Francesco Fera

Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine.

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 (val158-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 val/val genotype, who presumably have relatively less prefrontal synaptic dopamine, at all levels of task difficulty. In contrast, in subjects with the low activity met/met 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 met/met catechol O-methyltransferase genotype appear to be at increased risk for an adverse response to amphetamine.

Neocortical modulation of the amygdala response to fearful stimuli.

BACKGROUND The cortical circuitry involved in conscious cognitive processes and the subcortical circuitry involved in fear responses have been extensively studied with neuroimaging, but their interactions remain largely unexplored. A recent functional magnetic resonance imaging (fMRI) study demonstrated that the engagement of the right prefrontal cortex during the cognitive evaluation of angry and fearful facial expressions is associated with an attenuation of the response of the amygdala to these same stimuli, providing evidence for a functional neural network for emotional regulation. METHODS In the current study, we have explored the generalizability of this functional network by using threatening and fearful non-face stimuli derived from the International Affective Picture System (IAPS), as well as the influence of this network on peripheral autonomic responses. RESULTS Similar to the earlier findings with facial expressions, blood oxygen level dependent fMRI revealed that whereas perceptual processing of IAPS stimuli was associated with a bilateral amygdala response, cognitive evaluation of these same stimuli was associated with attenuation of this amygdala response and a correlated increase in response of the right prefrontal cortex and the anterior cingulate cortex. Moreover, this pattern was reflected in changes in skin conductance. CONCLUSIONS The current results further implicate the importance of neocortical regions, including the prefrontal and anterior cingulate cortices, in regulating emotional responses mediated by the amygdala through conscious evaluation and appraisal.

The Amygdala Response to Emotional Stimuli: A Comparison of Faces and Scenes

As a central fear processor of the brain, the amygdala initiates a cascade of critical physiological and behavioral responses. Neuroimaging studies have shown that the human amygdala responds not only to fearful and angry facial expressions but also to fearful and threatening scenes such as attacks, explosions, and mutilations. Given the relative importance of facial expressions in adaptive social behavior, we hypothesized that the human amygdala would exhibit a stronger response to angry and fearful facial expressions in comparison to other fearful and threatening stimuli. Twelve subjects completed two tasks while undergoing fMRI: matching angry or fearful facial expressions, and matching scenes depicting fearful or threatening situations derived from the International Affective Picture System (IAPS). While there was an amygdala response to both facial expressions and IAPS stimuli, direct comparison revealed that the amygdala response to facial expressions was significantly greater than that to IAPS stimuli. Autonomic reactivity, measured by skin conductance responses, was also greater to facial expressions. These results suggest that the human amygdala shows a stronger response to affective facial expressions than to scenes, a bias that should be considered in the design of experimental paradigms interested in probing amygdala function.

Neurophysiological correlates of age-related changes in human motor function

BackgroundThere are well-defined and characteristic age-related deficits in motor abilities that may reflect structural and chemical changes in the aging brain. ObjectiveTo delineate age-related changes in the physiology of brain systems subserving simple motor behavior. MethodsTen strongly right-handed young (<35 years of age) and 12 strongly right-handed elderly (>50 years of age) subjects with no evidence of cognitive or motor deficits participated in the study. Whole-brain functional imaging was performed on a 1.5-T MRI scanner using a spiral pulse sequence while the subjects performed a visually paced “button-press” motor task with their dominant right hand alternating with a rest state. ResultsAlthough the groups did not differ in accuracy, there was an increase in reaction time in the elderly subjects (mean score ± SD, young subjects = 547 ± 97 ms, elderly subjects = 794 ± 280 ms, p < 0.03). There was a greater extent of activation in the contralateral sensorimotor cortex, lateral premotor area, supplementary motor area, and ipsilateral cerebellum in the elderly subjects relative to the young subjects (p < 0.001). Additional areas of activation, absent in the young subjects, were seen in the ipsilateral sensorimotor cortex, putamen (left > right), and contralateral cerebellum of the elderly subjects. ConclusionsThe 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.

Dopamine Modulates the Response of the Human Amygdala: A Study in Parkinson's Disease

In addition to classic motor signs and symptoms, Parkinsons 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., ≥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 providein vivo evidence of the role of dopamine in modulating the response of the amygdala to sensory information in human subjects.

Dextroamphetamine Modulates the Response of the Human Amygdala

Amphetamine, a potent monoaminergic agonist, has pronounced effects on emotional behavior in humans, including the generation of fear and anxiety. Recent animal studies have demonstrated the importance of monoamines, especially dopamine, in modulating the response of the amygdala, a key brain region involved in the perception of fearful and threatening stimuli, and the generation of appropriate physiological and behavioral responses. We have explored the possibility that the anxiogenic effect of amphetamine in humans reflects the drugs influence on the activity of the amygdala. In a double-blind placebo controlled study, fMRI revealed that dextroamphetamine potentiated the response of the amygdala during the perceptual processing of angry and fearful facial expressions. Our results provide the first evidence of a specific neural substrate for the anxiogenic effects of amphetamine and are consistent with animal models of dopaminergic activation of the amygdala.

Monoamine Oxidase-A Genetic Variations Influence Brain Activity Associated with Inhibitory Control: New Insight into the Neural Correlates of Impulsivity

BACKGROUND Previous evidence has shown that genetic variations in the serotonergic system contribute to individual differences in personality traits germane to impulse control. The monoamine oxidase-A (MAO-A) gene, coding for an enzyme primarily involved in serotonin and noradrenaline catabolism, presents a well-characterized functional polymorphism consisting of a variable number of tandem repeats in the promoter region, with high-activity and low-activity variants. High-activity allele carriers have higher enzyme expression, lower amine concentration, and present higher scores on behavioral measures of impulsivity than low-activity allele carriers. METHODS We studied the relationship of this polymorphism to brain activity elicited by a response inhibition task (Go/NoGo task), using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging in 24 healthy men. RESULTS Direct comparison between groups revealed a greater BOLD response in the right ventrolateral prefrontal cortex (Brodmanns area [BA] 45/47) in high-activity allele carriers, whereas a greater response in the right superior parietal cortex (BA 7) and bilateral extrastriate cortex (BA 18) was found in low-activity allele carriers. CONCLUSIONS These data suggest that a specific genetic variation involving serotonergic catabolism can modulate BOLD response associated with human impulsivity.

Functional changes in the activity of brain regions underlying emotion processing in the elderly

Aging is associated with a decline in both cognitive and motor abilities that reflects deterioration of underlying brain circuitry. While age-related alterations have also been described in brain regions underlying emotional behavior (e.g., the amygdala), the functional consequence of such changes is less clear. To this end, we used blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) to explore age-related changes in brain regions underlying emotion processing. Twelve young (age <30 years) and 14 elderly subjects (age >60 years) were studied with BOLD fMRI during a paradigm that involved perceptual processing of fearful and threatening stimuli. Consistent with previous reports, direct group comparisons revealed relatively increased BOLD fMRI responses in prefrontal cortical regions, including Brocas area, and relatively decreased responses in the amygdala and posterior fusiform gyri in elderly subjects. Importantly, additional analyses using an elderly-specific brain template for spatial normalization of the elderly BOLD fMRI data confirmed these divergent regional response patterns. While there was no difference between groups in accuracy on the task, elderly subjects were significantly slower (delayed reaction times) in performing the task. Our current data suggest that elderly subjects engage a more distributed neocortical network during the perceptual processing of emotional facial expressions. In light of recent converging data from two other studies, our observed effects may reflect age-related compensatory responses and/or alternative strategies in processing emotions, as the elderly appear to engage cognitive/linguistic systems in the context of reduced sensory and/or limbic responses.

Transverse sinus stenoses persist after normalization of the CSF pressure in IIH

Background: Bilateral transverse sinus (TS) stenosis has been found in more than 90% of patients with idiopathic intracranial hypertension (IIH). Objective: To evaluate whether TS stenosis changed after normalization of CSF pressure in patients with IIH during medical treatment. Methods: Fourteen consecutive patients with IIH with bilateral TS stenosis on cerebral MR venography (MRV) during the medical treatment were studied. Patients were followed for over a 6-year period. During the follow-up, patients underwent repeated lumbar punctures (LPs) and cerebral MRV. MRV was always performed before each LP. Results: TS stenosis persisted in all the patients during the follow-up. In 9 of 14 (64%) patients with IIH, CSF pressure normalized during medical treatment. Conclusions: Transverse sinus (TS) stenoses, as revealed by MR venography, persist in patients with idiopathic intracranial hypertension after normalization of CSF pressure, suggesting the lack of a direct relationship between the caliber of TS and CSF pressure.

Randomized trial comparing two different high doses of methylprednisolone in MS : A clinical and MRI study

Objective To assess the efficacy of two different high doses of intravenous methylprednisolone (IVMP) for the treatment of relapses in MS. Background NMP is the treatment of choice for MS relapses, but it is unknown whether its effects are dose related. Methods We conducted a double-blind, randomized study. Follow-up included serial clinical and MRI recordings at baseline and at 7, 15, 30, and 60 days after the beginning of treatment. Outcome measures were the number of brain and cervical spinal cord MRI contrast-enhancing lesions, and the Expanded Disability Status Scale score. Results Both treatment regimens improved clinical scores and reduced the number of MRI enhancing lesions during the follow-up period. The higher dose of IVMP was significantly more effective than the lower dose in reducing the number of MRI contrast-enhanced lesions at 30 and 60 days, mainly by decreasing the rate of new lesion formation. Conclusions The higher dosage of IVMP has a more powerful and prolonged action in maintaining blood-brain barrier integrity after a clinical relapse.