Highlights Contemporary animal models of psychosis propose that: • Elevated dopamine function is driven by altered MTL output. • Alterations in the hippocampal–midbrain–striatal circuit have a ...critical role. • Data from human studies are broadly consistent with predictions from animal models. • Animal models are informing the development of new treatments of psychosis.
Functional neuroimaging studies have suggested activation of midline frontoparietal brain regions to be at the core of self-related processes. However, although some studies reported involvement of ...the insula, little attention has been paid to this region as forming part of the "self"-network.
Using functional magnetic resonance imaging (fMRI), we aimed at replicating and extending previous studies by scanning subjects whilst reflecting upon their own personal qualities as compared to those of an acquaintance. A third condition with statements about general knowledge was used to control for attention, semantic processing and decision making processes. The results showed a significant effect of task in brain activity, consistent with previous findings, by which both person conditions recruited a common set of medial prefrontal and posterior regions, yet significant differences between self and other were found in the medial prefrontal cortex (MPFC) and the anterior cingulate cortex (ACC). Notably, significant neural activation in the left anterior insula was observed as uniquely associated with self-reflection.
The results provide further evidence for the specific recruitment of anterior MPFC and ACC regions for self-related processing, and highlight a role for the insula in self-reflection. As the insula is closely connected with ascending internal body signals, this may indicate that the accumulation of changes in affective states that might be implied in self-processing may contribute to our sense of self.
Preclinical and human studies suggest that hippocampal dysfunction is a key factor in the onset of psychosis. People at Clinical High Risk for psychosis (CHR-P) present with a clinical syndrome that ...can include social withdrawal and have a 20-35% risk of developing psychosis in the next 2 years. Recent research shows that resting hippocampal blood flow is altered in CHR-P individuals and predicts adverse clinical outcomes, such as non-remission/transition to frank psychosis. Previous work in healthy males indicates that a single dose of intranasal oxytocin has positive effects on social function and marked effects on resting hippocampal blood flow. The present study examined the effects of intranasal oxytocin on hippocampal blood flow in CHR-P individuals. In a double-blind, placebo-controlled, crossover design, 30 CHR-P males were studied using pseudo-continuous Arterial Spin Labelling on 2 occasions, once after 40IU intranasal oxytocin and once after placebo. The effects of oxytocin on left hippocampal blood flow were examined in a region-of-interest analysis of data acquired at 22-28 and at 30-36 minutes post-intranasal administration. Relative to placebo, administration of oxytocin was associated with increased hippocampal blood flow at both time points (p = .0056; p = .034), although the effect at the second did not survive adjustment for the effect of global blood flow. These data indicate that oxytocin can modulate hippocampal function in CHR-P individuals and therefore merits further investigation as a candidate novel treatment for this group.
Preclinical models of psychosis propose that hippocampal glutamatergic neuron hyperactivity drives increased striatal dopaminergic activity, which underlies the development of psychotic symptoms. The ...aim of this study was to examine the relationship between hippocampal glutamate and subcortical dopaminergic function in people at clinical high risk for psychosis, and to assess the association with the development of psychotic symptoms.
H-MRS was used to measure hippocampal glutamate concentrations, and
F-DOPA PET was used to measure dopamine synthesis capacity in 70 subjects (51 people at clinical high risk for psychosis and 19 healthy controls). Clinical assessments were undertaken at baseline and follow-up (median 15 months). Striatal dopamine synthesis capacity predicted the worsening of psychotic symptoms at follow-up (r = 0.35; p < 0.05), but not transition to a psychotic disorder (p = 0.22), and was not significantly related to hippocampal glutamate concentration (p = 0.13). There were no differences in either glutamate (p = 0.5) or dopamine (p = 0.5) measures in the total patient group relative to controls. Striatal dopamine synthesis capacity at presentation predicts the subsequent worsening of sub-clinical total and psychotic symptoms, consistent with a role for dopamine in the development of psychotic symptoms, but is not strongly linked to hippocampal glutamate concentrations.
Preclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multimodal neuroimaging to ...examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high risk (CHR) for psychosis and investigated its association with subsequent clinical and functional outcomes. Ninety-five participants (67 CHR and 28 healthy controls) underwent arterial spin labeling MRI and
F-DOPA PET imaging at baseline. CHR participants were followed up for a median of 15 months to determine functional outcomes with the global assessment of function (GAF) scale and clinical outcomes using the comprehensive assessment of at-risk mental states (CAARMS). CHR participants with poor functional outcomes (follow-up GAF < 65, n = 25) showed higher rCBF in the right hippocampus compared to CHRs with good functional outcomes (GAF ≥ 65, n = 25) (p
= 0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (p
= 0.035); the association was negative in CHR with poor outcomes (p
= 0.012), but non-significant in CHR with good outcomes. Furthermore, the correlation between right hippocampal rCBF and striatal dopamine function predicted a longitudinal increase in the severity of positive psychotic symptoms within the total CHR group (p = 0.041). There were no differences in rCBF, dopamine, or their associations in the total CHR group relative to controls. These findings indicate that altered interactions between the hippocampus and the subcortical dopamine system are implicated in the pathophysiology of adverse outcomes in the CHR state.
The etymology of schizophrenia implies poor functional integration of sensory, cognitive and affective processes. Multisensory integration (MSI) is a spontaneous perceptual-cognitive process by which ...relevant information from multiple sensory modalities is extracted to generate a holistic experience. Deficits in MSI may hinder prompt and appropriate behavioural responses in a complex and transient environment. Despite extensive investigation of sensory, cognitive and affective processing in patients with schizophrenia, little is known about how MSI is affected in the illness. We systemically searched the PubMed electronic database and reviewed twenty-nine behavioural and neuroimaging studies examining MSI in patients with schizophrenia. The available evidence indicates impaired MSI for non-emotional stimuli in schizophrenia, especially for linguistic information. There is also evidence for altered MSI for emotional stimuli, although findings are inconsistent and may be modality-specific. Brain functional alterations in the superior temporal cortex and inferior frontal cortex appear to underlie the deficits in both non-emotional and emotional MSI. The limitations of the experimental paradigms used and directions for future research are also discussed.
Voxel-based morphometry (VBM) studies demonstrate grey matter volume (GMV) deficits in schizophrenia. This method is also applied for detecting associations between specific psychotic symptoms and ...brain structure, such as auditory verbal hallucinations (AVHs). However, due to differing methodological approaches, the available findings are inconsistent and difficult to integrate.
We used a novel voxel-based meta-analytical method to provide a robust quantitative review of neuroanatomical abnormalities specifically associated with the hallucinatory phenomenon in the schizophrenic brain. We reviewed all VBM studies of AVHs in schizophrenia published until July 2011 (n = 9). A total of 438 patients with a diagnosis of schizophrenia were included (307 with AVHs). Using a random-effects parametric voxel-based meta-analysis, coordinates of 83 foci reported as significant in the source studies were extracted and computed to estimate the brain locations most consistently associated with AVHs.
Severity of AVHs was significantly associated with GMV reductions in the left (p = .022) and marginally with the right (p = .062) superior temporal gyri (STGs, including Heschl’s gyri) across studies examining correlations with AVHs severity in patients (n = 8). Analysis of studies categorically comparing patients with and without AVHs did not reveal any significant findings, possibly due to the small number of studies using this approach (n = 3).
This meta-analysis implicates bilateral STG (including Heschl’s gyri) as key areas of structural pathology in AVHs in schizophrenia. These findings support a model postulating that aberrations within neural systems involved at different levels of language processing are critical to AVHs in schizophrenia.
Abstract
Hippocampal hyperactivity driven by GABAergic interneuron deficits and NMDA receptor hypofunction is associated with the hyperdopaminergic state often observed in schizophrenia. Furthermore, ...previous research in the methylazoxymethanol acetate (MAM) rat model has demonstrated that repeated peripubertal diazepam administration can prevent the emergence of adult hippocampal hyperactivity, dopamine-system hyperactivity, and associated psychosis-relevant behaviors. Here, we sought to characterize hippocampal GABA
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and NMDA receptors in MAM-treated rats and to elucidate the receptor mechanisms underlying the promising effects of peripubertal diazepam exposure. Quantitative receptor autoradiography was used to measure receptor density in the dorsal hippocampus CA1, ventral hippocampus CA1, and ventral subiculum. Specifically,
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H-Ro15-4513 was used to quantify the density of α5GABA
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receptors (α5GABA
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R),
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H-flumazenil to quantify α1-3;5GABA
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R, and
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H-MK801 to quantify NMDA receptors. MAM rats exhibited anxiety and schizophrenia-relevant behaviors as measured by elevated plus maze and amphetamine-induced hyperlocomotion (AIH), although diazepam only partially rescued these behaviors. α5GABA
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R density was reduced in MAM-treated rats in all hippocampal sub-regions, and negatively correlated with AIH. Ventral hippocampus CA1 α5GABA
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R density was positively correlated with anxiety-like behavior. Dorsal hippocampus CA1 NMDA receptor density was increased in MAM-treated rats, and positively correlated with AIH.
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H-flumazenil revealed no significant effects. Finally, we found no significant effect of diazepam treatment on receptor densities, potentially related to the only partial rescue of schizophrenia-relevant phenotypes. Overall, our findings provide first evidence of α5GABA
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R and NMDA receptor abnormalities in the MAM model, suggesting that more selective pharmacological agents may become a novel therapeutic mechanism in schizophrenia.
Preclinical rodent models suggest that psychosis involves alterations in the activity and glutamatergic function in the hippocampus, driving dopamine activity through projections to the striatum. The ...extent to which this model applies to the onset of psychosis in clinical subjects is unclear. We assessed whether interactions between hippocampal glutamatergic function and activity/striatal connectivity are associated with adverse clinical outcomes in people at clinical high-risk (CHR) for psychosis. We measured functional Magnetic Resonance Imaging of hippocampal activation/connectivity, and
H-Magnetic Resonance Spectroscopy of hippocampal glutamatergic metabolites in 75 CHR participants and 31 healthy volunteers. At follow-up, 12 CHR participants had transitioned to psychosis and 63 had not. Within the clinical high-risk cohort, at follow-up, 35 and 17 participants had a poor or a good functional outcome, respectively. The onset of psychosis (p
= 0.003, t = 4.4, z = 4.19) and a poor functional outcome (p
< 0.001, t = 5.52, z = 4.81 and p
< 0.001, t = 5.25, z = 4.62) were associated with a negative correlation between the hippocampal activation and hippocampal Glx concentration at baseline. In addition, there was a negative association between hippocampal Glx concentration and hippocampo-striatal connectivity (p
= 0.016, t = 3.73, z = 3.39, p
= 0.014, t = 3.78, z = 3.42, p
= 0.011, t = 4.45, z = 3.91, p
= 0.003, t = 4.92, z = 4.23) in the total CHR sample, not seen in healthy volunteers. As predicted by preclinical models, adverse clinical outcomes in people at risk for psychosis are associated with altered interactions between hippocampal activity and glutamatergic function.
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