Preethi Premkumar

Early intervention services, cognitive–behavioural therapy and family intervention in early psychosis: systematic review

Background Early intervention services for psychosis aim to detect emergent symptoms, reduce the duration of untreated psychosis, and improve access to effective treatments. Aims To evaluate the effectiveness of early intervention services, cognitive–behavioural therapy (CBT) and family intervention in early psychosis. Method Systematic review and meta-analysis of randomised controlled trials of early intervention services, CBT and family intervention for people with early psychosis. Results Early intervention services reduced hospital admission, relapse rates and symptom severity, and improved access to and engagement with treatment. Used alone, family intervention reduced relapse and hospital admission rates, whereas CBT reduced the severity of symptoms with little impact on relapse or hospital admission. Conclusions For people with early psychosis, early intervention services appear to have clinically important benefits over standard care. Including CBT and family intervention within the service may contribute to improved outcomes in this critical period. The longer-term benefits of this approach and its component treatments for people with early and established psychosis need further research.

Dorsolateral prefrontal cortex activity predicts responsiveness to cognitive-behavioral therapy in schizophrenia.

Background Given the variable response to cognitive–behavioral therapy (CBT) when added to antipsychotic medication in psychosis and the evidence for a role of pretherapy level of frontal lobe–based cognitive function in responsiveness to CBT in other disorders, this study examined whether pretherapy brain activity associated with working memory neural network predicts clinical responsiveness to CBT in schizophrenia. Methods Fifty-two outpatients stable on medication with at least one distressing symptom of schizophrenia and willing to receive CBT in addition to their usual treatment and 20 healthy participants underwent functional magnetic resonance imaging during a parametric n-back task. Subsequently, 26 patients received CBT for psychosis (CBT+treatment-as-usual [TAU], 19 completers) for 6–8 months, and 26 continued with TAU alone (17 completers). Symptoms in both patient groups were assessed (blindly) at entry and follow-up. Results The CBT+TAU and TAU-alone groups did not differ clinically or in performance at baseline. The CBT+TAU group showed significant improvement in relation to the TAU-alone group, which showed no change, at follow-up. Stronger dorsolateral prefrontal cortex (DLPFC) activity (within the normal range) and DLPFC–cerebellum connectivity during the highest memory load condition (2-back > 0-back) were associated with post-CBT clinical improvement. Conclusions DLPFC activity and its connectivity with the cerebellum predict responsiveness to CBT for psychosis in schizophrenia. These effects may be mediated by PFC–cerebellum contributions to executive processing.

Cortical grey matter volume and sensorimotor gating in schizophrenia

Prepulse inhibition (PPI) of the startle response, a cross-species measure of sensorimotor gating, provides a valuable tool to study the known inability of a large proportion of individuals with schizophrenia to effectively screen out irrelevant sensory input. The cortico-striato-pallido-thalamic circuitry is thought to be responsible for modulation of PPI in experimental animals. The involvement of this circuitry in human PPI is supported by observations of deficient PPI in a number of neuropsychiatric disorders that are characterised by abnormalities at some level in this circuitry, and findings of recent functional neuroimaging studies in healthy participants. The current study sought to investigate the structural neural correlates of PPI in a sample of 42 stable male outpatients with schizophrenia. Participants underwent magnetic resonance imaging (MRI) at 1.5 T and were assessed (off-line) on acoustic PPI using electromyographic recordings of the orbicularis oculi muscle beneath the right eye. Optimised volumetric voxel-based morphometry implemented in SPM2 was used to investigate the relationship of PPI (prepulse onset-to-pulse onset interval 120 msec) to regional grey matter (GM) volumes. Significant positive correlations were obtained between PPI and GM volume in the dorsolateral prefrontal, middle frontal and the orbital/medial prefrontal cortices. Our findings are consistent with (a) previous suggestions of susceptibility of PPI to cognitive processes controlled in a ‘top down’ manner by the cortex and (b) the hypothesis that compromised neural resources in the frontal cortex contribute to reduced PPI in schizophrenia.

Neural changes following cognitive behaviour therapy for psychosis: a longitudinal study

A growing body of evidence demonstrates that persistent positive symptoms, particularly delusions, can be improved by cognitive behaviour therapy for psychosis. Heightened perception and processing of threat are believed to constitute the genesis of delusions. The present study aimed to examine functional brain changes following cognitive behaviour therapy for psychosis. The study involved 56 outpatients with one or more persistent positive distressing symptoms of schizophrenia. Twenty-eight patients receiving cognitive behaviour therapy for psychosis for 6–8 months in addition to their usual treatment were matched with 28 patients receiving treatment as usual. Patients’ symptoms were assessed by a rater blind to treatment group, and they underwent functional magnetic resonance imaging during an affect processing task at baseline and end of treatment follow-up. The two groups were comparable at baseline in terms of clinical and demographic parameters and neural and behavioural responses to facial and control stimuli. The cognitive behaviour therapy for psychosis with treatment-as-usual group (22 subjects) showed significant clinical improvement compared with the treatment-as-usual group (16 subjects), which showed no change at follow-up. The cognitive behaviour therapy for psychosis with treatment-as-usual group, but not the treatment-as-usual group, showed decreased activation of the inferior frontal, insula, thalamus, putamen and occipital areas to fearful and angry expressions at treatment follow-up compared with baseline. Reduction of functional magnetic resonance imaging response during angry expressions correlated directly with symptom improvement. This study provides the first evidence that cognitive behaviour therapy for psychosis attenuates brain responses to threatening stimuli and suggests that cognitive behaviour therapy for psychosis may mediate symptom reduction by promoting processing of threats in a less distressing way.

Misattribution bias of threat-related facial expressions is related to a longer duration of illness and poor executive function in schizophrenia and schizoaffective disorder.

Background While it is known that patients with schizophrenia recognize facial emotions, specifically negative emotions, less accurately, little is known about how they misattribute these emotions to other emotions and whether such misattribution biases are associated with symptoms, course of the disorder, or certain cognitive functions. Method Outpatients with schizophrenia or schizoaffective disorder (n = 73) and healthy controls (n = 30) performed a computerised Facial Emotion Attribution Test and Wisconsin Card Sorting Test (WCST). Patients were also rated on the Positive and Negative Syndrome Scale (PANSS). Results Patients were poor at recognizing fearful and angry emotions and attributed fear to angry and angry to neutral expressions. Fear-as-anger misattributions were predicted independently by a longer duration of illness and WCST perseverative errors. Conclusion The findings show a bias towards misattributing fearful and angry facial emotions. The propensity for fear-as-anger misattribution biases increases as the length of time that the disorder is experienced increases and a more rigid style of information processing is used. This, at least in part, may be perpetuated by subtle fearfulness expressed by others while interacting with people with schizophrenia.

Functional MRI of Verbal Self-monitoring in Schizophrenia: Performance and Illness-Specific Effects

Previous small-sample studies have shown altered frontotemporal activity in schizophrenia patients with auditory hallucinations and impaired monitoring of self-generated speech. We examined a large cohort of patients with schizophrenia (n = 63) and a representative group of healthy controls (n = 20) to disentangle performance, illness, and symptom-related effects in functional magnetic resonance imaging–detected brain abnormalities during monitoring of self- and externally generated speech in schizophrenia. Our results revealed activation of the thalamus (medial geniculate nucleus, MGN) and frontotemporal regions with accurate monitoring across all participants. Less activation of the thalamus (MGN, pulvinar) and superior-middle temporal and inferior frontal gyri occurred in poorly performing patients (1 standard deviation below controls’ mean; n = 36), relative to the combined group of controls and well-performing patients. In patients, (1) greater deactivation of the ventral striatum and hypothalamus to own voice, combined with nonsignificant activation of the same regions to others’ voice, associated positively with negative symptoms (blunted affect, emotional withdrawal, poor rapport, passive social avoidance) regardless of performance and (2) exaggerated activation of the right superior-middle temporal gyrus during undistorted, relative to distorted, feedback associated with both positive symptoms (hallucinations, persecution) and poor performance. A further thalamic abnormality characterized schizophrenia patients regardless of performance and symptoms. We conclude that hypoactivation of a neural network comprised of the thalamus and frontotemporal regions underlies impaired speech monitoring in schizophrenia. Positive symptoms and poor monitoring share a common activation abnormality in the right superior temporal gyrus during processing of degraded speech. Altered striatal and hypothalamic modulation to own and others’ voice characterizes emotionally withdrawn and socially avoidant patients.

Emotional decision-making and its dissociable components in schizophrenia and schizoaffective disorder: A behavioural and MRI investigation

Cognitive decision-making is known to be deficient, but relatively less is known about emotional decision-making in schizophrenia. The Iowa gambling task (IGT) is considered a reliable probe of emotional decision-making and believed to reflect orbitofrontal cortex (OFC) function. The expectancy-valence model of IGT performance implicates three dissociable components, namely, attention to reward, memory for past, relative to recent, outcomes and impulsivity in emotional decision-making. We examined IGT performance, its three components, and their grey matter volume (GMV) correlates in 75 stable patients with schizophrenia, relative to 25 healthy individuals. Patients, relative to controls, showed impaired IGT performance and poor memory for past, relative to recent, outcomes. IGT performance correlated with GMV in the OFC in controls, but not patients. There were associations between (a) attention to reward and GMV in the frontal, temporal, parietal and striatal regions in controls, and in the temporal and thalamic regions in patients, (b) memory for past outcomes and GMV in the temporal region in controls, and the frontal and temporal regions in patients, and (c) low impulsivity and greater GMV in the frontal, temporal, posterior cingulate and occipital regions in controls, and in the frontal, temporal and posterior cingulate regions in patients. Most IGT-GMV associations were stronger in controls. It is concluded that (i) poor memory, rather than less attention to reward or impulsivity, contributes to IGT performance deficit, and (ii) the relationship of IGT performance and its components with GMVs especially in the frontal and temporal lobes is lost or attenuated in schizophrenia.

Neural processing of social rejection: The role of schizotypal personality traits

A fear of being rejected can cause perceptions of more insecurity and stress in close relationships. Healthy individuals activate the dorsal anterior cingulate cortex (dACC) when experiencing social rejection, while those who are vulnerable to depression deactivate the dACC presumably to downregulate salience of rejection cues and minimize distress. Schizotypal individuals, characterized by unusual perceptual experiences and/or odd beliefs, are more rejection sensitive than normal. We tested the hypothesis, for the first time, that individuals with high schizotypy also have an altered dACC response to rejection stimuli. Twenty‐six healthy individuals, 14 with low schizotypy (LS) and 12 with high schizotypy (HS), viewed depictions of rejection and acceptance and neutral scenes while undergoing functional MRI. Activation maps in LS and HS groups during each image type were compared using SPM5, and their relation to participant mood and subjective ratings of the images was examined. During rejection relative to neutral scenes, LS activated and HS deactivated the bilateral dACC, right superior frontal gyrus, and left ventral prefrontal cortex. Across both groups, a temporo‐occipito‐parieto‐cerebellar network was active during rejection, and a left fronto‐parietal network during acceptance, relative to neutral scenes, and the bilateral lingual gyrus during rejection relative to acceptance scenes. Our finding of dACC‐dorso‐ventral PFC activation in LS, but deactivation in HS individuals when perceiving social rejection scenes suggests that HS individuals attach less salience to and distance themselves from such stimuli. This may enable them to cope with their higher‐than‐normal sensitivity to rejection. Hum Brain Mapp, 2012.

Association between a longer duration of illness, age and lower frontal lobe grey matter volume in schizophrenia.

The frontal lobe has an extended maturation period and may be vulnerable to the long-term effects of schizophrenia. We tested this hypothesis by studying the relationship between duration of illness (DoI), grey matter (GM) and cerebro-spinal fluid (CSF) volume across the whole brain. Sixty-four patients with schizophrenia and 25 healthy controls underwent structural MRI scanning and neuropsychological assessment. We performed regression analyses in patients to examine the relationship between DoI and GM and CSF volumes across the whole brain, and correlations in controls between age and GM or CSF volume of the regions where GM or CSF volumes were associated with DoI in patients. Correlations were also performed between GM volume in the regions associated with DoI and neuropsychological performance. A longer DoI was associated with lower GM volume in the left dorsomedial prefrontal cortex (PFC), right middle frontal cortex, left fusiform gyrus (FG) and left cerebellum (lobule III). Additionally, age was inversely associated with GM volume in the left dorsomedial PFC in patients, and in the left FG and CSF excess near the left cerebellum in healthy controls. Greater GM volume in the left dorsomedial PFC was associated with better working memory, attention and psychomotor speed in patients. Our findings suggest that the right middle frontal cortex is particularly vulnerable to the long-term effect of schizophrenia illness whereas the dorsomedial PFC, FG and cerebellum are affected by both a long DoI and aging. The effect of illness chronicity on GM volume in the left dorsomedial PFC may be extended to brain structure-neuropsychological function relationships.

Functional magnetic resonance imaging of a parametric working memory task in schizophrenia: relationship with performance and effects of antipsychotic treatment

RationaleWorking memory dysfunction is frequently observed in schizophrenia. The neural mechanisms underlying this dysfunction remain unclear, with functional neuroimaging studies reporting increased, decreased or unchanged activation compared to controls.ObjectivesWe investigated the neural correlates of spatial working memory in schizophrenia with particular consideration of effects of antipsychotic treatment and relation to performance levels in the patient group.MethodWe used functional magnetic resonance imaging and studied the blood-oxygen-level-dependent (BOLD) response of 45 schizophrenia outpatients and 19 healthy controls during a parametric spatial n-back task.ResultsPerformance in both groups deteriorated with increasing memory load (0-back, 1-back, 2-back), but the two groups did not significantly differ in performance overall or as a function of load. Patients produced stronger BOLD signal in occipital and lateral prefrontal cortex during task performance than controls. This difference increased with increasing working memory load in the prefrontal areas. We also found that in patients with good task performance, the BOLD response in left prefrontal cortex showed a stronger parametric increase with working memory load than in patients with poor performance. Second-generation antipsychotics were independently associated with left prefrontal BOLD increase in response to working memory load, whereas first-generation antipsychotics were associated with BOLD decrease with increasing load in this area.ConclusionsTogether, these findings suggest that in schizophrenia patients, normal working memory task performance may be achieved through compensatory neural activity, especially in well-performing patients and in those treated with second-generation antipsychotics.