Mitochondrial complex I density is associated with IQ and cognition in cognitively healthy adults: an in vivo [18F]BCPP-EF PET study.

BACKGROUND: Mitochondrial function plays a key role in regulating neurotransmission and may contribute to general intelligence. Mitochondrial complex I (MC-I) is the largest enzyme of the respiratory chain. Recently, it has become possible to measure MC-I distribution in vivo, using a novel positron emission tomography tracer [18F]BCPP-EF, thus, we set out to investigate the association between MC-I distribution and measures of cognitive function in the living healthy brain. RESULTS: Analyses were performed in a voxel-wise manner and identified significant associations between [18F]BCPP-EF DVRCS-1 in the precentral gyrus and parietal lobes and WAIS-IV predicted IQ, WAIS-IV arithmetic and WAIS-IV symbol-digit substitution scores (voxel-wise Pearson's correlation coefficients transformed to Z-scores, thresholded at Z = 2.3 family-wise cluster correction at p < 0.05, n = 16). Arithmetic scores were associated with middle frontal and post-central gyri tracer uptake, symbol-digit substitution scores were associated with precentral gyrus tracer uptake. RAVLT recognition scores were associated with [18F]BCPP-EF DVRCS-1 in the middle frontal gyrus, post-central gyrus, occipital and parietal regions (n = 20). CONCLUSIONS: Taken together, our findings support the theory that mitochondrial function may contribute to general intelligence and indicate that interindividual differences in MC-I should be a key consideration for research into mitochondrial dysfunction in conditions with cognitive impairment.

Synaptic Terminal Density Early in the Course of Schizophrenia: An In Vivo UCB-J Positron Emission Tomographic Imaging Study of SV2A.

BACKGROUND: The synaptic hypothesis is an influential theory of the pathoetiology of schizophrenia (SCZ), which is supported by the finding that there is lower uptake of the synaptic terminal density marker [11C]UCB-J in patients with chronic SCZ than in control participants. However, it is unclear whether these differences are present early in the illness. To address this, we investigated [11C]UCB-J volume of distribution (VT) in antipsychotic-naïve/free patients with SCZ who were recruited from first-episode services compared with healthy volunteers. METHODS: Forty-two volunteers (SCZ n = 21, healthy volunteers n = 21) underwent [11C]UCB-J positron emission tomography to index [11C]UCB-J VT and distribution volume ratio in the anterior cingulate, frontal, and dorsolateral prefrontal cortices; the temporal, parietal and occipital lobes; and the hippocampus, thalamus, and amygdala. Symptom severity was assessed in the SCZ group using the Positive and Negative Syndrome Scale. RESULTS: We found no significant effects of group on [11C]UCB-J VT or distribution volume ratio in most regions of interest (effect sizes from d = 0.0-0.7, p > .05), with two exceptions: we found lower distribution volume ratio in the temporal lobe (d = 0.7, uncorrected p < .05) and lower VT/fp in the anterior cingulate cortex in patients (d = 0.7, uncorrected p < .05). The Positive and Negative Syndrome Scale total score was negatively associated with [11C]UCB-J VT in the hippocampus in the SCZ group (r = -0.48, p = .03). CONCLUSIONS: These findings indicate that large differences in synaptic terminal density are not present early in SCZ, although there may be more subtle effects. When taken together with previous evidence of lower [11C]UCB-J VT in patients with chronic illness, this may indicate synaptic density changes during the course of SCZ.

Reward processing in schizophrenia and its relation to Mu opioid receptor availability and negative symptoms: A [11C]-carfentanil PET and fMRI study.

BACKGROUND: Reward processing deficits are a core feature of schizophrenia and are thought to underlie negative symptoms. Pre-clinical evidence suggests that opioid neurotransmission is linked to reward processing. However, the contribution of Mu Opioid Receptor (MOR) signalling to the reward processing abnormalities in schizophrenia is unknown. Here, we examined the association between MOR availability and the neural processes underlying reward anticipation in patients with schizophrenia using multimodal neuroimaging. METHOD: 37 subjects (18 with Schizophrenia with moderate severity negative symptoms and 19 age and sex-matched healthy controls) underwent a functional MRI scan while performing the Monetary Incentive Delay (MID) task to measure the neural response to reward anticipation. Participants also had a [11C]-carfentanil PET scan to measure MOR availability. RESULTS: Reward anticipation was associated with increased neural activation in a widespread network of brain regions including the striatum. Patients with schizophrenia had both significantly lower MOR availability in the striatum as well as striatal hypoactivation during reward anticipation. However, there was no association between MOR availability and striatal neural activity during reward anticipation in either patient or controls (Pearson's Correlation, controls df = 17, r = 0.321, p = 0.18, patients df = 16, r = 0.295, p = 0.24). There was no association between anticipation-related neural activation and negative symptoms (r = -0.120, p = 0.14) or anhedonia severity (social r = -0.365, p = 0.14 physical r = -0.120, p = 0.63). CONCLUSIONS: Our data suggest reduced MOR availability in schizophrenia might not underlie striatal hypoactivation during reward anticipation in patients with established illness. Therefore, other mechanisms, such as dopamine dysfunction, warrant further investigation as treatment targets for this aspect of the disorder.

Neuroimaging in schizophrenia: an overview of findings and their implications for synaptic changes.

Over the last five decades, a large body of evidence has accrued for structural and metabolic brain alterations in schizophrenia. Here we provide an overview of these findings, focusing on measures that have traditionally been thought to reflect synaptic spine density or synaptic activity and that are relevant for understanding if there is lower synaptic density in the disorder. We conducted literature searches to identify meta-analyses or other relevant studies in patients with chronic or first-episode schizophrenia, or in people at high genetic or clinical risk for psychosis. We identified 18 meta-analyses including over 50,000 subjects in total, covering: structural MRI measures of gyrification index, grey matter volume, grey matter density and cortical thickness, neurite orientation dispersion and density imaging, PET imaging of regional glucose metabolism and magnetic resonance spectroscopy measures of N-acetylaspartate. We also review preclinical evidence on the relationship between ex vivo synaptic measures and structural MRI imaging, and PET imaging of synaptic protein 2A (SV2A). These studies show that schizophrenia is associated with lower grey matter volumes and cortical thickness, accelerated grey matter loss over time, abnormal gyrification patterns, and lower regional SV2A levels and metabolic markers in comparison to controls (effect sizes from ~ -0.11 to -1.0). Key regions affected include frontal, anterior cingulate and temporal cortices and the hippocampi. We identify several limitations for the interpretation of these findings in terms of understanding synaptic alterations. Nevertheless, taken with post-mortem findings, they suggest that schizophrenia is associated with lower synaptic density in some brain regions. However, there are several gaps in evidence, in particular whether SV2A findings generalise to other cohorts.

Integrating the Neurodevelopmental and Dopamine Hypotheses of Schizophrenia and the Role of Cortical Excitation-Inhibition Balance.

The neurodevelopmental and dopamine hypotheses are leading theories of the pathoetiology of schizophrenia, but they were developed in isolation. However, since they were originally proposed, there have been considerable advances in our understanding of the normal neurodevelopmental refinement of synapses and cortical excitation-inhibition (E/I) balance, as well as preclinical findings on the interrelationship between cortical and subcortical systems and new in vivo imaging and induced pluripotent stem cell evidence for lower synaptic density markers in patients with schizophrenia. Genetic advances show that schizophrenia is associated with variants linked to genes affecting GABA (gamma-aminobutyric acid) and glutamatergic signaling as well as neurodevelopmental processes. Moreover, in vivo studies on the effects of stress, particularly during later development, show that it leads to synaptic elimination. We review these lines of evidence as well as in vivo evidence for altered cortical E/I balance and dopaminergic dysfunction in schizophrenia. We discuss mechanisms through which frontal cortex circuitry may regulate striatal dopamine and consider how frontal E/I imbalance may cause dopaminergic dysregulation to result in psychotic symptoms. This integrated neurodevelopmental and dopamine hypothesis suggests that overpruning of synapses, potentially including glutamatergic inputs onto frontal cortical interneurons, disrupts the E/I balance and thus underlies cognitive and negative symptoms. It could also lead to disinhibition of excitatory projections from the frontal cortex and possibly other regions that regulate mesostriatal dopamine neurons, resulting in dopamine dysregulation and psychotic symptoms. Together, this explains a number of aspects of the epidemiology and clinical presentation of schizophrenia and identifies new targets for treatment and prevention.

Dopamine partial agonists and prodopaminergic drugs for schizophrenia: Systematic review and meta-analysis of randomized controlled trials.

Dopaminergic dysfunction is thought to be central to schizophrenia symptomatology. Previous meta-analyses of prodopaminergic drugs in schizophrenia have important limitations, and also did not include dopamine D2/D3 partial agonists. We investigated the effect of medications which increase dopamine signalling on schizophrenia symptoms by meta-analysing double-blind, placebo-controlled RCTs. 59 RCTs were included: 29 of prodopaminergic treatments, 30 of partial agonists. Partial agonists were significantly superior to placebo against positive (SMD=-0.33,p = 1.2 ×10-17), negative (SMD=-0.29,p = 2.2 × 10-31) and total symptoms (SMD =-0.39,p = 1.7 × 10-30) in schizophrenia. There were no significant differences between pooled pro-dopaminergic drugs and placebo in any symptom domain. In subgroup analysis of five studies where patients were selected for negative symptom severity, ar/modafinil was superior to placebo against negative symptoms (SMD=-0.34,p = 0.037). These data favour the clinical use of partial agonists for negative symptoms in schizophrenia, with clinically meaningful effect sizes. Our findings also suggest a benefit for ar/modafinil in patients with predominant negative symptoms. Future trials of other prodopaminergic therapies and dopamine partial agonists in patients with predominant negative symptoms are warranted.

The clinical significance of duration of untreated psychosis: an umbrella review and random-effects meta-analysis.

The idea that a longer duration of untreated psychosis (DUP) leads to poorer outcomes has contributed to extensive changes in mental health ser-vices worldwide and has attracted considerable research interest over the past 30 years. However, the strength of the evidence underlying this notion is unclear. To address this issue, we conducted an umbrella review of available meta-analyses and performed a random-effects meta-analysis of primary studies. MEDLINE, Web of Science, PsycINFO and EMBASE were searched from inception to September 3, 2020 to identify relevant meta-analyses of studies including patients with schizophrenia spectrum disorders, first-episode psychosis, or affective and non-affective psychosis. Thirteen meta-analyses were included, corresponding to 129 individual studies with a total sample size of 25,657 patients. We detected potential violations of statistical assumptions in some of these meta-analyses. We therefore conducted a new random-effects meta-analysis of primary studies. The association between DUP and each outcome was graded according to a standardized classification into convincing, highly suggestive, suggestive, weak, or non-significant. At first presentation, there was suggestive evidence for a relationship between longer DUP and more severe negative symptoms (beta=-0.07, p=3.6×10-5 ) and higher chance of previous self-harm (odds ratio, OR=1.89, p=1.1×10-5 ). At follow-up, there was highly suggestive evidence for a relationship between longer DUP and more severe positive symptoms (beta=-0.16, p=4.5×10-8 ), more severe negative symptoms (beta=-0.11, p=3.5×10-10 ) and lower chance of remission (OR=2.16, p=3.0×10-10 ), and suggestive evidence for a relationship between longer DUP and poorer overall functioning (beta=-0.11, p=2.2×10-6 ) and more severe global psychopathology (beta=-0.16, p=4.7×10-6 ). Results were unchanged when analysis was restricted to prospective studies. These effect sizes are clinically meaningful, with a DUP of four weeks predicting >20% more severe symptoms at follow-up relative to a DUP of one week. We conclude that DUP is an important prognostic factor at first presentation and predicts clinically relevant outcomes over the course of illness. We discuss conceptual issues in DUP research and methodological limitations of current evidence, and provide recommendations for future research.

Proton Magnetic Resonance Spectroscopy of N-acetyl Aspartate in Chronic Schizophrenia, First Episode of Psychosis and High-Risk of Psychosis: A Systematic Review and Meta-Analysis.

N-acetyl-aspartate (NAA) is a readily measured marker of neuronal metabolism. Previous analyses in schizophrenia have shown NAA levels are low in frontal, temporal and thalamic regions, but may be underpowered to detect effects in other regions, in high-risk states and in first episode psychosis. We searched for magnetic resonance spectroscopy studies comparing NAA in chronic schizophrenia, first episode psychosis and high risk of psychosis to controls. 182 studies were included and meta-analysed using a random-effects model for each region and illness stage. NAA levels were significantly lower than controls in the frontal lobe [Hedge's g = -0.36, p < 0.001], hippocampus [-0.52, p < 0.001], temporal lobe [-0.35, p = 0.031], thalamus [-0.32, p = 0.012] and parietal lobe [-0.25, p = 0.028] in chronic schizophrenia, and lower than controls in the frontal lobe [-0.26, p = 0.002], anterior cingulate cortex [-0.24, p = 0.016] and thalamus [-0.28, p = 0.028] in first episode psychosis. NAA was lower in high-risk of psychosis in the hippocampus [-0.20, p = 0.049]. In schizophrenia, NAA alterations appear to begin in hippocampus, frontal cortex and thalamus, and extend later to many other regions.

Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats.

Synaptic dysfunction is hypothesised to play a key role in schizophrenia pathogenesis, but this has not been tested directly in vivo.  Here, we investigated synaptic vesicle glycoprotein 2A (SV2A) levels and their relationship to symptoms and structural brain measures using [11C]UCB-J positron emission tomography in 18 patients with schizophrenia and 18 controls. We found significant group and group-by-region interaction effects on volume of distribution (VT). [11C]UCB-J VT was significantly lower in the frontal and anterior cingulate cortices in schizophrenia with large effect sizes (Cohen's d = 0.8-0.9), but there was no significant difference in the hippocampus. We also investigated the effects of antipsychotic drug administration on SV2A levels in Sprague-Dawley rats using western blotting, [3H]UCB-J autoradiography and immunostaining with confocal microscopy, finding no significant effects on any measure. These findings indicate that there are lower synaptic terminal protein levels in schizophrenia in vivo and that antipsychotic drug exposure is unlikely to account for them.