Relationships between functional and structural corticospinal tract integrity and walking post stroke.

OBJECTIVE: Studies on upper limb recovery following stroke have highlighted the importance of the structural and functional integrity of the corticospinal tract (CST) in determining clinical outcomes. However, such relationships have not been fully explored for the lower limb. We aimed to test whether variation in walking impairment was associated with variation in the structural or functional integrity of the CST. METHODS: Transcranial magnetic stimulation was used to stimulate each motor cortex while EMG recordings were taken from the vastus lateralis (VL) bilaterally; these EMG measures were used to calculate both ipsilateral and contralateral recruitment curves for each lower limb. The slope of these recruitment curves was used to examine the strength of functional connectivity from the motor cortex in each hemisphere to the lower limbs in chronic stroke patients and to calculate a ratio between ipsilateral and contralateral outputs referred to as the functional connectivity ratio (FCR). The structural integrity of the CST was assessed using diffusion tensor MRI to measure the asymmetry in fractional anisotropy (FA) of the internal capsule. Lower limb impairment and walking speed were also measured. RESULTS: The FCR for the paretic leg correlated with walking impairment, such that greater relative ipsilateral connectivity was associated with slower walking speeds. Asymmetrical FA values, reflecting reduced structural integrity of the lesioned CST, were associated with greater walking impairment. FCR and FA asymmetry were strongly positively correlated with each other. CONCLUSIONS: Patients with relatively greater ipsilateral connectivity between the contralesional motor cortex and the paretic lower limb were more behaviorally impaired and had more structural damage to their ipsilesional hemisphere CST. SIGNIFICANCE: Measures of structural and functional damage may be useful in the selection of therapeutic strategies, allowing for more tailored and potentially more beneficial treatments.

Modulating locomotor adaptation with cerebellar stimulation.

Human locomotor adaptation is necessary to maintain flexibility of walking. Several lines of research suggest that the cerebellum plays a critical role in motor adaptation. In this study we investigated the effects of noninvasive stimulation of the cerebellum to enhance locomotor adaptation. We found that anodal cerebellar transcranial direct current stimulation (tDCS) applied during adaptation expedited the adaptive process while cathodal cerebellar tDCS slowed it down, without affecting the rate of de-adaptation of the new locomotor pattern. Interestingly, cerebellar tDCS affected the adaptation rate of spatial but not temporal elements of walking. It may be that spatial and temporal control mechanisms are accessible through different neural circuits. Our results suggest that tDCS could be used as a tool to modulate locomotor training in neurological patients with gait impairments.

Human locomotor adaptive learning is proportional to depression of cerebellar excitability.

Human locomotor adaptive learning is thought to involve the cerebellum, but the neurophysiological mechanisms underlying this process are not known. While animal research has pointed to depressive modulation of cerebellar outputs, a direct correlation between adaptive learning and cerebellar depression has never been demonstrated. Here, we used transcranial magnetic stimulation to assess excitability changes occurring in the cerebellum and primary motor cortex (M1) after individuals learned a new locomotor pattern on a split-belt treadmill. To control for potential changes associated to task performance complexity, the same group of subjects was also assessed after performing 2 other locomotor tasks that did not elicit learning. We found that only adaptive learning resulted in reduction of cerebellar inhibition. This effect was strongly correlated with the magnitude of learning (r = 0.78). In contrast, M1 excitability changes were not specific to learning but rather occurred in association with task complexity performance. Our results demonstrate that locomotor adaptive learning in humans is proportional to cerebellar excitability depression. This finding supports the theory that adaptive learning is mediated, at least in part, by long-term depression in Purkinje cells. This knowledge opens the opportunity to target cerebellar processes with noninvasive brain stimulation to enhance motor learning.

The effects of transcranial stimulation on paretic lower limb motor excitability during walking.

Balanced transcallosal inhibition sustains symmetrical corticomotor excitability and assists the performance of bimanual voluntary movements. After stroke, transcallosal inhibition becomes asymmetric. This finding raised the notion that reducing poststroke asymmetry in transcallosal inhibition might prime the motor system before training and lead to improvements in walking recovery. In this study, we examined three neuromodulatory protocols applied during walking to determine if they could increase ipsilesional and decrease contralesional motor excitability in patients with chronic stroke. Inhibitory repetitive transcranial magnetic stimulation and inhibitory paired associative stimulation were applied to the contralesional motor system, and facilitatory anodal transcranial direct current stimulation was applied to the ipsilesional motor system. We tested the bilateral modulatory effects of each stimulation protocol on the tibialis anterior, medial gastrocnemius, medial hamstrings, and vastus lateralis of nine patients with chronic stroke. All stimulation protocols increased paretic limb and decreased nonparetic limb motor excitability. There was no statistical difference in the extent of modulation between these stimulation protocols. This result suggests these three protocols are promising candidate priming mechanisms for testing the hypothesis in a future study that reducing the poststroke asymmetry of between-hemisphere motor excitability will enhance the effect of gait therapy.

Modulation of cerebellar excitability by polarity-specific noninvasive direct current stimulation.

The cerebellum is a crucial structure involved in movement control and cognitive processing. Noninvasive stimulation of the cerebellum results in neurophysiological and behavioral changes, an effect that has been attributed to modulation of cerebello-brain connectivity. At rest, the cerebellum exerts an overall inhibitory tone over the primary motor cortex (M1), cerebello-brain inhibition (CBI), likely through dentate-thalamo-cortical connections. The level of excitability of this pathway before and after stimulation of the cerebellum, however, has not been directly investigated. In this study, we used transcranial magnetic stimulation to determine changes in M1, brainstem, and CBI before and after 25 min of anodal, cathodal, or sham transcranial direct current stimulation (tDCS) applied over the right cerebellar cortex. We hypothesized that anodal tDCS would result in an enhancement of CBI and cathodal would decrease it, relative to sham stimulation. We found that cathodal tDCS resulted in a clear decrease of CBI, whereas anodal tDCS increased it, in the absence of changes after sham stimulation. These effects were specific to the cerebello-cortical connections with no changes in other M1 or brainstem excitability measures. The cathodal effect on CBI was found to be dependent on stimulation intensity and lasted up to 30 min after the cessation of tDCS. These results suggest that tDCS can modulate in a focal and polarity-specific manner cerebellar excitability, likely through changes in Purkinje cell activity. Therefore, direct current stimulation of the cerebellum may have significant potential implications for patients with cerebellar dysfunction as well as to motor control studies.

Contralesional paired associative stimulation increases paretic lower limb motor excitability post-stroke.

Following stroke, an abnormally high interhemispheric inhibitory drive from the contralesional to the ipsilesional primary motor cortex (M1) is evident during voluntary movement. Down-regulating motor excitability of the contralesional M1 using inhibitory neuromodulatory protocols has demonstrated a correlation between balanced interhemispheric interactions and increased motor recovery. In 2005, our laboratory first reported bidirectional modulation of healthy subjects' tibialis anterior (TA) motor excitability during walking, using a stimulation paradigm known as paired associative stimulation (PAS). Suprathreshold transcranial magnetic stimulation (TMS) of the lower limb M1 paired with electrical stimulation of the common peroneal nerve produced a persistent modulation of TA corticomotor excitability. The present study tested the hypothesis that the excitability of the ipsilesional lower limb motor cortex during walking is increased when inhibitory PAS is applied to the contralesional motor cortex in chronic stroke survivors. We applied inhibitory PAS (120 pairs at 0.5 Hz) to the quiescent paretic TA of ten chronic stroke patients and the right TA of ten age-matched healthy subjects. Post intervention excitability measures were taken immediately following PAS, and again 5, 10 and 15 min later. When inhibitory PAS was applied to the non-paretic TA of chronic stroke subjects, the non-paretic TA motor evoked potential (MEP) amplitude decreased to 91% and paretic TA MEP amplitude increased to 130% (of pre-PAS values) during post-PAS walking. In healthy subjects, MEPs in response to TMS revealed that mean MEP amplitude from the stimulated TA decreased to 87% and the mean MEP amplitude from the non-stimulated TA increased to 126%. This is the first study to demonstrate that inhibitory PAS applied to the contralesional lower limb motor system of stroke survivors increases motor excitability of the paretic lower limb assessed during walking. This finding suggests that inhibitory PAS may be a useful tool to study how the human lower limb motor cortex recovers after neural injury, and that PAS may be a candidate adjuvant therapy for patients with neurological walking impairments.

Spike-timing-dependent plasticity induced in resting lower limb cortex persists during subsequent walking.

Transcranial magnetic stimulation (TMS) of human lower limb motor cortex paired with common peroneal nerve electrical stimulation produces a lasting modulation of motor cortex excitability following the principles of spike-timing-dependent plasticity. We previously demonstrated that this "paired associative stimulation" (PAS) protocol applied during walking induced a bidirectional modulation of cortical excitability. The present study tested the hypothesis that the excitability of lower limb motor cortex assessed during walking is increased when PAS is applied to the resting cortex. PAS was delivered as a block of 120 pairs at 0.5 Hz to healthy subjects (n=13) in three separate sessions. TMS intensity was related to the active threshold obtained in tibialis anterior (TA) during the late swing phase of walking. Therefore, intensities used were below resting thresholds. When PAS using TMS intensities above active threshold was applied to the resting cortex, the normalized amplitude of potentials evoked in TA during subsequent walking increased to 124%. Using the same parameters and applying PAS during the late swing phase of walking, response amplitude increased to 114% of baseline. When the TMS intensity was set to active threshold, PAS applied to the resting cortex did not significantly modulate cortical excitability.