Pre-frontal parvalbumin interneurons in schizophrenia: a meta-analysis of post-mortem studies.

Parvalbumin interneurons are fast-spiking GABAergic neurons that provide inhibitory control of cortical and subcortical circuits and are thought to be a key locus of the pathophysiology underlying schizophrenia. In view of the contradictory results regarding the nature of parvalbumin post-mortem findings in schizophrenia, we conducted a quantitative meta-analysis of the data on parvalbumin cell density and parvalbumin mRNA levels in pre-frontal regions in the brains of patients with schizophrenia (n = 274) compared with healthy controls (n = 275). The results suggest that parvalbumin interneurons are reduced in density in the frontal cortex of patients with schizophrenia (Hedges' g = - 0.27; p = 0.03) and there is a non-significant reduction in parvalbumin mRNA levels (g = - 0.44; p = 0.12). However, certain methodological issues need to be considered in interpreting such results and are discussed in more detail. A meta-regression was conducted for post-mortem interval and year of publication as covariates which were both non-significant, except in the mRNA meta-analysis where post-mortem interval was found to be significant. Overall our findings provide tentative support for the hypothesis that the GABAergic system is deficient in schizophrenia and that parvalbumin-containing interneurons offer a potential target for treatment. However, further well-controlled studies that examine multiple regions and layers are warranted to determine whether parvalbumin alterations are region or layer specific and to test the robustness of the findings further

Neural and behavioral correlates of aberrant salience in individuals at risk for psychosis

Correction to the original article published in Schizophrenia Bulletin, Volume 39, Issue 6, 1 November 2013, Pages 1328–1336; https://doi.org/10.1093/schbul/sbs147

The Relationship Between Dopamine Synthesis Capacity and Release: Implications for Psychosis

Berry and colleagues report that presynaptic striatal dopamine synthesis capacity (measured with [¹⁸F]FMT PET) is not associated with methylphenidate-induced striatal dopamine release (indexed as a reduction in [¹¹C]raclopride non-displaceable binding-potential) in healthy participants (Berry et al, 2017). The authors should be commended for the quality of this study, in which 40 subjects each received three PET scans within a short time window. The results are pertinent to the interpretation of neuroimaging studies investigating the dopamine hypothesis of schizophrenia

The histamine system and cognitive function: an in vivo H3 receptor PET imaging study in healthy volunteers and patients with schizophrenia

BACKGROUND: The histamine-3 receptor (H3R) is an auto- and heteroreceptor that inhibits the release of histamine and other neurotransmitters. Post-mortem evidence has found altered H3R expression in patients with psychotic disorders, which may underlie cognitive impairment associated with schizophrenia (CIAS). AIMS: We used positron emission tomography (PET) imaging to compare brain uptake of an H3R selective tracer between patients with schizophrenia and matched controls (healthy individuals). Regions of interest included the dorsolateral prefrontal cortex (DLPFC) and striatum. We explored correlations between tracer uptake and symptoms, including cognitive domains. METHODS: A total of 12 patients and 12 matched controls were recruited to the study and were assessed with psychiatric and cognitive rating scales. They received a PET scan using the H3R-specific radioligand [11C]MK-8278 to determine H3R availability. RESULTS: There was no statistically significant difference in tracer uptake between patients and controls in the DLPFC (t19 = 0.79, p = 0.44) or striatum (t21 = 1.18, p = 0.25). An exploratory analysis found evidence for lower volume of distribution in the left cuneus (pFWE-corrected = 0.01). DLPFC tracer uptake was strongly correlated with cognition in controls (trail making test (TMT) A: r = 0.77, p = 0.006; TMT B: rho = 0.74, p = 0.01), but not in patients (TMT A: r = -0.18, p = 0.62; TMT B: rho = -0.06, p = 0.81). CONCLUSIONS: These findings indicate H3R in the DLPFC might play a role in executive function and this is disrupted in schizophrenia in the absence of major alterations in H3R availability as assessed using a selective radiotracer for H3R. This provides further evidence for the role of H3R in CIAS

Salience Attribution and its Relationship to Cannabis-Induced Psychotic Symptoms

BACKGROUND: Cannabis is a widely used drug associated with increased risk for psychosis. The dopamine hypothesis of psychosis postulates that altered salience processing leads to psychosis. We therefore tested the hypothesis that cannabis users exhibit aberrant salience and explored the relationship between aberrant salience and dopamine synthesis capacity. METHODS: We tested 17 cannabis users and 17 age- and sex-matched non-user controls using the Salience Attribution Test (SAT), a probabilistic reward-learning task. Within users, cannabis-induced psychotic symptoms were measured with the Psychotomimetic States Inventory (PSI). Dopamine synthesis capacity, indexed as the influx rate constant Kicer, was measured in 10 users and 6 controls with 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine positron emission tomography. RESULTS: There was no significant difference in aberrant salience between the groups (F1,32 = 1.12, p=.30 [implicit]; F1,32=1.09, p=.30 [explicit]). Within users there was a significant positive relationship between cannabis-induced psychotic symptom severity and explicit aberrant salience scores (r=.61, p=.04) and there was a significant association between cannabis dependency/abuse status and high implicit aberrant salience scores (F1,15= 5.8, p=.03). Within controls, implicit aberrant salience was inversely correlated with whole striatal dopamine synthesis capacity (r=-.91, p=.01), whereas this relationship was non-significant within users (difference between correlations: Z=-2.05, p=.04). CONCLUSIONS: Aberrant salience is positively associated with cannabis-induced psychotic symptom severity, but is not seen in cannabis users overall. This is consistent with the hypothesis that the link between cannabis use and psychosis involves alterations in salience processing. Longitudinal studies are needed to determine whether these cognitive abnormalities are pre-existing or caused by long-term cannabis use

Chronic psychosocial stressors are associated with alterations in salience processing and corticostriatal connectivity

Psychosocial stressors including childhood adversity, migration, and living in an urban environment, have been associated with several psychiatric disorders, including psychotic disorders. The neural and psychological mechanisms mediating this relationship remain unclear. In parallel, alterations in corticostriatal connectivity and abnormalities in the processing of salience, are seen in psychotic disorders. Aberrant functioning of these mechanisms secondary to chronic stress exposure, could help explain how common environmental exposures are associated with a diverse range of symptoms. In the current study, we recruited two groups of adults, one with a high degree of exposure to chronic psychosocial stressors (the exposed group, n = 20), and one with minimal exposure (the unexposed group, n = 22). All participants underwent a resting state MRI scan, completed the Aberrant Salience Inventory, and performed a behavioural task - the Salience Attribution Test (SAT). The exposed group showed reduced explicit adaptive salience scores (cohen's d = 0.69, p = 0.03) and increased aberrant salience inventory scores (d = 0.65, p = 0.04). The exposed group also showed increased corticostriatal connectivity between the ventral striatum and brain regions previously implicated in salience processing. Corticostriatal connectivity in these regions negatively correlated with SAT explicit adaptive salience (r = -0.48, p = 0.001), and positively correlated with aberrant salience inventory scores (r = 0.42, p = 0.006). Furthermore, in a mediation analysis there was tentative evidence that differences in striato-cortical connectivity mediated the group differences in salience scores

Striatal dopamine D₂/₃ receptors in medication-naïve schizophrenia: an [¹²³I] IBZM SPECT study

BACKGROUND: The hyper-function of the striatal dopamine system has been suggested to underlie key pathophysiological mechanisms in schizophrenia. Moreover, patients have been observed to present a significant elevation of dopamine receptor availability compared to healthy controls. Although it is difficult to measure dopamine levels directly in humans, neurochemical imaging techniques such as single-photon emission computed tomography (SPECT) provide indirect indices of in vivo dopamine synthesis and release, and putative synaptic levels. METHODS: We focused on the role of dopamine postsynaptic regulation using [123I] iodobenzamide (IBZM) SPECT. We compared D2/3 receptor availability between 53 healthy controls and 21 medication-naive patients with recent-onset schizophrenia. RESULT: The mean specific striatal binding showed no significant difference between patients and controls (estimated difference = 0.001; 95% CI -0.11 to 0.11; F = 0.00, df = 1, 69; p = 0.99). There was a highly significant effect of age whereby IBZM binding declined with advancing age [estimated change per decade of age = -0.01(binding ratio); 95% CI -0.01 to -0.004; F = 11.5, df = 1, 69; p = 0.001]. No significant correlations were found between the mean specific striatal binding and psychopathological or cognitive rating scores. CONCLUSIONS: Medication-naïve patients with recent-onset schizophrenia have similar D2/3 receptor availability to healthy controls. We suggest that, rather than focusing exclusively on postsynaptic receptors, future treatments should target the presynaptic control of dopamine synthesis and release

Inflammatory markers in depression: a meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls

Importance The magnitude and variability of cytokine alterations in depression are not clear. Objective To perform an up to date meta-analysis of mean differences of immune markers in depression, and to quantify and test for evidence of heterogeneity in immune markers in depression by conducting a meta-analysis of variability to ascertain whether only a sub-group of patients with depression show evidence of inflammation. Data Sources Studies that reported immune marker levels in peripheral blood in patients with depression and matched healthy controls in the MEDLINE database from inception to August 29th 2018 were examined. Study Selection Case-control studies that reported immune marker levels in peripheral blood in patients with depression and healthy controls were selected. Data Extraction and Synthesis Means and variances (SDs) were extracted for each measure to calculate effect sizes, which were combined using multivariate meta-analysis. Main Outcomes and Measures Hedges g was used to quantify mean differences. Relative variability of immune marker measurements in patients compared with control groups as indexed by the coefficient of variation ratio (CVR). Results A total of 107 studies that reported measurements from 5,166 patients with depression and 5,083 controls were included in the analyses. Levels of CRP (g=0.71; 95%CI: 0.50-0.92; p<0.0001); IL-3 (g=0.60; 95%CI: 0.31-0.89; p<0.0001); IL-6 (g=0.61; 95%CI: 0.39-0.82; p<0.0001); IL-12 (g=1.18; 95%CI: 0.74-1.62; p<0.0001); IL-18 (g=1.97; 95%CI: 1.00-2.95; p<0.0001); sIL-2R (g=0.71; 95%CI: 0.44-0.98; p<0.0001); and TNFα (g=0.54; 95%CI: 0.32-0.76; p<0.0001) were significantly higher in patients with depression. These findings were robust to a range of potential confounds and moderators. Mean-scaled variability, measured as CVR, was significantly lower in patients with depression for CRP (CVR=0.85; 95%CI: 0.75-0.98; p=0.02); IL-12 (CVR=0.61; 95%CI: 0.46-0.80; p<0.01); and sIL-2R (CVR=0.85; 95%CI: 0.73-0.99; p=0.04), while it was unchanged for IL-3, IL-6, IL-18, and TNF α. Conclusions and Relevance Acute depression is confirmed as a pro-inflammatory state. Some of the inflammatory markers elevated in depression, including CRP and IL-12, show reduced variability in patients with depression, therefore supporting greater homogeneity in terms of an inflammatory phenotype in depression. Some inflammatory marker elevations in depression do not appear due to an inflamed sub-group, but rather to a right shift of the immune marker distribution

Dopaminergic organization of striatum is linked to cortical activity and brain expression of genes associated with psychiatric illness

Dopamine signaling is constrained to discrete tracts yet has brain-wide effects on neural activity. The nature of this relationship between local dopamine signaling and brain-wide neuronal activity is not clearly defined and has relevance for neuropsychiatric illnesses where abnormalities of cortical activity and dopamine signaling coexist. Using simultaneous PET-MRI in healthy volunteers, we find strong evidence that patterns of striatal dopamine signaling and cortical blood flow (an index of local neural activity) contain shared information. This shared information links amphetamine-induced changes in gradients of striatal dopamine receptor availability to changes in brain-wide blood flow and is informed by spatial patterns of gene expression enriched for genes implicated in schizophrenia, bipolar disorder, and autism spectrum disorder. These results advance our knowledge of the relationship between cortical function and striatal dopamine, with relevance for understanding pathophysiology and treatment of diseases in which simultaneous aberrations of these systems exist

The Topography of Striatal Dopamine and Symptoms in Psychosis: An Integrative PET and MRI study

Background: Striatal dopamine dysfunction is thought to underlie symptoms in psychosis, yet it remains unclear how a single neurotransmitter could cause the diverse presentations that are observed clinically. One hypothesis is that the consequences of aberrant dopamine signalling vary depending on where within the striatum the dysfunction occurs. Positron emission tomography (PET) allows for the quantification of dopamine function across the striatum. In the current study we use a novel method to investigate the relationship between spatial variability in dopamine synthesis capacity and psychotic symptoms. Methods: We used a multimodal imaging approach combining 18F-DOPA PET and resting state MRI in 29 patients with first episode psychosis and 21 healthy controls. In each participant, resting state functional connectivity maps were used to quantify the functional connectivity of each striatal voxel to well-established cortical networks. Network-specific striatal dopamine synthesis capacity(Kicer) was then calculated for the resulting connectivity defined parcellations. Results: The connectivity defined parcellations generated Kicer values with equivalent reliability, and significantly greater orthogonality to standard anatomical parcellation methods. As a result, dopamine-symptom associations were significantly different from one another for different subdivisions, whereas no unique subdivision relationships were found when using an anatomical parcellation. In particular, dopamine function within striatal areas connected to the default mode network was strongly associated with negative symptoms(p<0.001). Conclusion: These findings suggest that individual differences in the topography of dopamine dysfunction within the striatum contribute to shaping psychotic symptomatology. Further validation of the novel approach in future studies is necessary