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 [(11)C]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). [(11)C]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.

Antisaccade and smooth pursuit performance in positive- and negative-symptom schizotypy.

Schizophrenic patients have well-documented abnormalities in smooth pursuit eye movements and antisaccade performance. In populations at risk for schizophrenia, smooth pursuit abnormalities are also well documented. Antisaccade deficits have been replicated in high-risk populations as well, but the findings are more variable and the reasons for the variability are not clear. Some evidence suggests that antisaccade deficits increase in high-risk populations in relation to the presence of positive symptoms. Whether antisaccade deficits increase in relation to negative symptoms in high-risk populations is relatively uninvestigated. We evaluated antisaccade and pursuit performance in "psychometric schizotypes" who had elevated scores on either the Perceptual Aberration Scale (PerAb; i.e., positive symptoms) or the Physical Anhedonia Scale (PhysAnh; i.e., negative symptoms) but not both, and in normal controls. We used the standard version of the antisaccade task, for which results in positive-symptom schizotypes have previously been reported, and investigated performance on a gap and overlap version. We replicated the finding that a significantly larger percentage of positive-symptom schizotypes than controls have elevated antisaccade error rates on the standard antisaccade task (P=0.03); the percentage of negative-symptom schizotypes with elevated antisaccade error rates did not differ from that of control subjects. Neither schizotypal group was impaired on the gap or overlap versions of the task. On the pursuit task, a higher percentage of positive- and negative-symptom schizotypes were classified as having deviant performance than control subjects (both Ps<0.04). These findings suggest that antisaccade deficits may be better at identifying high-risk subjects with positive symptoms. Pursuit deficits identified both positive- and negative-symptom schizotypes, but was better at identifying the latter.

Executive functions and methylphenidate response in subtypes of attention-deficit/hyperactivity disorder.

BACKGROUND: Oculomotor tasks are a well-established means of studying executive functions and frontal-striatal functioning in both nonhuman primates and humans. Attention-deficit/hyperactivity disorder (ADHD) is thought to implicate frontal-striatal circuitry. We used oculomotor tests to investigate executive functions and methylphenidate response in two subtypes of ADHD. METHODS: Subjects were boys, aged 11.5-14 years, with ADHD-combined (n = 10), ADHD-inattentive (n = 12), and control subjects (n = 10). Executive functions assessed were motor planning (tapped with predictive saccades), response inhibition (antisaccades), and task switching (saccades-antisaccades mixed). RESULTS: The ADHD-combined boys were impaired relative to control subjects in motor planning (p < .003) and response inhibition (p < .007) but not in task switching (p > .92). They were also significantly impaired relative to ADHD-inattentive boys, making fewer predictive saccades (p < .03) and having more subjects with antisaccade performance in the impaired range (p < .04). Methylphenidate significantly improved motor planning and response inhibition in both subtypes. CONCLUSIONS: ADHD-combined but not ADHD-inattentive boys showed impairments on motor planning and response inhibition. These deficits might be mediated by brain structures implicated specifically in the hyperactive/impulsive symptoms. Methylphenidate improved oculomotor performance in both subtypes; thus, it was effective even when initial performance was not impaired.

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 x 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 x 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.