Antonio Cerasa

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.

Essential Head Tremor Is Associated with Cerebellar Vermis Atrophy: A Volumetric and Voxel-Based Morphometry MR Imaging Study

BACKGROUND AND PURPOSE: Our aim was to investigate the presence of brain gray matter (GM) abnormalities in patients with different forms of essential tremor (ET). MATERIALS AND METHODS: We used optimized voxel-based morphometry (VBM) and manually traced single region-of-interest analysis in 50 patients with familial ET and in 32 healthy subjects. Thirty patients with ET had tremor of the arms (a-ET), whereas the remaining 20 patients had both arm and head tremor (h-ET). RESULTS: VBM showed marked atrophy of the cerebellar vermis in the patients with h-ET with respect to healthy subjects (Pcorrected < .001). Patients with a-ET showed a trend toward a vermal GM volume loss that did not reach a significant difference with respect to healthy controls (Puncorrected < .01). The region-of-interest analysis showed a reduction of the cerebellar volume (CV) in the h-ET group (98.2 ± 13.6 mm3) compared with healthy controls (110.5 ± 15.5 mm3, P < .012) as well as in the entire vermal area (790.3 ± 94.5 mm2, 898.6 ± 170.6 mm2, P < .04 in h-ET and control groups, respectively). CONCLUSIONS: Atrophy of the cerebellar vermis detected in patients with h-ET strongly supports the evidence for the involvement of the cerebellum in the pathophysiology of ET. The lack of a significant CV loss observed in patients with a-ET suggests that a-ET and h-ET might represent distinct subtypes of the same disease.

Functional changes in the activity of cerebellum and frontostriatal regions during externally and internally timed movement in Parkinson's disease.

We used fMRI to investigate the neurofunctional basis of externally and internally timed movements in Parkinsons disease (PD) patients. Ten PD patients whose medication had been withheld for at least 18h and 11 age- and sex-matched healthy controls were scanned while performing continuation paradigm with a visual metronome. Compared with the controls, PD patients displayed an intact capability to store and reproduce movement frequencies but with a significantly increased movement latencies. No differences in BOLD response were found in both groups when comparing the continuation with the preceding synchronization phase and viceversa, except for activity in visually related regions. Relative to healthy controls during the synchronization phase, PD patients exhibited an overall signal increase in the cerebellum and frontostriatal circuit (putamen, SMA and thalamus) activity together with specific brain areas (right inferior frontal gyrus and insula cortex) that are also implicated in primary timekeeper processes. By contrast, in the continuation phase the only neural network involved to a greater extent by the PD group was the cerebello-thalamic pathway. The lack of neurofunctional differences between the two timing phases suggests that rhythmic externally and internally guided movements engage similar neural networks in PD and matched healthy controls. Moreover, between-group comparison indicates that PD patients OFF medication may compensate for their basal ganglia-cortical loops dysfunction using different motor pathways involving cerebellum and basal ganglia relays during the two phases of rhythmic movement.

Patterns of brain atrophy in Parkinson’s disease, progressive supranuclear palsy and multiple system atrophy

BACKGROUND AND PURPOSE Quantitative analysis of brain atrophy may be useful in differentiating Parkinsons Disease (PD) from Progressive Supranuclear Palsy (PSP) and parkinsonian variant of Multiple System Atrophy (MSA-P); the aim of this study was to identify the volumetric differences of subcortical structures in patients with PD, PSP and MSA-P using a novel and validated fully-automated whole brain segmentation method. METHODS Volumetric MRIs were obtained in 72 patients with PD, 32 patients with PSP, 15 patients with MSA-P, and in 46 control subjects. Subcortical volume was measured automatically by FreeSurfer. Multivariate analysis of covariance, adjusted for intracranial volume (ICV), sex and age, was used to explore group differences. RESULTS No volumetric differences were found between PD and controls group; otherwise the volumes of the cerebellum, the thalamus, the putamen, the pallidum, the hippocampus, and the brainstem were significantly reduced in PSP and MSA-P compared to patients with PD and control subjects. PSP and MSA-P patients only differed in thalamus volume which was smaller in PSP group (p < 0.001). Moreover, patients with PSP and MSA-P showed a ventricular system (including lateral, third and fourth ventricles) larger than that detected in PD and controls (p < 0.001). CONCLUSIONS Volumetric data obtained with automated segmentation of cerebral regions show a significant atrophy of different brain structures in parkinsonisms rather than in PD. Our study also demonstrates that the atrophy of the thalamus only occurs in PSP while the enlargement of the whole ventricular system characterizes both PSP and MSA-P.

Neuroanatomic correlates of psychogenic nonepileptic seizures: A cortical thickness and VBM study

Purpose:  Psychogenic nonepileptic seizures (PNES) are among the most common clinical manifestations of conversion disorder and consist of paroxysmal behavior that resembles epileptic seizures. Preliminary data from functional neuroimaging studies gave plausible evidence that limbic circuits and sensorimotor cortex might be engaged in conversion disorder. Nonetheless, no advanced magnetic resonance imaging (MRI) studies have focused on patients with PNES.

Cerebellar Atrophy in Essential Tremor Using an Automated Segmentation Method

BACKGROUND AND PURPOSE: Essential tremor (ET) is a slowly progressive disorder characterized by postural and kinetic tremors most commonly affecting the forearms and hands. Several lines of evidence from physiologic and neuroimaging studies point toward a major role of the cerebellum in this disease. Recently, voxel-based morphometry (VBM) has been proposed to quantify cerebellar atrophy in ET. However, VBM was not originally designed to study subcortical structures, and the complicated anatomy of the cerebellum may hamper the automatic processing of VBM. The aim of this study was to determine the efficacy and utility of using automated subcortical segmentation to identify atrophy of the cerebellum and other subcortical structures in patients with ET. MATERIALS AND METHODS: We used a recently developed automated volumetric method (FreeSurfer) to quantify subcortical atrophy in ET by comparing results obtained with this method with those provided by previous evidence. The study included T1-weighted MR images of 46 patients with ET grouped into those having arm ET (n = 27, a-ET) or head ET (n = 19, h-ET) and 28 healthy controls. RESULTS: Results revealed the expected reduction of cerebellar volume in patients with h-ET with respect to healthy controls after controlling for intracranial volume. No significant difference was detected in any other subcortical area. CONCLUSIONS: Volumetric data obtained with automated segmentation of subcortical and cerebellar structures approximate data from a previous study based on VBM. The current findings extend the literature by providing initial validation for using fully automated segmentation to derive cerebellar volumetric information from patients with ET.

Hippocampal and thalamic atrophy in mild temporal lobe epilepsy : A VBM study

Background: Patients with temporal lobe epilepsy (TLE) often have mild drug-responsive epilepsy which is frequently associated with MRI detectable mesial temporal sclerosis (MTS), indicating that MTS is not necessarily related to seizure severity. To better define the anatomic substrates associated with TLE, we applied voxel-based morphometry (VBM) analysis to patients with mild TLE. Methods: Optimized VBM was applied to the MRI brain images of 95 consecutive unrelated patients who were diagnosed with mild TLE and to 37 healthy controls. We complemented the investigation by calculating the gray matter volume of regions of interest (ROIs) in the bilateral hippocampus. Standard MRI scans revealed evidence of MTS (pTLE) in 34 patients, and no evidence of MTS in the remaining 61 (nTLE). Results: The VBM analysis provided evidence of a reduction in gray matter volume in the hippocampus and thalami. The gray matter volume reduction in the thalamic and hippocampal networks was significantly more severe in patients with pTLE than in the nTLE or the control groups (at a threshold of FWE-corrected p < 0.05). Patients with nTLE showed the same gray matter abnormalities at an uncorrected statistical threshold (p < 0.001) compared to normal controls. ROI analysis confirmed the ipsilateral hippocampal atrophy that was detected in routine MRI scans. Conclusions: The structural abnormalities seen in patients with mild temporal lobe epilepsy (TLE) demonstrate that a temporo-limbic pathway, which includes the thalamus, plays a major role in the pathogenesis of TLE. It is likely that other factors, especially genetic ones, play a major role in the causation and severity of TLE. GLOSSARY: ANCOVA = analysis of covariance; ANOVA = analysis of variance; FC = febrile convulsion; FWE = family-wise error; GM = gray matter; Hf = hippocampus; MTLE = mesial TLE; MTS = mesial temporal sclerosis; nTLE = patients with TLE without mesial temporal sclerosis; pTLE = patients with TLE with mesial temporal sclerosis; ROI = region of interest; TIV = total intracranial volume; TLE = temporal lobe epilepsy; VBM = voxel-based morphometry; WM = white matter.

Computer-Assisted Cognitive Rehabilitation of Attention Deficits for Multiple Sclerosis: A Randomized Trial With fMRI Correlates

Background. Although a growing body of evidence has highlighted the role of cognitive rehabilitation (CR) in the management of cognitive dysfunctions in multiple sclerosis (MS), there is still no evidence for a validated therapeutic approach. Objective. We propose a new therapeutic strategy characterized by a computer-based intensive attention training program in MS patients with predominant attention deficits. We aim to investigate the effectiveness of our rehabilitation procedure, tailored for those with impaired abilities, using functional magnetic resonance imaging (fMRI). Methods. Using a double-blind randomized controlled study, we enrolled 12 MS patients, who underwent a CR program (experimental group), and 11 age-gender–matched MS patients, who underwent a placebo intervention (control group). fMRI was recorded during the execution of a cognitive task broadly used for assessing attention abilities in MS patients (paced visual serial addition test). Results. Significant effects were detected both at a phenotypic and at an intermediate phenotypic level. After CR, the experimental group, in comparison with the control group, showed a specific enhanced performance in attention abilities as assessed by the Stroop task with an effect size of 0.88, which was associated with increased activity in the posterior cerebellar lobule and in the superior parietal lobule. Conclusions. Our study demonstrates that intensive CR tailored for those with impaired abilities affects neural plasticity and improves some aspects of cognitive deficits in MS patients. The reported neurophysiological and behavioral effects corroborate the benefits of our therapeutic approach, which might have a reliable application in the clinical management of cognitive deficits in MS.

Altered cortical-cerebellar circuits during verbal working memory in essential tremor

Essential tremor is a common neurological disorder characterized by motor and cognitive symptoms including working memory deficits. Epidemiological research has shown that patients with essential tremor are at a higher risk to develop dementia relative to age-matched individuals; this demonstrates that cognitive impairments reflect specific, although poorly understood, disease mechanisms. Neurodegeneration of the cerebellum has been implicated in the pathophysiology of essential tremor itself; however, whether cerebellar dysfunctions relate to cognitive abnormalities is unclear. We addressed this issue using functional neuroimaging in 15 patients with essential tremor compared to 15 sex-, education- and age-matched healthy controls while executing a verbal working memory task. To remove confounding effects, patients with integrity of the nigrostriatal terminals, no dementia and abstinent from medications altering cognition were enrolled. We tested whether patients displayed abnormal activations of the cerebellum (posterior lobules) and other areas typically engaged in working memory (dorsolateral prefrontal cortex, parietal lobules). Between-groups differences in the interactions of these regions were also assessed with functional connectivity methods. Finally, we determined whether individual differences in neuropsychological and clinical measures modulated the magnitude of regional brain responses and functional connectivity data in patients with essential tremor. Despite similar behavioural performances, patients showed greater cerebellar response (crus I/lobule VI) compared to controls during attentional-demanding working memory trials (F = 8.8; P < 0.05, corrected). They also displayed altered functional connectivity between crus I/lobule VI and regions implicated in focusing attention (executive control circuit including dorsolateral prefrontal cortex, inferior parietal lobule, thalamus) and in generating distracting self-related thoughts (default mode network including precuneus, ventromedial prefrontal cortex and hippocampus) (T-values > 3.2; P < 0.05, corrected). These findings were modulated by the variability in neuropsychological measures: patients with low cognitive scores displayed reduced connectivity between crus I/lobule VI and the dorsolateral prefrontal cortex and enhanced connectivity between crus I/lobule VI and the precuneus (T-values > 3.7; P < 0.05, corrected). It is likely that cerebellar neurodegeneration underlying essential tremor is reflected in abnormal communications between key regions responsible for working memory and that adaptive mechanisms (enhanced response of crus I/lobule VI) occur to limit the expression of cognitive symptoms. The connectivity imbalance between the executive control circuit and the default mode network in patients with essential tremor with low cognitive scores may represent a dysfunction, driven by the cerebellum, in suppressing task irrelevant thoughts via focused attention. Overall, our results offer new insights into pathophysiological mechanisms of cognition in essential tremor and suggest a primary role of the cerebellum in mediating abnormal interactions between the executive control circuit and the default mode network.

The appreciation of wine by sommeliers: a functional magnetic resonance study of sensory integration

We set out to investigate how the expertise of a sommelier is embodied in neural circuitry by comparing brain activity elicited by wine tasting with that found in naive drinkers of wine. We used fMRI to study 7 sommeliers and 7 age- and sex-matched control subjects to test the hypothesis that any difference in brain activity would reflect a learned ability to integrate information from gustatory and olfactory senses with past experience. A group analysis showed activation of a cerebral network involving the left insula and adjoining orbito-frontal cortex in sommeliers. Both these areas have been implicated in gustatory/olfactory integration in primates. In addition, activation was found bilaterally in the dorsolateral prefrontal cortex, which is implicated in high-level cognitive processes such as working memory and selection of behavioral strategies. Naive individuals activated the primary gustatory cortex and brain areas, including the amygdala, implicated in emotional processing.