Adaptive Cortical Reorganization In MS

Evidence from recent Functional Magnetic Resonance Imaging studies suggests that Adaptive Cortical changes ('plasticity') could participate in the maintenance of function in Multiple Sclerosis (MS).

Here, we addressed the impact of Brain Atrophy on the pattern of Cerebral Activation in an MS patient with a Relapsing/Remitting course.

This patient showed mildly disabling Hemiparesis of the left side (EDSS 2.0), and corresponding Brain HemiAtrophy (15% volume reduction) of the Right Hemisphere.

The clinical syndrome was considered to result from a lesion in the Corona Radiata involving CorticoSpinal Fibers.

Motor Evoked Potential recordings confirmed substantial Axonal Damage to the Pyramidal Tract arising from that Hemisphere.

Irrespective of these asymmetries, normal Brain Activation was found for hand and foot movements for both Brain sides.

This demonstrates that Brain Atrophy itself does not necessarily induce Cortical Adaptive changes, even if mild disability is present.

On the other hand, significantly disabling distinct clinical syndromes e.g. arising from Spinal Cord lesions may evoke Cortical changes irrespective of Brain Atrophy. This issue has to be studied in longitudinal investigations.

Copyright 2004 S. Karger AG, Basel

Background And Purpose
Verbal Working Memory (VWM) deficits have been a well-replicated finding among patients with Multiple Sclerosis (MS).

Functional Magnetic Resonance Imaging (fMRI) studies have described a VWM system in healthy samples; however, Functional NeuroImaging of this system among MS patients is just beginning to appear.

Methods
Fifteen MS patients and 15 sex-, age-, education-, and IQ-matched Healthy Control (HC) participants completed a 2-Back VWM task as Whole-Brain FMRI was conducted.

Results
Each group exhibited increased Brain activity compared to the O-Back control task in regions associated with the 2-Back in previous NeuroImaging Studies.

These included Broca's Area, Supplementary Motor Area (SMA), PreMotor Cortices (PMC), and DorsoLateral PreFrontal Cortices (DLPFC).

MS patients exhibited greater Cortical activity than did HC participants in Left Primary Motor and SomatoSensory Cortices, PMC, DLPFC, Anterior Cingulate, and BiLateral SMA.

MS patients exhibited relatively less activation in Broca's Area, BiLateral Cerebellum, and other regions not typically associated with the 2-Back (e.g., Right Fusiform Gyrus, Left Lingual Gyrus, Right Hippocampus).

Performance accuracy and reaction time did not differ between groups.

Conclusions
Normal performance of a challenging VWM task among high-functioning MS patients is associated with a shift toward greater activity in regions related to SensoriMotor functions and Anterior Attentional/Executive components of the VWM System.

Posterior Memory Storage Systems appeared unaffected, while portions of the Visual Processing and SubVocal Rehearsal Systems were less active.

Although a shift in Neural activity was noted relative to HC participants, deviation from regions normally involved in VWM function was not observed in this patient sample.

Functional Magnetic Resonance Imaging (fMRI) data on Motor Function have shown Adaptive Functional Changes related to Brain Injury in Multiple Sclerosis (MS).

We investigated whether patients with MS have altered fMRI activation patterns during Attention and Memory Tasks, and whether functional changes in the Brain correlate with the extent of overall tissue damage on conventional MRI.

Twenty-two right-handed patients with Relapsing/Remitting MS (RRMS) and no or only mild deficits at NeuroPsychological Testing and 22 matched healthy subjects were scanned during the Paced Auditory Serial Addition Test (PASAT) and a recall task.

fMRI data were analyzed using Statistical Parametric Mapping (SPM99). The relation between fMRI changes during both tasks and T₂ lesion load was investigated.

During both tasks, patients exhibited significantly greater Brain Activation than controls and recruited additional Brain Areas.

Task-related functional changes were more significant in patients whose performance matched that of controls than in patients with a lower performance.

During the PASAT, Brain functional changes involved the Right Supplementary Motor Area and Cingulate, the BiLateral PreFrontal, Temporal and Parietal Areas.

Whereas during the Recall Task, they involved the PreFrontal and Temporal Cortex and Basal Ganglia BiLaterally, and the Left Thalamus.

In patients, activation in specific Brain areas during performance of both tasks positively correlated with T₂ Brain lesions.

Patients with RRMS exhibit altered patterns of activation during tasks exploring Sustained Attention, Information Processing and Memory.

During these tasks, fMRI activity is greater in patients with better Cognitive function than in those with lower Cognitive function.

Functional changes in specific Brain areas increase with increasing tissue damage suggesting that they may also represent adaptive mechanisms that reflect underlying Neural disorganization or disinhibition, possibly associated with MS.

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.

Using functional Magnetic Resonance Imaging (fMRI), we investigated whether movement-associated functional changes of the Brain are present in patients who are, most likely, at the earliest stage of Multiple Sclerosis (MS).

Functional MRI exams were obtained from 16 patients at presentation with Clinically Isolated Syndromes (CIS) suggestive of MS and 15 sex- and age-matched healthy volunteers.

During, the performance of three simple and one more complex motor tasks with fully normal functioning extremities. fMRI analysis was performed using Statistical Parametric Mapping (SPM99).

Compared to healthy volunteers, CIS patients had increased activations of the ContraLateral Primary SensoriMotor Cortex (SMC), Secondary SomatoSensory Cortex (SII), and Inferior Frontal Gyrus (IFG), when performing a Simple Motor Task with the dominant hand.

The increased recruitment of the ContraLateral Primary SMC was also found during the performance of the same Motor Task with the non-dominant hand and with the dominant foot.

In this latter case, an anterior shift of the center of activation of this region was detected.

During the performance of a Complex Motor Task with the dominant upper and lower limbs, CIS patients had an increased recruitment of a widespread network.

Including the Frontal Lobe, The Insula, The Thalamus, usually considered to function in Motor, Sensory, and multimodal Integration Processing.

The comparison of Brain activations during the performance of simple vs. complex Motor Tasks showed that the movement-associated Somatotopic organization of the Cerebral and Cerebellar Cortices was retained in patients with CIS.

Cortical reorganization occurs in patients at presentation with CIS highly suggestive of MS.

Local synaptic reorganization, recruitment of parallel existing pathways, and reorganization of distant sites are all likely to contribute to the observed functional changes.

Hum. Brain Mapping 21:106-115, 2004. Copyright 2003 Wiley-Liss, Inc.

The combination of mapping functional Cortical Neurons by intraoperative Cortical stimulation and Axonal architecture by Diffusion Tensor MRI fiber tracking can be used to delineate the pathways between functional regions.

In this study the authors investigated the feasibility of combining these techniques to yield connectivity associated with Motor Speech and Naming.

Diffusion tensor MRI Fiber tracking provides maps of Axonal bundles and was combined with intraoperative mapping of eloquent Cortex for a patient undergoing Brain Tumor surgery.

Tracks from eight stimulated sites in the Inferior Frontal Cortex including Mouth Motor, Speech Arrest, and Anomia were generated from the Diffusion Tensor MRI data.

The regions connected by the Fiber tracking were compared to foci from previous Functional Imaging reports on language tasks.

Connections were found between Speech Arrest, Mouth Motor, and Anomia sites and the SMA proper and Cerebral Peduncle.

The Speech Arrest and a Mouth Motor Site were also seen to connect to the Putamen via the External Capsule.

This is the first demonstration of delineation of SubCortical Pathways using Diffusion Tensor MRI Fiber tracking with intraoperative Cortical stimulation.

The combined techniques may provide improved preservation of eloquent regions during Neurological surgery, and may provide access to direct connectivity information between functional regions of the Brain.

Background
Previous work has suggested that functional reorganization of Cortical Motor Areas might have a role in limiting the Motor Deficits in patients with MS.

Objective
To test whether movement-associated Cortical changes in MS might extend beyond the "classic" Motor Areas and involve sites for multimodal integration.

Methods
fMRI was used to assess patterns of Brain activations associated with 3 different Motor Tasks in 30 right-handed patients with Primary/Progressive MS (PPMS).

And variable degrees of Motor Impairment, which were compared with those from 15 right-handed, sex- and age-matched control subjects.

Results
Compared with control subjects, patients with MS showed increased activation of Brain regions within both traditional Motor planning and execution regions.

Including the Supplementary Motor Area and the Cingulate Motor Area, the Insula (a region implicated in sensory processing), and several multimodal Cortical regions in the Temporal, Parietal, and Occipital Lobes.

In patients, the extent of the fMRI activations was strongly correlated with MR lesion burden (r ranging from 0.70 to 0.86, p < 0.001).

Conclusions
This study shows that movement-associated Cortical activation in patients with PPMS is widely distributed and also involves multimodal "NonMotor" Cortical Networks.

It also suggests that adaptive Cortical reorganization might be one of the mechanisms limiting the clinical impact of MS in the Progressive phases of the disease.

Background
The Cerebellum is of potential interest for understanding Adaptive Responses in Motor Control in patients with Multiple Sclerosis because of the high intrinsic Synaptic plasticity of this Brain region.

Objective
To assess the relative roles of interactions between the NeoCortex and the Cerebellum using measures of functional connectivity.

Methods
A role for altered NeoCortical-Cerebellar functional connectivity in adaptive responses to injury from Multiple Sclerosis was tested.

Using 1.5 T functional Magnetic Resonance Imaging (fMRI) during figure writing with the dominant right hand in patients with predominantly early Relapsing/Remitting Multiple Sclerosis.

Results
Patients (n = 14) showed a more BiHemispheric pattern of activation in Motor Cortex than healthy controls (n = 11).

Correlations between task related signal changes in NeocCrtical and Cerebellar regions of interest were used as a measure of Functional Connectivity.

Healthy controls showed strong Functional Connectivity between the Left Motor Cortex and the Right Cerebellar Dentate Nucleus.

Significant connectivity between the Left Primary Motor Cortex and the Right Dentate was not found in patients.

However, patients had significant connectivity between the Left PreMotor NeoCortex and the IpsiLateral (left) CerebellumCerebellar Cortex (crus I), which was not found in healthy controls.

Conclusions
Changes in apparent Cerebellar-NeoCortical functional connectivity may mediate potentially adaptive changes in Brain Motor Control in patients with Multiple Sclerosis.

Similar changes in the Cerebellum and PreMotor Cortex have been reported in the healthy Brain during motor learning.

Suggesting that common mechanisms may contribute to normal Motor Learning and Motor recovery after injury from Multiple Sclerosis.

Cerebral reorganization may limit the effects of Central Nervous System tissue damage on Cognition in patients with Multiple Sclerosis (MS).

This study investigated fMRI activation patterns in patients with Relapsing/Remitting MS and healthy control subjects during performance of a delayed recognition task.

As intended, fMRI task performance was similar in the MS and the control group, whereas NeuroPsychological Testing revealed reduced performance in the patient group on the Paced Serial Addition Test.

A reference task for the assessment of Cognitive function in MS.

Patients overall showed more activation in Left Posterior Parietal Cortex than healthy control subjects. Global Gray Matter Atrophy in the patient group was associated with low PASAT scores.

In a multiple regression analysis including White Matter lesion load and Gray Matter Atrophy as covariates, PASAT performance correlated with activation in Left Posterior Parietal Cortex and Right Anterior MidFrontal Gyrus.

Indicating a reallocation of Neuronal resources to help preserve function.

Global Gray Matter Atrophy correlated with activation in BiLateral PreFrontal Cortex, Dorsal ACC and Left Posterior Parietal Cortex, and furthermore, was associated with a low degree of deactivation in Rostral ACC.

Suggesting Neural inefficiency and consistent with a reduced capacity to modulate between FrontoParietal task-associated activation and 'default network' activity.

The current study provides evidence that altered Brain activation in MS patients has two distinct components, one related to compensatory processes and one to Neural inefficiency associated with tissue damage.

Cognitive deficits affecting Memory, Attention and Speed Of Information Processing are common in Multiple Sclerosis (MS).

The mechanisms of cognitive impairment remain unclear. Here, we examined the association between NeuroPsychological Test performance and Brain Atrophy in a group of mildly disabled patients with Relapsing/Remitting MS.

We applied voxel-based morphometry (SPM2) to investigate the distribution of Brain Atrophy in relation to Cognitive performance.

Patients had lower scores than control subjects on tests of Memory and Executive Function, including the PASAT, Digit Span Backward and a test of Short-Term Verbal Memory (Memo).

Among patients, but not healthy controls, performance on the PASAT, a comprehensive measure of Cognitive function and reference task for the Cognitive evaluation of MS-patients, correlated with Global Gray Matter Volume.

As well as with Gray Matter Volume in regions associated with Working Memory and Executive function, including BiLateral PreFrontal Cortex, PreCentral Gyrus and Superior Parietal Cortex as well as Right Cerebellum.

Compared to healthy subjects, patients showed a Volume reduction in Left Temporal and PreFrontal Cortex, recently identified as areas predominantly affected by Diffuse Brain Atrophy in MS.

A comparison of low performers in the patient group with their matched control subjects showed more extensive and BiLateral Temporal and Frontal Volume reductions as well as BiLateral Parietal Volume loss, compatible with the progression of Atrophy found in more advanced MS-patients.

These findings indicate that MS-related deficits in Cognition are closely associated with Cortical Atrophy.

If Fatigue in Multiple Sclerosis (MS) is related to an abnormal activation of the SensoriMotor Brain Network, the activity of such a network should vary with varying Fatigue.

We studied 22 patients treated with Interferon-beta-1a (IFN-ß-1a; Avonex, Biogen, Cambridge, MA) with No Fatigue (10) and with reversible Fatigue (12).

fMRI examinations were performed:
1. The same day of IFN-ß-1a injection (No Fatigue)
2. The day after IFN-ß-1a injection (Fatigue; time 1)
3. 4 days after IFN-ß-1a injection (No Fatigue; time 2)

Patients performed a simple motor task with the right, clinically unaffected hand.

At time 1, compared with entry and time 2, MS patients with reversible Fatigue showed an increased activation of the Thalamus bilaterally.

In MS patients without Fatigue, Thalamus was more activated at entry than at time 1. In both groups at entry the primary SMC and the SMA were more activated than at times 1 and 2.

At entry and time 1, when compared to patients with reversible Fatigue, those without showed increased activations of the SII.

Conversely, patients with reversible Fatigue had increased activations of the Thalamus and of several regions of the Frontal Lobes.

An abnormal recruitment of the Fronto-Thalamic circuitry is associated with IFN-ß-1a-induced Fatigue in MS patients.

Hum Brain Mapp, 2007. (c) 2006 Wiley-Liss, Inc.