Ingrid Aasen

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.

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.

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.

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 Alzheimers 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.

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.

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.

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.

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.

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 17β-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.