Pituitary volume reduction in schizophrenia following cognitive behavioural therapy.

Cognitive behavioural therapy (CBT) for psychosis (CBTp) aims to lower the stress of psychotic symptoms. Given that the pituitary is involved in stress regulation, CBT-led stress reduction may be accompanied by a change in pituitary volume. This study aimed to determine whether CBTp reduces pituitary volume in schizophrenia. The relation between pre-therapy memory and CBTp-led pituitary volume change was also examined given that poor memory relates to a blunted cortisol awakening response, denoting impaired stress response, in schizophrenia. Pituitary volume was measured at baseline in 40 schizophrenia or schizoaffective disorder patients and 30 healthy participants before therapy. Pituitary volume was measured again 6-9months after patients had either received CBTp in addition to standard care (CBTp+SC, n=24), or continued with standard care alone (SC, n=16). CBTp+SC and SC groups were compared on pituitary volume change from baseline to follow-up. Pre-therapy memory performance (Hopkins Verbal Learning and Wechsler Memory Scale - Logical memory) was correlated with baseline-to-follow-up pituitary volume change. Pituitary volume reduced over time in CBTp+SC patients. Additionally, pre-therapy verbal learning correlated more strongly with longitudinal pituitary volume reduction in the CBTp+SC group than the SC group. To conclude, CBTp reduces pituitary volume in schizophrenia most likely by enhancing stress regulation and lowering the distress due to psychotic symptoms.

Common and distinct neural effects of risperidone and olanzapine during procedural learning in schizophrenia: a randomised longitudinal fMRI study.

RATIONALE: Most cognitive domains show only minimal improvement following typical or atypical antipsychotic treatments in schizophrenia, and some may even worsen. One domain that may worsen is procedural learning, an implicit memory function relying mainly on the integrity of the fronto-striatal system. OBJECTIVES: We investigated whether switching to atypical antipsychotics would improve procedural learning and task-related neural activation in patients on typical antipsychotics. Furthermore, we explored the differential effects of the atypical antipsychotics risperidone and olanzapine. METHODS: Thirty schizophrenia patients underwent functional magnetic resonance imaging during a 5-min procedural (sequence) learning task on two occasions: at baseline and 7-8 weeks later. Of 30 patients, 10 remained on typical antipsychotics, and 20 were switched randomly in equal numbers to receive either olanzapine (10-20 mg) or risperidone (4-8 mg) for 7-8 weeks. RESULTS: At baseline, patients (all on typical antipsychotics) showed no procedural learning. At follow-up, patients who remained on typical antipsychotics continued to show a lack of procedural learning, whereas those switched to atypical antipsychotics displayed significant procedural learning (p = 0.001) and increased activation in the superior-middle frontal gyrus, anterior cingulate and striatum (cluster-corrected p < 0.05). These neural effects were present as a linear increase over five successive 30-s blocks of sequenced trials. A switch to either risperidone or olanzapine resulted in comparable performance but with both overlapping and distinct task-related activations. CONCLUSIONS: Atypical antipsychotics restore procedural learning deficits and associated neural activity in schizophrenia. Furthermore, different atypical antipsychotics produce idiosyncratic task-related neural activations, and this specificity may contribute to their differential long-term clinical profiles.

Orbitofrontal cortex, emotional decision-making and response to cognitive behavioural therapy for psychosis.

Grey matter volume (GMV) in the orbitofrontal cortex (OFC) may relate to better response to cognitive behavioural therapy for psychosis (CBTp) because of the region׳s role in emotional decision-making and cognitive flexibility. This study aimed to determine the relation between pre-therapy OFC GMV or asymmetry, emotional decision-making and CBTp responsiveness. Emotional decision-making was measured by the Iowa Gambling task (IGT). Thirty patients received CBTp+standard care (CBTp+SC; 25 completers) for 6-8 months. All patients (before receiving CBTp) and 25 healthy participants underwent structural magnetic resonance imaging. Patients׳ symptoms were assessed before and after therapy. Pre-therapy OFC GMV was measured using a region-of-interest approach, and IGT performance was measured as overall learning, attention to reward, memory for past outcomes and choice consistency. Both these measures, were comparable between patient and healthy groups. In the CBTp+SC group, greater OFC GMV correlated with positive symptom improvement, specifically hallucinations and persecution. Greater rightward OFC asymmetry correlated with improvement in several negative and general psychopathology symptoms. Greater left OFC GMV was associated with lower IGT attention to reward. The findings suggest that greater OFC volume and rightward asymmetry, which maintain the OFC׳s function in emotional decision-making and cognitive flexibility, are beneficial for CBTp responsiveness.

Sensorimotor gating and clinical outcome following cognitive behaviour therapy for psychosis.

BACKGROUND: Prepulse inhibition (PPI) of the startle response refers to the ability of a weak prestimulus to transiently inhibit the response to a closely following strong sensory stimulus. PPI provides an operational index of sensorimotor gating and is reduced, on average, in people with schizophrenia, relative to healthy people. Given the variable response to Cognitive Behaviour Therapy for psychosis (CBTp) and positive associations between pre-therapy brain and cognitive functions and CBT outcome across disorders, we examined whether pre-therapy level of PPI is associated with clinical outcome following CBTp. METHOD: Fifty-six outpatients stable on medication with at least one distressing symptom of schizophrenia and willing to receive CBTp in addition to their usual treatment were assessed on acoustic PPI. Subsequently, 28 patients received CBTp (CBTp+treatment-as-usual, 23 completers) for 6-8months and 28 continued with their treatment-as-usual (TAU-alone, 17 completers). Symptoms were assessed (blindly) at entry and follow-up. RESULTS: The CBTp+TAU and TAU-alone groups did not differ demographically, clinically or in PPI at baseline. The CBTp+TAU group showed improved symptoms relative to the TAU-alone group, which showed no change, at follow-up. Pre-therapy PPI level correlated positively with post-CBTp symptom improvement. CONCLUSIONS: Relatively intact sensorimotor gating is associated with a good clinical response following a 6-8months course of NICE compliant CBTp in schizophrenia. Pharmacological or psychological interventions capable of improving PPI may enhance the effectiveness of CBTp in people with schizophrenia, particularly in those who fail to show clinical improvement with currently available antipsychotic drugs and adjunctive CBTp.

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.

Coping styles predict responsiveness to cognitive behaviour therapy in psychosis.

The study aimed to determine the clinical and neuropsychological predictors of responsiveness to cognitive behavioural therapy for psychosis (CBTp). Sixty patients with schizophrenia or schizoaffective disorder and 25 healthy individuals took part in the study. Thirty patients (25 protocol completers) received CBTp in addition to standard care (SC); 30 patients (18 protocol completers) received SC only. All patients were assessed on symptoms using the Positive and Negative Syndrome Scale (PANSS) and clinical and neuropsychological function before and after CBTp. Symptoms and self-esteem improved to a greater extent in the CBTp+SC than SC control group. Greater pre-therapy coping ability and the self-reflectiveness dimension of cognitive insight at baseline predicted improvement in symptoms in the CBTp+SC group, but not the SC control group, explaining up to 21% of the variance in symptom improvement. Pre-therapy neuropsychological function, duration of illness, clinical insight and gender did not predict CBTp responsiveness. Being able to have a range of coping strategies and reflect on one's experiences while refraining from overconfidence in one's interpretations before therapy is conducive to better CBTp responsiveness.

Emotion processing in schizophrenia: fMRI study of patients treated with risperidone long-acting injections or conventional depot medication.

We employed two event-related functional magnetic resonance imaging tasks using the pictures of mild and intense facial emotions of fear or happiness. The sample comprised 16 chronic schizophrenia patients treated with risperidone long-acting injections (RLAI), 16 patients treated with conventional antipsychotic depots (CONV) and 16 healthy controls (HC). The HC and RLAI groups demonstrated greater activation in the left amygdala in response to intensively fearful faces, and in right cerebellum to intensively happy faces compared with CONV patients. The CONV group demonstrated under-activation in the right temporal pole in response to intensively happy faces (compared with HC) and over-activation in ventro-medial prefrontal cortex (VMPFC) in response to both intensively happy and fearful expressions, compared with HC and RLAI groups. Our results suggest that networks implicated in the allocation of attentional resources (VMPFC) and emotion processing (amygdala, cerebellum) are differentially affected in patients on CONV versus RLAI.

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.

A longer duration of schizophrenic illness has sex-specific associations within the working memory neural network in schizophrenia.

An association has previously been demonstrated between prefrontal cortex (PFC) volume decreases and illness progression in schizophrenia. The impact of illness duration on the fronto-parietal working memory neural network, however, remains unexplored. We investigated the effect of ageing and duration of illness, and explored possible sex-specific effects of duration of illness, in working memory-related brain activity in schizophrenia. Fifty individuals (25 stable schizophrenia outpatients, 25 healthy controls) underwent functional magnetic resonance imaging during performance of an 'n-back' task. Patients performed significantly worse than controls. Duration of illness correlated with reduced dorsolateral prefrontal cortex activity in males and reduced cerebellum activity in females, regardless of performance and age. Sex-specific effects of illness duration were also evident in the inferior frontal and superior temporal gyri (females) and the inferior parietal cortex (males) which generally show sexually dimorphic activation in healthy people. We detected no significant effect of ageing on neural activation of the working memory network in patients though such an effect was present in healthy controls. In conclusion, our findings demonstrate that a longer duration of schizophrenic illness has sex-specific associations within the working memory neural network, with expected association between illness duration and impaired PFC activation apparent in male, but not in female patients. Additionally, brain regions that exhibit sexually dimorphic activation in healthy people may become compromised in the corresponding sex with illness progression.

Effects of acute nicotine on brain function in healthy smokers and non-smokers: estimation of inter-individual response heterogeneity.

The present study used functional magnetic resonance imaging (fMRI) to investigate the neural mechanisms of nicotine effects on antisaccades (an oculomotor measure of the conflict between a reflexive response and a spatially complex volitional response) and prosaccades (involving reflexive overt attentional shifts). Given the known inter-individual variability in drug response we aimed to identify oculomotor variables and brain areas in which significant inter-individual heterogeneity in response to nicotine is observed. To do so we calculated within-session intraclass correlation (ICC) coefficients over measurements obtained before and after nicotine/placebo administration and reasoned that a significant reduction in ICC with nicotine compared to placebo would reflect the operation of significant inter-individual response heterogeneity. Thirteen light-to-moderate smokers and 11 non-smokers completed fMRI during antisaccades before and after subcutaneous injection of 12 microg/kg nicotine or saline placebo in a double-blind, randomised, cross-over design. All participants were healthy, right-handed males. Nicotine and placebo were given on separate occasions approximately 1 week apart with time of injection kept constant. Nicotine significantly reduced antisaccade latencies in both groups. At the level of brain function, during antisaccades the blood oxygen level dependent (BOLD) response in the left frontal eye field was non-significantly reduced by nicotine while it significantly increased following placebo in non-smokers, but there was no discernible effect in smokers. During prosaccades, it was found that deactivation areas (posterior cingulate gyrus and precuneus; right superior temporal gyrus) showed enhanced deactivations following nicotine administration in both groups. ICC analysis identified significant inter-individual response heterogeneity in antisaccade reflexive errors in smokers, and in a number of brain regions, particularly in non-smokers. These findings suggest that nicotine has beneficial effects at the cognitive level and leads to reductions in task-related activations and further decreases of BOLD in deactivation areas. The comparison of within-session ICCs across drug conditions suggests that the effects of nicotine are subject to inter-individual variability at behavioural and neural levels.

Uncontrollable voices and their relationship to gating deficits in schizophrenia.

BACKGROUND: Prepulse inhibition (PPI) of the startle response refers to the ability of a weak prestimulus to transiently inhibit the response to a closely following strong sensory stimulus. This effect is reduced in a number of disorders known to be associated with impaired gating of sensory, cognitive or motor information. The aim of this study was to investigate PPI deficit in relation to the dimensions of auditory hallucinations in patients with schizophrenia or schizoaffective disorder. METHOD: PPI of the acoustically elicited eye blink startle response was measured electromyographically in 62 patients with schizophrenia (n=55) or schizoaffective disorder (n=7) (26 of 62 with current auditory hallucinations) and 22 healthy participants matched, on average, to age and sex of the patient group. RESULTS: Patients, as a group, showed reduced PPI compared to healthy participants. The presence of auditory hallucinations was associated with a marked PPI deficit if the patients felt that they had no control over their occurrence and that they were unable to dismiss them. Hearing voices with a high degree of negative content was associated with high mean startle amplitude in patients with current auditory hallucinations. CONCLUSIONS: Although auditory hallucinations in patients with schizophrenia are theorised to result from impaired monitoring of inner speech, the inability to consciously ignore them appears to be associated with a gating deficit. Hearing voices with negative content is associated with hyper-startle responding, possibly because such voices are threatening and thus provoke anxiety.

An fMRI study of face encoding and recognition in first-episode schizophrenia.

BACKGROUND: Schizophrenia has been associated with limited abilities to interact effectively in social situations. Face perception and ability to recognise familiar faces are critical for social interaction. Patients with chronic schizophrenia are known to show impaired face recognition. Studying first-episode (FE) patients allows the exclusion of confounding effects of chronicity, medication and institutionalisation in this deficit. OBJECTIVE: To determine brain (dys)functions during a face encoding and recognition paradigm in FE schizophrenia. METHODS: Thirteen antipsychotic-naïve FE schizophrenia patients and 13 age- and sex-matched healthy controls underwent functional magnetic resonance imaging during a face encoding and recognition paradigm. Behavioural responses were recorded on line. RESULTS: Patients recognised significantly fewer of previously presented faces than the controls (p = 0.008). At the neural level, both groups activated a network of regions including the fusiform area, occipital, temporal and frontal regions. In brain activity, the two groups did not differ in any region during encoding or recognition conditions (p > 0.05, corrected or uncorrected). CONCLUSIONS: Our findings show impaired face recognition without a significant alteration of related brain activity in FE schizophrenia patients. It is possible that neural changes become more strongly evident with progression of the illness, and manifest themselves as behavioural impairments during the early course.

The effect of long-acting risperidone on working memory in schizophrenia: a functional magnetic resonance imaging study.

Cognitive abnormalities represent an important therapeutic target in the treatment of schizophrenia. Working memory deficits are among the core abnormalities and affect social functioning. We used functional magnetic resonance imaging to examine cortical systems supporting working memory in patients with schizophrenia treated with risperidone long-acting injections (RLAIs) versus those on conventional depot medication (CONV). Sixteen patients on RLAI, 16 patients on CONV matched for clinical symptoms and other illness variables, and 8 HCs performed an n-back task (1-, 2-, 3-back) in the scanner. The level of performance decreased with increasing memory load, which was particularly evident in the CONV group. Patients on RLAI and controls demonstrated task-dependent decreases in activation in medial PFC, whereas the CONV group overactivated that region. The CONV group also showed underactivation of VLPFC compared with controls under conditions of increasing memory load, with the RLAI group showing an activation pattern not significantly different from either group. We conclude that RLAI may contribute to normalization of brain activation in regions involved in working memory functioning in people with chronic schizophrenia.

Insight, distress and coping styles in schizophrenia.

BACKGROUND: The stigma and negative societal views attached to schizophrenia can make the diagnosis distressing. There is evidence that poor insight into symptoms of the disorder and need for treatment may reflect the use of denial as a coping style. However, the relationships between insight and other coping styles have seldom been investigated. METHOD: We examined the associations between insight, distress and a number of coping styles in 65 outpatients with schizophrenia (final n=57) in a cross-sectional study. RESULTS: We found that (i) awareness of symptoms and problems correlated with greater distress, (ii) 'preference for positive reinterpretation and growth' coping style correlated with lower distress and with lower symptom awareness (re-labelling), (iii) 'preference for mental disengagement' coping style correlated with greater distress and lower awareness of problems, and (iv) 'social support-seeking' coping style correlated with greater awareness of illness, but not distress. No relationship occurred between the use of 'denial' as a coping style and insight or distress. CONCLUSIONS: Our findings demonstrate that awareness of illness and related problems is associated with greater distress in schizophrenia. However, this investigation has not supported a simple psychological denial explanation for this relationship, as complex relationships emerged between different dimensions of insight and coping styles. The negative association between 'positive reinterpretation and growth' and distress suggests that adopting this style may lead to re-labelling symptoms in a less distressing way. Avoidant and isolating styles of coping both appear unhelpful. Psychological interventions should aim to promote more active coping such as discussing a mental health problem with others.

Prefrontal cortex and insight in schizophrenia: a volumetric MRI study.

Previous studies have suggested a relationship between frontal lobe-based neuropsychological functions and insight in schizophrenia. There is some evidence linking both smaller whole brain volume and frontal cortical atrophy to poor insight in this population. We investigated the relationship between total as well as specific prefrontal regional volumes and insight in schizophrenia. Twenty-eight stable outpatients with schizophrenia underwent magnetic resonance imaging scanning and assessment for insight. Insight was measured using the Birchwood self-report Insight Scale and the Expanded Schedule of Assessment of Insight. The whole brain and prefrontal regional (superior frontal, middle frontal, inferior frontal and orbitofrontal) volumes were then manually measured using the Cavalieri method and established criteria. Twenty healthy subjects were also scanned to provide control data for volumetric assessments. Smaller total prefrontal grey matter volume was moderately associated with a lower level of insight into the presence of illness. At the prefrontal sub-regional level, volumes of the superior, inferior and orbitofrontal regions contributed to this relationship, especially in males. It is concluded that smaller prefrontal grey matter volume is associated with poor insight into the presence of illness in stable schizophrenia patients. Future research should examine the association of specific dimensions of insight with frontal as well as non-frontal regional brain volumes.