Giancarlo Comi

YNICL Journal 2023 Journal Article

The spatio-temporal relationship between concurrent lesion and brain atrophy changes in early multiple sclerosis: A post-hoc analysis of the REFLEXION study

• Giordano Gentile
• Rozemarijn M. Mattiesing
• Iman Brouwer
• Ronald A. van Schijndel
• Bernard M.J. Uitdehaag
• Jos W.R. Twisk
• Ludwig Kappos
• Mark S. Freedman

BACKGROUND: White matter (WM) lesions and brain atrophy are present early in multiple sclerosis (MS). However, their spatio-temporal relationship remains unclear. METHODS: Yearly magnetic resonance images were analysed in 387 patients with a first clinical demyelinating event (FCDE) from the 5-year REFLEXION study. Patients received early (from baseline; N = 258; ET) or delayed treatment (from month-24; N = 129; DT) with subcutaneous interferon beta-1a. FSL-SIENA/VIENA were used to provide yearly percentage volume change of brain (PBVC) and ventricles (PVVC). Yearly total lesion volume change (TLVC) was determined by a semi-automated method. Using linear mixed models and voxel-wise analyses, we firstly investigated the overall relationship between TLVC and PBVC and between TLVC and PVVC in the same follow-up period. Analyses were then separately performed for: the untreated period of DT patients (first two years), the first year of treatment (year 1 for ET and year 3 for DT), and a period where patients had received at least 1 year of treatment (stable treatment; ET: years 2, 3, 4, and 5; DT: years 4 and 5). RESULTS: Whole brain: across the whole study period, lower TLVC was related to faster atrophy (PBVC: B = 0.046, SE = 0.013, p < 0.001; PVVC: B = -0.466, SE = 0.118, p < 0.001). Within the untreated period of DT patients, lower TLVC was related to faster atrophy (PBVC: B = 0.072, SE = 0.029, p = 0.013; PVVC: B = -0.917, SE = 0.306, p = 0.003). A similar relationship was found within the first year of treatment of ET patients (PBVC: B = 0.081, SE = 0.027, p = 0.003; PVVC: B = -1.08, SE = 0.284, p < 0.001), consistent with resolving oedema and pseudo-atrophy. Voxel-wise: overall, higher TLVC was related to faster ventricular enlargement. Lower TLVC was related to faster widespread atrophy in year 1 in both ET (first year of treatment) and DT (untreated) patients. In the second untreated year of DT patients and within the stable treatment period of ET patients (year 4), faster periventricular and occipital lobe atrophy was associated with higher TLVC. CONCLUSIONS: WM lesion changes and atrophy occurred simultaneously in early MS. Spatio-temporal correspondence of these two processes involved mostly the periventricular area. Within the first year of the study, in both treatment groups, faster atrophy was linked to lower lesion volume changes, consistent with higher shrinking and disappearing lesion activity. This might reflect the pseudo-atrophy phenomenon that is probably related to the therapy driven (only in ET patients, as they received treatment from baseline) and "natural" (both ET and DT patients entered the study after a FCDE) resolution of oedema. In an untreated period and later on during stable treatment, (real) atrophy was related to higher lesion volume changes, consistent with increased new and enlarging lesion activity.

YNICL Journal 2022 Journal Article

The spatio-temporal relationship between white matter lesion volume changes and brain atrophy in clinically isolated syndrome and early multiple sclerosis

• Rozemarijn M. Mattiesing
• Giordano Gentile
• Iman Brouwer
• Ronald A. van Schijndel
• Bernard M.J. Uitdehaag
• Jos W.R. Twisk
• Ludwig Kappos
• Mark S. Freedman

BACKGROUND: White matter lesions and brain atrophy are both present early in multiple sclerosis. However, the spatio-temporal relationship between atrophy and lesion processes remains unclear. METHODS: Yearly magnetic resonance images were analyzed in 392 patients with clinically isolated syndrome from the 5-year REFLEX/REFLEXION studies. Patients received early treatment (from baseline; N = 262) or delayed treatment (from month-24; N = 130) with subcutaneous interferon beta-1a. Global and central atrophy were assessed using FSL-SIENA to provide yearly percentage volume change of brain and ventricles, respectively. Yearly total lesion volume change was calculated by subtracting the sum of the negative lesion volume change (disappearing + shrinking) from the positive lesion volume change (new + enlarging) for each yearly interval, as determined by an in-house developed semi-automated method. Using linear mixed models, during the period where patients had received ≥1 year of treatment, we investigated whether total lesion volume change was associated with percentage brain volume change or percentage ventricular volume change in the next year, and vice versa. RESULTS: Higher total lesion volume change was related to significantly faster global atrophy (percentage brain volume change) in the next year (B = - 0.113, SE = 0.022, p < 0.001). In patients receiving early treatment only, total lesion volume change was also associated with percentage ventricular volume change in the next year (B = 1.348, SE = 0.181, p < 0.001). Voxel-wise analyses showed that in patients receiving early treatment, higher total lesion volume change in years 2, 3, and 4 was related to faster atrophy in the next year, and in year 4 this relationship was stronger in patients receiving delayed treatment. Interestingly, faster atrophy was related to higher total lesion volume change in the next year (percentage brain volume change: B = - 0.136, SE = 0.062, p = 0.028; percentage ventricular volume change: B = 0.028, SE = 0.008, p < 0.001). CONCLUSIONS: Higher lesion volume changes were associated with faster atrophy in the next year. Interestingly, there was also an association between faster atrophy and higher lesion volume changes in the next year.

YNICL Journal 2018 Journal Article

Fast progressive lower motor neuron disease is an ALS variant: A two-centre tract of interest-based MRI data analysis

• Hans-Peter Müller
• Federica Agosta
• Nilo Riva
• Edoardo G. Spinelli
• Giancarlo Comi
• Albert C. Ludolph
• Massimo Filippi
• Jan Kassubek

BACKGROUND: The criteria for assessing upper motor neuron pathology in pure lower motor neuron disease (LMND) still remain a major issue of debate with respect to the clinical classification as an amyotrophic lateral sclerosis (ALS) variant. OBJECTIVE: The study was designed to investigate white matter damage by a hypothesis-guided tract-of-interest-based approach in patients with LMND compared with healthy controls and ´classical´ ALS patients in order to identify in vivo brain structural changes according to the neuropathologically defined ALS affectation pattern. Data were pooled from two previous studies at two different study sites (Ulm, Germany and Milano, Italy). METHODS: DTI-based white matter integrity mapping was performed by voxelwise statistical comparison and by a tractwise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern for 65 LMND patients (clinically differentiated in fast and slow progressors) vs. 92 matched controls and 101 ALS patients with a 'classical' phenotype to identify white matter structural alterations. RESULTS: The analysis of white matter structural connectivity by regional FA reductions demonstrated the characteristic alteration patterns along the CST and also in frontal and prefrontal brain areas in LMND patients compared to controls and ALS. Fast progressing LMND showed substantial involvement, like in ALS, while slow progressors showed less severe alterations. In the tract-specific analysis according to the ALS-staging pattern, fast progressing LMND showed significant alterations of ALS-related tract systems as compared to slow progressors and controls. CONCLUSIONS: This study showed an affectation pattern for corticoefferent fibers in LMND with fast disease progression as defined for ALS, that way confirming the hypothesis that fast progressing LMND is a phenotypical variant of ALS.

YNICL Journal 2017 Journal Article

Multimodal structural MRI in the diagnosis of motor neuron diseases

• Pilar M. Ferraro
• Federica Agosta
• Nilo Riva
• Massimiliano Copetti
• Edoardo Gioele Spinelli
• Yuri Falzone
• Gianni Sorarù
• Giancarlo Comi

This prospective study developed an MRI-based method for identification of individual motor neuron disease (MND) patients and test its accuracy at the individual patient level in an independent sample compared with mimic disorders. 123 patients with amyotrophic lateral sclerosis (ALS), 44 patients with predominantly upper motor neuron disease (PUMN), 20 patients with ALS-mimic disorders, and 78 healthy controls were studied. The diagnostic accuracy of precentral cortical thickness and diffusion tensor (DT) MRI metrics of corticospinal and motor callosal tracts were assessed in a training cohort and externally proved in a validation cohort using a random forest analysis. In the training set, precentral cortical thickness showed 0. 86 and 0. 89 accuracy in differentiating ALS and PUMN patients from controls, while DT MRI distinguished the two groups from controls with 0. 78 and 0. 92 accuracy. In ALS vs controls, the combination of cortical thickness and DT MRI metrics (combined model) improved the classification pattern (0. 91 accuracy). In the validation cohort, the best accuracy was reached by DT MRI (0. 87 and 0. 95 accuracy in ALS and PUMN vs mimic disorders). The combined model distinguished ALS and PUMN patients from mimic syndromes with 0. 87 and 0. 94 accuracy. A multimodal MRI approach that incorporates motor cortical and white matter alterations yields statistically significant improvement in accuracy over using each modality separately in the individual MND patient classification. DT MRI represents the most powerful tool to distinguish MND from mimic disorders.

YNIMG Journal 2010 Journal Article

Dysfunctional brain circuitry in obsessive–compulsive disorder: Source and coherence analysis of EEG rhythms

• Svetla Velikova
• Marco Locatelli
• Chiara Insacco
• Enrico Smeraldi
• Giancarlo Comi
• Letizia Leocani

Background Morphological and functional studies suggested involvement of several cortical and subcortical circuitries in patients with obsessive–compulsive disorder (OCD). The aim of the present study was to investigate networks involved in OCD pathophysiology, using power (coupling of EEG bands, low-resolution electromagnetic tomography—LORETA) and coherence analysis in drug naïve patients. Method EEG was obtained from 37 drug-naïve patients with OCD and 37 age- and sex-matched controls. Resting EEG was recorded from 29 scalp channels. Coupling (ratio and correlation) between low and high frequencies was analyzed on Fz. For each frequency band, LORETA current density distribution, intra-hemispheric and inter-hemispheric coherence analysis were computed. Results OCD had increased current density for delta in the insula and for beta in frontal, parietal and limbic lobes. OCD also had decreased inter-hemispheric coherence and reduced coupling between delta and beta frequencies. Conclusions In OCD, increased frontal beta is consistent with previous evidence of frontal dysfunction. Hyperactivity of insular delta sources, together with rhythms decoupling and reduced interhemispheric alpha coherence are consistent with additional involvement of cortico-subcortical functional connections. Combined use of power and coherence analysis may provide functional measures on different levels of involvement of cortico-subcortical circuits in neuropsychiatric disorders.

YNIMG Journal 2009 Journal Article

Cognitive learning is associated with gray matter changes in healthy human individuals: A tensor-based morphometry study

• Antonia Ceccarelli
• Maria Assunta Rocca
• Elisabetta Pagani
• Andrea Falini
• Giancarlo Comi
• Massimo Filippi

Longitudinal voxel-based morphometry studies have demonstrated morphological changes in cortical structures following motor and cognitive learning. In this study, we applied, for the first time, tensor-based morphometry (TBM) to assess the short-term structural brain gray matter (GM) changes associated with cognitive learning in healthy subjects. Using a 3 T scanner, a 3D T1-weighted sequence was acquired from 32 students at baseline and after two weeks. Students were separated into two groups: 13 defined as “students in cognitive training”, who underwent a two-week cognitive learning period, and 19 “students not in cognitive training”, who were not involved in any teaching activity. GM changes were assessed using TBM and statistical parametric mapping. Baseline regional GM volume did not differ between the two groups. At follow up, compared to “students not in cognitive training”, the “students in cognitive training” had a significant GM volume increase in the dorsomedial frontal cortex, the orbitofrontal cortex, and the precuneus (p <0. 001). These results suggest that cognitive learning results in short-term structural GM changes of neuronal networks of the human brain, which are known to be involved in cognition. This may have important implications for the development of rehabilitation strategies in patients with neurological diseases.

YNIMG Journal 2008 Journal Article

A voxel-based morphometry study of grey matter loss in MS patients with different clinical phenotypes

• Antonia Ceccarelli
• Maria A. Rocca
• Elisabetta Pagani
• Bruno Colombo
• Vittorio Martinelli
• Giancarlo Comi
• Massimo Filippi

To assess regional grey matter (GM) changes in a large cohort of multiple sclerosis (MS) patients with different clinical phenotypes, using voxel-based morphometry (VBM) and their correlation with the extent of global and regional T2 lesion volumes (LV), we acquired conventional MRI scans from 71 MS patients with different clinical phenotypes (26 with relapsing-remitting [RR] MS, 27 with secondary progressive [SP] MS and 18 with primary progressive [PP] MS), 28 patients with a clinically isolated syndrome (CIS) suggestive of MS, and 21 controls. No GM loss was found in CIS patients. Compared to CIS patients, those with RRMS had a significant GM loss in the right pre and postcentral gyri. Compared to RRMS, SPMS patients had a significant GM loss in several regions of the fronto-parieto-temporo-occipital lobes, the cerebellum and superior and inferior colliculus, bilaterally, and deep GM structures. Compared to PPMS, SPMS patients had a significant GM loss in the postcentral gyrus, the cuneus, the middle occipital gyrus, the thalamus, the cerebellum, and the superior and inferior colliculus. In all MS groups, regional GM loss was strongly/moderately correlated with brain T2 LV. In SPMS and PPMS patients, a correlation was found between cortical regional GM loss and T2 LV of the corresponding or adjacent lobes. In MS patients, GM volume loss follows different patterns of regional distribution according to the clinical phenotype of the disease, is likely secondary to the presence and topography of focal WM inflammatory-demyelinating lesions, and is more evident in the progressive forms of the disease.

YNIMG Journal 2008 Journal Article

The topographical distribution of tissue injury in benign MS: A 3T multiparametric MRI study

• Antonia Ceccarelli
• Maria A. Rocca
• Elisabetta Pagani
• Angelo Ghezzi
• Ruggero Capra
• Andrea Falini
• Giuseppe Scotti
• Giancarlo Comi

We compared the global and regional distribution of white matter (WM) and gray matter (GM) damage and T2-visible lesion between patients with benign (B) and relapsing remitting (RR) multiple sclerosis (MS). BMS and RRMS patients did not differ in terms of global volumes and diffusion tensor (DT) MRI metrics of the WM and GM. Compared to controls, BMS and RRMS patients had bilateral thalamic loss. Compared to controls, BMS and RRMS patients had lower WM fractional anisotropy (FA) in the corpus callosum (CC) and in several regions of temporal and occipital lobes. BMS also had a decreased WM FA in the parietal lobes. RRMS patients had also lower WM FA in several regions of the frontal lobes. Compared to BMS, RRMS patients had decreased WM FA in the frontal lobes, while the opposite comparison showed lower WM FA in the CC, the temporal lobes and the cuneus in BMS. Contrasted to controls, both MS groups showed several regions of increased MD in WM and GM, but no difference was found between MS sub-groups. T2-visible lesions were mainly located in the posterior regions of the brain in BMS patients, while they involved also regions in the frontal lobes, in RRMS patients. BMS and RRMS patients differ in terms of the topographical distribution of WM damage rather than in the overall extent of brain structural changes. The less prominent involvement of the frontal lobe WM and of the NAWM in general in BMS might be associated to their favorable clinical status.

YNIMG Journal 2006 Journal Article

An fMRI study of the motor system in patients with neuropsychiatric systemic lupus erythematosus

• Maria A. Rocca
• Federica Agosta
• Domenico M. Mezzapesa
• Gianfranco Ciboddo
• Andrea Falini
• Giancarlo Comi
• Massimo Filippi

Functional cortical changes have been demonstrated in patients with several neurological conditions, including stroke, tumors and MS. The correlation found between the extent of fMRI activations and the extent and severity of brain structural damage suggests an adaptive role of these functional changes. In this study, we assess, using fMRI, the brain pattern of movement-associated cortical activations in neuropsychiatric systemic lupus erythematosus (NPSLE) patients and investigate whether the extent of cortical reorganization is associated with the extent of brain pathology, measured on dual-echo and diffusion tensor (DT) MR images. From 14 right-handed NPSLE patients and 14 matched controls, we obtained: (a) fMRI during the performance of repetitive flexion–extension of the last four fingers of the right hand; (b) dual-echo and (c) pulsed-gradient spin-echo echo-planar sequence to calculate DT MRI maps of the normal-appearing white (NAWM) and gray (NAGM) matter. Brain T2-visible abnormalities were detected in 11 NPSLE patients. Compared with controls, NPSLE patients had significantly higher NAWM fractional anisotropy histogram peak height (P = 0. 005), and more significant activations of the contralateral primary sensorimotor cortex, putamen and dentate nucleus. They also had more significant activations of several regions located in the frontal and parietal lobes as well as of MT/V5 and the middle occipital gyrus, bilaterally. Strong correlations (r values ranging from 0. 79 to 0. 87) were found between relative activations of sensorimotor areas and the extent and severity of brain damage. Movement-associated functional cortical changes do occur in patients with NPSLE and might contribute to the maintenance of their normal functional capacities.

YNIMG Journal 2006 Journal Article

The level of spinal cord involvement influences the pattern of movement-associated cortical recruitment in patients with isolated myelitis

• Maria A. Rocca
• Federica Agosta
• Vittorio Martinelli
• Andrea Falini
• Giancarlo Comi
• Massimo Filippi

Using fMRI, an increased recruitment of the ipsilateral primary sensorimotor cortex (SMC), supplementary motor area, and middle frontal gyrus has been detected in patients with cervical cord myelitis of possible demyelinating origin. The aim of this study was to evaluate, using fMRI, whether the level of cord involvement influences cortical reorganization by comparing patients with isolated myelitis of the cervical and the dorsal portions of the cord, and to investigate whether the extent of cortical reorganization is associated with the extent of cervical cord pathology measured using magnetization transfer (MT) MRI. We studied 24 right-handed patients (14 with a previous involvement of the cervical cord and 10 with an involvement of the dorsal cord) in a chronic and clinically stable phase following an isolated myelitis of possible demyelinating origin and 15 sex- and age-matched healthy controls. During a single session, we obtained fMRI during repetitive flexion–extension of the last four fingers of the right and left hands and cervical cord MT MRI. Average cord MTR was lower in patients with cervical (P < 0. 0001) and dorsal (P = 0. 0001) myelitis than in controls. Compared to controls and for both tasks, patients with myelitis had an increased recruitment of the ipsilateral primary SMC, which was independent of the level of cord involvement. On the contrary, patients with cervical myelitis had a more widespread recruitment of frontal and parietal regions, whereas those with dorsal myelitis had a more widespread recruitment of temporal and cerebellar regions. Strong correlations (r values ranging from −0. 72 to −0. 88) were found between relative activations of cortical areas and the severity of cervical cord damage. Patients with isolated myelitis have different patterns of movement-associated cortical activations according to the level of cord involvement. This “level-dependent” functional reorganization of the cortex is likely to have an adaptive role in limiting the clinical outcome of cord damage and should be considered when designing rehabilitation strategies for these patients.

YNIMG Journal 2005 Journal Article

Mean diffusivity and fractional anisotropy histogram analysis of the cervical cord in MS patients

• Paola Valsasina
• Maria A. Rocca
• Federica Agosta
• Beatrice Benedetti
• Mark A. Horsfield
• Antonio Gallo
• Marco Rovaris
• Giancarlo Comi

The spinal cord is frequently involved in multiple sclerosis (MS), and cord damage may be an important contributor to disability. Diffusion tensor magnetic resonance imaging (DT-MRI) provides quantitative information about the structural and orientational features of the central nervous system. In order to assess whether diffusion tensor-derived measures of cord tissue damage are related to clinical disability, mean diffusivity (MD) and fractional anisotropy (FA) histograms from the cervical cord were acquired from a large cohort of MS patients. Diffusion-weighted sensitivity-encoded (SENSE) echo planar images of the cervical cord, and brain dual-echo and diffusion-weighted scans were acquired from 44 patients with MS and 17 healthy controls. Cord and brain MD and FA histograms were produced. An analysis of variance model, adjusting for cord volume and patient age, was used to compare cord DT-MRI parameters from controls and patients. A multivariate linear regression model was used to identify DT-MRI variables independently associated with disability. Average cervical cord FA was significantly lower in MS patients compared to controls. Cord cross-sectional area, average FA and average MD were all significantly correlated with the degree of disability (r values ranging from 0. 36 to 0. 51). The multivariate linear regression model retained average cord FA and average brain MD as variables independently associated with disability, with a correlation coefficient of 0. 73 (P < 0. 001). DT-MRI reveals a loss of cervical cord tissue structure in MS patients. The strong correlation found between a composite DT-MRI score and disability suggests that a full and accurate assessment of cervical cord damage in MS provides information that usefully contributes to an explanation of the clinical manifestations of the disease.

YNIMG Journal 2005 Journal Article

Short-term accrual of gray matter pathology in patients with progressive multiple sclerosis: an in vivo study using diffusion tensor MRI

• Marco Rovaris
• Antonio Gallo
• Paola Valsasina
• Beatrice Benedetti
• Domenico Caputo
• Angelo Ghezzi
• Enrico Montanari
• Maria Pia Sormani

The mechanisms underlying the progressive course of multiple sclerosis (MS) are not fully understood yet. Since diffusion tensor (DT) MRI can provide quantitative estimates of both MRI-visible and MRI-occult brain damage related to MS, the present study investigated the value of DT MRI-derived measures for the assessment of the short-term accumulation of white and gray matter (GM) pathology in patients with primary progressive (PP) and secondary progressive (SP) MS. Fifty-four patients with PPMS and 22 with SPMS were studied at baseline and after a mean follow-up of 15 months. Dual-echo, T1-weighted, and DT MRI scans of the brain were acquired on both occasions. Total lesion volumes (TLV) and percentage brain volume changes (PBVC) were computed. Mean diffusivity (MD) and fractional anisotropy (FA) maps of the normal-appearing white (NAWM) and gray matter (NAGM) were produced, and histogram analysis was performed. In both patient groups, a significant increase of average lesion MD (P = 0. 01) and of average NAGM MD (P = 0. 007) was found at follow-up. No significant differences between PPMS and SPMS patient groups were found for the on-study changes of any MRI-derived measure. No significant correlations were found between the percentage changes of DT MRI-derived measures and those of TLV and PBVC. No significant changes of DT MRI-derived measures were observed in age-matched healthy controls over the same study period. Over a 1-year period of follow-up, DT MRI can detect tissue changes beyond the resolution of conventional MRI in the NAGM of patients with progressive MS. The accumulation of DT MRI-detectable gray matter damage does not seem to merely depend upon the concomitant increase of T2-visible lesion load and the reduction of brain volume. These observations suggest that progressive NAGM damage might yet be an additional factor leading to the accumulation of disability in progressive MS.

YNIMG Journal 2004 Journal Article

A functional MRI study of cortical activations associated with object manipulation in patients with MS

• Massimo Filippi
• Maria A Rocca
• Domenico M Mezzapesa
• Andrea Falini
• Bruno Colombo
• Giuseppe Scotti
• Giancarlo Comi

Previous functional magnetic resonance imaging (fMRI) studies of simple motor tasks have shown that in patients with multiple sclerosis (MS), there is an increased recruitment of several regions part of a complex sensorimotor network. These studies have suggested that this might be the case because patients tend to activate, when performing a simple motor task, regions that are usually activated in healthy subjects during the performance of more complex tasks due to the presence of subcortical structural damage. In this study, we tested this hypothesis by comparing the patterns of cortical activations during the performance of two tasks with different levels of complexity from 16 MS patients and 16 age- and sex-matched controls. The first task (simple) consisted of flexion–extension of the last four fingers of the right hand, and the second task (complex) consisted of object manipulation. During the simple task, MS patients had, when compared to controls, more significant activations of the supplementary motor area (SMA), secondary sensorimotor area, posterior lobe of the cerebellum, superior parietal gyrus (SPG), and inferior frontal gyrus (IFG). These three latter regions are part of a fronto-parietal circuit, whose activation occurs typically in the contralateral hemisphere of healthy subjects during object manipulation, as shown also by the present study. During the performance of the complex task, MS patients showed an increased bilateral recruitment of several areas of the fronto-parietal circuit associated with object manipulation, as well of several other areas, which were mainly in the frontal lobes. This study confirms that some of the regions that are activated by MS patients during the performance of simple motor tasks are part of more complex pathways, recruited by healthy subjects when more complex and difficult tasks have to be performed.

YNIMG Journal 2004 Journal Article

Pyramidal tract lesions and movement-associated cortical recruitment in patients with MS

• Maria A. Rocca
• Antonio Gallo
• Bruno Colombo
• Andrea Falini
• Giuseppe Scotti
• Giancarlo Comi
• Massimo Filippi

Cortical functional changes, with the potential to limit the functional consequences of tissue injury, have been shown in patients with multiple sclerosis (MS). In this study, we assessed the influence of MS-related tissue damage of the brain portion of the left pyramidal tract on the corresponding movement-associated patterns of cortical recruitment in a large sample of MS patients when performing a simple motor task with their fully normal functioning right upper limbs. We investigated 76 right-handed patients with definite MS. In each subject, functional magnetic resonance imaging (fMRI) was acquired during the performance of a simple motor task with the dominant, right upper limb. During the same session, dual-echo, magnetization transfer (MT) and diffusion tensor (DT) MRI sequences were also obtained to quantify the extent and the severity of pyramidal tract damage. Lesions along the left pyramidal tract were identified in 43 patients. Compared to patients without pyramidal tract lesions, patients with such lesions had more significant activations of the contralateral primary sensorimotor cortex (SMC), secondary sensorimotor cortex (SII), inferior central sulcus, and cingulate motor area (CMA). They also showed more significant activations of several regions of the ipsilateral hemisphere, including the primary SMC and the precuneus. In these patients, T2 lesion load of left pyramidal tract was correlated with the extent of activation of the contralateral primary SMC (r 2 = 0. 25, P < 0. 0001), whereas no correlations were found between the extent of fMRI activations and the severity of intrinsic lesion damage, as well as with left pyramidal tract normal-appearing white matter damage. This study shows that, in patients with MS, following injury of the motor pathways, there is an increased recruitment of a widespread sensorimotor network, which is likely to contribute to limit the appearance of overt clinical deficits.

YNIMG Journal 2003 Journal Article

A functional magnetic resonance imaging study of patients with secondary progressive multiple sclerosis

• Maria A Rocca
• Cinzia Gavazzi
• Domenico M Mezzapesa
• Andrea Falini
• Bruno Colombo
• Mario Mascalchi
• Giuseppe Scotti
• Giancarlo Comi

Although several functional magnetic resonance imaging (fMRI) studies have shown adaptive cortical changes in patients with early multiple sclerosis (MS), the presence of brain plasticity and its role in limiting the functional consequences of brain tissue damage in patients with secondary progressive (SP) MS have not been fully investigated yet. In this study, we assessed the movement-associated brain pattern of cortical activations in patients with SPMS and investigated whether the extent of cortical brain activations is correlated with the extent of brain structural changes. From 13 right-handed SPMS patients and 15 sex- and age-matched healthy volunteers, we obtained: (a) brain dual-echo scans; (b) brain mean diffusivity and fractional anisotropy maps of the normal-appearing white (NAWM) and gray matter (NAGM); (c) fMRI during the performance of simple motor tasks [flexion–extension of the last four fingers of the right hand (task 1) and flexion–extension of the right foot (task 2)]. Compared to healthy volunteers, during task 1 performance, SPMS patients showed more significant activations of the ipsilateral inferior frontal gyrus, middle frontal gyrus, bilaterally, and contralateral intraparietal sulcus. During task 2 performance, SPMS patients had more significant activations of the contralateral primary sensorimotor cortex and thalamus and of the ipsilateral upper bank of sylvian fessure. For both tasks, strong correlations (r values ranging from −0. 83 to 0. 88) were found between relative activations of cortical areas of the motor network and the severity of structural changes of the NAWM and NAGM. This study demonstrates that cortical plasticity does occur in patients with SPMS and that it might have a role in limiting the clinical impact of MS-related damage. It also suggests that, in these patients, functional abilities are sustained by increased recruitment of highly specialized cortical areas.

YNIMG Journal 2003 Journal Article

Demyelination and cortical reorganization: functional MRI data from a case of subacute combined degeneration

• Massimo Filippi
• Maria A Rocca
• Paolo Rossi
• Andrea Falini
• Letizia Leocani
• Vittorio Martinelli
• Giancarlo Comi

Although it is accepted that functional changes of the cortex can occur in patients with white matter diseases of the brain and might have an adaptive role in limiting the clinical consequences of subcortical injury, the pathological substrates able to elicit such cortical changes are still unknown. This multiparametric magnetic resonance study of a patient with an early diagnosis of subacute combined degeneration suggests that demyelination alone does not necessarily induce adaptive functional changes of the cerebral cortex.

YNIMG Journal 2003 Journal Article

Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis

• Maria A Rocca
• Domenico M Mezzapesa
• Andrea Falini
• Angelo Ghezzi
• Vittorio Martinelli
• Giuseppe Scotti
• Giancarlo Comi
• Massimo Filippi

Previous work has suggested that functional reorganization of cortical areas might have a role in limiting the clinical impact of axonal pathology in patients with established multiple sclerosis (MS). Since there is evidence for irreversible tissue damage even in patients with early MS, we assessed, using functional MRI (fMRI) and a general search method, the brain pattern of movement-associated cortical activations in patients at presentation with clinically isolated syndromes (CIS) suggestive of MS. To elucidate the role of cortical reorganization in these patients, we also investigated the extent to which the fMRI changes correlated with the extent of overall axonal injury of the brain. From 16 right-handed patients at presentation with CIS and 15 right-handed, age- and sex-matched healthy volunteers, we obtained: (1) fMRI (repetitive flexion–extension of the last four fingers of the right hand), (2) conventional MRI scans, and (3) a new, unlocalized proton MR spectroscopy (1HMRS) sequence to measure the concentration of N-acetylaspartate of the whole brain (WBNAA). Compared to controls, patients with CIS had more significant activations of the contralateral primary somatomotor cortex (SMC), secondary somatosensory cortex, and inferior frontal gyrus. They also had significant decreased WBNAA concentration. Relative activation of the contralateral primary SMC was strongly correlated with WBNAA levels (r = −0. 78, P < 0. 001). This study shows that axonal pathology and functional cortical changes over a rather distributed sensorimotor network occur in patients at presentation with CIS suggestive of MS and that these two aspects of the disease are strictly correlated. This suggests that the increased functional recruitment of the cortex in these patients might have an adaptive role in limiting the clinical impact of irreversible tissue damage.

YNIMG Journal 2003 Journal Article

Functional cortical changes in patients with multiple sclerosis and nonspecific findings on conventional magnetic resonance imaging scans of the brain

• Maria A Rocca
• Elisabetta Pagani
• Angelo Ghezzi
• Andrea Falini
• Mauro Zaffaroni
• Bruno Colombo
• Giuseppe Scotti
• Giancarlo Comi

Recent functional magnetic resonance imaging (fMRI) work has suggested that cortical reorganisation might have an adaptive role in limiting the clinical impact of multiple sclerosis (MS) structural damage. In this study, we investigated whether, in patients with MS, the presence and extent of structural damage of the normal-appearing brain tissue are associated with the extent of the movement-associated pattern of cortical activations. Using fMRI and a general search method, we assessed the patterns of brain activations associated with simple motor tasks in 12 right-handed patients with clinically definite MS and nonspecific T2-weighted abnormalities on conventional MRI scans of the brain and compared them with those from 12 sex- and age-matched right- handed healthy controls. Also investigated were the extent to which the fMRI changes correlated with normal-appearing white matter and grey matter (GM) pathology, measured using diffusion tensor MRI. When performing the simple motor task with the dominant hand, MS patients had more significant activations of the ipsilateral supplementary motor area (SMA), the ipsilateral superior frontal sulcus, the contralateral superior temporal gyrus, and the thalamus than controls. On the contrary, healthy subjects showed more significant activations of the medial part of the contralateral parieto-occipital fissure and the ipsilateral primary sensorimotor cortex (SMC) than patients with MS. In patients with MS, the relative activation of the ipsilateral SMA was correlated with the peak height (r = −0. 88, P < 0. 001) and position (r = 0. 87, P < 0. 001) of the GM mean diffusivity histogram. This study shows that cortical reorganisation occurs over a rather distributed sensorimotor network even in patients with MS and nonspecific abnormalities on conventional brain MRI scans. This suggests that, in patients with MS, an increased recruitment of movement-associated cortical network can be elicited by the presence of normal-appearing tissue pathology, which is independent of macroscopic T2-weighted abnormalities.

YNIMG Journal 2001 Journal Article

A functional magnetic resonance imaging study in multiple sclerosis patients with fatigue

• Massimo Filippi
• Maria Assunta Rocca
• Maria Codella
• Bruno Colombo
• Paolo Rossi
• Filippo Martinelli-Boneschi
• Giancarlo Comi

YNIMG Journal 2001 Journal Article

Brain adaptive changes following tissue damage in PPMS: a multiparametric study using F-MRI, MTI and DTI

• Massimo Filippi
• Maria Assunta Rocca
• Maria Codella
• Giancarlo Comi

YNIMG Journal 2001 Journal Article

Fatigue in Multiple Sclerosis Is Associated with Abnormal Cortical Activation to Voluntary Movement—EEG Evidence

• Letizia Leocani
• Bruno Colombo
• Giuseppe Magnani
• Filippo Martinelli-Boneschi
• Marco Cursi
• Paolo Rossi
• Vittorio Martinelli
• Giancarlo Comi

Converging evidence is consistent with the view that fatigue in Multiple Sclerosis is independent from pyramidal tract involvement, suggesting a possible involvement of frontal areas. During voluntary movement, changes of the EEG rhythms can be observed over sensorimotor areas. Event-related desynchronization (ERD) of the 10 and 20 Hz frequency bands occurs during motor planning and execution and is followed after movement termination by event-related synchronization (ERS), expressing cortical idling or inhibition. We evaluated the pattern of cortical activation to voluntary movement in MS patients complaining of fatigue assessed using the Fatigue Severity Scale. Fifteen MS patients complaining of fatigue, 18 MS patients without fatigue, and 14 normal controls were studied. The two patients groups were similar for age, sex, disease duration, and were not disabled (score <1. 5 at the Expanded Disability Status Scale). Twenty-nine channel EEG was recorded during about 60 self-paced extensions of the right thumb. The onset latency and amount of the contralateral sensorimotor (C3 electrode) 10 and 18–22 Hz ERD were similar in the three groups. ERD was more widespread anteriorly in the fatigue group compared with normal controls (P < 0. 01 over Fz electrode). Postmovement contralateral sensorimotor 18–22 Hz ERS was significantly lower in fatigue MS patients compared with normal subjects (P < 0. 005) and with nonfatigue MS patients (P = 0. 02). These findings are consistent with a central origin of fatigue in MS and indicate cortical dysfunction even during a simple motor task, resulting in hyperactivity during movement execution and failure of the inhibitory mechanisms intervening after movement termination.