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Social-cognitive deficits contribute to poor functional outcomes in early psychosis; however, no effective pharmacological treatments exist for these problems. This study was the first to investigate the efficacy of an extended treatment of oxytocin nasal spray combined with social cognition training (SCT) to improve social cognition, clinical symptoms, and social functioning in early psychosis. In a double-blind, randomized, placebo-controlled, between-subjects trial, 52 individuals (aged 16–35 years) diagnosed with an early psychosis schizophrenia-spectrum illness were recruited. Participants received oxytocin (24 International Units) or placebo nasal spray twice-daily for 6 weeks, combined with group SCT (2 × 1 hour weekly sessions for 6 weeks). An additional dose of oxytocin was administered before each weekly session. Assessments were conducted at baseline, post-treatment, and at 3-month follow-up. Primary outcomes included the Reading the Mind in the Eyes Test, the Scale for the Assessment of Positive and Negative Symptoms, and the Social Functioning Scale. Secondary outcomes included self-report and behavioral assessments of social cognition, symptom severity, and social functioning. Results showed that on all primary and secondary outcomes, there was no benefit of oxytocin nasal spray treatment in comparison to placebo. Exploratory post hoc analysis suggested that increased use of nasal spray was, however, associated with reductions in negative symptoms in the oxytocin condition only. This study represents the first evaluation of oxytocin treatment for early psychosis. Although results suggest no benefit of oxytocin treatment, results also highlight an urgent need to consider nasal spray delivery and dose-related variables for future clinical trials.

Recent neuroimaging evidence has led to the proposal that freezing of gait in Parkinson's disease is due to dysfunctional interactions between frontoparietal cortical regions and subcortical structures, such as the striatum. However, to date, no study has employed task-based functional connectivity analyses to explore this hypothesis. In this study, we used a data-driven multivariate approach to explore the impaired communication between distributed neuronal networks in 10 patients with Parkinson's disease and freezing of gait, and 10 matched patients with no clinical history of freezing behaviour. Patients performed a virtual reality gait task on two separate occasions (once ON and once OFF their regular dopaminergic medication) while functional magnetic resonance imaging data were collected. Group-level independent component analysis was used to extract the subject-specific time courses associated with five well-known neuronal networks: the motor network, the right- and left cognitive control networks, the ventral attention network and the basal ganglia network. We subsequently analysed both the activation and connectivity of these neuronal networks between the two groups with respect to dopaminergic state and cognitive load while performing the virtual reality gait task. During task performance, all patients used the left cognitive control network and the ventral attention network and in addition, showed increased connectivity between the bilateral cognitive control networks. However, patients with freezing demonstrated functional decoupling between the basal ganglia network and the cognitive control network in each hemisphere. This decoupling was also associated with paroxysmal motor arrests. These results support the hypothesis that freezing behaviour in Parkinson's disease is because of impaired communication between complimentary yet competing neural networks.

Freezing of gait is a devastating symptom of advanced Parkinson's disease yet the neural correlates of this phenomenon remain poorly understood. In this study, severity of freezing of gait was assessed in 18 patients with Parkinson's disease on a series of timed 'up and go' tasks, in which all patients suffered from episodes of clinical freezing of gait. The same patients also underwent functional magnetic resonance imaging with a virtual reality gait paradigm, performance on which has recently been shown to correlate with actual episodes of freezing of gait. Statistical parametric maps were created that compared the blood oxygen level-dependent response associated with paroxysmal motor arrests (freezing) to periods of normal motor output. The results of a random effects analysis revealed that these events were associated with a decreased blood oxygen level-dependent response in sensorimotor regions and an increased response within frontoparietal cortical regions. These signal changes were inversely correlated with the severity of clinical freezing of gait. Motor arrests were also associated with decreased blood oxygen level-dependent signal bilaterally in the head of caudate nucleus, the thalamus and the globus pallidus internus. Utilizing a mixed event-related/block design, we found that the decreased blood oxygen level-dependent response in the globus pallidus and the subthalamic nucleus persisted even after controlling for the effects of cognitive load, a finding which supports the notion that paroxysmal increases in basal ganglia outflow are associated with the freezing phenomenon. This method also revealed a decrease in the blood oxygen level-dependent response within the mesencephalic locomotor region during motor arrests, the magnitude of which was positively correlated with the severity of clinical freezing of gait. These results provide novel insights into the pathophysiology underlying freezing of gait and lend support to models of freezing of gait that implicate dysfunction across coordinated neural networks.

Epidemiological data link adolescent cannabis use to psychosis and schizophrenia, but its contribution to schizophrenia neuropathology remains controversial. First-episode schizophrenia (FES) patients show regional cerebral grey- and white-matter changes as well as a distinct pattern of regional grey-matter loss in the vermis of the cerebellum. The cerebellum possesses a high density of cannabinoid type 1 receptors involved in the neuronal diversification of the developing brain. Cannabis abuse may interfere with this process during adolescent brain maturation leading to 'schizophrenia-like' cerebellar pathology. Magnetic resonance imaging and cortical pattern matching techniques were used to investigate cerebellar grey and white matter in FES patients with and without a history of cannabis use and non-psychiatric cannabis users. In the latter group we found lifetime dose-dependent regional reduction of grey matter in the right cerebellar lobules and a tendency for more profound grey-matter reduction in lobule III with younger age at onset of cannabis use. The overall regional grey-matter differences in cannabis users were within the normal variability of grey-matter distribution. By contrast, FES subjects had lower total cerebellar grey-matter:total cerebellar volume ratio and marked grey-matter loss in the vermis, pedunculi, flocculi and lobules compared to pair-wise matched healthy control subjects. This pattern and degree of grey-matter loss did not differ from age-matched FES subjects with comorbid cannabis use. Our findings indicate small dose-dependent effects of juvenile cannabis use on cerebellar neuropathology but no evidence of an additional effect of cannabis use on FES cerebellar grey-matter pathology.

Reduced mismatch negativity (MMN) in response to auditory change is a well-established finding in schizophrenia and has been shown to be correlated with impaired daily functioning, rather than with hallmark signs and symptoms of the disorder. In this study, we investigated (1) whether the relationship between reduced MMN and impaired daily functioning is mediated by cortical volume loss in temporal and frontal brain regions in schizophrenia and (2) whether this relationship varies with the type of auditory deviant generating MMN. MMN in response to duration, frequency, and intensity deviants was recorded from 18 schizophrenia subjects and 18 pairwise age- and gender-matched healthy subjects. Patients’ levels of global functioning were rated on the Social and Occupational Functioning Assessment Scale. High-resolution structural magnetic resonance scans were acquired to generate average cerebral cortex and temporal lobe models using cortical pattern matching. This technique allows accurate statistical comparison and averaging of cortical measures across subjects, despite wide variations in gyral patterns. MMN amplitude was reduced in schizophrenia patients and correlated with their impaired day-to-day function level. Only in patients, bilateral gray matter reduction in Heschl's gyrus, as well as motor and executive regions of the frontal cortex, correlated with reduced MMN amplitude in response to frequency deviants, while reduced gray matter in right Heschl's gyrus also correlated with reduced MMN to duration deviants. Our findings further support the importance of MMN reduction in schizophrenia by linking frontotemporal cerebral gray matter pathology to an automatically generated event-related potential index of daily functioning.

Deluded people differ from nondeluded controls on attributional style questionnaires and probabilistic-reasoning and theory-of-mind (ToM) tasks. No study to date has examined the relations between these 3 reasoning anomalies in the same individuals so as to evaluate their functional independence and potentially inform theories of delusion formation. We did so in 35 schizophrenic patients with a history of delusions, 30 of whom were currently deluded, and 34 healthy controls. Compared with healthy controls, patients showed (a) a jumping-to-conclusions bias and a bias to overadjust when confronted with a change of evidence on probabilistic-reasoning tasks, (b) an excessive externalizing attributional bias, and (c) performance deficits on 3 ToM tasks. Probabilistic-reasoning and ToM measures correlated, while attributional-bias scores were independent of other task measures. A general proneness to delusional ideation correlated with probabilistic-reasoning and ToM measures, while externalizing bias was unrelated to the study measures of delusional ideation. Personalizing bias associated specifically with paranoia across the clinical and nonclinical participants. Findings are consistent with a common underlying mechanism in schizophrenia which contributes to the anomalies on probabilistic-reasoning and ToM tasks associated with delusions. We speculate that this mechanism is impairment of the normal capacity to inhibit “perceived reality” (the evidence of our senses), a capacity that evolved as part of the “social brain” to facilitate intersubjective communication within a shared reality.

Two approaches dominate research on the lack of awareness of illness that characterizes schizophrenia. The "deficit" approach uses standardized neuropsychological batteries to identify the neural underpinnings of intact insight ; the "nondeficit" approach investigates the psychological defense mechanisms that motivate denial of illness. We adopt, instead, a cognitive neuropsychological approach to model the cognitive processes which underpin insight and which might be either damaged (because of neuropathology) or not used (because of motivational forces). We conceive of these processes in terms of a metacognitive capacity "to see ouvselves as others see us." We predict that a general difficulty with adopting other mental perspectives (with "seeing the world as others do"), indexed by performance deficits on theory of mind (ToM) tasks, will impair insight in schizophrenia. Thirty schizophrenic patients (also assessed for insight) and 26 healthy controls completed a battery of ToM tasks which varied presentation modality, response mode and instruction type (picture sequencing, joke appreciation and story comprehension tasks). While patients performed more poorly than controls on all ToM tasks, impairment in patients was not concordant across tasks. ToM scores from the picture sequencing and joke appreciation tasks, and not the story comprehension task, intercorrelated significantly in patients and predicted insight. Findings support the view that insight relies upon a cognitive capacity to adopt the other perspective, which, if intact, contributes to the metacognitive capacity to reflect upon "one's own" mental health from the other perspective. Findings also suggest that the nature of perspective-taking difficulty which disrupts insight in schizophrenia is best revealed using ToM tasks with "indirect" instructions.

Reliability, specificity, and Validity of three event-related potential (ERP) indices of non-attended and attended auditory information processing [the mismatch negativity (MMN), the novelty-P3a and the target-P3b] were assessed in 21 healthy subjects and 25 schizophrenic patients while performing a Visual discrimination task (Ignore condition) and, subsequently, an auditory discrimination task (Attend condition). Re-test reliability, as measured in a subset of 10 healthy subjects and 9 patients respectively, ranged from r = 0.4 to r = 0.8 In both groups P3a was found to be smaller in the Ignore than in the Attend condition. Patients had significantly larger P3a amplitudes than healthy subjects while their MMN and P3b amplitudes were smaller. Two ERP factors were extracted in healthy subjects: (I) 'novelty reaction' with high loading scores for P3a and (2) 'deviant detection' with high loading scores for MMN. P3b was predominantly loading on the first factor thus confirming partly overlapping P3a and P3b generators. However, considerable variance was also shared by the second factor, particularly in patients. External validity of the ERP factors was confirmed post hoc. Particularly ERP indices of deviant detection were found to be associated with negative symptoms. In order to assess further clinical relevance, therapy response to clozapine was followed-up over 3 yr in a sub-sample of 17 patients. Poor treatment response was associated with high Novelty Factor scores and large P3a amplitudes whereas good response was associated with high Deviant Factor scores and relatively intact MMN. It is concluded that ERP abnormalities provide a severity index of brain impairment and a measure of predicting therapeutic outcome.