortical networks.

We hypothesized that NMDA-R hypofunction would induce alterations in the amplitude and organisation of high-frequency oscillations that are similar to disturbances observed in ScZ. We identified 24 pre-clinical and 9 human studies that examined the effects of NMDA-Rs antagonists on spontaneous gamma-band oscillations.

2. Method

PubMed, Google Scholar and the reference lists of relevant articles were searched for studies investigating the effects of Ketamine on gamma-band oscillations in resting state EEG/MEG-data as well as EEG, Local Field Potentials (LFP) and Electrocorticography (EcoG) for preclinical studies.

For pre-clinical studies on NMDA-R antagonists, Ketamine, PCP and/or MK801 administration, in vivo studies, subanaesthetic dosage and EEG/LFP/ EcoG-recordings were required. Human Ketamine studies required EEG/MEG-recordings, and ScZ patients required EEG/MEG-recordings.

Information was retrieved from pre-clinical studies, human Ketamine studies, and patient studies regarding number of participants, recording, frequency range, drug type and dosage.

2.2. Statistical analysis

Effect sizes were estimated using the Comprehensive Meta-Analysis (CMA) software version 2.0 and Hedges’ g was calculated based on mean scores of gamma-band power values. R was used to plot the standardized mean differences with 95 % confidence intervals and Egger’s regression test was performed to assess potential asymmetry.

3.1. Study selection

A total of 137 records were identified, of which 72 were excluded after abstract screening. Of the remaining 65 articles, 40 were excluded based on eligibility criteria, bringing the total to 25 studies.

We included 79 studies on Ketamine, MK801 and PCP in healthy volunteers, of which 22 were excluded because they did not report resting-state data, were only clinical studies, or included additional drugs to NMDA-R antagonists.

Resting-State EEG/MEG studies in ScZ were identified from 289 records. Of these 115 studies, 39 did not include analysis of gamma-band frequencies, 21 consisted of pharmacological studies, 36 did not report resting-state data, 12 studies had a clinical group other than ScZ diagnosis, and 7 studies had a clinical sample smaller than n = 10.

3.2. Study characteristics: preclinical studies of NMDA-R antagonists

Of the 24 studies, 21 were performed in rats, while the remaining two were performed in monkeys and mice. The majority of studies were conducted in freely-moving animals, and 19 were administered Ketamine, 14 MK-801 and 3 PCP.

3.3. Study characteristics: human ketamine EEG/MEG-studies

The majority of studies used a crossover design, except for one study in which all participants underwent the same protocol. Only male participants were recruited in 6 studies, and Ketamine infusion varied between .25 – .65 mg/kg. Six studies used EEG and 3 studies used MEG to study the brain. Most studies obtained amplitude estimates of EEG/MEG-data at both sensor and source-level, and 2 studies reported connectivity analysis of MEG-data.

3.4. Study characteristics: EEG/MEG resting-state in ScZ-Patients

Of the 27 studies, 19 examined chronic schizophrenia patients, 10 examined FEP-patients, 3 CHR-P participants, and 17 used EEG, 8 employed MEG, and 6 obtained data from unmedicated ScZ patients. Most studies obtained amplitude estimates at sensor-level, while 10 studies used source estimates.

3.5.1. Preclinical ketamine studies

N = 22 studies included a vehicle condition, 8 studies used a between-subject design, and 4 studies included a single observational group. Of these, 14 studies were considered at low overall risk of bias, 5 studies were considered at unclear overall risk of bias, and 5 studies were considered at high overall risk of bias.

3.5.2. Human ketamine studies

8 studies were placebo-controlled, 4 studies reported double-blinding and randomisation, 4 studies reported single-blinding and randomization, and 1 study reported no blinding and included solely one observational group of healthy controls.

3.5.3. Schizophrenia resting-state studies

Twenty-five out of 27 studies were matched-cohort studies, two studies were not, and 7 studies were considered to have high risk of bias. The remaining 14 studies showed low risk of bias.

3.5.4. Risk of publication bias

NMDA-R antagonists (Ketamine, PCP and MK801) increased gamma-band power in the majority of preclinical studies included (n = 20). Mixed findings emerged from n = 3 studies (Hunt et al., 2010; Kittelberger et al., 2012; Hiyoshi et al., 2014).

In preclinical studies, NMDA-R antagonists reduced gamma-band activity in 2 studies, but in the remaining 9 studies, there was no change in gamma-band activity following increased dosages.

In 6 studies, gamma-band coherence was increased following ketamine administration.

3.6. Effects of ketamine on gamma-band oscillations in human EEG/ MEG-studies

In 3 studies, correlations between psychopathology and gamma band-activity were observed. A negative correlation was observed between positive symptoms and gamma-band power following Ketamine administration.

3.7. Gamma-band oscillations in ScZ in EEG/MEG-recordings

In 27 studies, gamma-band activity was upregulated in ScZ patients, while in 7 studies gamma-band power was reduced. In 8 studies, there was no difference between ScZ patients and healthy controls.

14 studies reported connectivity results. 1 study reported increased sensor-level connectivity in ScZ, 4 studies revealed decreased sensor-level connectivity in ScZ, and 3 studies reported mixed results.

In 15 out of 27 schizophrenia studies, gamma-band power was correlated with positive symptoms, and in 2 studies, gamma-band power was correlated with negative symptoms. In 7 studies, gamma-band power was not correlated with psychopathology.

Associations between gamma band dysregulation and cognitive deficits have been shown in schizophrenia, especially in the high gamma frequency range.

3.8. Contrasting ScZ-studies with different effects on gamma-band power

We systematically compared studies that reported increases in gamma-band power in ScZ patients vs. those studies reporting a downregulation, as well as those studies reporting no differences. We found no differences in regard to illness stage, duration of illness, medication status, recording method, frequency range, recording design.

4. Discussion

The current systematic review examined whether NMDA-R antagonists affect spontaneous gamma-band activity in pre-clinical electrophysiological recordings as well as in human participants and whether these changes would be compatible with observations from ScZ-patients at different illness stages.

NMDA-R antagonists were associated with increased low- and high gamma-band power across cortical and subcortical regions, and increased gamma-band connectivity. Moreover, we did not observe differential effects of MK-801, Ketamine and PCP on low vs. high frequency ranges.

Ketamine, MK-801 and PCP increased gamma-band power when administered acutely, while chronic administration was associated with more pronounced cognitive deficits in animal models.

The current review indicates that the upregulation of gamma-band power induced by NMDA-R antagonists is not consistent with the effects observed in EEG/MEG-recordings in ScZ-patients. Furthermore, the pattern of gamma-band activity was not moderated by medication status.

There is only moderate evidence that alterations in resting-state gamma-band activity in clinical populations is associated with particular symptoms and/or neurocognitive deficits, and that positive symptoms of ScZ are closely correlated with the effects of Ketamine.

The current findings challenge predictions of the E/I-balance model of ScZ, as NMDA-R antagonists do not have a similar effect on gamma-band activity in pre-clinical as well as human EEG/MEG-recordings as observed in ScZ.

Examining gamma-band activity may provide complementary insights into the neurobiology of circuit functions during NMDA-R hypofunctioning and its involvement in ScZ. This is because different classes of interneurons, in particular PV + cells, are involved in generating high-frequency activity.

The current findings raise a number of important questions that need to be addressed by future studies, such as the importance of providing further data on potential abnormalities in at-risk and FEP-populations, and the importance of employing effective artefact-correction procedures for resting-state EEG/MEG-recordings.

Oscillatory activity is characterised by a circumscribed modulation within a particular frequency, and it is important to establish in future studies whether changes induced by NMDA-R antagonists are characterized by similar spectral characteristics.

There is a critical lack of studies on the differences and similarities between acute and chronic effects of NMDA-R antagonists on gamma-band oscillations. Additionally, additional variables such as illness-stages as well as task-parameters need to be systematically evaluated to confirm this hypothesis.

5. Limitations

Ketamine, MK-801 and PCP impact other neurotransmitter and receptor systems apart from NMDA-Rs, and the effects observed on gamma-band oscillations are consistent across studies. Furthermore, previous research established that NMDA-R 2A subunits are specifically involved in the generation of gamma-band oscillations.

The systematic review highlights that NMDA-R antagonists have an unspecific frequency and topographic effect on spontaneous gamma-band activity in pre-clinical and human EEG/MEG-data.