Cognitive deficits are commonly observed in patients with schizophrenia. Converging lines of evidence suggest that these deficits are associated with impaired long-term potentiation (LTP). In our systematic review, this hypothesis is evaluated using neuroimaging literature focused on proton magnetic resonance spectroscopy, positron emission tomography, and single-photon emission computed tomography. The review provides evidence for abnormal dopaminergic, GABAergic, and glutamatergic neurotransmission in antipsychotic-naive/free patients with schizophrenia compared with healthy controls. The review concludes with a model illustrating how these abnormalities could lead to impaired LTP in patients with schizophrenia and consequently cognitive deficits.

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SummaryObjectiveTo perform a systematic review and meta‐analysis of real‐world evidence for the use of low‐frequency repetitive transcranial magnetic stimulation (rTMS) in the treatment of drug‐resistant epilepsy.MethodsWe systematically searched PubMed, Scopus, Medline, and clinicaltrials.gov for all relevant articles. Relevant patient and stimulation predictors as well as seizure outcomes were assessed. For studies with and without individual participant data (IPD), the primary outcomes were the rate of “favorable response” (reduction in seizure frequency ≥50%) and pooled event rate of mean reduction in seizure frequency, respectively. Outcomes were assessed with comparative statistics and random‐effects meta‐analysis models.ResultsOf 3,477 identified articles, 12 met eligibility and were included in this review. We were able to obtain IPD for 5 articles constituting 34 participants. Univariate analysis on IPD identified greater favorable response event rates between participants with temporal seizure focus versus extratemporal (50% vs. 14%, p = 0.045) and between participants who were stimulated with a figure‐8 coil versus other types (47% vs. 0%, p = 0.01). We also performed study‐level meta‐analysis on the remaining 7 studies without IPD, which included 212 participants. The pooled mean event rate of 50% seizure reduction using low‐frequency rTMS was 30% (95% confidence interval [CI] 12–57%). Sensitivity analysis revealed that studies with a mean age ≤21 years and studies using targeted stimulation had the highest seizure reduction rates compared to studies with a mean age >21 years (69% vs. 18%) and not using a targeted stimulation (47% vs. 14–20%). Moreover, we identified high interstudy heterogeneity, moderate study bias, and high publication bias.SignificanceReal‐world evidence suggests that low‐frequency rTMS using a figure‐8 coil may be an effective therapy for the treatment of drug‐resistant epilepsy in pediatric patients. This meta‐analysis can inform the design and expedite recruitment of a subsequent randomized clinical trial.

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In people with schizophrenia, cognitive abilities - including memory - are strongly associated with functional outcome. Long-term potentiation (LTP) is a form of neuroplasticity that is believed to be the physiological basis for memory. It has been postulated that antipsychotic medication can impair long-term potentiation and cognition by altering dopaminergic transmission. Thus, a systematic review was performed in order to assess the relationship between antipsychotics and D2 antagonists on long-term potentiation. The majority of studies on LTP and antipsychotics have found that acute administration of antipsychotics was associated with impairments in LTP in wild type animals. In contrast, chronic administration and acute antipsychotics in animal models of schizophrenia were not. Typical and atypical antipsychotics and other D2 antagonists behaved similarly, with the exception of clozapine and olanzapine. Clozapine caused potentiation independent of tetanization, while olanzapine facilitated tetanus-induced potentiation. These studies are limited in their ability to model the effects of antipsychotics in patients with schizophrenia as they were largely performed in wild type animals as opposed to humans with schizophrenia, and assessed after acute rather than chronic treatment. Further studies using patients with schizophrenia receiving chronic antipsychotic treatment are needed to better understand the effects of these medications in this population.

Cortical inhibition (CI) occurs largely through GABA receptor-mediated inhibitory neurotransmission, which can be modulated by cholinergic, dopaminergic, and glutamatergic inputs. Transcranial magnetic stimulation (TMS) can be used to index CI through a paradigm known as long-interval CI (LICI). When TMS is combined with electroencephalography (EEG), LICI can index GABA receptor-mediated inhibitory neurotransmission in the dorsolateral prefrontal cortex (DLPFC). We conducted a hypothesis-driven pharmacological study to assess the role of cholinergic, dopaminergic, GABAergic, and glutamatergic neurotransmission on LICI from the DLPFC using TMS-EEG. In this randomized controlled, double-blind crossover within-subject study, 12 healthy participants received five sessions of LICI to the DLPFC in a random order, each preceded by the administration of placebo or one of the four active drugs. LICI was assessed after each drug administration and compared to LICI after placebo. Relative to placebo, baclofen resulted in a significant increase in LICI, while rivastigmine resulted in a significant decrease in LICI. Dextromethorphan and L-DOPA did not result in a significant change in LICI relative to placebo. Our study confirms that LICI in the DLPFC is largely mediated by GABA receptor-mediated inhibitory neurotransmission and also suggests that cholinergic modulation decreases LICI in the DLPFC. Such findings may help guide future work examining the neurophysiological impact of these neurotransmitters in healthy and diseased states.

Background: Long-term potentiation (LTP) depends on glutamatergic neurotransmission and is modulated by cholinergic, dopaminergic and GABAergic inputs. Paired associative stimulation (PAS) is a neurostimulation paradigm that, when combined with electroencephalography (EEG), assesses LTP-like activity (PAS-induced LTP) in the dorsolateral prefrontal cortex (DLPFC). Thus, we conducted a study to assess the role of cholinergic, dopaminergic, GABAergic and glutamatergic neurotransmission on PAS-induced LTP in the DLPFC. We hypothesized that increasing the dopaminergic tone with L-DOPA and the cholinergic tone with rivastigmine will enhance PAS-induced LTP, while increasing the GABAergic tone with baclofen and inhibiting glutamatergic neurotransmission with dextromethorphan will reduce it compared to placebo.Methods: In this randomized controlled, double-blind cross-over within-subject study, 12 healthy participants received five sessions of PAS to the DLPFC in a random order, each preceded by the administration of placebo or one of the four active drugs. PAS-induced LTP was assessed after each drug administration and compared to PAS-induced LTP after placebo.Results: As predicted, L-DOPA and rivastigmine resulted in enhanced PAS-induced LTP in the DLPFC and dextromethorphan inhibited it compared to placebo. In contrast, baclofen did not significantly suppress PAS-induced LTP compared to placebo.Conclusions: This study provides a novel approach to study DLPFC neuroplasticity and its modulation in patients with brain disorders that are associated with abnormalities in these neurochemical systems. This study was based on a single dose administration of each drug. Given that these drugs are typically administered chronically, future studies should assess the effects of chronic administration.

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