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.

Cognitive insight in psychosis: the relationship between self-certainty and self-reflection dimensions and neuropsychological measures.

Cognitive insight in schizophrenia encompasses the evaluation and reinterpretation of distorted beliefs and appraisals. We investigated the neuropsychological basis of cognitive insight in psychosis. It was predicted that, like clinical insight, cognitive insight would be associated with a wide range of neuropsychological functions, but would be most strongly associated with measures of executive function. Sixty-five outpatients with schizophrenia or schizoaffective disorder were assessed on tests of intelligence quotient (IQ), executive function, verbal fluency, attention and memory, and completed the Beck Cognitive Insight Scale, which includes two subscales, self-certainty and self-reflection. Higher self-certainty scores reflect greater certainty about being right and more resistant to correction (poor insight), while higher self-reflection scores indicate the expression of introspection and the willingness to acknowledge fallibility (good insight). The self-certainty dimension of poor cognitive insight was significantly associated with lower scores on the Behavioural Assessment of Dysexecutive Syndrome; this relationship was not mediated by IQ. There were no relationships between self-reflection and any neuropsychological measures. We conclude that greater self-certainty (poor cognitive insight) is modestly associated with poorer executive function in psychotic individuals; self-reflection has no association with executive function. The self-certainty and self-reflection dimensions of cognitive insight have differential correlates, and probably different mechanisms, in psychosis.

Low baseline startle and deficient affective startle modulation in remitted bipolar disorder patients and their unaffected siblings.

We examined whether startle abnormalities are present in bipolar disorder (BD) patients and their unaffected siblings. Twenty-one remitted patients with BD, 19 unaffected siblings, and 42 controls were presented with 18 pleasant, 18 unpleasant, and 18 neutral pictures. Acoustic probes (104 dB) were presented during 12 of 18 pictures in each affective category at 300, 3000, and 4500 ms after picture onset, so that there were 4 pictures per valence per probe onset type. Baseline startle was assessed during blank screens and was found reduced in patients and sibling groups. We found startle inhibition with the 300 probes and a linear increase in amplitude with valence with the late probes in controls; these effects were absent in patients and their siblings. Low startle and blunted startle reactivity may represent trait deficits in remitted BD patients and their relatives, possibly associated with attentional deficits and adaptive down-regulation of emotion.

Evidence for a role of progesterone in menstrual cycle-related variability in prepulse inhibition in healthy young women.

Prepulse inhibition (PPI) of the startle response is sensitive to sex, with healthy young women showing less PPI compared with age-matched men, and varies according to the menstrual cycle phase in women. Relatively less is known regarding sex and hormonal influences in prepulse facilitation (PPF). Menstrual phase-related variability in PPI is suggested to be mediated by fluctuating estrogen level, based on the observations of more PPI in women during the follicular, relative to the luteal, phase. No study has directly assessed the relationship between fluctuating hormones and PPI or PPF levels over the human ovarian cycle. To examine the roles of circulating ovarian hormones in PPI and PPF, 16 non-smoking regularly menstruating healthy women were tested during both the follicular and luteal phases on PPI and PPF and provided saliva samples for measurement of 17beta-estradiol (estrogen), progesterone and testosterone. The results showed higher levels of 17beta-estradiol and progesterone during the luteal, relative to the follicular, phase; and more PPI during the follicular phase and more PPF during the luteal phase with comparable startle amplitude and habituation during the two phases. A larger increase in progesterone was associated with a smaller decrease in PPI from the follicular to the luteal phase. No significant associations were found between changes in PPI/PPF and estrogen levels. The findings confirm lower PPI during the luteal, compared with the follicular, phase and suggest a role for progesterone, more specifically an antipsychotic-like PPI-restoration action of progesterone, during the luteal phase in PPI of young women.

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.

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.

A comparison of prepulse inhibition in pre- and postmenopausal women and age-matched men.

Prepulse inhibition (PPI) of the startle response is sensitive to sex with women showing less PPI compared with age-matched men and varies according to the menstrual cycle in women. Relatively less is known about sex differences in prepulse facilitation (PPF). To examine further the roles of sex and circulating sex hormones, pre- (n=20) and postmenopausal women (n=20) were compared with men of similar ages (n=17, 18-40 years; n=18, 55-69 years). All participants were assessed on PPI and PPF, and provided saliva samples for measurement of 17beta-estradiol (estrogen) and testosterone. Premenopausal women showed less PPI compared with age-matched men, with no significant difference in PPF. Postmenopausal women did not differ in PPI but showed more PPF than age-matched men. There was less PPI and PPF in older, relative to young, men; pre- and postmenopausal women did not differ significantly. PPI showed no association with the levels of sex hormones. PPF showed small positive associations with both the levels of estrogen and testosterone, especially in young men. The present findings extend recent observations in mice showing less PPI in premenopausal, but not postmenopausal, female compared with male mice of similar ages (Ison and Allen, Behav Brain Res, 2007) to humans. There appear to be no substantial relationships between individual differences in endogenous levels of sex hormones and PPI; fluctuations within an individual may have a stronger role.

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.

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.

Cognitive effects of adjunctive 24-weeks Rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, double-blind investigation.

Cognitive impairment has the greatest impact on illness outcome in schizophrenia. The most significant challenge in schizophrenia therapeutics, thus, is to develop an efficacious treatment for cognitive impairments. Acetylcholinesterase inhibitors, such as Physostigmine and Rivastigmine, are considered effective treatments for cognitive decline in Alzheimer's Disease, where the loss of cholinergic neurons is thought to be responsible for various cognitive deficits. The current study investigated the cognitive effects of Rivastigmine given as an add-on therapy to antipsychotic-treated schizophrenia patients in a placebo-controlled double-blind design. The study initially involved 40 patients, of which 21 patients (11 assigned to Rivastigmine and 10 assigned to placebo) agreed to continued participation, remained on the study drug, and underwent assessment of executive functioning, verbal skills, verbal and spatial working memory, attention and psychomotor speed on three occasions: (i) at baseline, and then (ii) after 12 weeks and (iii) 24 weeks of treatment with placebo or Rivastigmine. The results failed to reveal significant improvement on any cognitive measure with Rivastigmine treatment, compared with the placebo treatment. Some cognitive variables showed significant practice effects in both the placebo and Rivastigmine groups. No effects were noted in symptoms or side effects ratings. The beneficial cognitive effects of Rivastigmine seen in an open-label preliminary study are not substantiated by this study. Future studies should investigate the effects of other procholinergic drugs, such as Galantamine, which also act on the nicotine receptors and may produce stronger cognitive effects in schizophrenia.

Neural dysfunction and violence in schizophrenia: an fMRI investigation.

Contemporary theories and evidence implicate frontal lobe dysfunction in violent behaviour as well as in schizophrenia. We applied functional magnetic resonance imaging (fMRI) to investigate and compare brain activation during an 'n-back' working memory task in groups of men with (i) schizophrenia and a history of serious physical violence (VS; n=13), (ii) schizophrenia without a history of violence (NVS: n=12), (iii) antisocial personality disorder (APD) and a history of serious physical violence (n=10), and (iv) no history of violence or a mental disorder (n=13). We observed comparable performance in all four groups during the control (0-back) condition. Subtle working memory deficits were seen in the NVS and APD groups but severe deficits emerged in the VS group relative to the healthy group. The VS group showed activation deficit bilaterally in the frontal lobe and precuneus when compared to the healthy group, and in the right inferior parietal region when compared to the NVS group during the working memory load condition. Frontal (bilateral) as well as right inferior parietal activity was negatively associated with the ratings of violence across all schizophrenia patients, with the right parietal region showing this association most strongly. APD patients, relative to healthy subjects, showed activation deficit in the left frontal gyrus, anterior cingulate and precuneus. It is concluded that reduced functional response in the frontal and inferior parietal regions leads to serious violence in schizophrenia perhaps via impaired executive functioning.

Neural correlates of adjunctive rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, double-blind fMRI study.

Facilitation of central cholinergic activity may form a potential treatment strategy for cognitive impairment in schizophrenia. In a randomized, placebo-controlled, double-blind, parallel-group design, we investigated the neural correlates of cognitive effects of rivastigmine, an acetylcholinesterase inhibitor, given as an add-on therapy to antipsychotic-treated schizophrenia patients. Thirty-six chronic schizophrenia patients with mild cognitive impairment took part. After 1 week on placebo (baseline), all patients entered a double-blind protocol; 18 were allocated to receive rivastigmine and 18 placebo for the next 12 weeks (final sample with usable imaging data: 11 patients on rivastigmine, 10 on placebo). All patients underwent functional magnetic resonance imaging during a parametric 'n-back' task, involving monitoring of dots in particular locations on a screen at a given delay from the original occurrence, twice: at baseline and 12 weeks post-rivastigmine/placebo treatment. Compared to placebo, rivastigmine produced only a small and non-significant improvement in task accuracy across all conditions with no change in response latency, and increased activity in the extrastriate visual cortex in areas associated with visual and spatial attention but not in any region within the working memory network. Our observations suggest that cholinergic enhancement with rivastigmine at doses known to be effective in Alzheimer's disease does not produce strong and clinically meaningful cognitive and neural changes in schizophrenia patients treated with atypical antipsychotics although the neural effects in terms of enhanced neuronal activity in regions associated with visual and spatial attention are consistent with those reported previously with cholinergic enhancement in healthy subjects.

Effects of rivastigmine on sustained attention in schizophrenia: an FMRI study.

This study assessed the neural correlates of the effects of rivastigmine, a CNS-selective cholinesterase inhibitor, given as an add-on therapy to antipsychotics-treated patients with schizophrenia who displayed moderate cognitive impairments, using functional magnetic resonance imaging (fMRI) during a sustained attention task. The study used a placebo-controlled, randomized, double-blind longitudinal design. Twenty patients stable on antipsychotics, 11 assigned to receive rivastigmine and 9 to receive placebo, underwent fMRI and clinical assessments at baseline and after 12 weeks. The fMRI task used a periodic block design and involved 3 conditions: rest, detecting a nonzero number ("nonzero" condition), and detecting a specific number ("specific number" condition) among a series of 6-digit numbers. Online data (via button presses) were acquired on both occasions. Behavioral results showed a trend (P = 0.075) for the rivastigmine-treated patients to have more correct responses and the placebo group to have fewer correct responses at 12 weeks compared with baseline in the "nonzero" condition. There was also an increase in regional brain activity in the cerebellum in the rivastigmine group at 12 weeks in both conditions, which was only partially explained by change in behavioral measures; no change was observed in the placebo group. Our results showed that rivastigmine treatment increased cerebellar activity and influenced attentional processes.

Structural brain correlates of prepulse inhibition of the acoustic startle response in healthy humans.

Neural regions modulating prepulse inhibition (PPI) of the startle response, an operational measure of sensorimotor gating, are well established from animal studies using surgical and pharmacological procedures. The limbic and cortico-pallido-striato-thalamic circuitry is thought to be responsible for modulation of PPI in the rat. The involvement of this circuitry in human PPI is suggested by observations of deficient PPI in a number of neuropsychiatric disorders characterized by abnormalities at some level in this circuitry and recent functional neuroimaging studies in humans. The current study sought to investigate structural neural correlates of PPI in a sample of twenty-four right-handed, healthy subjects (10 men, 14 women). Subjects 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. Optimized volumetric voxel-based morphometry (VBM) implemented in SPM99 was used to investigate the relationship of PPI (prepulse onset-to-pulse onset interval 120 ms) to regional grey matter volumes, covarying for sex. Significant positive correlations were obtained between PPI and grey matter volume in the hippocampus extending to parahippocampal gyrus, basal ganglia including parts of putamen, globus pallidus, and nucleus accumbens, superior temporal gyrus, thalamus, and inferior frontal gyrus. These findings identify the relationship between PPI and grey matter availability on a highly spatially localized scale in brain regions shown to be activated in recent functional neuroimaging studies in association with PPI in healthy humans and demonstrate the validity of structural neuroimaging methods in delineating the neural mechanisms underlying human PPI.

Sex effects in prepulse inhibition and facilitation of the acoustic startle response: implications for pharmacological and treatment studies.

Prepulse inhibition (PPI) refers to the reduction in the response amplitude to a startling stimuli (pulse) if it is preceded (i.e. 30-500 ms) by a weak stimulus (prepulse). If the time interval between the prepulse and pulse is more than 500 ms, then an increase in this response amplitude can be seen, termed prepulse facilitation (PPF). PPI is thought to represent an operational index of sensorimotor function whereas PPF is thought to reflect, at least to some degree, sustained attention. Interestingly, PPI is found to be sexually dimorphic, with men exhibiting more PPI than women when subjects are tested without regard to where they are in the menstrual cycle, and to be impaired in several neuropsychiatric disorders known to exhibit sex differences in their clinical presentation. PPF has received relatively less attention in both normal and clinical studies. This study examined sex differences in both PPI and PPF in 62 healthy subjects (34 women, 28 men) using a range of prepulse-to-pulse intervals to elicit PPI (30, 60, 120, 240 and 480 ms) and PPF (1000 and 2000 ms). Men showed higher PPI than women but women showed higher PPF compared to men. These results suggest that reduced PPI in healthy women is not a simple reduction but rather a shift of the inhibition/facilitation curve in the direction of facilitation in women, relative to men. Future studies investigating pharmacological and treatment effects using a prepulse modification paradigm in normal and clinical populations of both sexes would benefit from an examination of sex effects and assessments of both PPI and PPF.

Sex differences in prepulse inhibition deficits in chronic schizophrenia.

Recent years have seen a dramatic growth in the number of studies using prepulse inhibition (PPI) paradigms to index information processing deficits in schizophrenia. There are, however, robust sex differences in PPI in healthy subjects, with women exhibiting less PPI than men in the absence of any psychopathology. To investigate the role of sex in prepulse modification deficits in the long-term course of schizophrenia, we assessed PPI (response inhibition with the prepulse preceding the pulse by 30-150 ms) and prepulse facilitation (PPF; response facilitation with the prepulse preceding the pulse by 1000 ms) of the acoustic startle response in 42 chronic schizophrenia patients (27 men; all 42 on typical antipsychotics) and 35 controls (15 men). The results revealed that healthy women showed less PPI than healthy men. Men with schizophrenia showed less PPI compared to healthy men, but women with schizophrenia did not differ in PPI from healthy women. Age of illness onset negatively correlated to PPI in male patients. There was no significant effect of sex in PPF, and although patients (regardless of sex) showed less PPF relative to controls, this effect was abolished when the current age was co-varied for. These findings indicate sex differences in PPI deficits in schizophrenia. Future studies of schizophrenia patients need to take sex and age of subjects into account to optimise the investigation of PPI deficits, and their clinical, neural, and pharmacological correlates.