Adrian Galea

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.

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.

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.

Gender differences in immediate memory in bipolar disorder

BACKGROUND Gender is known to modulate the clinical course and severity of bipolar disorder (BD). Although cognitive abnormalities are an established feature of BD, there is limited information regarding whether gender also influences the pattern and severity of cognitive impairment. METHOD We evaluated the performance of 86 remitted patients with BD, type 1, (BD-I) (36 male and 50 female) and 46 healthy participants (21 male and 25 female) on tasks of general intellectual ability, memory encoding, recognition and retrieval, response inhibition and executive function (abstraction and perseveration). The impact of illness severity in patients was assessed using the global assessment of functioning (GAF). RESULTS We found a gender effect and an interaction between diagnosis and gender on immediate memory, implicating encoding and retrieval processes, both showing male BD-I patients being disadvantaged compared with female patients and healthy controls. Immediate memory correlated with GAF scores and this association was statistically significant for male BD-I patients. CONCLUSIONS Our findings suggest that gender differences in BD-I are associated with memory function, particularly processes relating to encoding and retrieval, and may contribute to poor functional outcome particularly in men.

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.

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.

Vulnerability indicators in bipolar disorder

Materials and methods We recruited 75 unaffected relatives and 71 controls. 33 had lifetime (23 offspring and 10 siblings) diagnoses of major depressive disorder (n=21), anxiety disorders (n=4), substance abuse (n=11) and eating disorder (n=1). All participants underwent assessment of their general intellectual ability, memory, working memory, response inhibition and emotional learning (EL). Level of symptomatology was assessed using Hamilton Depressive Rating Scale (HDRS), Young Mania Rating Scale (YMRS) and Brief Psychiatric Rating Scale (BPRS). We conducted two analyses; one with whole sample siblings and offspring and another including asymptomatic ones defined as scoring 24 on the BPRS.