Restorative Neurology and Neuroscience

Stroke is the most common cause of homonymous visual field defects (HVFDs). Yet, there is no standard protocol for composing a rehabilitation program.

In this study we assess ADL gain of visual training for vision restoration in HVFD patients by means of Goal Attainment Scaling.

Thirty-five patients trained two predefined regions of the visual field successively at home. In each region we compared the effects of both training rounds, one of which was thus ‘directed’ and the other ‘undirected’. Visual fields were measured with Humphrey and Goldmann perimetry. QoL was assessed with three stroke-related questionnaires and ADL with Goal Attainment Scaling (GAS).

Visual training improved the visual field for both Goldmann (ECSG = 5.82±0.94 mm; p = <0.001; n = 31) and Humphrey (0.79±0.20 dB; p = <0.001; n = 28) perimetry. All standardized stroke questionnaires were significantly improved after training (p < 0.039; n = 29), but showed no significant relation with either type of field improvement (p > 0.359). About 75% of the patients improved on their (personalized) GAS score. Interestingly, after both training rounds the GAS score increased in proportion to the extent of visual field improvement, for Goldmann border shift (p = 0.042; r = 0.38; n = 29) but not for Humphrey sensitivity increase (p = 0.337; r = 0.192; n = 28). Multiple regression revealed that GAS score was linearly related to the directed training component for Humphrey perimetry, but not for undirected training.

Together these data suggest that (1) visual training aimed at vision restoration leads to visual field improvement and (2) the extent of visual field improvement is linearly related to the improvement of personal activities of daily living as evaluated by means of GAS. In conclusion, a personalized evaluation to assess treatment success showed the clinical significance of a visual training for vision restoration.

Parkinson’s Disease (PD) is characterized by progressive and disabling symptoms. An impaired oxidative metabolism efficiency was supposed to be involved in the systemic impairment. Rehabilitative treatment represents a valid tool in promoting skeletal muscle’s adaptations, even if no solid studies on muscle metabolic features are still available.

To evaluate the efficiency of skeletal muscle oxidative metabolism in PD patients in comparison with age-matched controls and test the role of an intensive aerobic treatment on muscle oxidative metabolism and its clinical effects.

60 PD patients and 32 age-matched healthy controls participated. Haematic lactate values were detected during and after a submaximal incremental exercise on treadmill. The number of steps completed during the exercise was recorded. From these patients 10 underwent to an intensive aerobic treatment on treadmill (4 sessions/week for 4 weeks). Haematic lactate values and functional scales were recorded before (T0) and after (T1) treatment.

At rest no significant difference in hematic lactate values between PD and control subjects was found. Lactate blood levels were significantly higher (p < 0,001) after the aerobic exercise test in PD patients compared to controls. These values remained higher at any time during recovery period (p < 0,001). No significant relationship between lactate values and the number of completed steps was found. After the rehabilitation treatment haematic value of lactate showed a significant reduction (p < 0,05) at 0, 5 and 10 minutes of recovery period with a normalization of value at 30’. All functional scales showed an improvement trend at T1, in particular Berg Balance Scale and 6 Meter Walking Test showed a significant reduction (p < 0,001 and p < 0,05 respectively).

Our data clearly show an impaired muscle oxidative efficiency in PD subjects. The intensive rehabilitation program on treadmill showed a beneficial effect on muscle oxidative metabolism, endurance and balance, confirming the focal role of rehabilitation in PD patients.

Both high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) and low-frequency rTMS (LF-rTMS) are reported to benefit upper limb motor function rehabilitation in patients with stroke. However, the efficacy of combining LF- and HF-rTMS (LF-HF rTMS) has not been adequately explored, especially in the early phase of stroke.

To compare the effects of LF- and LF-HF rTMS on the upper limb motor function in the early phase post stroke.

Sixty-two patients were randomly assigned to three groups: LF-rTMS group (1 Hz rTMS to the contralesional hemisphere), LF-HF rTMS group (1 Hz rTMS to the contralesional hemisphere followed by 10 Hz rTMS to the lesional hemisphere) and sham group. The patients received the same conventional rehabilitation accompanied with sessions of rTMS for 15 consecutive days. The upper limb motor function was evaluated using the Fugl-Meyer Assessment (FMA) and the Wolf Motor Function Test (WMFT) before the first session, after the last session, and at 3 months after the last session.

All patients finished the study without any adverse reaction. Three groups exhibited improvement in terms of the FMA score and the log WMFT time at the end of the treatment and 3 months later. Better improvement was found in the LF-HF rTMS group than in the LF-rTMS and sham groups.

The results indicated that both LF- and LF-HF rTMS were effective in promoting upper limb motor recovery in patients with acute stroke. Combining HF- and LF-rTMS protocol in the present study is tolerable and more beneficial for motor improvement than the unilateral use of LF-rTMS alone.

Retinal ganglion cells (RGCs) of mammals lose the ability to regenerate injured axons during postnatal maturation, but little is known about the underlying molecular mechanisms.

It remains of particular importance to understand the mechanisms of axonal regeneration to develop new therapeutic approaches for nerve injuries.

Retinas from newborn to adult monkeys (Callithrix jacchus) 1 were obtained immediately after death and cultured in vitro. Growths of axons were monitored using microscopy and time-lapse video cinematography. Immunohistochemistry, Western blotting, qRT-PCR, and genomics were performed to characterize molecules associated with axonal regeneration and growth. A genomic screen was performed by using retinal explants versus native and non-regenerative explants obtained from eye cadavers on the day of birth, and hybridizing the mRNA with cross-reacting cDNA on conventional human microarrays. Followed the genomic screen, siRNA experiments were conducted to identify the functional involvement of identified candidates.

Neuron-specific human ribonucleoprotein N (snRPN) was found to be a potential regulator of impaired axonal regeneration during neuronal maturation in these animals. In particular, up-regulation of snRPN was observed during retinal maturation, coinciding with a decline in regenerative ability. Axon regeneration was reactivated in snRPN-knockout retinal ex vivo explants of adult monkey.

These results suggest that coordinated snRPN-driven activities within the neuron-specific ribonucleoprotein complex regulate the regenerative ability of RGCs in primates, thereby highlighting a potential new role for snRPN within neurons and the possibility of novel postinjury therapies.

The acetylcholinesterase inhibitor (AChEI) donepezil (DON) is recommended as a potential treatment for cognition after clinical traumatic brain injury (TBI) and therefore may be prescribed as an adjunct therapy during rehabilitation. However, a dose-response study evaluating DON after a controlled cortical impact (CCI) injury in rats did not reveal cognitive benefits.

The aim of this study was to determine the effect of DON on behavioral and histological outcome when combined with environmental enrichment (EE), a preclinical model of neurorehabilitation. It was hypothesized that the combined treatments would produce a synergistic effect yielding improved recovery over neurorehabilitation alone.

Isoflurane-anesthetized adult male rats received a CCI or sham injury and then were randomly assigned to EE or standard (STD) housing plus systemic injections of DON (0.25 mg/kg) or vehicle (VEH; 1.0 mL/kg saline) once daily for 19 days beginning 24 hr after injury. Function was assessed by established motor and cognitive tests on post-injury days 1–5 and 14–19, respectively. Cortical lesion volume was quantified on day 19.

DON was ineffective when administered alone. In contrast, EE conferred significant motor and cognitive benefits, and reduced cortical lesion volume vs. STD (p < 0.05). Combining the therapies weakened the efficacy of rehabilitation as revealed by diminished motor and cognitive recovery in the TBI+EE+DON group vs. the TBI+EE+VEH group (p < 0.05).

These data replicate previous findings showing that EE is beneficial and DON is ineffective after CCI and add to the literature a novel and unpredicted finding that supports neither the hypothesis nor the use of DON for TBI. Investigation of other AChEIs after CCI injury is necessary to gain further insight into the value of this therapeutic strategy.

As a promising technique, transcranial direct current stimulation (tDCS) has gained so much attention in its potential effects on functional recovery of lower limb following stroke. However, individual studies have yielded inconsistent or conflicting results.

To investigate the efficacy and safety of tDCS for the functional recovery of lower limb following stroke reported in the randomized controlled trials by using a meta-analysis.

MEDLINE, EMBASE, CINAHL, PsycINFO, Web of Science, CENTRAL, and Physiotherapy Evidence Database was comprehensively searched for randomized controlled trials published until April 2017 that investigated the effects of tDCS on lower limb function. Main outcomes included walking speed, walking endurance, mobility, balance function, muscle strength of lower limb and adverse events.

A total of 10 trials (n = 194) met the inclusion criteria. Meta-analysis demonstrated a significant effect of tDCS on mobility (SMD 0.44, 95% CI: 0.01 to 0.87, P = 0.04) and muscle strength of lower limb (SMD 1.54, 95% CI: 0.29 to 2.78, P = 0.02). No significant effects were found in walking speed (SMD 0.39, 95% CI: –0.06 to 0.85, P = 0.09), walking endurance (SMD 0.28, 95% CI: –0.28 to 0.84, P = 0.33) and balance function (SMD 0.44, 95% CI: –0.06 to 0.94, P = 0.08).

tDCS might have beneficial effects on improving mobility and muscle strength of lower limb among individuals with stroke. Future studies with larger sample sizes and an adequate follow-up period are needed.

Tendon transfer is a surgical technique for restoring upper limb motor control in patients with cervical spinal cord injuries (SCI), and offers a rare window into cortical neuroplasticity following regained arm and hand function.

Here, we aimed to examine neuroplasticity mechanisms related to re-established voluntary motor control of thumb flexion following tendon transfer.

We used functional Magnetic Resonance Imaging (fMRI) to test the hypothesis that restored limb control following tendon transfer is mediated by activation of that limb’s area of the primary motor cortex. We examined six individuals with tetraplegia who underwent right-sided surgical grip reconstruction at Sahlgrenska University Hospital, Sweden. All were right-handed males, with a SCI at the C6 or C7 level, and a mean age of 40 years (range = 31–48). The average number of years elapsed since the SCI was 13 (range = 6–26). Six right-handed gender- and age-matched control subjects were included (mean age 39 years, range = 29–46). Restoration of active thumb flexion in patients was achieved by surgical transfer of one of the functioning elbow flexors (brachioradialis), to the paralyzed thumb flexor (flexor pollicis longus). We studied fMRI responses to isometric right-sided elbow flexion and key pinch, and examined the cortical representations within the left hemisphere somatomotor cortex a minimum of one year after surgery.

Cortical activations elicited by elbow flexion did not differ in topography between patients and control participants. However, in contrast to control participants, patients’ cortical thumb flexion activations were not topographically distinct from their elbow flexion activations.

This result speaks against a topographic reorganization in which the thumb region regains thumb control following surgical tendon transfer. Instead, our findings suggest a neuroplastic mechanism in which motor cortex resources previously dedicated to elbow flexion adapt to control the thumb.

Reciprocal inhibition (RI) may be important for recovering locomotion after stroke. Patterned electrical stimulation (PES) can modulate RI in a manner that could be enhanced by voluntary muscle contraction (VC).

To investigate whether VC enhances the PES-induced spinal RI in patients with stroke.

Twelve patients with chronic stroke underwent three 20 min tasks, each on different days: (1) PES (10 pulses, 100 Hz every 2 s) applied to the common peroneal nerve; (2) VC consisting of isometric contraction of the affected-side tibialis anterior muscle; (3) PES combined with VC (PES + VC). RI from the tibialis anterior to the soleus muscle was assessed before, immediately after, and 10, 20, and 30 min after the task.

Compared to the baseline, PES + VC significantly increased the changes in reciprocal inhibition at immediately after and 10 min after the task. PES alone significantly increased this change immediately after the task, while VC alone showed no significant increase.

VC enhanced the PES-induced plastic changes in RI in patients with stroke. This effect can potentially increase the success rate of newer neurorehabilitative approaches in achieving functional recovery after stroke.

Small clinical trials reported that repetitive sessions of tDCS could improve naming abilities in post-stroke aphasia. However, systematic meta-analyses found no effect, but all of these analyses pooled data from both single and repetitive sessions at the group level. The aim of this paper was to perform a meta-analysis based on individual patient data to explore the effects of repetitive tDCS sessions on naming in post-stroke aphasia and in prespecified subgroups.

We searched for published sham-controlled trials using the keywords “aphasia OR language” AND “transcranial direct current stimulation OR tDCS” AND “stroke”. We computed an active and sham improvement ratio by dividing the difference between naming scores after and before the active or sham sessions, respectively, by the total number of picture items. Because of heterogeneity (I² = 66%, p: 0.002), we used random-effects models to estimate the standardized mean difference (SMD) for the naming outcome. We then analyzed subgroups according to number of sessions, polarity, side/location of the active electrode, post-stroke delay, aphasia severity and comprehension disorders.

Seven eligible studies were identified, including 68 chronic stroke patients. tDCS was beneficial on naming ability (35% ±34% in the active vs. 25% ±37% in the sham condition). An SMD of 0.8 (95% CI: 0.27–1.33) was found for the naming outcome. Additionally, there was a dose-dependent effect (5 vs. >5 sessions). We also demonstrated a prevalence of anodal vs. cathodal condition and left vs. right targeting electrode. Finally, repetitive sessions were beneficial regardless of the severity of aphasia, comprehension disorders or post-stroke delay.

Repetitive sessions of tDCS are likely to be valuable in enhancing naming accuracy in post-stroke aphasia.

Motor rehabilitation after brain damage relies on motor re-learning as induced by specific training. Non-invasive brain stimulation (NIBS) can alter cortical excitability and thereby has a potential to enhance subsequent training-induced learning. Knowledge about any priming effects of NIBS on motor learning in healthy subjects can help to design targeted therapeutic applications in brain-damaged subjects.

To examine whether complex motor learning in healthy subjects can be enhanced by intermittent theta burst stimulation (iTBS) to primary motor or sensory cortical areas.

Eighteen young healthy subjects trained eight different arm motor tasks (arm ability training, AAT) once a day for 5 days using their left non-dominant arm. Except for day 1 (baseline), training was performed after applying an excitatory form of repetitive transcranial magnetic stimulation (iTBS) to either (I) right M1 or (II) S1, or (III) sham stimulation to the right M1. Subjects were randomly assigned to conditions I, II, or III.

A principal component analysis of the motor behaviour data suggested eight independent motor abilities corresponding to the 8 trained tasks. AAT induced substantial motor learning across abilities with generalisation to a non-trained test of finger dexterity (Nine-Hole-Peg-Test, NHPT). Participants receiving iTBS (to either M1 or S1) showed better performance with the AAT tasks over the period of training compared to sham stimulation as well as a bigger improvement with the generalisation task (NHPT) for the trained left hand after training completion.

Priming with an excitatory repetitive transcranial magnetic stimulation as iTBS of either M1 or S1 can enhance motor learning across different sensorimotor abilities.

The use of transcranial magnetic stimulation (TMS) to evaluate corticomotor excitability of lower limb (LL) muscles can provide insights about neuroplasticity mechanisms underlying LL rehabilitation. However, to date, a majority of TMS studies have focused on upper limb muscles. Posture-related activation is an important under-investigated factor influencing corticomotor excitability of LL muscles.

The purpose of this study was to evaluate effects of posture and background activation on corticomotor excitability of ankle muscles.

Fourteen young neurologically-unimpaired participants (26.1±4.1 years) completed the study. TMS-evoked motor evoked potentials (MEPs) were recorded from the tibialis anterior (TA) and soleus during 4 conditions – standing, standing coactivation, sitting, and sitting coactivation. TA and soleus MEP amplitudes were compared during: (1) standing versus sitting;(2) standing coactivation (standing while activating both TA and soleus) versus sitting coactivation; and (3) standing coactivation versus standing. For each comparison, background EMG for TA and soleus were matched. Trial-to-trial coefficient of variation of MEP amplitude and coil-positioning errors were additional dependent variables.

No differences were observed in TA or soleus MEP amplitudes during standing versus sitting. Compared to sitting coactivation, larger MEPs were observed during standing coactivation for soleus but not TA. Compared to standing, the standing coactivation task demonstrated larger MEPs and reduced trial-to-trial MEP variability.

Our findings suggest that incorporation of measurements in standing in future TMS studies may provide novel insights into neural circuits controlling LL muscles. Standing and standing coactivation tasks may be beneficial for obtaining functionally-relevant neuroplasticity assessments of LL musculature.