Abnormal Function in Dentate Nuclei Precedes the Onset of Psychosis: A Resting-State fMRI Study in High-Risk Individuals

ObjectiveThe cerebellum serves a wide range of functions and is suggested to be composed of discrete regions dedicated to unique functions. We recently developed a new parcellation of the dentate nuclei (DN), the major output nuclei of the cerebellum, which optimally divides the structure into 3 functional territories that contribute uniquely to default-mode, motor-salience, and visual processing networks as indexed by resting-state functional connectivity (RsFc). Here we test for the first time whether RsFc differences in the DN, precede the onset of psychosis in individuals at risk of developing schizophrenia.MethodsWe used the magnetic resonance imaging (MRI) dataset from the Shanghai At Risk for Psychosis study that included subjects at high risk to develop schizophrenia (N = 144), with longitudinal follow-up to determine which subjects developed a psychotic episode within 1 year of their functional magnetic resonance imaging (fMRI) scan (converters N = 23). Analysis used the 3 functional parcels (default-mode, salience-motor, and visual territory) from the DN as seed regions of interest for whole-brain RsFc analysis.ResultsRsFc analysis revealed abnormalities at baseline in high-risk individuals who developed psychosis, compared to high-risk individuals who did not develop psychosis. The nature of the observed abnormalities was found to be anatomically specific such that abnormal RsFc was localized predominantly in cerebral cortical networks that matched the 3 functional territories of the DN that were evaluated.ConclusionsWe show for the first time that abnormal RsFc of the DN may precede the onset of psychosis. This new evidence highlights the role of the cerebellum as a potential target for psychosis prediction and prevention.     

Dopaminergic Function in the Psychosis Spectrum: An [18F]-DOPA Imaging Study in Healthy Individuals With Auditory Hallucinations

Background: The psychosis phenotype appears to exist in the population as a continuum, but it is not clear if subclinical psychotic symptoms and psychotic disorders share the same neurobiology. We investigated whether the dopaminergic dysfunction seen in psychotic disorders is also present in healthy, well-functioning people with hallucinations. Methods: We compared dopamine synthesis capacity (using 6-[¹⁸F]fluoro-L-DOPA [[¹⁸F]-DOPA] positron emission tomography imaging) in 16 healthy individuals with frequent persistent auditory verbal hallucinations (hallucinating group) with that in 16 matched controls. Results: There was no significant difference in dopamine synthesis capacity in the striatum, or its functional subdivisions, between groups and no relationship between subclinical psychotic symptom severity or schizotypal traits and dopamine synthesis capacity in the hallucinating group. Conclusions: Altered dopamine synthesis capacity is unlikely to underlie subclinical hallucinations, suggesting that although there may be a phenomenological psychosis continuum, there are distinctions at the neurobiological level.     

Lifestyles and Cardiovascular Risk in Individuals With Functional Psychoses

PURPOSE.  This study aims to examine known determinants of cardiovascular risk in Italian patients with functional psychoses.
DESIGN AND METHODS.  A cross-sectional study design was used to examine cardiovascular risk factors and lifestyle behaviors of 123 individuals with functional psychosis and compare clinically relevant data with those of the general Italian population.
FINDINGS.  A significant proportion of patients manifested frank hypertension (6.9%), hypercholesterolemia (20.5%), diabetes (6.5%), or a body mass index of more than 30 (20.3%). Many also smoked (63.0%) or ingested alcohol every day (26.0%), did not eat fruits or vegetables (8.0%), or did not exercise on a daily basis (34.0%).
PRACTICE IMPLICATIONS.  Patients with psychosis manifest significant rates of potentially reversible risk factors for cardiovascular diseases. Mental health nurses should advocate for and implement well-resourced counseling programs to reduce the prevalence of smoking and metabolic syndrome in mental health populations.     

Transition to Psychosis Associated With Prefrontal and Subcortical Dysfunction in Ultra High-Risk Individuals

Background: People at ultra high risk (UHR) of psychosis have an elevated risk of developing a psychotic disorder, but it is difficult to predict which individuals will make a transition to frank illness. We investigated whether functional magnetic resonance imaging (fMRI) in conjunction with a phonological fluency task at presentation could distinguish subjects who subsequently developed psychosis from those who did not. Methods: Sixty-five subjects (41 with an UHR and 24 healthy controls) were assessed at clinical presentation using fMRI, in conjunction with a verbal fluency task. [18F]-DOPA positron emission tomography (PET) data were also available in a subgroup of 21 UHR and 14 healthy controls subjects. UHR subjects were followed clinically for at least 2 years. Results: Compared with UHR subjects who did not become psychotic, UHR subjects who subsequently developed psychosis showed increased activation in bilateral prefrontal cortex (PFC), brainstem (midbrain/basilar pons), the left hippocampus, and greater midbrain-PFC connectivity. Furthermore, exploratory analysis of [18F]-DOPA PET data showed that transition to psychosis was associated with elevated dopaminergic function in the brainstem region. Conclusions: In people at high risk of psychosis, increased activation in a network of cortical and subcortical regions may predict the subsequent onset of illness. Functional neuroimaging, in conjunction with clinical assessment and other investigations, may facilitate the prediction of outcome in subjects who are vulnerable to psychosis.     

Disruption of Conscious Access in Psychosis Is Associated with Altered Structural Brain Connectivity

According to global neuronal workspace (GNW) theory, conscious access relies on long-distance cerebral connectivity to allow a global neuronal ignition coding for conscious content. In patients with schizophrenia and bipolar disorder, both alterations in cerebral connectivity and an increased threshold for conscious perception have been reported. The implications of abnormal structural connectivity for disrupted conscious access and the relationship between these two deficits and psychopathology remain unclear. The aim of this study was to determine the extent to which structural connectivity is correlated with consciousness threshold, particularly in psychosis. We used a visual masking paradigm to measure consciousness threshold, and diffusion MRI tractography to assess structural connectivity in 97 humans of either sex with varying degrees of psychosis: healthy control subjects (n = 46), schizophrenia patients (n = 25), and bipolar disorder patients with (n = 17) and without (n = 9) a history of psychosis. Patients with psychosis (schizophrenia and bipolar disorder with psychotic features) had an elevated masking threshold compared with control subjects and bipolar disorder patients without psychotic features. Masking threshold correlated negatively with the mean general fractional anisotropy of white matter tracts exclusively within the GNW network (inferior frontal-occipital fasciculus, cingulum, and corpus callosum). Mediation analysis demonstrated that alterations in long-distance connectivity were associated with an increased masking threshold, which in turn was linked to psychotic symptoms. Our findings support the hypothesis that long-distance structural connectivity within the GNW plays a crucial role in conscious access, and that conscious access may mediate the association between impaired structural connectivity and psychosis.     

Functional imaging of emotional memory in bipolar disorder and schizophrenia

Objectives: Although in current diagnostic criteria there exists a distinction between bipolar disorder and schizophrenia, many patients manifest features of both disorders, and it is unclear which aspects, if any, confer diagnostic specificity. In the present study, we investigate whether there are differences in medial temporal lobe (MTL) activation in bipolar disorder and schizophrenia. We also investigate associations between activation levels and symptom severity across the disorders. Methods: Functional magnetic resonance imaging scans were conducted on 14 healthy controls, 14 patients with bipolar disorder, and 15 patients with schizophrenia undergoing an emotional memory paradigm. Results: All groups demonstrated the expected pattern of behavioural responses during encoding and retrieval, and there were no significant group differences in performance. Robust MTL activation was seen in all three groups during viewing of emotional scenes, which correlated significantly with recognition memory for emotional stimuli. The bipolar group demonstrated relatively greater increases in activation for emotional versus neutral scenes in the left hippocampus than both controls and patients with schizophrenia. There was a significant positive correlation between mania scores and activation in the anterior cingulate, and a significant negative correlation between depression scores and activation in the dorsolateral prefrontal cortex. Conclusion: These results provide evidence that there are distinct patterns of activation in the MTL during an emotional memory task in bipolar disorder and schizophrenia. They also demonstrate that different mood states are associated with different neurobiological responses to emotion across the patient groups.     

Alterations in White Matter Evident Before the Onset of Psychosis

Background

Psychotic disorders are associated with widespread reductions in white matter (WM) integrity. However, the stage at which these abnormalities first appear and whether they are correlates of psychotic illness, as opposed to an increased vulnerability to psychosis, is unclear. We addressed these issues by using diffusion tensor imaging (DTI) to study subjects at ultra high risk (UHR) of psychosis before and after the onset of illness.

Methods

Thirty-two individuals at UHR for psychosis, 32 controls, and 15 patients with first-episode schizophrenia were studied using DTI. The UHR subjects and controls were re-scanned after 28 months. During this period, 8 UHR subjects had developed schizophrenia. Between-group differences in fractional anisotropy (FA) and diffusivity were evaluated cross sectionally and longitudinally using a nonparametric voxel-based analysis.

Results

At baseline, WM DTI properties were significantly different between the 3 groups (P < .001). Relative to controls, first-episode patients showed widespread reductions in FA and increases in diffusivity. DTI indices in the UHR group were intermediate relative to those in the other 2 groups. Longitudinal analysis revealed a significant group by time interaction in the left frontal WM (P < .001). In this region, there was a progressive reduction in FA in UHR subjects who developed psychosis that was not evident in UHR subjects who did not make a transition.

Conclusions

People at UHR for psychosis show alterations in WM qualitatively similar to, but less severe than, those in patients with schizophrenia. The onset of schizophrenia may be associated with a progressive reduction in the integrity of the frontal WM.     

A review of aripiprazole in the treatment of patients with schizophrenia or bipolar I disorder

Aripiprazole has been approved by regulatory agencies for the treatment of schizophrenia and bipolar I disorder. Although it is a dopamine partial agonist, it also has substantial binding affinity for the serotonin 5HT2A receptor. Several double-blind randomized clinical trials have established the efficacy and tolerability of aripiprazole within the dose range of 10–30 mg/day for schizophrenia, and 15–30 mg/day for manic or mixed states associated with bipolar I disorder. Relatively few comparative trials with other second-generation antipsychotics have been published for schizophrenia, with none available for bipolar disorder. The evidence so far suggests that in terms of efficacy for schizophrenia, aripiprazole is superior to placebo and haloperidol (long term), similar to perphenazine and risperidone, and inferior to olanzapine. Its tolerability profile in patients with schizophrenia appears superior to haloperidol, perphenazine, risperidone, and olanzapine. Efficacy in treating manic or mixed states was established in placebo-controlled trials. Among some patients with bipolar disorder, akathisia and gastrointestinal (GI) complaints can emerge at the start of treatment; however, the GI symptoms were time-limited in many instances. Appropriate dosing may also be important in individualizing therapy to improve tolerability, with lower starting doses becoming more important when adding to, or switching from, another antipsychotic. Aripiprazole appears to have a low propensity for weight gain, a favorable metabolic profile, and no association with hyperprolactinemia.     

Remote Ecological Momentary Testing of Learning and Memory in Adults With Serious Mental Illness

Smartphone-based ecological mobile cognitive tests (EMCTs) can measure cognitive abilities in the real world, complementing traditional neuropsychological assessments. We evaluated the validity of an EMCT of recognition memory designed for use with people with serious mental illness, as well as relevant contextual influences on performance. Participants with schizophrenia (SZ), schizoaffective disorder, and bipolar disorder (BD) completed in-lab assessments of memory (Hopkins Verbal Learning Test, HVLT), other cognitive abilities, functional capacity, and symptoms, followed by 30 days of EMCTs during which they completed our Mobile Variable Difficulty List Memory Test (VLMT) once every other day (3 trials per session). List length on the VLMT altered between 6, 12, and 18 items. On average, participants completed 75.3% of EMCTs. Overall performance on VLMT 12 and 18 items was positively correlated with HVLT (ρ = 0.52, P < .001). People with BD performed better on the VLMT than people with SZ. Intraindividual variability on the VLMT was more specifically associated with HVLT than nonmemory tests and not associated with symptoms. Performance during experienced distraction, low effort, and out of the home location was reduced yet still correlated with the in-lab HVLT. The VLMT converged with in-lab memory assessment, demonstrating variability within person and by different contexts. Ambulatory cognitive testing on participants’ personal mobile devices offers more a cost-effective and “ecologically valid” measurement of real-world cognitive performance.     

fMRI evidence of aberrant neural adaptation for objects in schizophrenia and bipolar disorder

Functional magnetic resonance imaging (fMRI) adaptation (also known as fMRI repetition suppression) has been widely used to characterize stimulus selectivity in vivo, a fundamental feature of neuronal processing in the brain. We investigated whether SZ patients and BD patients show aberrant fMRI adaptation for object perception. About 52 SZ patients, 55 BD patients, and 53 community controls completed an object discrimination task with three conditions: the same object presented twice, two exemplars from the same category, and two exemplars from different categories. We also administered two functional localizer tasks. A region of interest analysis was employed to evaluate a priori hypotheses about the lateral occipital complex (LOC) and early visual cortex (EVC). An exploratory whole brain analysis was also conducted. In the LOC and EVC, controls showed the expected reduced fMRI responses to repeated presentation of the same objects compared with different objects (i.e., fMRI adaptation for objects, p < .001). SZ patients showed an adaptation effect that was significantly smaller compared with controls. BD patients showed a lack of fMRI adaptation. The whole brain analyses showed enhanced fMRI responses to repeated presentation of the same objects only in BD patients in several brain regions including anterior cingulate cortex. This study was the first to employ fMRI adaptation for objects in SZ and BD. The current findings provide empirical evidence of aberrant fMRI adaptation in the visual cortex in SZ and BD, but in distinctly different ways.     

Affective Instability Prior to and after Thoughts about Self-Injury in Individuals With and At-Risk of Psychosis: A Mobile Phone Based Study

It has been proposed that affective instability may be associated with thoughts about self-injury. The aim of this study was to test the hypotheses that instability in feelings of depression, but not anxiety, guilt, or hostility, would predict greater concurrent and subsequent thoughts about self-injury. Thirty-six individuals with psychosis completed questions on touch-screen mobile phones at semi-random times each day for one week. The instability of depression predicted greater concurrent and subsequent levels of thoughts about self-injury, even when controlling for depression level. Conversely, self-injurious thoughts predicted more stable depression. The instability of guilt, anxiety, and hostility did not significantly predict levels of thoughts about self-injury. Results indicate that a variable depressive state may trigger the onset of thoughts about self-injury, which increases the risk of its subsequent recurrence. The onset of self-injurious thoughts may, however, have a stabilizing effect on subsequent depression.