The neural and molecular basis of working memory function in psychosis: a multimodal PET-fMRI study

Working memory (WM) deficits predict clinical and functional outcomes in schizophrenia but are poorly understood and unaddressed by existing treatments. WM encoding and WM retrieval have not been investigated in schizophrenia without the confounds of illness chronicity or the use of antipsychotics and illicit substances. Moreover, it is unclear if WM deficits may be linked to cannabinoid 1 receptor dysfunction in schizophrenia. Sixty-six volunteers (35 controls, 31 drug-free patients with diagnoses of schizophrenia or schizoaffective disorder) completed the Sternberg Item-Recognition paradigm during an fMRI scan. Neural activation during WM encoding and WM retrieval was indexed using the blood-oxygen-level-dependent hemodynamic response. A subset of volunteers (20 controls, 20 drug-free patients) underwent a dynamic PET scan to measure [11C] MePPEP distribution volume (ml/cm3) to index CB1R availability. In a whole-brain analysis, there was a significant main effect of group on task-related BOLD responses in the superior parietal lobule during WM encoding, and the bilateral hippocampus during WM retrieval. Region of interest analyses in volunteers who had PET/fMRI indicated that there was a significant main effect of group on task-related BOLD responses in the right hippocampus, left DLPFC, left ACC during encoding; and in the bilateral hippocampus, striatum, ACC and right DLPFC during retrieval. Striatal CB1R availability was positively associated with mean striatal activation during WM retrieval in male patients (R = 0.5, p = 0.02) but not male controls (R = −0.20, p = 0.53), and this was significantly different between groups, Z = −2.20, p = 0.02. Striatal CB1R may contribute to the pathophysiology of WM deficits in male patients and have implications for drug development in schizophrenia.</p

Sex difference in brain CB1 receptor availability in man

none12The endocannabinoid system (ECS) has a widespread neuromodulatory function in the central nervous system and is involved in important aspects of brain function including brain development, cortical rhythms, plasticity, reward, and stress sensitivity. Many of these effects are mediated via the cannabinoid CB1 receptor (CB1R) subtype. Animal studies convincingly show an interaction between the ECS and sex hormones, as well as a sex difference of higher brain CB1R in males. Human in vivo studies of sex difference have yielded discrepant findings. Gender differences in CB1R availability were investigated in vivo in 11 male and 11 female healthy volunteers using a specific CB1R tracer [18F]FMPEP-d2 and positron emission tomography (PET). Regional [18F]FMPEP-d2 distribution volume was used as a proxy for CB1R availability. In addition, we explored whether CB1R availability is linked to neuropsychological functioning. Relative to females, CB1R availability was on average 41% higher in males (p = 0.002) with a regionally specific effect larger in the posterior cingulate and retrosplenial cortices (p = 0.001). Inter-subject variability in CB1R availability was similar in both groups. Voxel-based analyses revealed an inverse association between CB1R availability and visuospatial working memory task performance in both groups (p noneLaurikainen, Heikki; Tuominen, Lauri; Tikka, Maria; Merisaari, Harri; Armio, Reetta-Liina; Sormunen, Elina; Borgan, Faith; Veronese, Mattia; Howes, Oliver; Haaparanta-Solin, Merja; Solin, Olof; Hietala, JarmoLaurikainen, Heikki; Tuominen, Lauri; Tikka, Maria; Merisaari, Harri; Armio, Reetta-Liina; Sormunen, Elina; Borgan, Faith; Veronese, Mattia; Howes, Oliver; Haaparanta-Solin, Merja; Solin, Olof; Hietala, Jarm

Variability and magnitude of brain glutamate levels in schizophrenia:a meta and mega-analysis

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan’s unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p &lt; 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p &lt; 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = −0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = −0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = −0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p &lt; 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p &lt; 0.001). Proportion of males was negatively associated with MFC glutamate (z = −0.02, p &lt; 0.001) and frontal white matter Glx (z = −0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.</p

N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study

N-methyl-D-aspartate receptor (NMDAR) hypofunction is hypothesised to underlie psychosis but this has not been tested early in illness. To address this, we studied 40 volunteers (21 patients with first-episode psychosis and 19 matched healthy controls) using PET imaging with an NMDAR selective ligand, [18F]GE-179, that binds to the ketamine binding site to index its distribution volume ratio (DVR) and volume of distribution (VT). Hippocampal DVR, but not VT, was significantly lower in patients relative to controls (p = 0.02, Cohen’s d = 0.81; p = 0.15, Cohen’s d = 0.49), and negatively associated with total (rho = −0.47, p = 0.04), depressive (rho = −0.67, p = 0.002), and general symptom severity (rho = −0.74, p < 0.001). Exploratory analyses found no significant differences in other brain regions (anterior cingulate cortex, thalamus, striatum and temporal cortex). These findings are consistent with the NMDAR hypofunction hypothesis and identify the hippocampus as a key locus for relative NMDAR hypofunction, although further studies should test specificity and causality

An automatic analysis framework for FDOPA PET neuroimaging

In this study we evaluate the performance of a fully automated analytical framework for FDOPA PET neuroimaging data, and its sensitivity to demographic and experimental variables and processing parameters. An instance of XNAT imaging platform was used to store the King's College London institutional brain FDOPA PET imaging archive, alongside individual demographics and clinical information. By re-engineering the historical Matlab-based scripts for FDOPA PET analysis, a fully automated analysis pipeline for imaging processing and data quantification was implemented in Python and integrated in XNAT. The final data repository includes 892 FDOPA PET scans organized from 23 different studies. We found good reproducibility of the data analysis by the automated pipeline (in the striatum for the Kicer: for the controls ICC = 0.71, for the psychotic patients ICC = 0.88). From the demographic and experimental variables assessed, gender was found to most influence striatal dopamine synthesis capacity (F = 10.7, p < 0.001), with women showing greater dopamine synthesis capacity than men. Our automated analysis pipeline represents a valid resourse for standardised and robust quantification of dopamine synthesis capacity using FDOPA PET data. Combining information from different neuroimaging studies has allowed us to test it comprehensively and to validate its replicability and reproducibility performances on a large sample size