Corpus callosum (CC) is involved in the performance of bimanual motor tasks. We asked whether its functional role could be investigated by combining a motor behavioral study on bimanual movements in multiple sclerosis (MS) patients with a quantitative magnetic resonance diffusion tensor imaging (DTI) analysis of CC, which is shown to be damaged in this disease. MS patients and normal subjects were asked to perform sequences of bimanual finger opposition movements at different metronome rates; then we explored the structural integrity of CC by means of DTI. Significant differences in motor performance, mainly referred to timing accuracy, were observed between MS patients and control subjects. Bimanual motor coordination was impaired in MS patients as shown by the larger values of the interhand interval observed at all the tested metronome rates with respect to controls. Furthermore, DTI revealed a significant reduction of fractional anisotropy (FA), indicative of microstructural tissue damage, in the CC of MS patients. By correlating the mean FA values with the different motor behavior parameters, we found that the degree of damage in the anterior callosal portions mainly influences the bimanual coordination and, in particular, the movement phase preceding the finger touch. Finally, the described approach, which correlates quantitative measures of tissue damage obtained by advanced magnetic resonance imaging tools with appropriate behavioral measurements, may help the exploration of different aspects of motor performance impairment attributable to the disease.

In the human brain, homologous regions of the primary motor cortices (M1s) are connected through transcallosal fibers. Interhemispheric communication between the two M1s plays a major role in the control of unimanual hand movements, and the strength of this connection seems to be dependent on arm activity. For instance, a lesion in the M1 can induce an increase in the excitability of the intact M1 and an abnormal high inhibitory influence onto the damaged M1. This can be attributable to either the disuse of the affected limb or the overuse of the unaffected one. Here, to directly investigate cortical modifications induced by an abnormal asymmetric use of the two limbs, we studied both the excitability of the two M1s and transcallosal interaction between them in healthy subjects whose right hand was immobilized for 10 h. The left “not-immobilized” arm was completely free to move in one group of participants (G1) and limited in the other one (G2). We found that the non-use reduced the excitability of the left M1 and decreased the inhibitory influence onto the right hemisphere in the two groups. However, an increase in the excitability of right M1 and a deeper inhibitory interaction onto the left hemisphere were evident only in G1. Thus, modifications in the right M1 were not directly produced by the non-use but would depend on the overuse of the “not-immobilized” arm. Our findings suggest that the balance between the two M1s is strongly use dependent.

Several investigations suggest that actual and mental actions trigger similar neural substrates. Motor learning via physical practice results in long-term potentiation (LTP)-like plasticity processes, namely potentiation of M1 and a temporary occlusion of additional LTP-like plasticity. However, whether this neuroplasticity process contributes to improve motor performance through mental practice remains to be determined. Here, we tested skill learning-dependent changes in primary motor cortex (M1) excitability and plasticity by means of transcranial magnetic stimulation in subjects trained to physically execute or mentally perform a sequence of finger opposition movements. Before and after physical practice and motor-imagery practice, M1 excitability was evaluated by measuring the input-output (IO) curve of motor evoked potentials. M1 long-term potentiation (LTP) and long-term depression (LTD)-like plasticity was assessed with paired-associative stimulation (PAS) of the median nerve and motor cortex using an interstimulus interval of 25 ms (PAS25) or 10 ms (PAS10), respectively. We found that even if after both practice sessions subjects significantly improved their movement speed, M1 excitability and plasticity were differentially influenced by the two practice sessions. First, we observed an increase in the slope of IO curve after physical but not after motor-imagery practice. Second, there was a reversal of the PAS25 effect from LTP-like plasticity to LTD-like plasticity following physical and motor-imagery practice. Third, LTD-like plasticity (PAS10 protocol) increased after physical practice, whilst it was occluded after motor-imagery practice. In conclusion, we demonstrated that motor-imagery practice lead to the development of neuroplasticity, as it affected the PAS25- and PAS10- induced plasticity in M1. These results, expanding the current knowledge on how motor-imagery training shapes M1 plasticity, might have a potential impact in rehabilitation.

Upper limb impairments can occur in patients with multiple sclerosis, affecting daily living activities; however there is at present no definite agreement on the best rehabilitation treatment strategy to pursue. Moreover, motor training has been shown to induce changes in white matter architecture in healthy subjects. This study aimed at evaluating the motor behavioral and white matter microstructural changes following a 2-month upper limb motor rehabilitation treatment based on task-oriented exercises in patients with multiple sclerosis. Thirty patients (18 females and 12 males; age=43.3 ± 8.7 years) in a stable phase of the disease presenting with mild or moderate upper limb sensorimotor deficits were randomized into two groups of 15 patients each. Both groups underwent twenty 1-hour treatment sessions, three times a week. The "treatment group" received an active motor rehabilitation treatment, based on voluntary exercises including task-oriented exercises, while the "control group" underwent passive mobilization of the shoulder, elbow, wrist and fingers. Before and after the rehabilitation protocols, motor performance was evaluated in all patients with standard tests. Additionally, finger motor performance accuracy was assessed by an engineered glove. In the same sessions, every patient underwent diffusion tensor imaging to obtain parametric maps of fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. The mean value of each parameter was separately calculated within regions of interest including the fiber bundles connecting brain areas involved in voluntary movement control: the corpus callosum, the corticospinal tracts and the superior longitudinal fasciculi. The two rehabilitation protocols induced similar effects on unimanual motor performance, but the bimanual coordination task revealed that the residual coordination abilities were maintained in the treated patients while they significantly worsened in the control group (p=0.002). Further, in the treatment group white matter integrity in the corpus callosum and corticospinal tracts was preserved while a microstructural integrity worsening was found in the control group (fractional anisotropy of the corpus callosum and corticospinal tracts: p=0.033 and p=0.022; radial diffusivity of the corpus callosum and corticospinal tracts: p=0.004 and p=0.008). Conversely, a significant increase of radial diffusivity was observed in the superior longitudinal fasciculi in both groups (p=0.02), indicating lack of treatment effects on this structure, showing damage progression likely due to a demyelination process. All these findings indicate the importance of administering, when possible, a rehabilitation treatment consisting of voluntary movements. We also demonstrated that the beneficial effects of a rehabilitation treatment are task-dependent and selective in their target; this becomes crucial towards the implementation of tailored rehabilitative approaches.

Cognitive impairment is common in multiple sclerosis (MS), but the definition of the best cognitive rehabilitation tools and features is still an open issue among researchers. The aims of the present study were to evaluate the effectiveness of COGNI-TRAcK (a customized application software delivering personalized working memory-based exercises) on cognitively impaired people with MS and to investigate the effects of an adaptive vs. a non-adaptive cognitive training administered by means of COGNI-TRAcK. Twenty eight patients (20 women, age 47.5 ± 9.3 years, Expanded Disability Status Scale score 3.8 ± 1.9) were randomized in two homogeneous groups, both performing a 8-week home-based cognitive rehabilitation treatment by means of COGNI-TRAcK. The study group (ADAPT-gr) underwent an adaptive training given by the automatic adjustment of tasks difficulty to the subjects’ performance, whilst the control group (CONST-gr) was trained at constant difficulty levels. Before and after the treatment, patients’ cognitive status was assessed using a gold standard neuropsychological evaluation. Moreover, the mostly affected cognitive domains in MS (i.e., attention, concentration and information processing speed) were also assessed 6 months after the end of the treatment. The analysis of variance showed a significant Group*Time interaction in six out of ten tests of the cognitive evaluation. Post-hoc analysis revealed a significant improvement between the performances before and after the intervention only in the ADAPT-gr in tests evaluating verbal memory acquisition (p <0.05) and delayed recall (p = 0.001), verbal fluency (p = 0.01), sustained attention, concentration and information processing speed (p < 0.01). This last effect was maintained also after 6 months (p < 0.05). We concluded that COGNI-TRAcK represents a suitable tool to administer a personalized training to cognitively impaired subjects and that an adaptive working load is a crucial feature determining the effectiveness of cognitive treatment, allowing transfer effects to several cognitive domains and long-term maintenance of results.

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