ABSTRACT
Objective@#Striatal dopamine dysfunction caused by cortical abnormalities is a leading hypothesis of schizophrenia. Although prefrontal cortical pathology is negatively correlated with striatal dopamine synthesis, the relationship between structural frontostriatal connectivity and striatal dopamine synthesis has not been proved in patients with schizophrenia with different treatment response. We therefore investigated the relationship between frontostriatal connectivity and striatal dopamine synthesis in treatment-responsive schizophrenia (non-TRS) and compared them to treatment-resistant schizophrenia (TRS) and healthy controls (HC). @*Methods@#Twenty-four patients with schizophrenia and twelve HC underwent [18F] DOPA PET scans to measure dopamine synthesis capacity (the influx rate constant Kicer) and diffusion 3T MRI to measure structural connectivity (fractional anisotropy, FA). Connectivity was assessed in 2 major frontostriatal tracts. Associations between Kicer and FA in each group were evaluated using Spearman’s rho correlation coefficients. @*Results@#Non-TRS showed a negative correlation (r=-0.629, p=0.028) between connectivity of dorsolateral prefrontal cortex-associative striatum (DLPFC-AST) and dopamine synthesis capacity of associative striatum but this was not evident in TRS (r=-0.07, p=0.829) and HC (r=-0.277, p=0.384). @*Conclusion@#Our findings are consistent with the hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology localized to connectivity of DLPFC-AST in non-TRS, and also extend the hypothesis to suggest that different mechanisms underlie the pathophysiology of non-TRS and TRS.
ABSTRACT
SummaryO_ST_ABSBackgroundC_ST_ABSThe impact of COVID-19 on human health extends beyond the morbidity and death toll directly caused by the SARS-CoV-2 virus. In fact, accumulating evidence indicates a global increase in the incidence of fatigue, brain fog and depression, including among non-infected, since the pandemic onset. Motivated by previous evidence linking those symptoms to neuroimmune activation in other pathological contexts, we hypothesized that subjects examined after the enforcement of lockdown/stay-at-home measures would demonstrate increased neuroinflammation. MethodsWe performed simultaneous brain Positron Emission Tomography / Magnetic Resonance Imaging in healthy volunteers either before (n=57) or after (n=15) the 2020 Massachusetts lockdown, using [11C]PBR28, a radioligand for the glial marker 18 kDa translocator protein (TSPO). First, we compared [11C]PBR28 signal across pre- and post-lockdown cohorts. Then, we evaluated the link between neuroinflammatory signals and scores on a questionnaire assessing mental and physical impacts of the pandemic. Further, we investigated multivariate associations between the spatial pattern of [11C]PBR28 post-lockdown changes and constitutive brain gene expression in post-mortem brains (Allen Human Brain Atlas). Finally, in a subset (n=13 pre-lockdown; n=11 post-lockdown), we also used magnetic resonance spectroscopy to quantify brain (thalamic) levels of myoinositol (mIns), another neuroinflammatory marker. FindingsBoth [11C]PBR28 and mIns signals were overall stable pre-lockdown, but markedly elevated after lockdown, including within brain regions previously implicated in stress, depression and "sickness behaviors". Moreover, amongst the post-lockdown cohort, subjects endorsing higher symptom burden showed higher [11C]PBR28 PET signal compared to those reporting little/no symptoms. Finally, the post-lockdown [11C]PBR28 signal changes were spatially aligned with the constitutive expression of several genes highly expressed in glial/immune cells and/or involved in neuroimmune signaling. InterpretationOur results suggest that pandemic-related stressors may have induced sterile neuroinflammation in healthy individuals that were not infected with SARS-CoV-2. This work highlights the possible impact of the COVID-19 pandemic-related lifestyle disruptions on human brain health. FundingR01-NS094306-01A1, R01-NS095937-01A1, R01-DA047088-01, The Landreth Family Foundation.