Discussion
The main findings of this study were that 1) there were no significant differences in neurometabolites in SZ compared to healthy controls, 2) the MAP group had lower NAA+NAAG/Cr+PCr than healthy controls in the left DLPFC and left FWM, 3) There were significant positive associations between glutamatergic neurometabolites and neuronal integrity markers in the ACC in the SZ group, and 4) there were significant positive associations between mI in the left thalamus and mI in bilateral ACC in the MAP group.
The lack of a significant differences between 1H-MRS neurometabolite findings in SZ group and healthy controls could be attributed to the chronic use of antipsychotic medicine in these patients. Antipsychotic medicine has been shown to normalize neurometabolites over time and thus increase metabolic activity in the thalamus, reduce neuroinflammation and partially reverse NMDAR dysfunction in patients with SZ .
The finding of altered lower NAA+NAAG in left DLPFC and left FWM in MAP is consistent with previous studies of MA abuse and one study of MAP and could indicate compromised neuronal health, density and metabolism . Previous studies found lower NAA and NAA+NAAG in frontal brain areas in MA abuse , and the present work extends this finding by showing lower NAA+NAAG/Cr+PCr in the left DLPFC and left FWM in the MAP group, suggesting that neuronal integrity remains compromised over time.
The associations between glutamatergic neurometabolites and neuronal integrity markers in the ACC in SZ, but not in healthy controls, may suggest disruptions in the glutamate-glutamine cycle. Few studies on these associations have been done and much further work is needed to understand the relevant underlying causal mechanisms. The brain areas investigated in the present study form part of the thalamo-cortical circuitry and previous studies, limited to post-mortem , structural magnetic resonance imaging and imaging techniques to assess neurocognitive functioning (PET/SPECT) and fMRI, did not specifically investigate the thalamo-cortical circuit) . Two previous studies report positive relationships between NAA and Glu concentrations in healthy controls, but not in SZ patients . Considering that no individual neurometabolite differences for the SZ were found, it could be considered that the mechanism of dysfunction in SZ lies within associations between neurometabolites and not changes in specific standalone neurometabolites.
Stronger associations of mI between the left thalamus and bilateral ACC were also found in the MAP group, compared to healthy controls. Higher thalamic mI was positively associated with higher mI in the left and right ACC, suggesting neuroinflammation in the thalamus-ACC circuit in chronic MAP. MA has been shown to disrupt the thalamo-cortical circuit at the ventral striatum, within the ACC-thalamus circuit . This is supported by previous studies in MA abstinence where higher concentrations of mI have been reported . These are the first data on higher mI concentrations, suggestive of neuroinflammation, within the thalamus-ACC circuit in chronic MAP.
Several limitations deserve emphasis. First, use of antipsychotic medication use was obtained through retrospective self-report and may not be accurate. Second, studies of substance abuse are almost invariably confounded by selective disclosure and polysubstance use. Third, the effect of alcohol and nicotine could potentially have influenced neurometabolite concentrations, as participants did not cease their alcohol or nicotine use during the study.