Deterioration in cognitive control related mPFC function underlying development of treatment resistance in early psychosis.

One third of people with psychosis become antipsychotic treatment-resistant and the underlying mechanisms remain unclear. We investigated whether altered cognitive control function is a factor underlying development of treatment resistance. We studied 50 people with early psychosis at a baseline visit (mean < 2 years illness duration) and follow-up visit (1 year later), when 35 were categorized at treatment-responsive and 15 as treatment-resistant. Participants completed an emotion-yoked reward learning task that requires cognitive control whilst undergoing fMRI and MR spectroscopy to measure glutamate levels from Anterior Cingulate Cortex (ACC). Changes in cognitive control related activity (in prefrontal cortex and ACC) over time were compared between treatment-resistant and treatment-responsive groups and related to glutamate. Compared to treatment-responsive, treatment-resistant participants showed blunted activity in right amygdala (decision phase) and left pallidum (feedback phase) at baseline which increased over time and was accompanied by a decrease in medial Prefrontal Cortex (mPFC) activity (feedback phase) over time. Treatment-responsive participants showed a negative relationship between mPFC activity and glutamate levels at follow-up, no such relationship existed in treatment-resistant participants. Reduced activity in right amygdala and left pallidum at baseline was predictive of treatment resistance at follow-up (67% sensitivity, 94% specificity). The findings suggest that deterioration in mPFC function over time, a key cognitive control region needed to compensate for an initial dysfunction within a social-emotional network, is a factor underlying development of treatment resistance in early psychosis. An uncoupling between glutamate and cognitive control related mPFC function requires further investigation that may present a future target for interventions.

Understanding the mechanisms underlying cognitive control in psychosis.

BACKGROUND: Cognitive control (CC) involves a top-down mechanism to flexibly respond to complex stimuli and is impaired in schizophrenia. METHODS: This study investigated the impact of increasing complexity of CC processing in 140 subjects with psychosis and 39 healthy adults, with assessments of behavioral performance, neural regions of interest and symptom severity. RESULTS: The lowest level of CC (Stroop task) was impaired in all patients; the intermediate level of CC (Faces task) with explicit emotional information was most impaired in patients with first episode psychosis. Patients showed activation of distinct neural CC and reward networks, but iterative learning based on the higher-order of CC during the trust game, was most impaired in chronic schizophrenia. Subjects with first episode psychosis, and patients with lower symptom load, demonstrate flexibility of the CC network to facilitate learning, which appeared compromised in the more chronic stages of schizophrenia. CONCLUSION: These data suggest optimal windows for opportunities to introduce therapeutic interventions to improve CC.

Alpha3/alpha2 power ratios relate to performance on a virtual reality shopping task in ageing adults.

Background: Aspects of cognitive function decline with age. This phenomenon is referred to as age-related cognitive decline (ARCD). Improving the understanding of these changes that occur as part of the ageing process can serve to enhance the detection of the more incapacitating neurodegenerative disorders such as Alzheimer's disease (AD). In this study, we employ novel methods to assess ARCD by exploring the utility of the alpha3/alpha2 electroencephalogram (EEG) power ratio - a marker of AD, and a novel virtual reality (VR) functional cognition task - VStore, in discriminating between young and ageing healthy adults. Materials and methods: Twenty young individuals aged 20-30, and 20 older adults aged 60-70 took part in the study. Participants underwent resting-state EEG and completed VStore and the Cogstate Computerised Cognitive Battery. The difference in alpha3/alpha2 power ratios between the age groups was tested using t-test. In addition, the discriminatory accuracy of VStore and Cogstate were compared using logistic regression and overlying receiver operating characteristic (ROC) curves. Youden's J statistic was used to establish the optimal threshold for sensitivity and specificity and model performance was evaluated with the DeLong's test. Finally, alpha3/alpha2 power ratios were correlated with VStote and Cogstate performance. Results: The difference in alpha3/alpha2 power ratios between age cohorts was not statistically significant. On the other hand, VStore discriminated between age groups with high sensitivity (94%) and specificity (95%) The Cogstate Pre-clinical Alzheimer's Battery achieved a sensitivity of 89% and specificity of 60%, and Cogstate Composite Score achieved a sensitivity of 83% and specificity of 85%. The differences between the discriminatory accuracy of VStore and Cogstate models were statistically significant. Finally, high alpha3/alpha2 power ratios correlated strongly with VStore (r = 0.73), the Cogstate Pre-clinical Alzheimer's Battery (r = -0.67), and Cogstate Composite Score (r = -0.76). Conclusion: While we did not find evidence that the alpha3/alpha2 power ratio is elevated in healthy ageing individuals compared to young individuals, we demonstrated that VStore can classify age cohorts with high accuracy, supporting its utility in the assessment of ARCD. In addition, we found preliminary evidence that elevated alpha3/alpha2 power ratio may be linked to lower cognitive performance.

The role of cognitive control in the positive symptoms of psychosis.

BACKGROUND: Positive symptoms of psychosis (e.g., hallucinations) often limit everyday functioning and can persist despite adequate antipsychotic treatment. We investigated whether poor cognitive control is a mechanism underlying these symptoms. METHODS: 97 patients with early psychosis (30 with high positive symptoms (HS) and 67 with low positive symptoms (LS)) and 40 healthy controls (HC) underwent fMRI whilst performing a reward learning task with two conditions; low cognitive demand (choosing between neutral faces) and high cognitive demand (choosing between angry and happy faces - shown to induce an emotional bias). Decision and feedback phases were examined. RESULTS: Both patient groups showed suboptimal learning behaviour compared to HC and altered activity within a core reward network including occipital/lingual gyrus (decision), rostral Anterior Cingulate Cortex, left pre-central gyrus and Supplementary Motor Cortex (feedback). In the low cognitive demand condition, HS group showed significantly reduced activity in Supplementary Motor Area (SMA)/pre-SMA during the decision phase whilst activity was increased in LS group compared to HC. Recruitment of this region suggests a top-down compensatory mechanism important for control of positive symptoms. With additional cognitive demand (emotional vs. neutral contrast), HS patients showed further alterations within a subcortical network (increased left amygdala activity during decisions and reduced left pallidum and thalamus activity during feedback) compared to LS patients. CONCLUSIONS: The findings suggest a core reward system deficit may be present in both patient groups, but persistent positive symptoms are associated with a specific dysfunction within a network needed to integrate social-emotional information with reward feedback.

Cognitive control network connectivity differentially disrupted in treatment resistant schizophrenia.

Antipsychotic treatment resistance affects a third of people with schizophrenia and the underlying mechanism remains unclear. We used an fMRI emotion-yoked reward learning task, allied to prefrontal cortical glutamate levels, to explain the role of cognitive control in differentiating treatment-resistant from responsive patients. We investigated how reward learning is disrupted at the network level in 21 medicated treatment-responsive and 20 medicated treatment-resistant patients with schizophrenia compared with 24 healthy controls (HC). Dynamic Causal Modelling assessed how effective connectivity between regions in a cortico-striatal-limbic network is disrupted in each patient group compared to HC. Connectivity was also examined with respect to symptoms, salience and anterior cingulate (ACC) glutamate levels measured from the same region of the ACC. We found that ACC connectivity differentiated these patient groups, with responsive patients exhibiting increased top-down connectivity from ACC to sensory regions and reduced ACC drive to the striatum, while resistant patients showed altered connectivity within the ACC itself. In these resistant patients, the ACC drive to striatum was positively correlated with their symptom severity. ACC glutamate levels were found to correlate with ACC control over sensory regions in responsive patients but not in resistant patients. We suggest a central non-dopaminergic impairment that impacts cognitive control networks in treatment-resistant schizophrenia. This impairment was associated with disrupted reward learning and could be underpinned by aberrant glutamate function. These findings should form the focus of future treatment strategies (e.g. glutamatergic targets and giving clozapine earlier) in resistant patients.

Cognitive performance in early, treatment-resistant psychosis patients: Could cognitive control play a role in persistent symptoms?

Approximately one third of psychosis patients fail to respond to conventional antipsychotic medication, which exerts its effect via striatal dopamine receptor antagonism. The present study aimed to investigate impaired cognitive control as a potential contributor to persistent positive symptoms in treatment resistant (TR) patients. 52 medicated First Episode Psychosis (FEP) patients (17 TR and 35 non-TR (NTR)) took part in a longitudinal study in which they performed a series of cognitive tasks and a clinical assessment at two timepoints, 12 months apart. Cognitive performance at baseline was compared to that of 39 healthy controls (HC). Across both timepoints, TR patients were significantly more impaired than NTR patients in a task of cognitive control, while performance on tasks of phonological and semantic fluency, working memory and general intelligence did not differ between patient groups. No significant associations were found between cognitive performance and psychotic symptomatology, and no significant performance changes were observed from the first to second timepoint in any of the cognitive tasks within patient groups. The results suggest that compared with NTR patients, TR patients have an exacerbated deficit specific to cognitive control, which is established early in psychotic illness and stabilises in the years following a first episode.

Neural correlates of positive and negative symptoms through the illness course: an fMRI study in early psychosis and chronic schizophrenia.

Psychotic illness is associated with cognitive control deficits and abnormal recruitment of neural circuits subserving cognitive control. It is unclear to what extent this dysfunction underlies the development and/or maintenance of positive and negative symptoms typically observed in schizophrenia. In this study we compared fMRI activation on a standard Stroop task and its relationship with positive and negative symptoms in early psychosis (EP, N = 88) and chronic schizophrenia (CHR-SZ, N = 38) patients. CHR-SZ patients showed reduced frontal, striatal, and parietal activation across incongruent and congruent trials compared to EP patients. Higher positive symptom severity was associated with reduced activation across both trial types in supplementary motor area (SMA), middle temporal gyrus and cerebellum in EP, but not CHR-SZ patients. Higher negative symptom severity was associated with reduced cerebellar activation in EP, but not in CHR-SZ patients. A negative correlation between negative symptoms and activation in SMA and precentral gyrus was observed in EP patients and in CHR-SZ patients. The results suggest that the neural substrate of positive symptoms changes with illness chronicity, and that cognitive control related neural circuits may be most relevant in the initial development phase of positive symptoms. These findings also highlight a changing role for the cerebellum in the development and later maintenance of both positive and negative symptoms.