Dorsolateral Prefrontal Cortex Glutamate/Gamma-Aminobutyric Acid (GABA) Alterations in Clinical High Risk and First-Episode Schizophrenia: A Preliminary 7-T Magnetic Resonance Spectroscopy Imaging Study.

Converging lines of evidence suggest that an imbalance between excitation and inhibition is present in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia (SCZ). Gamma-aminobutyric-acid (GABA) and, to a lesser extent, glutamate (Glu) abnormalities were reported in the DLPFC of SCZ patients, especially on the right hemisphere, by post-mortem studies. However, in vivo evidence of GABA, Glu, and Glu/GABA DLPFC abnormalities, particularly on the right side and the early stages of illness, is limited. In this preliminary study, we utilized 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to investigate bilateral Glu/Creatine (Cre), GABA/Cre, and Glu/GABA in the DLPFC of sixteen first episode schizophrenia (FES), seventeen clinical high risk (CHR), and twenty-six healthy comparison (HC) subjects. FES and CHR had abnormal GABA/Cre and Glu/GABA in the right DLPFC (rDLPFC) compared with HC participants, while no differences were observed in the left DLPFC (lDLPFC) among the three groups. Furthermore, HC had higher Glu/GABA in rDLPFC compared to lDLPFC (R > L), whereas the opposite relationship (R < L) was observed in the DLPFC Glu/GABA of FES patients. Altogether, these findings indicate that GABA/Cre and Glu/GABA DLPFC alterations are present before illness manifestation and worsen in FES patients, thus representing a putative early pathophysiological biomarker for SCZ and related psychotic disorders.

A longitudinal investigation of GABA, glutamate, and glutamine across the insula during antipsychotic treatment of first-episode schizophrenia.

Individuals with first-episode schizophrenia (FES) typically present with acute psychotic symptoms. Though antipsychotic drugs are the mainstay for treatment, the neurobiology underlying successful treatment remains largely elusive. Recent evidence from functional connectivity studies highlights the insula as a key structure in the neural mechanism of response. However, molecular contributions to response across insular regions remain largely unknown. We used 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to measure glutamate (Glu), Glutamine (Gln), and GABA from anterior and posterior regions of the insula across antipsychotic treatment. A total of 36 participants were examined, including 15 individuals with FES and moderate to severe psychosis who were scanned at two time points, while starting and after 6 weeks of antipsychotic treatment. Symptoms were carefully monitored across the study period to characterize treatment response. GABA, Glu, and Gln levels were calculated relative to creatine in anterior and posterior insular regions, bilaterally. In relation to psychotic symptom reduction, we observed a significant increase in Glu across all insular regions with (p < 0.001), but no corresponding changes in Gln or GABA. In group analyses, the FES cohort showed lower levels of Glu (p < 0.001) and GABA (p = 0.02) at baseline. Finally, in exploratory analyses, treatment remitters demonstrated a normalization of lower insular Glu levels across treatment, unlike non-remitters. Overall, these findings contribute to our understating of molecular changes associated with antipsychotic response and demonstrate abnormalities specific to the insula in FES.

Changes in corticostriatal connectivity and striatal tissue iron associated with efficacy of clozapine for treatment­resistant schizophrenia.

RATIONALE: Though numerous studies demonstrate the superiority of clozapine (CLZ) for treatment of persistent psychotic symptoms that are characteristic of treatment-refractory schizophrenia (TRS), what remains unknown are the neural and molecular mechanisms underlying CLZ's efficacy. Recent work implicates increased corticostriatal functional connectivity as a marker of response to non-CLZ, dopamine (DA) D2-receptor blocking antipsychotic drugs. However, it is undetermined whether this connectivity finding also relates to CLZ's unique efficacy, or if response to CLZ is associated with changes in striatal DA functioning. OBJECTIVE: In a cohort of 22 individuals with TRS, we examined response to CLZ in relation to the following: (1) change in corticostriatal functional connectivity; and (2) change in a magnetic resonance-based measure of striatal tissue iron (R2'), which demonstrates utility as a proxy measure for elements of DA functioning. METHODS: Participants underwent scanning while starting CLZ and after 12 weeks of CLZ treatment. We used both cortical and striatal regions of interest to examine changes in corticostriatal interactions and striatal R2' in relation to CLZ response (% reduction of psychotic symptoms). RESULTS: We first found that response to CLZ was associated with an increase in corticostriatal connectivity between the dorsal caudate and regions of the frontoparietal network (P < 0.05, corrected). Secondly, we observed no significant changes in striatal R2' across CLZ treatment. CONCLUSION: Overall, these results indicate that changes in corticostriatal networks without gross shifts in striatal DA functioning underlies CLZ response. Our results provide novel mechanistic insight into response to CLZ treatment.

Relationship between plasma clozapine/N-desmethylclozapine and changes in basal forebrain-dorsolateral prefrontal cortex coupling in treatment-resistant schizophrenia.

Clozapine (CLZ) demonstrates a unique clinical efficacy relative to other antipsychotic drugs. Previous work has linked the plasma ratio of CLZ and its major metabolite, N-desmethylclozapine (NDMC), to an inverse relationship with cognition via putative action on the cholinergic system. However, neuroimaging correlates of CLZ/NDMC remain unknown. Here, we examined changes in basal forebrain functional connectivity with the dorsolateral prefrontal cortex, and secondly, cognition in relation to the CLZ/NDMC ratio. A cohort of nineteen chronically ill participants with treatment-resistant schizophrenia (TRS) undergoing 12 weeks of CLZ treatment were included. Measures of cognition and plasma CLZ/NDMC ratios were obtained in addition to resting-state functional neuroimaging scans, captured at baseline and after 12 weeks of CLZ treatment. We observed a significant correlation between basal forebrain-DLPFC connectivity and CLZ/NDMC ratios across CLZ treatment (p = 0.02). Consistent with previous findings, we also demonstrate a positive relationship between CLZ/NDMC ratio and working memory (p = 0.03). These findings may reflect the action of CLZ and NDMC on the muscarinic cholinergic system, highlighting a possible neural correlate of cognition across treatment.

Independent support for corticopallidal contributions to schizophrenia-related functional impairment.

BACKGROUND: Abnormalities between the prefrontal cortex and basal ganglia have been described by numerous studies of schizophrenia (SZ). We recently reported that individuals with first episode SZ who develop greater vocational and social impairments show lower baseline functional connectivity between the globus pallidus (GP) and regions of the intrinsic salience network. Here we extend these findings to probe the integrity of this system in individuals with chronic illness. METHODS: All data were obtained from a publicly available Center of Biomedical Research Excellence dataset (http://fcon_1000. PROJECTS: nitric.org/indi/retro/cobre.html) that included resting-state fMRI and structural scans, and an array of clinical and neuropsychological measures. Participants with SZ were divided into high- or low-functioning groups based on scores across measures of psychopathology and cognitive functioning. Corticopallidal functional connectivity was examined between low- and high-functioning individuals with SZ and matched healthy control participants. We focused on connectivity between GP structures and a priori regions of the salience network that were significant in our previous study. Exploratory voxel-wise analyses were also conducted. RESULTS: Lower functioning individuals with SZ demonstrated less connectivity between bilateral GP externa and nodes within the salience network, relative to healthy controls. No connectivity differences were observed between low- and high-functioning individuals with SZ. Exploratory voxel-wise analyses highlighted additional large-scale corticopallidal abnormalities in lower-functioning participants with SZ. CONCLUSIONS: These results confirm our previous work in a more chronic cohort of individuals with SZ. Our findings further advance corticopallidal connectivity as a biomarker of functional impairments in SZ and lay the groundwork for treatment-based studies.