Restorative Neurology and Neuroscience

Motor impairment induced by traumatic brain injury (TBI) may be mediated through changes in spinal molecular systems regulating neuronal plasticity. We assessed whether a focal controlled cortical impact (CCI) TBI in the rat alters expression of the Tgfb1, c-Fos, Bdnf, and Gap43 neuroplasticity genes in lumbar spinal cord.

Adult male Sprague-Dawley rats (n = 8) were subjected to a right-side CCI over the anterior sensorimotor hindlimb representation area or sham-injury (n = 8). Absolute expression levels of Tgfb1, c-Fos, Bdnf, and Gapd43 genes were measured by droplet digital PCR in ipsi-and contralesional, dorsal and ventral quadrants of the L4 and L5 spinal cord. The neuronal activity marker c-Fos was analysed by immunohistochemistry in the dorsal L4 and L5 segments. The contra- vs. ipsilesional expression pattern was examined as the asymmetry index, AI.

The Tgfb1 mRNA levels were significantly higher in the CCI vs. sham-injured rats, and in the contra- vs. ipsilesional dorsal domains in the CCI group. The number of c-Fos-positive cells was elevated in the L4 and L5 segments; and on the contralesional compared to the ipsilesional side in the CCI group. The c-Fos AI in the dorsal laminae was significantly increased by CCI.

The results support the hypothesis that focal TBI induces plastic alterations in the lumbar spinal cord that may contribute to either motor recovery or maladaptive motor responses.

The neural organization of locomotion involves motor patterns generated by spinal interneuronal networks and supraspinal structures, which are approachable by noninvasive stimulation techniques. Recent evidences supported the hypothesis that transcranial direct current stimulation (combined with transcutaneous spinal direct current stimulation) may actually enhance the effects of robot-assisted gait training in chronic stroke patients. The cerebellum has many connections to interact with neocortical areas and may provide some peculiar plasticity mechanisms. So, it has been proposed as “non-lesioned entry” to the motor or cognitive system for the application of noninvasive stimulation techniques in patients with supratentorial stroke.

To compare the effects of two different protocols of cerebellar transcranial direct current stimulation combined with transcutaneous spinal direct current stimulation on robotic gait training in patients with chronic supratentorial stroke.

Forty patients with chronic supratentorial stroke were randomly assigned into two groups. All patients received ten, 20-minute robotic gait training sessions, five days a week, for two consecutive weeks. Group 1 underwent cathodal transcranial direct current stimulation over the contralesional cerebellar hemisphere + cathodal transcutaneous spinal direct current stimulation in combination with robotic training. Group 2 underwent cathodal transcranial direct current stimulation over the ipsilesional cerebellar hemisphere + cathodal transcutaneous spinal direct current stimulation in combination with robotic training. The primary outcome was the 6-minute walk test performed before, after, and at follow-up at 2 and 4 weeks post-treatment.

No significant difference in the 6-minute walk test between groups was found at the first post-treatment evaluation (P = 0.976), as well as at the 2-week (P = 0.178) and the 4-week (P = 0.069) follow-up evaluations. Both groups showed significant within-group improvements in the 6-minute walk test at all time points.∥Conclusions: Our findings support the hypothesis that cathodal transcranial direct current stimulation over the contralesional or ipsilesional cerebellar hemisphere in combination with cathodal transcutaneous spinal direct current stimulation may lead to similar effects on robotic gait training in chronic supratentorial stroke patients.

Transcranial direct current stimulation (tDCS) is a well-established non-invasive brain stimulation technique that has been widely applied to modulate cortical excitability in human brain. The results of previous tDCS studies on modulating contrast sensitivity, one of the most fundamental visual functions, were mixed.

We aim to systematically investigate the effects of anodal tDCS on contrast sensitivity functions (CSF), evaluate the responsiveness explanation of tDCS effects, and discuss results along with measurement precision.

We designed a single-blinded, sham-controlled within-subject study. Twenty-seven healthy adult subjects received three sets of 15 min tDCS (two 2-mA anodal and one sham) that delivered at Oz, with CSF measured before and after each tDCS stimulation. Experimental sessions were separated by at least twenty-four hours. CSF was assessed with a Bayesian procedure that accurately estimated CSF within minutes. The anodal tDCS-induced effect was gauged with the change in CSF after stimulation; responsiveness was indexed by correlation between CSF changes in different stimulation; precision was calculated from resampling.

Our results indicated that neither the first nor the second session anodal tDCS altered the CSF significantly. Responsiveness was inconsistent between the two anodal sessions, indicating the usual responder/non-responder explanation of tDCS effects was unconvincing. Precision was less than 2 dB and constant throughout the whole experiment.

The anodal tDCS, at least with two sessions, has no effect on modulating CSF. The absence of anodal tDCS effect on CSF was not due to subject’s responsiveness to tDCS or measurement precision. More studies were needed to determine the optimal vision modulation configuration.

Patients with moderate-to-severe stroke-related upper limb impairment can benefit from repetitive robot-assisted training. However, predicting motor performance in these patients from baseline measurements, including robot-based parameters would help clinicians to provide optimal treatments for each individual.

Forty-six patients with sub-acute stroke underwent a 16-session upper limb rehabilitation combining usual care and robotic therapy. Motor outcomes (Fugl-Meyer Assessment Upper Extremity (FMA) score) were retrospectively analysed and potential predictors of motor outcome (including baseline FMA scores, kinematics and number of repetitions performed in the first session etc.) were determined.

The 16-sessions upper limb combined training program led to significantly improved clinical outcomes (gains of 13.8±11.2 for total FMA score and 7.3±6.7 for FMA Shoulder/Elbow score). For the prediction model, time since stroke poorly explained the FMA total score (R² < 35%). The model however found that time since stroke and initial value of FMA Shoulder/Elbow score were predictors of the FMA Shoulder/Elbow score: (R² = 59.6%).

This study found that clinical prediction of motor outcomes after moderate-to-severe upper-limb paresis is limited. However, initial proximal motor impairment severity predicted proximal motor performance. The value of baselines kinematics and of the number of repeated movements at initiation in the prediction would need further studies.

Patients with a complex regional pain syndrome (CRPS) in the upper limb show a sensory and motor impairment of the hand. Decreased intra-cortical-inhibition (ICI) of the motor representation of the affected hand muscle and decreased somatosensory hand representation size were related to maladaptive plasticity.

To achieve new insights about CRPS we examined whether these alterations were present in a single cohort.

We used a multi-modal approach comprising behavioral testing, transcranial magnetic stimulation, and high resolution fMRI combined with a new analysis technique for improved neuronal specificity.

We found a decreased pinch-grip performance, two-point discrimination on the fingertips, ICI in the motor cortex, and representation size of the hand in Brodmann Area 3b (BA3b) in the somatosensory cortex. Our analysis further showed that correlations with ICI on the non-affected side were absent on the affected side.

This study is the first to gather behavioral, neurophysiologic and imaging measurements for one patient cohort and it therefore enables a comprehensive view of collapsed associations of function and representation focused on the hemisphere contralateral to the affected hand.

Hearing loss is becoming a real social and health problem. Its prevalence in the elderly is an epidemic. The risk of developing hearing loss is also growing among younger people. If left untreated, hearing loss can perpetuate development of neurodegenerative diseases, including dementia. Despite recent advancements in hearing aid (HA) and cochlear implant (CI) technologies, hearing impaired users still encounter significant practical and social challenges, with or without aids. In particular, they all struggle with understanding speech in challenging acoustic environments, especially in presence of a competing speaker.

In the current proof-of-concept study we tested whether multisensory stimulation, pairing audition and a minimal-size touch device would improve intelligibility of speech in noise.

To this aim we developed an audio-to-tactile sensory substitution device (SSD) transforming low-frequency speech signals into tactile vibrations delivered on two finger tips. Based on the inverse effectiveness law, i.e., multisensory enhancement is strongest when signal-to-noise ratio is lowest between senses, we embedded non-native language stimuli in speech-like noise and paired it with a low-frequency input conveyed through touch.

We found immediate and robust improvement in speech recognition (i.e. in the Signal-To-Noise-ratio) in the multisensory condition without any training, at a group level as well as in every participant. The reported improvement at the group-level of 6 dB was indeed major considering that an increase of 10 dB represents a doubling of the perceived loudness.

These results are especially relevant when compared to previous SSD studies showing effects in behavior only after a demanding cognitive training. We discuss the implications of our results for development of SSDs and of specific rehabilitation programs for the hearing impaired either using or not using HAs or CIs. We also discuss the potential application of such a set-up for sense augmentation, such as when learning a new language.

Intensive robot-assisted arm training in the chronic phase of stroke recovery can lead to clinical improvement. Combinatorial therapeutic approaches are sought to further optimize stroke recovery. Transcranial direct current stimulation (tDCS) is one candidate to combine with robotic training, as transient increases in excitability and improvements in motor behavior have separately been reported.

To determine whether tDCS, delivered prior to robotic training, could augment clinical improvement.

We conducted a dual-site, randomized controlled trial in 82 chronic ischemic stroke patients (inclusion > 6 m post-injury, dominant hemisphere, first stroke; residual hemiparesis) who were split into two groups to receive tDCS (M1-SO montage, anode ipsilesional, 5×7 cm electrodes, 2 mA, 20 mins) or sham tDCS, prior to robotic upper-limb training (12 weeks; 36 sessions; shoulder-elbow robot or wrist robot on alternating sessions). The primary end-point was taken after 12 weeks of training, and assessed with the Upper Extremity Fugl-Meyer impairment scale (FM). Corticomotor conduction was assessed with transcranial magnetic stimulation (TMS).

For the combined group (n = 82; post-training) robotic training increased the FM by 7.36 points compared to baseline (p < 0.0001). There was no difference in the FM increase between the tDCS and sham groups (6.97 and 7.73 respectively, p = 0.46). In both groups, clinically meaningful improvement (≥5 points) from baseline was evident in the majority of patients (56/77), was sustained six months later (54/72), and could be attained in severe, moderate and mild baseline hemiparesis. Clinical improvement was associated with increased excitability in the affected hemisphere as assessed by resting motor threshold (pre-post p = 0.029; pre-post 6 months p = 0.029), but not with threshold-adjusted assessment of MEP amplitude (pre-post p = 0.09; pre-post 6 months p = 0.15). Participants with motor evoked potentials were more likely to improve clinically than those without (17/18, 94%, versus 39/59, 66%, p = 0.018).

Our study confirms the benefit of intensive robot-assisted training in stroke recovery, and indicates that conventional tDCS does not confer further advantage to robotic training. We also showed that corticospinal integrity, as assessed by TMS, is a predictor of clinically meaningful response to intensive arm therapy in chronic stroke.

The “post-paralytic syndrome” after facial nerve reconstruction has been attributed to (i) malfunctioning axonal guidance at the fascicular (branches) level, (ii) collateral branching of the transected axons at the lesion site, and (iii) intensive intramuscular terminal sprouting of regenerating axons which causes poly-innervation of the neuromuscular junctions (NMJ).

The first two reasons were approached by an innovative technique which should provide the re-growing axons optimal conditions to elongate and selectively re-innervate their original muscle groups.

The transected facial nerve trunk was inserted into a 3-way-conduit (from isogeneic rat abdominal aorta) which should “guide” the re-growing facial axons to the three main branches of the facial nerve (zygomatic, buccal and marginal mandibular). The effect of this method was tested also on hypoglossal axons after hypoglossal-facial anastomosis (HFA). Coaptational (classic) FFA (facial-facial anastomosis) and HFA served as controls.

When compared to their coaptation (classic) alternatives, both types of 3-way-conduit operations (FFA and HFA) promoted a trend for reduction in the collateral axonal branching (the proportion of double- or triple-labelled perikarya after retrograde tracing was slightly reduced). In contrast, poly-innervation of NMJ in the levator labii superioris muscle was increased and vibrissal (whisking) function was worsened.

The use of 3-way-conduit provides no advantages to classic coaptation. Should the latter be impossible (too large interstump defects requiring too long interpositional nerve grafts), this type of reconstruction may be applied. (230 words)