Long-range gamma phase synchronization as a compensatory strategy during working memory in high-performing patients with schizophrenia.

Working memory deficits in schizophrenia may be associated with impairments in the integration of neural activity across a distributed network of cortical areas. However, evaluation of the contribution of this integration to working memory impairments in patients is severely confounded by behavioral performance. In the present multidimensional-neuroimaging study, measures of neural oscillations at baseline and during a working memory task, baseline gamma-aminobutyric acid (GABA) level in the left dorsolateral prefrontal cortex (DLPFC), and behavioral performance were obtained. Controlling behavioral performance by recruiting only "high-performing" patients with schizophrenia, we investigated whether the strength of cross-area communications differs between patients with schizophrenia and healthy participants under accurate and equivalent behavioral performance. Results of phase-locking value indicated that these high-performing patients recruited significantly more between frontal and occipital regions in the left hemisphere, t(13) = -2.16, p = .05, Cohen's d = -1.20, and between frontal and temporal regions in the right hemisphere, t(13) = -2.63, p = .02, Cohen's d = -1.46. These cross-area communication patterns may be associated with visuoverbal and visuospatial working memory networks of the left and right hemispheres, respectively. Moreover, correlations of patient's cross-area communication with in vivo GABA levels of the left DLPFC revealed a significant positive relationship (r = .77, p = .04), demonstrating that the critical role of GABA functions in gamma band oscillations may go beyond local neuronal assemblies in the left DLPFC. Altogether, these exploratory findings point to the heterogeneity among schizophrenia patients and highlight the notion that high-performing patients may engage in potential compensatory mechanisms and may represent a subgroup of patients that may be categorically or dimensionally divergent in psychopathology.

Effects of davunetide on N-acetylaspartate and choline in dorsolateral prefrontal cortex in patients with schizophrenia.

Schizophrenia is associated with extensive neurocognitive and behavioral impairments. Studies indicate that N-acetylaspartate (NAA), a marker of neuronal integrity, and choline, a marker of cell membrane turnover and white matter integrity, may be altered in schizophrenia. Davunetide is a neurotrophic peptide that can enhance cognitive function in animal models of neurodegeneration. Davunetide has recently demonstrated modest functional improvement in a study of people with schizophrenia. In a subset of these subjects, proton magnetic resonance spectroscopy ((1)H-MRS) was conducted to explore the effects of davunetide on change in NAA/creatine (NAA/Cr) and choline/creatine (choline/Cr) over 12 weeks of treatment. Of 63 outpatients with schizophrenia who received randomized davunetide (5 and 30 mg/day) or placebo in the parent clinical trial, 18 successfully completed (1)H-MRS in dorsolateral prefrontal cortex (DLPFC) at baseline and at 12 weeks. Cognition was assessed using the MATRICS Consensus Cognitive Battery (MCCB). NAA/Cr was unchanged for combined high- and low-dose davunetide groups (N=11). NAA/Cr in the high-dose davunetide group (N=8) suggested a trend increase of 8.0% (P=0.072) over placebo (N=7). Choline/Cr for combined high- and low-dose davunetide groups suggested a 6.4% increase (P=0.069), while the high-dose group showed a 7.9% increase (P=0.040) over placebo. Baseline NAA/Cr correlated with the composite MCCB score (R=0.52, P=0.033), as did individual cognitive domains of attention/vigilance, verbal learning, and social cognition; however, neither metabolite correlated with functional capacity. In this exploratory study, 12 weeks of adjunctive davunetide appeared to produce modest increases in NAA/Cr and choline/Cr in DLPFC in people with schizophrenia. This is consistent with a potential neuroprotective mechanism for davunetide. The data also support use of MRS as a useful biomarker of baseline cognitive function in schizophrenia. Future clinical and preclinical studies are needed to fully define the mechanism of action and cognitive effects of davunetide in schizophrenia.