Gillian A. O'Driscoll

Nicotine and Behavioral Markers of Risk for Schizophrenia: A Double-Blind, Placebo- Controlled, Cross-Over Study

We investigated the effect of nicotine on three behavioral markers of risk for schizophrenia: sustained attention (using the Continuous Performance Task (CPT)), antisaccade performance, and smooth pursuit. Smooth pursuit was investigated in two conditions, one in which attention was enhanced (monitoring target changes) and one in which attention was not enhanced (no monitoring). Patients with schizophrenia (n = 15) and controls (n = 14) were given a 14-mg nicotine patch in a double-blind, placebo-controlled, crossover design and plasma nicotine concentrations were monitored. Nicotine concentrations were similar in both groups. A Group × Drug interaction (p < .02) on CPT hits indicated that nicotine improved sustained attention in patients but not in controls. Nicotine significantly decreased antisaccade errors (p < .01) in both groups. A Drug × Monitoring condition interaction (p < .01) on pursuit gain indicated that nicotine significantly increased pursuit gain in the no-monitoring condition in patients and controls equally, but did not improve pursuit in the monitoring condition. Thus, improvement in pursuit may have been mediated via an effect on attention rather than by an effect on oculomotor function per se. In patients, the magnitude of improvement in attention on nicotine was correlated with the improvement on eye movement tasks. Thus, nicotine improves performance on both attention and oculomotor markers of risk for schizophrenia, possibly via common mechanisms.

Stress-induced dopamine release in humans at risk of psychosis: a [11C]raclopride PET study.

Drugs that increase dopamine levels in the brain can cause psychotic symptoms in healthy individuals and worsen them in schizophrenic patients. Psychological stress also increases dopamine release and is thought to play a role in susceptibility to psychotic illness. We hypothesized that healthy individuals at elevated risk of developing psychosis would show greater striatal dopamine release than controls in response to stress. Using positron emission tomography and [11C]raclopride, we measured changes in synaptic dopamine concentrations in 10 controls and 16 psychometric schizotypes; 9 with perceptual aberrations (PerAb, ie positive schizotypy) and 7 with physical anhedonia (PhysAn, ie negative schizotypy). [11C]Raclopride binding potential was measured during a psychological stress task and a sensory-motor control. All three groups showed significant increases in self-reported stress and cortisol levels between the stress and control conditions. However, only the PhysAn group showed significant stress-induced dopamine release. Dopamine release in the entire sample was significantly negatively correlated with smooth pursuit gain, an endophenotype linked to frontal lobe function. Our findings suggest the presence of abnormalities in the dopamine response to stress in negative symptom schizotypy, and provide indirect evidence of a link to frontal function.

Amygdala–hippocampal volume and verbal memory in first-degree relatives of schizophrenic patients

Verbal memory deficits have been related to reduced volume of medial temporal structures in several neurological and psychiatric populations, including schizophrenic patients. Impairments in verbal memory have been proposed to be a marker of risk for schizophrenia. Recently, relatives of schizophrenic patients have been reported to have reduced volume of the amygdala-hippocampal complex. In this study, we evaluate the possibility that amygdala-hippocampal volume reductions may constitute one neural substrate of verbal memory deficits in first-degree relatives. Subjects were 20 healthy first-degree relatives of schizophrenic patients and 14 demographically similar controls. Verbal memory was assessed with the Logical Memory Test. Subjects were scanned with high-resolution MRI and the images were transformed into Talairach space. Volumes of interest were amygdala-anterior hippocampus and posterior hippocampus. Relatives of schizophrenic patients had intact immediate verbal memory but significantly poorer delayed verbal memory than controls. Relatives also had significantly reduced amygdala-anterior hippocampus volumes. Across all subjects, delayed verbal memory was significantly correlated with amygdala-anterior hippocampus volume. The magnitude of the correlation did not differ between the groups. These data provide an empirical link between memory performance and volumetric abnormalities in the amygdala-hippocampal complex in the relatives of schizophrenic patients.

Antisaccade performance in biological relatives of schizophrenia patients: a meta-analysis

Poor performance on the antisaccade (AS) task has been interpreted as a potential indicator of genetic liability that may enhance the power of linkage studies of a multidimensional phenotype for schizophrenia. Every study has replicated the finding of significantly worse performance in schizophrenia patients regardless of which specific antisaccade paradigm was employed. In some studies involving a standard version of the antisaccade task, relatives of schizophrenia patients made an increased number of errors, but in other studies that used this same paradigm, relatives of schizophrenia patients did not differ from controls. In this paper, we report the results of a meta-analysis on studies that used the standard antisaccade paradigm. The meta-analysis shows that those studies that reported large effect sizes and statistically significant differences between relatives of schizophrenia patients and controls used inclusion/exclusion criteria that were not symmetrical between the two groups, whereas those studies that reported small and nonsignificant differences between relatives of schizophrenia patients and controls used symmetrical inclusion/exclusion criteria. Specifically, studies that applied stricter psychopathology exclusion criteria to controls than to relatives of schizophrenia patients had larger effect sizes than studies that applied comparable exclusion criteria to both groups, suggesting that antisaccade performance is compromised by psychopathology in general rather than by schizophrenia per se. Since symmetrical inclusion/exclusion criteria between relatives of schizophrenia patients and controls are essential for a genetic analysis, and those studies that did apply symmetrical criteria had small effect sizes, the available data suggest that poor antisaccade performance is unlikely to be useful in identifying clinically unaffected carriers of genes for schizophrenia.

Neuropsychological impairments in neuroleptic-responder vs. -nonresponder schizophrenic patients and healthy volunteers.

To determine whether two groups of schizophrenic patients representing the two extremes of the neuroleptic response-spectrum (consistent responders vs. consistent nonresponders) differ with respect to their neuropsychological profile. Neuroleptic-responder (R; n=36) and -nonresponder (NR; n=39) schizophrenic patients were recruited according to a priori defined criteria of responsiveness to typical neuroleptics. Seven neuropsychological domains were assessed and compared between groups: attention-vigilance, abstraction-flexibility, spatial organization, visual-motor processing, visual memory, verbal abilities, and verbal memory and learning. All measures were standardized using the scores of 36 healthy volunteers. NR schizophrenic patients performed worse in all neuropsychological domains compared to normal controls and R schizophrenic patients. However, only performances on visual memory, verbal abilities, and verbal memory and learning were significantly poorer in NR compared to R patients. Only the latter domain significantly differentiated NR patients from the other two groups. R patients performed at an intermediate level in all domains. This report of differences in neuropsychological profile between neuroleptic-responder and -nonresponder schizophrenic patients adds to the growing evidence supporting the value of distinguishing schizophrenic patients on the basis of their therapeutic response to neuroleptics.

Transcranial magnetic stimulation of frontal oculomotor regions during smooth pursuit.

Both the frontal eye fields (FEFs) and supplementary eye fields (SEFs) are known to be involved in smooth pursuit eye movements. It has been shown recently that stimulation of the smooth-pursuit area of the FEF [frontal pursuit area (FPA)] in monkey increases the pursuit response to unexpected changes in target motion during pursuit. In the current study, we applied transcranial magnetic stimulation (TMS) to the FPA and SEF in humans during sinusoidal pursuit to assess its effects on the pursuit response to predictable, rather than unexpected, changes in target motion. For the FPA, we found that TMS applied immediately before the target reversed direction increased eye velocity in the new direction, whereas TMS applied in mid-cycle, immediately before the target began to slow, decreased eye velocity. For the SEF, TMS applied at target reversal increased eye velocity in the new direction but had no effect on eye velocity when applied at mid-cycle. TMS of the control region (leg region of the somatosensory cortex) did not affect eye velocity at either point. Previous stimulation studies of FPA during pursuit have suggested that this region is involved in controlling the gain of the transformation of visual signals into pursuit motor commands. The current results suggest that the gain of the transformation of predictive signals into motor commands is also controlled by the FPA. The effect of stimulation of the SEF is distinct from that of the FPA and suggests that its role in sinusoidal pursuit is primarily at the target direction reversal.

Smooth pursuit eye movement and schizotypy in the community.

Deficits in smooth pursuit eye movements are well documented in schizophrenia and schizotypic psychopathology. The status of eye tracking dysfunction (ETD) as an endophenotype for schizophrenia liability is relatively robust. However, the relation of ETD to schizophrenia-related deviance in the general population has not been confirmed. This study examined smooth pursuit eye tracking and schizotypal personality features in the general population. Smooth pursuit eye movement and schizotypal features were measured in 300 adult community subjects. The sample included both sexes, subjects with a wide age and educational range, and subjects with no prior history of psychosis. Primary outcome measures were peak gain (eye velocity/target velocity), catch-up saccade rate, and schizotypal feature scores. Total schizotypal features were significantly associated with decreased peak gain and were associated at the trend level with increased catch-up saccade rate. These associations were essentially unchanged after controlling for age, sex, and intellectual level effects. These data confirm a hypothesized association between schizotypal features and poorer eye tracking performance (principally, peak gain) in the general population as well as support the conceptualization of ETD as an endophenotype for schizophrenia liability.

Schizotypy, attention deficit hyperactivity disorder, and dopamine genes

Abstract  Previous research has suggested that there may be overlap between schizophrenia and attention‐deficit hyperactivity disorder (ADHD). The relationship between schizotypal personality traits, ADHD features and polymorphisms was evaluated in dopamine‐related genes. Thirty‐one healthy, Caucasian men completed the Rust Inventory of Schizotypal Cognitions (RISC) and the ADHD Self‐Report Scale (ASRS). Catechol‐O‐methyltransferase (COMT) Val158Met, dopamine receptors of the D3 type (DRD3) Ser9Gly, DRD4 variable number of tandem repeats (VNTR), and SLC6A3 VNTR polymorphisms were analyzed. RISC score was correlated with ASRS score (r = 0.54, P = 0.003). COMT Met homozygotes had higher ASRS scores than Val homozygotes (P = 0.005). These findings are consistent with evidence of overlap between schizophrenia and ADHD and support an involvement of COMT genotype in ADHD features.

Limbic response to psychosocial stress in schizotypy: A functional magnetic resonance imaging study

Psychological stress causes dopamine release in the striatum and is thought to play a role in susceptibility to psychotic illness. Previous work suggests that an elevated dopaminergic response to stress may index vulnerability to psychosis in certain individuals. With functional magnetic resonance imaging, we measured stress-induced changes in brain activity in healthy individuals at elevated risk of developing psychosis. Participants were 15 controls and 25 psychometric schizotypes: 12 with positive symptom schizotypy (perceptual aberrations) and 13 with negative symptom schizotypy (physical anhedonia), as determined by questionnaires (Chapman et al., 1976; Chapman and Chapman, 1978). In the scanner, participants performed the Montreal Imaging Stress Task and a matched sensory-motor control task. Measures of self-reported stress and salivary cortisol levels were taken throughout the experiment. All three groups showed significant increases in self-reported stress and significant fMRI signal change in the striatal, limbic and cortical regions. However, the Physical Anhedonia group showed greater stress-induced striatal and limbic deactivation than the other two groups. Deactivation in the striatum was significantly correlated with Physical Anhedonia score across all subjects. Our findings suggest the presence of abnormalities in striatal response to stress in negative symptom schizotypy.

Amphetamine-Induced Dopamine Release and Neurocognitive Function in Treatment-Naive Adults with ADHD

Converging evidence from clinical, preclinical, neuroimaging, and genetic research implicates dopamine neurotransmission in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The in vivo neuroreceptor imaging evidence also suggests alterations in the dopamine system in ADHD; however, the nature and behavioral significance of those have not yet been established. Here, we investigated striatal dopaminergic function in ADHD using [11C]raclopride PET with a d-amphetamine challenge. We also examined the relationship of striatal dopamine responses to ADHD symptoms and neurocognitive function. A total of 15 treatment-free, noncomorbid adult males with ADHD (age: 29.87±8.65) and 18 healthy male controls (age: 25.44±6.77) underwent two PET scans: one following a lactose placebo and the other following d-amphetamine (0.3 mg/kg, p.o.), administered double blind and in random order counterbalanced across groups. In a separate session without a drug, participants performed a battery of neurocognitive tests. Relative to the healthy controls, the ADHD patients, as a group, showed greater d-amphetamine-induced decreases in striatal [11C]raclopride binding and performed more poorly on measures of response inhibition. Across groups, a greater magnitude of d-amphetamine-induced change in [11C]raclopride binding potential was associated with poorer performance on measures of response inhibition and ADHD symptoms. Our findings suggest an augmented striatal dopaminergic response in treatment-naive ADHD. Though in contrast to results of a previous study, this finding appears consistent with a model proposing exaggerated phasic dopamine release in ADHD. A susceptibility to increased phasic dopamine responsivity may contribute to such characteristics of ADHD as poor inhibition and impulsivity.