A functional polymorphism in the promoter region of the human serotonin transporter gene (SLC6A4) has been associated with several dimensions of neuroticism and psychopathology, especially anxiety traits, but the predictive value of this genotype against these complex behaviors has been inconsistent. Serotonin [5- hydroxytryptamine, (5-HT)] function influences normal fear as well as pathological anxiety, behaviors critically dependent on the amygdala in animal models and in clinical studies. We now report that individuals with one or two copies of the short allele of the serotonin transporter (5-HTT) promoter polymorphism, which has been associated with reduced 5-HTT expression and function and increased fear and anxiety-related behaviors, exhibit greater amygdala neuronal activity, as assessed by BOLD functional magnetic resonance imaging, in response to fearful stimuli compared with individuals homozygous for the long allele. These results demonstrate genetically driven variation in the response of brain regions underlying human emotional behavior and suggest that differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele.

Monamines subserve many critical roles in the brain, and monoaminergic drugs such as amphetamine have a long history in the treatment of neuropsychiatric disorders and also as a substance of abuse. The clinical effects of amphetamine are quite variable, from positive effects on mood and cognition in some individuals, to negative responses in others, perhaps related to individual variations in monaminergic function and monoamine system genes. We explored the effect of a functional polymorphism (val 158 -met) in the catechol O-methyltransferase gene, which has been shown to modulate prefrontal dopamine in animals and prefrontal cortical function in humans, on the modulatory actions of amphetamine on the prefrontal cortex. Amphetamine enhanced the efficiency of prefrontal cortex function assayed with functional MRI during a working memory task in subjects with the high enzyme activity val͞val genotype, who presumably have relatively less prefrontal synaptic dopamine, at all levels of task difficulty. In contrast, in subjects with the low activity met͞met genotype who tend to have superior baseline prefrontal function, the drug had no effect on cortical efficiency at low-to-moderate working memory load and caused deterioration at high working memory load. These data illustrate an application of functional neuroimaging in pharmacogenomics and extend basic evidence of an inverted-''U'' functional-response curve to increasing dopamine signaling in the prefrontal cortex. Further, individuals with the met͞met catechol O-methyltransferase genotype appear to be at increased risk for an adverse response to amphetamine. A mphetamine (AMP) and other psychostimulants are among the most effective psychotropic medications in clinical use and the mainstay of treatment for patients with attention deficit hyperactivity disorder (ADHD), narcolepsy, chronic fatigue syndrome, and apathy and anhedonia of diverse etiologies. There is general consensus that these drugs increase CNS alertness, modulate attention, and enhance mood and cognitive performance by potentiating monaminergic neurotransmission. Because of these effects, and the reinforcing properties of monoaminergic stimulation, AMP and related compounds are popular substances of abuse. Although it has been well known that there are dose-and behavior-dependent differential effects of psychostimulants (1, 2), there is also considerable evidence that the response to these drugs varies across individuals, even to fixed doses (3-5). These variable effects have been difficult to predict a priori and to date no neurobiological explanation for them has been established. It is possible that some of the intersubject differences can be explained by functional polymorphisms in monoamine system genes (e.g., synaptic proteins, metabolic enzymes, etc.) that effect baseline monoaminergic tone.While AMP blocks the action of transporters at dopaminergic, serotonergic, and noradrenergic neurons, its positive effects on attention and cognition appear to be mediated principally at the prefrontal cor...

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The MR parkinsonism index can help distinguish patients with PSP from those with PD and MSA-P on an individual basis.

The results of this study show that elderly subjects recruit additional cortical and subcortical areas even for the performance of a simple motor task. These changes may represent compensatory mechanisms invoked by the aging brain, such as reorganization and redistribution of functional networks to compensate for age-related structural and neurochemical changes.

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In addition to classic motor signs and symptoms, Parkinson's disease (PD) is characterized by neuropsychological and emotional deficits, including a blunted emotional response. In the present study, we explored both the neural basis of abnormal emotional behavior in PD and the physiological effects of dopaminergic therapy on the response of the amygdala, a central structure in emotion processing. PD patients and matched normal controls (NCs) were studied with blood oxygenation level-dependent functional magnetic resonance imaging during a paradigm that involved perceptual processing of fearful stimuli. PD patients were studied twice, once during a relatively hypodopaminergic state (i.e., > or =12 hr after their last dose of dopamimetic treatment) and again during a dopamine-replete state. The imaging data revealed a robust bilateral amygdala response in NCs that was absent in PD patients during the hypodopaminergic state. Dopamine repletion partially restored this response in PD patients. Our results demonstrate an abnormal amygdala response in PD that may underlie the emotional deficits accompanying the disease. Furthermore, consistent with findings in experimental animal paradigms, our results provide in vivo evidence of the role of dopamine in modulating the response of the amygdala to sensory information in human subjects.