Elsevier

NeuroImage

Volume 57, Issue 2, 15 July 2011, Pages 495-501
NeuroImage

Impairment in explicit visuomotor sequence learning is related to loss of microstructural integrity of the corpus callosum in multiple sclerosis patients with minimal disability

https://doi.org/10.1016/j.neuroimage.2011.04.037Get rights and content

Abstract

Sequence learning can be investigated by serial reaction-time (SRT) paradigms. Explicit learning occurs when subjects have to recognize a test sequence and has been shown to activate the frontoparietal network in both contralateral and ipsilateral hemispheres. Thus, the left and right superior longitudinal fasciculi (SLF), connecting the intra-hemispheric frontoparietal circuits, could have a role in explicit unimanual visuomotor learning. Also, as both hemispheres are involved, we could hypothesize that the corpus callosum (CC) has a role in this process. Pathological damage in both SLF and CC has been detected in patients with Multiple Sclerosis (PwMS), and microstructural alterations can be quantified by Diffusion Tensor Imaging (DTI).

In light of these findings, we inquired whether PwMS with minimal disability showed impairments in explicit visuomotor sequence learning and whether this could be due to loss of white matter integrity in these intra- and inter-hemispheric white matter pathways. Thus, we combined DTI analysis with a modified version of SRT task based on finger opposition movements in a group of PwMS with minimal disability.

We found that the performance in explicit sequence learning was significantly reduced in these patients with respect to healthy subjects; the amount of sequence-specific learning was found to be more strongly correlated with fractional anisotropy (FA) in the CC (r = 0.93) than in the left (r = 0.28) and right SLF (r = 0.27) (p for interaction = 0.005 and 0.04 respectively). This finding suggests that an inter-hemispheric information exchange between the homologous areas is required to successfully accomplish the task and indirectly supports the role of the right (ipsilateral) hemisphere in explicit visuomotor learning. On the other hand, we found no significant correlation of the FA in the CC and in the SLFs with nonspecific learning (assessed when stimuli are randomly presented), supporting the hypothesis that inter-hemispheric integrity is specifically relevant for explicit sequence learning.

Highlights

► We evaluate the explicit sequence learning in patients with Multiple Sclerosis. ► We assess corpus callosum and superior longitudinal fasciculi integrity with DTI. ► Patients with Multiple Sclerosis show an impairment in explicit sequence learning. ► Callosal integrity significantly correlate with explicit sequence-specific learning.

Introduction

People learn most of daily life activities, such as driving a car, dialing a phone number or playing a ball-game, through the acquisition of sequences of motor actions. From a research point of view, sequence learning has been extensively investigated by means of serial reaction-time (SRT) paradigms. In general, in these paradigms subjects are required to press a key corresponding to each visual cue presented according to a sequence; performance improvements with practice are measured as decrease in response time (RT) (Nissen and Bullemer, 1987).

Explicit sequence learning is based on the conscious recollection of previous experiences and can occur when subjects are asked to recognize and then tell the experimenter the test sequence. This learning process has been shown to activate the frontoparietal network (Honda et al., 1998, Jenkins et al., 1994, Sakai et al., 1998, Schlaug et al., 1994); further, a role of the ipsilateral hemisphere has been demonstrated during unimanual explicit learning (Honda et al., 1998, Muller et al., 2002). Indeed, right prefrontal and parietal cortices have been found to be involved in the initial phase of motor learning during a right-hand task (Deiber et al., 1997, Halsband and Lange, 2006, Jenkins et al., 1994).

Thus, both intra-hemispheric white matter pathways connecting the frontoparietal circuits of the left and right hemispheres, such as the superior longitudinal fasciculus (SLF), and the main inter-hemispheric connection in the brain linking homologous areas of the two hemispheres, i.e., the corpus callosum (CC), could be essential to explicitly learn a unimanual visuomotor skill.

Pathological damage in both SLF and CC has been demonstrated to occur in patients with Multiple Sclerosis (PwMS), and microstructural integrity can be quantified by Magnetic Resonance Diffusion Tensor Imaging (DTI) (Bonzano et al., 2009, Coombs et al., 2004, Inglese and Bester, 2010). DTI allows the description of the magnitude and directionality (anisotropy) of water molecules motion, which can be hindered by the presence of highly organized myelinated fiber tracts in the brain's white matter. Among the different DTI-derived parameters, fractional anisotropy (FA) is the one that best represents a measure of fiber integrity and directionality (Basser, 1995). Furthermore, the degree of diffusion anisotropy increases with normal myelination processes and with the organization of axons during development (Neil et al., 1998). For these reasons, FA is particularly suitable to study the white matter pathological processes in demyelinating diseases such as multiple sclerosis (MS); low values of FA indicate loss of white matter integrity. In fact, for instance, reduced FA values have been shown in the CC of PwMS with respect to healthy subjects (Ge et al., 2004, Hasan et al., 2005, Oh et al., 2004).

In this context, a possible relationship between the performance in explicit sequence learning and the structural integrity of the SLF and the CC can be investigated by means of appropriate behavioral protocols and neuroimaging techniques. In a recent work, the left frontoparietal network was probed in PwMS to assess the influence of reduced white matter integrity on cortical reorganization by combining the Paced Visual Serial Addition Test (PVSAT) with fMRI-guided fiber tractography (Bonzano et al., 2009). The left SLF was found to be the main white matter tract connecting the brain activation areas elicited by the PVSAT task in the control group. The PwMS group showed a significantly lower performance at the PVSAT with respect to the control group, concomitantly with reduced FA values in the left SLF; particularly, the patients with less white matter integrity in this tract had an altered pattern of cortical activation with respect to the control group. Moreover, a study combining bifocal transcranial magnetic stimulation and DTI tractography in healthy subjects has demonstrated that different fiber bundles of the left SLF connect parietal areas to motor areas involved in the planning of grasping actions (Koch et al., 2010).

Furthermore, following an experimental approach based on the combination of DTI data with quantitative analyses of finger opposition movements in PwMS, it was previously found that anterior callosal portions are essential for bimanual coordination (Bonzano et al., 2008), while the inter-manual transfer of motor-skill learning during a pure motor reaction-time task (nonspecific transfer) was correlated with the reduced white matter integrity in a specific callosal subregion, including midbody (Bonzano et al., 2011).

Following all these findings, we inquired: (i) Do patients with Multiple Sclerosis with minimal disability show impairments in explicit sequence learning? (ii) Do the superior longitudinal fasciculi of both the left and right cerebral hemispheres and the corpus callosum have a role in this process? (iii) If so, what is more important to successfully accomplish this learning process? A preservation of the intra-hemispheric or of the inter-hemispheric circuits?

We could expect that a disruption of the frontoparietal circuits might induce an impairment in the performance of an explicit visuomotor sequence learning task. However, since it has been demonstrated that during an explicit learning process both cortical hemispheres are activated, we can hypothesize that CC could play a major role in the accomplishment of explicit visuomotor sequence learning and that damage in this structure could induce a considerable impairment in the process.

In the present work, we investigated the functional role of intra- and inter-hemispheric white matter pathways in explicit sequence learning by correlating FA values in the left and right SLFs and in the CC with the analysis of visuomotor sequence learning in a group of PwMS with minimal disability, which constitutes a homogenous population of patients showing only subtle motor impairments at both neurological examination and behavioral measures of fine finger movements (Bonzano et al., 2011). A modified version of the SRT task based on finger opposition movements was adopted: a group of PwMS and a group of control subjects wore a sensor-engineered glove on their right hand (Bove et al., 2007) and were asked to respond as fast and accurately as possible to a series of visual cues presented on the fingertips of a pictured right hand, by tapping the appropriate finger with the thumb. The amount of explicit sequence-specific learning was evaluated on the basis of the reduction of response time.

Section snippets

Subjects

Thirteen PwMS with minimal disability (Expanded Disability Status Scale—EDSS  2) (Kurtzke, 1983) were included in this study (4 males and 9 females; mean age: 39.0 ± 4.9 years; mean disease duration: 7.4 ± 5.3 years; mean EDSS: 1.3 ± 0.4). All patients were affected by relapsing–remitting multiple sclerosis and were in a stable phase of the disease, without relapses in the last 3 months, without visual impairment, cerebellar manifestation (e.g., gait ataxia, nystagmus, tremor) and upper limb sensorimotor

Explicit sequence learning

All the patients and control subjects were able to complete the experimental protocol without reporting fatigue.

The initial performance was different between the two groups, in fact RT in R2 was significantly longer in the PwMS group with respect to the control group (RT in R2: 409.99 ± 57.36 ms vs. 347.64 ± 52.24 ms; Student's t-test: t = 2.76, p = 0.01). RM-ANOVA conducted on RT values in blocks S (S1 ÷ S10) indicated a significant effect of GROUP factor (F(1,22) = 10.89, p = 0.003), with longer mean RT in

Discussion

In this work, behavioral data showed that PwMS with minimal disability were able to significantly shorten RT values with sequence repetition during an explicit visuomotor learning task. This finding is in agreement with the results shown in (Tomassini et al., (2011) indicating that motor skill learning is partially preserved in PwMS. However, the improvement we observed was significantly smaller than in control subjects. This reduced visuomotor ability could be due to attentional deficits which

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