E Zachariah

Smooth pursuit and antisaccade eye movements in siblings discordant for schizophrenia.

Smooth pursuit eye movement (SPEM) and antisaccade deficits have been proposed as endophenotypes in the search for schizophrenia genes. We assessed these measures in 24 schizophrenia patients, 24 of their healthy siblings, and 24 healthy controls closely matched to the siblings. Between-group differences were assessed using a random effects regression model taking into account the relatedness between patients and siblings. Patients showed reduced SPEM gain, increased frequency of saccades during pursuit, increased antisaccade error rate, and reduced antisaccade gain compared to controls. Siblings performed intermediate, i.e. between patients and controls, on most measures, but were particularly characterised by reduced antisaccade gain. SPEM gain at one target velocity was significantly correlated between patients and siblings, highlighting the necessity of taking into account within-family correlations in the statistical analysis of between-group differences. It is concluded that subtle SPEM and antisaccade deficits are observed in clinically unaffected siblings of schizophrenia patients; these deficits may be useful markers of genetic liability to 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.

Cognitive functioning in siblings discordant for schizophrenia

Objective:  The objective of this study was to investigate neuropsychological impairment as a genetically mediated risk indicator for schizophrenia while accounting for prevalence of schizotypy signs/symptoms in siblings.

Association between violent behaviour and impaired prepulse inhibition of the startle response in antisocial personality disorder and schizophrenia

Violent behaviour has a strong association with antisocial personality disorder (APD) and schizophrenia. Although developments in the understanding of socio-environmental factors associated with violence should not be ignored, advances in prevention and treatment of violent behaviour would benefit by improved understanding of its neurobiological and cognitive basis. The authors, therefore, investigated prepulse inhibition (PPI) of the startle response in APD and schizophrenia in relation to a history of serious violence. The neural substrates of PPI, especially the hippocampus, amygdala, thalamus and basal ganglia, are implicated in violence as well as in APD and schizophrenia. The study included four groups: (i) patients with APD and a history of violence, (ii) patients with schizophrenia and a history of violence, (iii) patients with schizophrenia without a history of violence, and (iv) healthy subjects with no history of violence or a mental disorder. All subjects were assessed identically on acoustic PPI. Compared to healthy subjects, significantly reduced PPI occurred in APD, violent schizophrenia and non-violent schizophrenia patients. Although PPI did not significantly differentiate the three clinical groups, high ratings of violence were modestly associated with reduced PPI across the entire study sample. Violent patients with impulsive and premeditated violence showed comparable PPI. The association between violent behaviour and impaired PPI suggests that neural structures and functions underlying PPI are implicated in (inhibition of) violence.

N100 and P300 amplitude to Go and No-Go variants of the auditory oddball in siblings discordant for schizophrenia.

BACKGROUND P300 amplitude reduction is reliably seen in schizophrenia. Inconsistent reports of isolated frontal and/or parietal deficits in unaffected family members may be clarified using a task that places greater load on frontal function. METHOD Go and No-Go versions of the auditory oddball task were performed by eighteen schizophrenia patients, age-matched unaffected siblings and healthy controls matched closely to unaffected siblings on age, sex, education, socioeconomic-status, handedness and ethnicity. Groups were compared on P300 and N100 amplitude and latency. Spearman correlations were used to test the relationship between ERP amplitudes and neuropsychological measures of executive function and memory. The relationship between schizotypy--as measured using the structured interview--and ERPs was explored in a combined group of siblings and controls. RESULTS Independent of task, patients had lower P300 than controls and reduced parietal amplitude compared to siblings. Siblings had enhanced frontocentral N100 compared to controls. No-Go P300 amplitude and N100 latency was associated with executive function measures. There were significant intraclass correlations between patients and siblings for No-Go P300 amplitude, particularly at the central midline electrode. Frontocentral N100 and P300 amplitude were positively correlated with anxiety-related aspects of schizotypy. CONCLUSION Enhanced N100 is present in unaffected siblings. Parietal P300 is intact in unaffected siblings, but reduced in patients. The No-Go-oddball is more sensitive than the Go-oddball to executive function deficits in patients and as an index of heritability.

Effects of Procyclidine on Eye Movements in Schizophrenia

Smooth pursuit eye movement (SPEM) and antisaccade deficits are observed in the schizophrenia spectrum and have been used to study the pathophysiology as well as the genetic basis of this condition. The neurotransmitter acetylcholine has been implicated in a number of cognitive processes thought to underlie SPEM and antisaccade performance. This study investigates effects on eye movements of procyclidine, an anticholinergic drug often administered to schizophrenic patients. A total of 13 patients completed a double-blind placebo-controlled crossover design, receiving 15 mg procyclidine and placebo. Seven participants received procyclidine first and placebo second, six participants were tested in the reverse order. SPEM and antisaccade (as well as fixation and prosaccade) eye movements were recorded using infrared oculography. Results showed that procyclidine overall, relative to placebo, mildly worsened SPEM performance, as indicated by nonsignificantly reduced gain (p=0.08) and increased frequency of intrusive anticipatory saccades during pursuit (p=0.06). A significant interaction of group and order of administration indicated that procyclidine increased the rate of antisaccade reflexive errors only when administered first; the opposite pattern was observed when placebo was administered first, likely due to the operation of practice effects at second assessment. These findings indicate that acute administration of a clinically relevant dose of procyclidine leads to mild impairments in eye movement performance in schizophrenic patients, suggesting the need to consider this compound in oculomotor studies in schizophrenia. The action of this anticholinergic drug on oculomotor performance is consistent with the hypothesized role of the cholinergic system in the cognitive mechanisms of attention and working memory, processes thought to underlie SPEM and antisaccade performance. Effects of order of administration and practice on the antisaccade task suggest that these factors need to be taken into consideration in future pharmacological studies.

Effects of acute procyclidine administration on prepulse inhibition of the startle response in schizophrenia: a double-blind, placebo-controlled study.

Prepulse inhibition (PPI) of the startle response refers to a reduction in response to a strong stimulus (pulse) if this is preceded shortly by a weak non-startling stimulus (prepulse). Consistent with theories of deficiencies in early stages of information processing, PPI is found to be reduced in patients with schizophrenia. Atypical antipsychotics are found to be more effective than typical antipsychotics in improving PPI in this population. Anticholinergic drugs are often used to control extrapyramidal symptoms induced by antipsychotic medication, especially by typical antipsychotics, in schizophrenic patients and are known to disrupt cognitive functions in both normal and schizophrenic populations. The effect of anticholinergics on PPI in schizophrenia has not yet been examined. This study determined the effects of procyclidine, an anticholinergic drug, on PPI in patients with schizophrenia given risperidone or quetiapine and not on any anticholinergic drugs, employing a placebo-controlled, cross-over design. Under double-blind conditions, subjects were administered oral 15 mg procyclidine and placebo on separate occasions, 2 weeks apart, and tested for acoustic PPI (prepulse 8 dB and 15 dB above the background and delivered with 30-ms, 60-ms and 120-ms prepulse-to-pulse intervals). Procyclidine significantly impaired PPI compared to placebo (assessed as percentage reduction) with 60-ms prepulse-to-pulse trials and increased the latencies to response peak across all trials. The use of anticholinergics needs to be carefully controlled/examined in investigations of information processing deficits using a PPI model and reduced to the minimum level in clinical care of schizophrenia.

Neurophysiological correlates of excitement in schizophrenia

OBJECTIVE The excitement cluster (excitement, hostility, uncooperativeness and impulsivity) may contribute to the risk of violent behaviour, treatment non-adherence, likelihood of discharge and substance use in psychosis. Evidence suggests involvement of frontal executive mechanisms that may show sex differences in their association with symptom severity. The current study tests the association between excitement and the frontal N200 and P300 components of the auditory event-related potential in schizophrenia as a function of sex. METHOD Fourteen men and 14 women with schizophrenia (mean illness duration=20years) completed a novelty oddball and clinical interview. RESULTS Men showed higher midline N200 and lower novelty P300 amplitude than women. They had more pronounced differences between midline and lateral N200 amplitude, and did not show the same Novel>Target effect for right frontal P300 as did women. Right frontal N200 amplitude to target stimuli was positively associated with excitement in women and inversely associated with excitement in men. Novelty P300 amplitude was inversely associated with excitement, particularly in women and over the right hemisphere. CONCLUSION Results suggest that mechanisms underpinning frontal N200 and P300 subcomponents are differentially involved in excitement depending on sex. Understanding these individual differences may have implications for developing personalised treatment.

Effects of 10 mg and 15 mg oral procyclidine on critical flicker fusion threshold and cardiac functioning in healthy human subjects

The critical flicker fusion threshold (CFFT) is thought to index alertness and cortical arousal. Sedative drugs reduce CFFT while psychostimulants increase it. Procyclidine is an anticholinergic that is used to control the extrapyramidal side-effects of antipsychotics in schizophrenia. This study examined the effects of clinically relevant doses of oral procyclidine administration on CFFT and heart rate in two separate experiments (Experiment 1, drug dose: 10 mg, n = 16; Experiment 2, drug dose: 15 mg, n = 12) involving healthy subjects using a double-blind, placebo-controlled, cross-over design. 10 mg procyclidine had no significant effect on CFFT, heart rate or self-ratings of mood, but the 15 mg dose significantly lowered CFFT at 1 h and 2 h after procyclidine administration, increased drowsiness ratings and produced a drop in heart rate. The effects observed in this study may have implications for treatment compliance of schizophrenic patients, choice of antipsychotics, prescribing to patients with heart disease and monitoring of cardiac function under treatment. Further investigations are required to quantify the effects of procyclidine on CFFT and cardiac function in patients with schizophrenia.