Introduction
There are similarities in the phenomenology and psychobiology of schizophrenia (SZ) and methamphetamine (MA)-induced psychosis (MAP) , with evidence of alterations in glutamatergic function in both conditions , and of involvement of neuroinflammatory pathways in SZ and MA abuse . In SZ, positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies suggest hypofunction of N-methyl-D-aspartate receptors (NMDAR) , while 1H-MRS studies of myo-inositol (mI), which may indicate neuroinflammation , are inconsistent . Studies of prefrontal glutamatergic function in MA abuse and MAP are inconsistent, with some reporting higher glutamate (Glu) or glutamate with glutamine (Glx) , others reporting lower Glx , and several reporting no glutamatergic metabolite changes . In MAP, higher concentration of prefrontal mI , suggestive of neuroinflammation have been reported. Cytokines have been proposed to be involved during psychotic states as IL-1β, TNF-α, IFN-γ, IL-8 and IL-10 are all reported to be elevated during acute . IL-1β however is reported to return to normal concentrations outside of psychotic state, whereas TNF-α, IFN-γ, IL-8 remain elevated even in remission . It is proposed that IL-1β, TNF-α, IFN-γ can therefore reflect neuroinflammation, and subsequent disruption in thalamo-cortical circuitry. Pre-clinical studies and animal models of MA abuse, and post-mortem studies of SZ have shown that higher concentrations of IL-1β and IFN-γ have been associated with lower concentrations of NAA , while higher concentration of IL-8 has been associated with increased Glu .
Few studies have, however, directly compared glutamatergic (Glu, Gln and Glx) and neuroinflammatory (mI) neurometabolites and neuronal integrity markers (NAA and NAA+NAAG) in thalamo-cortical circuitry across SZ and MA abuse and none have assessed the relationship between these neurometabolites and peripheral inflammatory markers in either disorder aside from preclinical and post-mortem studies and animal models. The small literature on associations between neurometabolites and peripheral inflammatory markers has found an association between higher concentrations of TNF-α and IL-1β and lower NAA concentrations in active psychosis in SZ as well as MA abuse . Increased IL-8 concentrations have been associated with increased NMDAR in SZ and with withdrawal symptoms in MA abuse . Lower concentrations of interferon gamma (IFN-γ) and IL-10 were associated with decreased neuronal integrity in the prefrontal cortex and thalamus in SZ , and MA abuse . However, these associations have not been explored using a combination of neuroimaging and peripheral cytokine measures in living patients with SZ and MAP.
This study had two aims. First, to compare glutamatergic and neuroinflammatory neurometabolites and neuronal integrity in thalamo-cortical circuitry in SZ and MAP. It was hypothesized that glutamatergic neurometabolites would be increased in SZ compared to healthy controls, and that mI would be higher in SZ and MAP than in healthy controls, consistent with neuroinflammation. It was also hypothesized that NAA/NAA+NAAG concentrations would be lower in both SZ and MAP groups. Second, this study aimed to investigate associations between glutamatergic and neuroinflammatory neurometabolites, neuronal integrity markers and peripheral cytokine levels in both disorders. It was hypothesized that associations between neurometabolites, brain areas and peripheral cytokines would differ in SZ compared with MAP.