Functional magnetic resonance imaging investigation of the amphetamine sensitization model of schizophrenia in healthy male volunteers.

CONTEXT Recent work suggests that the amphetamine sensitization model of schizophrenia can safely be induced in healthy volunteers and is associated both with behavioral and dopaminergic hypersensitivity to amphetamine. However, the effects of a sensitization on brain function remain unclear. OBJECTIVE To assess the impact of a sensitizing dosage regimen of dextroamphetamine on human cortical functioning and cognition. DESIGN Randomized, double-blind, parallel-groups design using pharmacological functional magnetic resonance imaging. SETTING The neuroimaging research unit at the Institute of Psychiatry, King's College London, London, England. PARTICIPANTS Healthy male volunteers (n = 22). INTERVENTIONS Dextroamphetamine (20 mg) or placebo administration at 4 testing sessions, using a dosage regimen shown to induce sensitization (ie, 3 doses administered with a 48-hour interdose interval and a final dose after a 2-week washout period). MAIN OUTCOME MEASURES Sensitization was characterized by enhanced subjective response to the drug, changes in behavioral performance (reaction time and accuracy), and functional magnetic resonance imaging measurements of brain activity during an N-back working memory task. RESULTS Sensitization was associated with more rapid responding during the performance of an intermediate-load working memory challenge. During a high-load cognitive challenge, sensitization did not produce performance deficits, but functional magnetic resonance imaging showed hyperactivity of the dorsolateral prefrontal cortex and aberrant recruitment of the superior temporal gyrus, caudate nucleus, and thalamus. Furthermore, the change in striatal activity was negatively correlated with the enhanced subjective effects of the drug, whereas prefrontal hyperactivity was positively correlated with sensitized measures of alertness. CONCLUSIONS These transient load-dependent abnormalities of frontal and temporal activity induced by amphetamine sensitization support neuroimaging findings in schizophrenic patients, implying that amphetamine sensitization may help to bridge pathophysiological theories of schizophrenia that focus on pharmacological (dopaminergic) and cognitive mechanisms, respectively.