Structural 'connectomic' alterations in the limbic system of multiple sclerosis patients with major depression.

BACKGROUND: Major depression (MD) is a common psychiatric disorder in multiple sclerosis (MS). Despite the negative impact of MD on the quality of life of MS patients, little is known about its underlying brain mechanisms. OBJECTIVE: We studied the whole-brain connectivity patterns that were associated with MD in MS. Alterations were mainly expected within limbic circuits. METHODS: Diffusion tensor imaging data were collected in 20 MS patients with MD, 22 non-depressed MS patients and 16 healthy controls. We used deterministic tractography and graph analysis to study the white-matter connectivity patterns that characterized MS patients with MD. RESULTS: We found that MD in MS was associated with increased local path length in the right hippocampus and right amygdala. Further analyses revealed that these effects were driven by an increased shortest distance between both the right hippocampus and right amygdala and a series of regions including the dorsolateral and ventrolateral prefrontal cortex, orbitofrontal cortex, sensory-motor cortices and supplementary motor area. CONCLUSION: Our data provide strong support for neurobiological accounts positing that MD in MS is mediated by abnormal 'communications' within limbic circuits. We also found evidence that MD in MS may be linked with connectivity alterations at the limbic-motor interface, a group of regions that translates emotions into survival-oriented behaviors.

Hippocampal BOLD response during category learning predicts subsequent performance on transfer generalization.

To test a prediction of our previous computational model of cortico-hippocampal interaction (Gluck and Myers [1993, 2001]) for characterizing individual differences in category learning, we studied young healthy subjects using an fMRI-adapted category-learning task that has two phases, an initial phase in which associations are learned through trial-and-error feedback followed by a generalization phase in which previously learned rules can be applied to novel associations (Myers et al. [2003]). As expected by our model, we found a negative correlation between learning-related hippocampal responses and accuracy during transfer, demonstrating that hippocampal adaptation during learning is associated with better behavioral scores during transfer generalization. In addition, we found an inverse relationship between Blood Oxygenation Level Dependent (BOLD) activity in the striatum and that in the hippocampal formation and the orbitofrontal cortex during the initial learning phase. Conversely, activity in the dorsolateral prefrontal cortex, orbitofrontal cortex and parietal lobes dominated over that of the hippocampal formation during the generalization phase. These findings provide evidence in support of theories of the neural substrates of category learning which argue that the hippocampal region plays a critical role during learning for appropriately encoding and representing newly learned information so that that this learning can be successfully applied and generalized to subsequent novel task demands.

Dopamine-transporter levels drive striatal responses to apomorphine in Parkinson's disease.

Dopaminergic therapy in Parkinson's disease (PD) can improve some cognitive functions while worsening others. These opposite effects might reflect different levels of residual dopamine in distinct parts of the striatum, although the underlying mechanisms remain poorly understood. We used functional magnetic resonance imaging (fMRI) to address how apomorphine, a potent dopamine agonist, influences brain activity associated with working memory in PD patients with variable levels of nigrostriatal degeneration, as assessed via dopamine-transporter (DAT) scan. Twelve PD patients underwent two fMRI sessions (Off-, On-apomorphine) and one DAT-scan session. Twelve sex-, age-, and education-matched healthy controls underwent one fMRI session. The core fMRI analyses explored: (1) the main effect of group; (2) the main effect of treatment; and (3) linear and nonlinear interactions between treatment and DAT levels. Relative to controls, PD-Off patients showed greater activations within posterior attentional regions (e.g., precuneus). PD-On versus PD-Off patients displayed reduced left superior frontal gyrus activation and enhanced striatal activation during working-memory task. The relation between DAT levels and striatal responses to apomorphine followed an inverted-U-shaped model (i.e., the apomorphine effect on striatal activity in PD patients with intermediate DAT levels was opposite to that observed in PD patients with higher and lower DAT levels). Previous research in PD demonstrated that the nigrostriatal degeneration (tracked via DAT scan) is associated with inverted-U-shaped rearrangements of postsynaptic D2-receptors sensitivity. Hence, it can be hypothesized that individual differences in DAT levels drove striatal responses to apomorphine via D2-receptor-mediated mechanisms.

Dysfunctions within limbic-motor networks in amyotrophic lateral sclerosis.

Previous studies have shown that affective symptoms are part of the clinical picture in amyotrophic lateral sclerosis (ALS), the most common motor neuron disorder in elderly people. Diffuse neurodegeneration of limbic regions (e.g., prefrontal cortex [PFC], amygdala) was demonstrated in ALS post-mortem, although the mechanisms of emotional dysregulation in ALS in vivo remain unclear. Using functional imaging, we assessed the brain responses to emotional faces in 11 cognitively unimpaired ALS patients and 12 healthy controls (HCs). We tested whether regional activities and connectivity patterns in the limbic system differed between ALS patients and HCs and whether the variability in clinical measures modulated the neuroimaging data. Relative to HCs, ALS patients displayed greater activation in a series of PFC areas and altered left amygdala-PFC connectivity. Anxiety modulated the right amygdala-PFC connectivity in HCs but not in ALS patients. Reduced right premotor cortex activity and altered left amygdala-supplementary motor area connectivity were associated with longer disease duration and greater disease severity, respectively. Our findings demonstrate dysfunctions of the limbic system in ALS patients at early stages of the disease, and extend our knowledge about the interplay between emotional brain areas and the regions traditionally implicated in motor control.

The BDNF Val66Met polymorphism has opposite effects on memory circuits of multiple sclerosis patients and controls.

Episodic memory deficits are frequent symptoms in Multiple Sclerosis and have been associated with dysfunctions of the hippocampus, a key region for learning. However, it is unclear whether genetic factors that influence neural plasticity modulate episodic memory in MS. We thus studied how the Brain Derived Neurotrophic Factor Val(66)Met genotype, a common polymorphism influencing the hippocampal function in healthy controls, impacted on brain networks underlying episodic memory in patients with Multiple Sclerosis. Functional magnetic resonance imaging was used to assess how the Brain Derived Neurotrophic Factor Val(66)Met polymorphism modulated brain regional activity and functional connectivity in 26 cognitively unimpaired Multiple Sclerosis patients and 25 age- and education-matched healthy controls while performing an episodic memory task that included encoding and retrieving visual scenes. We found a highly significant group by genotype interaction in the left posterior hippocampus, bilateral parahippocampus, and left posterior cingulate cortex. In particular, Multiple Sclerosis patients homozygous for the Val(66) allele, relative to Met(66) carriers, showed greater brain responses during both encoding and retrieval while the opposite was true for healthy controls. Furthermore, a robust group by genotype by task interaction was detected for the functional connectivity between the left posterior hippocampus and the ipsilateral posterior cingulate cortex. Here, greater hippocampus-posterior cingulate cortex connectivity was observed in Multiple Sclerosis Met(66) carriers relative to Val(66) homozygous during retrieval (but not encoding) while, again, the reverse was true for healthy controls. The Val(66)Met polymorphism has opposite effects on hippocampal circuitry underlying episodic memory in Multiple Sclerosis patients and healthy controls. Enhancing the knowledge of how genetic factors influence cognitive functions may improve the clinical management of memory deficits in patients with Multiple Sclerosis.

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 effects of BDNF Val66Met polymorphism on brain function in controls and patients with multiple sclerosis: an imaging genetic study.

Relatively little is known about genetic determinants of cognitive dysfunction in multiple sclerosis (MS). A growing body of evidence demonstrates that a functional variant of the brain-derived neurotrophic factor (BDNF) gene, the Val(66)Met polymorphism, contributes to poor hippocampal and prefrontal functions, particularly memory processes, in healthy controls. In contrast, findings from previous association studies examining this polymorphism and memory performance in MS patients yielded conflicting results. However, the way in which this BDNF polymorphism affects brain function in MS patients has not been examined. In line with the "intermediate phenotype" approach, we assessed effects of the BDNF Val(66)Met polymorphism on brain activity during a spatial working memory task. We used functional magnetic resonance imaging (fMRI) to measure brain responses in a total of 61 subjects comprising 29 relapsing-remitting MS patients and 32 healthy controls. The fMRI results demonstrated association of the BDNF polymorphism with brain activity during working memory, with opposite effects in MS patients and controls. Healthy carriers of the Met(66) allele showed increased activation of the parieto-prefrontal network and altered disengagement of the ventro-medial prefrontal cortex and hippocampus in comparison with their respective Val(66) counterparts. Analysis within the group demonstrated that this working memory-related activation pattern was absent in MS patients. Our imaging genetic study demonstrates that the Val(66)Met polymorphism of the BDNF gene contributes to some of the individual variability in the functional response to a working memory challenge in healthy controls but it does not provide evidence for an MS-specific pattern of gene action.

Neurofunctional correlates of personality traits in relapsing-remitting multiple sclerosis: an fMRI study.

Extraversion and Neuroticism are two fundamental dimensions of human personality that influence cognitive functioning in healthy subjects. Little is known about personality changes that may occur in patients with multiple sclerosis (MS) nor about, in particular, their neurofunctional basis. The aim of this study is to determine the impact of personality characteristics on brain activity in patients with MS. Eighteen patients with clinically definite relapsing-remitting MS without any evidence of psychiatric or cognitive disorders and thirteen healthy controls matched for age, gender and education were investigated using functional magnetic resonance imaging (fMRI) during the execution of an "n-back" task. No differences were detected on the behavioral tests between the two groups, although the MS patients had lower total IQ and showed a trend towards higher Extraversion and Neuroticism scores than did the controls. fMRI analyses demonstrated that Extraversion scores were positively associated with brain activity in the fronto-parietal network including the superior parietal lobule and dorsolateral prefrontal cortex in both groups during the high load condition of the n-back task. Given the overlapping neural systems found in the two groups, we suggest that the neural activity associated with specific personality dimension is a neurophysiological characteristic preserved in patients with MS at an early stage in the course of their disease.

Neurobiological mechanisms underlying emotional processing in relapsing-remitting multiple sclerosis.

Affective disorders are frequent and disabling conditions in multiple sclerosis; however, the underlying neurobiological mechanisms are still poorly understood and investigated. Previous structural imaging studies have suggested that damage of frontal and temporal cortices plays an important role in the genesis of emotional disorders in multiple sclerosis, although psychosocial factors have been also implicated. However, this initial research may not have fully characterized the brain's functional dynamics of emotional processes in multiple sclerosis. Functional magnetic resonance imaging (fMRI) appears, therefore, to be a sensible tool to explore neurobiological mechanisms of emotions in multiple sclerosis since it also allows investigation of the functional connectivity or 'communication' between critical regions in affective behaviour [e.g. the prefrontal cortex (PFC) and amygdala]. In the present study, functional imaging was used to investigate the neural substrate of processing emotions in 12 multiple sclerosis patients relative to 12 healthy subjects matched for age and educational level. Only relapsing-remitting multiple sclerosis patients, who were cognitively unimpaired and who did not assume disease-modifying therapies, were included, given the potential confounding effect of these variables in the genesis of emotional symptoms. Brain responses were recorded in all participants while they executed an active task that consisted of processing emotional relative to neutral stimuli. Structural measures (i.e. total lesion load, grey matter, white matter and total brain volume) were also recorded to control for any effect of these variables. Despite similar performances during the task, and no differences in structural measures, multiple sclerosis patients displayed significantly greater responses within the ventrolateral PFC [t's > 5, P's < 0.02, Family Wise Error (FWE), small volume correction (svc)], compared to controls. Multiple sclerosis patients also showed a lack of functional connectivity between two prefrontal areas and the amygdala, a subcortical region critically involved in the generation of negative feelings (t's > 4, P's < 0.05, FWE, svc). It is likely that pathological changes related to the disease are reflected in an abnormal 'communication' between key emotional regions and that adaptive processes take place and become evident as enhanced responses of task-specific areas (i.e. the ventrolateral PFC). Local reorganizations in the brain can be viewed as compensatory mechanisms aimed to limit the clinical expression of emotional symptoms in multiple sclerosis. Overall our findings offer new insights into the neurobiological mechanisms of emotions in multiple sclerosis and provide evidence that they resemble those described for some psychiatric disorders.

A longitudinal observation of brain-derived neurotrophic factor mRNA levels in patients with relapsing-remitting multiple sclerosis.

This report is part of a 2-year study assessing the functional effect of Brain-Derived Neurotrophic Factor (BDNF) and its Val66Met polymorphism on a selected population of Relapsing-Remitting Multiple Sclerosis (RRMS) patients from Southern Italy. For this purpose, we measured the peripheral BDNF expression in RRMS patients compared to healthy controls. The influence of concomitant IFNbeta therapy was also evaluated. Thirty-six inactive RRMS patients and 37 healthy controls were genotyped for BDNF Val66Met, and total RNA was extracted at time-points 0-24 months. The BDNF level was quantified by ABI Prism 7900 HT Sequence Detection System, and its relative expression was calculated by the comparative method of 2(-DeltaDeltaCt). At baseline and after 24 months, the BDNF levels of RRMS patients resulted significantly higher than controls (p=0.001), independently of the concomitant IFNbeta treatment; no correlations were found with the investigated clinical and MRI features of MS. Otherwise, carriers of the Met-allele showed significantly higher levels of BDNF in RRMS patients than healthy controls (p=0.005). These data was replicated after a 24-month interval. The present study confirms the increased levels of peripheral BDNF levels in RRMS, even during the inactive phase of the disease. Although with caution due to the small sample size, it also underscores the potential role of the Val66Met polymorphism on the peripheral BDNF expression in RRMS. Functional studies are needed to better clarify this issue.

Ventro-lateral prefrontal activity during working memory is modulated by MAO A genetic variation.

Several lines of evidence have highlighted the role of the serotonergic system in working memory (WM) processes. The X-linked Mono-Amine Oxidase A (MAO A) gene, coding for an enzyme especially involved in the serotonin (5-HT) catabolism, presents a well-characterized functional polymorphism consisting in a variable number of tandem repeats (VNTR) in the promoter region with high activity and low activity variants. The high activity allele carriers have been associated with higher enzyme expression, lower amine concentration and altered prefrontal cortex (PFC) function during motor inhibition, but a direct effect of MAO A genotype on WM-related brain activity has not been demonstrated. We have studied the relationship of this polymorphism to brain activity elicited by a spatial working memory task (n-back) using blood oxygenation level-dependent functional magnetic resonance imaging in 30 healthy male individuals matched for a series of demographic and genetic variables (COMT Val108/158Met). We show that the high activity allele was significantly (p-level<0,001) associated with increased activity of the right ventro-lateral PFC (VLPFC, BA 47) during the high load condition of the n-back task. Our data reveal pronounced genotype-related functional changes in specific prefrontal region (VLPFC) subserving spatial working memory. Moreover, given the well-known role of this area in inhibitory control, our finding also provides new evidence for the involvement of 5-HT in PFC-mediated WM function.

Genetically dependent modulation of serotonergic inactivation in the human prefrontal cortex.

Previous research suggests that genetic variations regulating serotonergic neurotransmission mediate individual differences in the neural network underlying impulsive and aggressive behaviour. Although with conflicting findings, the monoamine oxidase-A (MAOA) and the serotonin transporter (5HTT) gene polymorphisms have been associated with an increased risk to develop impulsive and aggressive behaviour. Double knock-out mice studies have also demonstrated that MAOA and 5HTT genes strongly interact in the metabolic pathway leading to the serotonergic inactivation; however, their potential interactive effect in human brain remains uninvestigated. We used blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to assess the independent and interactive effects of both MAOA and 5HTT polymorphisms on the brain activity elicited by a response inhibition task in healthy volunteers. Multivariate analysis demonstrated an individual effect of both MAOA and 5HTT polymorphisms and a strong allele-allele interaction in the anterior cingulate cortex (ACC), a key region implicated in cognitive control and in the pathophysiology of impulsive and aggressive behaviour. These findings suggest that the MAOAx5HTT allelic interaction exerts a significant modulation on the BOLD response associated with response inhibition and contribute to validate haplotype models as useful tools for a better understanding of the neurobiology underlying complex cognitive functions.

MR imaging index for differentiation of progressive supranuclear palsy from Parkinson disease and the Parkinson variant of multiple system atrophy.

PURPOSE: To prospectively assess sensitivity and specificity of magnetic resonance (MR) imaging measurements of midbrain, pons, middle cerebellar peduncles (MCPs), and superior cerebellar peduncles (SCPs) for differentiating progressive supranuclear palsy (PSP) from Parkinson disease (PD) and Parkinson variant of multiple system atrophy (MSA-P), with established consensus criteria as reference standard. MATERIALS AND METHODS: All study participants provided informed consent; study was approved by the institutional review board. Pons area, midbrain area, MCP width, and SCP width were measured in 33 consecutive patients with PSP (16 possible, 17 probable), 108 consecutive patients with PD, 19 consecutive patients with MSA-P, and 50 healthy control participants on T1-weighted MR images. The pons area-midbrain area ratio (P/M) and MCP width-SCP width ratio (MCP/SCP) were also used, and an index termed MR parkinsonism index was calculated [(P/M).(MCP/SCP)]. Differences in MR imaging measurements among groups were evaluated with Kruskal-Wallis test, Mann-Whitney U test, and Bonferroni correction. RESULTS: Midbrain area and SCP width in patients with PSP (23 men, 10 women; mean age, 69.3 years) were significantly (P < .001) smaller than in patients with PD (62 men, 46 women; mean age, 65.8 years), patients with MSA-P (five men, 14 women; mean age, 64.0 years), and control participants (25 men, 25 women; mean age, 66.6 years). P/M and MCP/SCP were significantly larger in patients with PSP than in patients in other groups and control participants. All measurements showed some overlap of values between patients with PSP and patients from other groups and control participants. MR parkinsonism index value was significantly larger in patients with PSP (median, 19.42) than in patients with PD (median, 9.40; P < .001), patients with MSA-P (median, 6.53; P < .001), and control participants (median, 9.21; P < .001), without overlap of values among groups. No patient with PSP received a misdiagnosis when the index was used (sensitivity and specificity, 100%). CONCLUSION: The MR parkinsonism index can help distinguish patients with PSP from those with PD and MSA-P on an individual basis.

Dopaminergic modulation of cognitive interference after pharmacological washout in Parkinson's disease.

The dopaminergic modulation of prefrontal function in Parkinson's disease (PD) has been consistently demonstrated. There is evidence that the effects of pharmacological manipulations on cognitive performances are described by an "Inverted-U" shaped curve. Neuroimaging studies performed before and after an overnight withdrawal from therapy showed significant differences between drug states, but did not control for the relative impact of the long duration response to levodopa. Here we evaluate the brain response after a complete pharmacological washout by correlating dopaminergic-related changes of this response to changes in performance during cognitive interference. Twelve idiopathic PD patients were studied with functional MRI while performing a modified version of the Stroop task. Patients were scanned twice: (1) following a prolonged washout procedure ("OFF" state) and (2) 90-120 min after the administration of levodopa ("ON" state). Task-related changes of PD patients were compared to those of matched healthy controls. Healthy controls displayed prefrontal and parietal responses that were positively correlated with task accuracy. In the "OFF" state, PD patients showed significant responses in anterior cingulate and pre-supplementary motor area, which are hypothesized to operate at a higher level of basal dopaminergic modulation. Levodopa administration attenuated such responses and enhanced the response of prefrontal cortex (PFC), which was correlated with improved accuracy. Results demonstrate that the behavioral effects of pharmacological manipulations of the dopamine system are highly dependent on the baseline status of PFC. When a true hypodopaminergic state is induced in PD patients, cognitive interference might significantly benefit from the administration of levodopa via an enhanced PFC response.

Impact of individual cognitive profile on visuo-motor reorganization in relapsing-remitting multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), relationships between disease-related MRI changes, cognitive function and brain responses are complex and still unclear. This study addresses the relative effects of cognitive impairment and brain atrophy on the cortical reorganization associated with a visuo-motor task. METHODS: Multivariate analysis was applied to compare functional MRI brain responses of 28 relapsing-remitting (RR) MS patients (16 cognitively preserved and 12 cognitively impaired) to that of 35 matched healthy controls during the execution of visuo-motor integration task. Regression analysis was performed to test for linear effects of structural variables (grey matter (GM) and white matter (WM) volumes) and cognitive profiles--and their combined effect--on the same response. RESULTS: Compared to preserved MS patients or normal controls, cognitively impaired MS patients showed significant decreases of brain parenchymal and GM volumes, but only a trend for lower WM volume. Multivariate analysis showed that cognitive profile, GM and WM atrophy independently contributed to the activation of parieto-premotor cortices. Baseline cognition predicted the greatest response of the entire network, whereas WM and GM losses predicted selective responses of parietal and premotor regions. CONCLUSIONS: Visuo-motor function in MS is associated with altered patterns of brain activation that vary as a function of cognitive decline. This is confirmed by a larger effect size of the individual cognitive profile compared to the structural damage. Both effects contribute in an additive way to cortical reorganization, which is primarily driven by such a cognitive gradient in RR-MS patients.

Apparent diffusion coefficient measurements of the middle cerebellar peduncle differentiate the Parkinson variant of MSA from Parkinson's disease and progressive supranuclear palsy.

Clinical differentiation of parkinsonian syndromes such as the Parkinson variant of multiple system atrophy (MSA-P) and progressive supranuclear palsy (PSP) from Parkinson's disease is difficult in the early stage of the disease. In order to identify objective markers for differential diagnosis, we studied these three groups of patients with diffusion-weighted MRI (DWI). Sixteen MSA-P patients, 16 with PSP, 16 with Parkinson's disease and 15 healthy volunteers were studied. Regional apparent diffusion coefficients (rADC) were determined in different brain regions including basal ganglia, thalamus, white matter, pons and middle cerebellar peduncles (MCPs). rADC calculated in the MCP completely differentiated MSA-P patients (median: 0.93 x 10(-3) mm2/s) from PSP patients (median: 0.82 x 10(-3) mm2/s, P < 0.001), Parkinson's disease patients (median: 0.79 x 10(-3) mm2/s, P < 0.001) and healthy volunteers (median: 0.81 x 10(-3) mm2/s, P < 0.001). Other regions considered showed an overlapping among groups. DWI discriminates MSA-P from PSP and Parkinson's disease and healthy volunteers on the basis of MCP rADC values. These in vivo results confirm the pathological findings that the majority of MSA-P patients have moderate or severe degenerative changes not only in the nigrostriatal but also in the olivopontocerebellar systems. Our findings indicate that, in order to substantially contribute to the in vivo differential diagnosis of MSA-P, PSP and Parkinson's disease, rADC measurements should not be limited to the basal ganglia but should also include the MCP.

Adaptive cortical changes and the functional correlates of visuo-motor integration in relapsing-remitting multiple sclerosis.

Cortical reorganization has been demonstrated during performance of a motor task in patients with multiple sclerosis. Converging evidence suggests that changes in gray matter volume represent an early hallmark of the disease. We used functional MRI to investigate the role of cortical adaptive mechanisms in maintaining visuo-motor function in the face of structural damage. Two cohorts of patients with clinically definite relapsing-remitting multiple sclerosis were compared with healthy controls matched for demographic, motor and cognitive characteristics during the performance of a visuo-motor integration task. Direct comparison between the two groups demonstrated a greater response of the contralateral dorsal premotor cortex and of the ipsilateral superior parietal cortex in relapsing-remitting multiple sclerosis patients. The functional MRI changes in these areas were strongly correlated with decreased gray matter volumes and increased lesion burden, respectively. Our study demonstrated a selective involvement of the parieto-premotor circuitry in a relatively early stage of the disease, which was not influenced by clinical, motor or cognitive variables. Moreover these results confirm the potential for functional recovery and the adaptive role of these areas in the motor reorganization of multiple sclerosis patients.

MR imaging of middle cerebellar peduncle width: differentiation of multiple system atrophy from Parkinson disease.

PURPOSE: To prospectively assess if middle cerebellar peduncle (MCP) atrophy, evaluated at magnetic resonance (MR) imaging, can help differentiate multiple system atrophy (MSA) from Parkinson disease (PD). MATERIALS AND METHODS: All participants provided informed consent for participation in the study, which was approved by the institutional review board. Sixteen consecutive patients with MSA, 26 consecutive patients with PD, and 14 healthy control subjects were examined with MR imaging. Images were interpreted independently by two experienced neuroradiologists blinded to clinical information, who visually inspected the images for the presence or absence of putaminal atrophy, putaminal hypointensity, slitlike hyperintensity in the posterolateral margin of the putamen, brainstem atrophy, hyperintensity of the MCP, and cruciform hyperintensity of the pons. Measurements of MCP width on T1-weighted volumetric spoiled gradient-echo images were performed in all subjects. Differences in MCP width among the groups were evaluated by using the Kruskall-Wallis test, followed by the Mann-Whitney U test for multiple comparisons and Bonferroni correction. RESULTS: All patients (mean age, 63.88 years; range, 55-72 years) with MSA had at least one of the features commonly observed in this disease on MR images, whereas control subjects (mean age, 66.93 years; range, 61-77 years) and all but one patient with PD (mean age, 65.31 years; range, 51-79 years) had normal MR images. The average MCP width was significantly smaller in patients with MSA (6.10 mm+/-1.18 [standard deviation]) than in those with PD (9.32 mm+/-0.77, P<.001) or control subjects (9.80 mm+/-0.66, P<.001). CONCLUSION: Measurement of MCP width on MR images may be useful for distinguishing patients with MSA from those with PD.

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 (Brodmann's 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.