HUMAN PSYCHOPHYSIOLOGICAL CORRELATES OF SENSORIMOTOR FUNCTIONING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. a) Certain neuropsychiatric disorders are characterized by a brain-based deficit in the ability to effectively inhibit, or "gate" sensory, cognitive or motor information. To study the physiological basis of this inhibitory deficit, we use prepulse inhibition of the acoustic startle reflex as an operational measure of sensorimotor gating. We study the acoustic startle reflex, including prepulse inhibition (PPI) and prepulse facilitation of startle, in Psychiatric and Neurologic patients (Obsessive Compulsive Disorder, Huntington's Disease, Schizophrenia, Impulse Control Disorders, Tourette's Syndrome, and Attention Deficit Disorder), and in appropriate control comparison populations. A substantial literature of preclinical studies demonstrates that prepulse modification of the startle reflex, including PPI, is regulated by specific neurochemical substrates. Among these, brain dopamine (DA) activity is known to regulate PPI via D2-family receptors in portions of the striatum. PPI is disrupted or eliminated in rats by systemic or intracerebral treatment with DA agonists. These and related animal studies have allowed us to identify a specific neural circuitry, connecting limbic cortical structures, through their basal ganglia efferents, to pontine structures, that regulates the amount of sensorimotor gating, as measured by PPI. It would be critically important to determine whether these same substrates regulating PPI in rats, could be extrapolated to humans, and thus allow us to interpret the neural basis for abnormal patterns of PPI in neurologic and psychiatric patients. In a series of studies, we investigated the neurochemistry of PPI in humans, by documenting changes in PPI in response to specific pharmacologic probes, using adequate sample sizes, agonist-antagonist interactions and informative dose-response profiles where possible. The similarities and differences between the responses to pharmacological manipulations in humans and rats provide important evidence for understanding the neural circuit substrates of PPI in humans. b) Differences in sensorimotor gating also distinguish certain groups of normal subjects. Specifically, prepulse inhibition is sexually dimorphic, and differs in systematic and predictable ways across certain normal personality dimensions. To facilitate studies of the biological substrates for these "normal" differences in sensorimotor gating, our studies have identified the optimal stimulus parameters for studying sex differences in prepulse modulation of startle in men and women in control and patient populations. c) Differences in sensorimotor inhibition will be detected by some, but not other laboratory-based measures, reflecting differences in the particular psychophysical demands of the measure. To add to our understanding of patterns of sensorimotor inhibition across patient and normal populations, and of changes in sensorimotor inhibition in response to specific manipulations of brain circuitry thought to regulate one form of sensorimotor inhibition (PPI), we also assess Latent Inhibition, Negative Priming and the Stroop Test in our subjects. d) Particular characteristics of the test subjects are useful grouping variables for understanding patterns of sensorimotor gating in control populations. Specific questionnaires are used to evaluate personality and behavioral characteristics of the control populations.