Enriched Environment Contributes to the Recovery from Neurotoxin-Induced Parkinson's Disease Pathology.

Parkinson's disease (PD) is a neurological disorder that affects dopaminergic neurons. The lack of understanding of the underlying molecular mechanisms of PD pathology makes treating it a challenge. Several pieces of evidence support the protective role of enriched environment (EE) and exercise on dopaminergic neurons. The specific aspect(s) of neuroprotection after exposure to EE have not been identified. Therefore, we have investigated the protective role of EE on dopamine dysregulation and subsequent downregulation of DJ1 protein using in vitro and in vivo models of PD. Our study for the first time demonstrated that DJ1 expression has a direct correlation with dopamine downregulation in PD models and exposure to EE has a significant impact on improving the behavioral changes in PD mice. This research provides evidence that exercise in EE has a positive effect on PD without interfering with the current line of therapy.

Moving toward elucidating alternative motor pathway structures post-stroke: the value of spinal cord neuroimaging.

Stroke results in varying levels of motor and sensory disability that have been linked to the neurodegeneration and neuroinflammation that occur in the infarct and peri-infarct regions within the brain. Specifically, previous research has identified a key role of the corticospinal tract in motor dysfunction and motor recovery post-stroke. Of note, neuroimaging studies have utilized magnetic resonance imaging (MRI) of the brain to describe the timeline of neurodegeneration of the corticospinal tract in tandem with motor function following a stroke. However, research has suggested that alternate motor pathways may also underlie disease progression and the degree of functional recovery post-stroke. Here, we assert that expanding neuroimaging techniques beyond the brain could expand our knowledge of alternate motor pathway structure post-stroke. In the present work, we will highlight findings that suggest that alternate motor pathways contribute to post-stroke motor dysfunction and recovery, such as the reticulospinal and rubrospinal tract. Then we review imaging and electrophysiological techniques that evaluate alternate motor pathways in populations of stroke and other neurodegenerative disorders. We will then outline and describe spinal cord neuroimaging techniques being used in other neurodegenerative disorders that may provide insight into alternate motor pathways post-stroke.

Stratifying chronic stroke patients based on the influence of contralesional motor cortices: An inter-hemispheric inhibition study.

OBJECTIVE: A recent "bimodal-balance recovery" model suggests that contralesional influence varies based on the amount of ipsilesional reserve: inhibitory when there is a large reserve, but supportive when there is a low reserve. Here, we investigated the relationships between contralesional influence (inter-hemispheric inhibition, IHI) and ipsilesional reserve (corticospinal damage/impairment), and also defined a criterion separating subgroups based on the relationships. METHODS: Twenty-four patients underwent assessment of IHI using Transcranial Magnetic Stimulation (ipsilateral silent period method), motor impairment using Upper Extremity Fugl-Meyer (UEFM), and corticospinal damage using Diffusion Tensor Imaging and active motor threshold. Assessments of UEFM and IHI were repeated after 5-week rehabilitation (n = 21). RESULTS: Relationship between IHI and baseline UEFM was quadratic with criterion at UEFM 43 (95%conference interval: 40-46). Patients less impaired than UEFM = 43 showed stronger IHI with more impairment, whereas patients more impaired than UEFM = 43 showed lower IHI with more impairment. Of those made clinically-meaningful functional gains in rehabilitation (n = 14), more-impaired patients showed further IHI reduction. CONCLUSIONS: A criterion impairment-level can be derived to stratify patient-subgroups based on the bimodal influence of contralesional cortex. Contralesional influence also evolves differently across subgroups following rehabilitation. SIGNIFICANCE: The criterion may be used to stratify patients to design targeted, precision treatments.

Effectiveness of anodal transcranial direct current stimulation to improve muscle strength and motor functionality after incomplete spinal cord injury: a systematic review and meta-analysis.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVES: We aimed to investigate the effects of anodal transcranial direct current stimulation (tDCS) against sham on muscle strength and motor functionality after incomplete spinal cord injury (iSCI). SETTING: University of São Paulo, Brazil. METHODS: A preplanned protocol was registered (PROSPERO, CRD42016050444). Pubmed, Embase, Web of Science, Cochrane Central Library and BVS databases were searched independently by two authors up to March 2018. Cochrane Collaboration's Tool was used for the risk of bias assessments. Generic inverse variance and random-effects model were used to calculate pooled effect sizes (ES), 95% confidence intervals (CIs) and p-values in meta-analyses. RESULTS: Six randomized clinical trials met inclusion criteria (n = 78 iSCI individuals) and were included in the meta-analysis. Results showed a marginal significant pooled effect of active tDCS in improving motor functionality with a small ES (SMD = 0.26, 95% CI = -0.00 to 0.53, p = 0.05, I2 = 0%). On the other hand, the pooled effect of active tDCS on muscle strength did not reach statistical significance, in parallel with a small ES (SMD = 0.35, 95% CI = -0.21 to 0.92, p = 0.22, I2 = 0%) when compared with sham tDCS. No significant adverse events were reported. CONCLUSIONS: Overall, there was a significant effect of tDCS in improving motor functionality following iSCI. However, a small ES and the marginal p-value suggest that these results should be interpreted with caution. Further high-quality clinical trials are needed to support or refute the use of tDCS in daily clinical practice.

Bilateral Contralaterally Controlled Functional Electrical Stimulation Reveals New Insights Into the Interhemispheric Competition Model in Chronic Stroke.

Background. Upper-limb chronic stroke hemiplegia was once thought to persist because of disproportionate amounts of inhibition imposed from the contralesional on the ipsilesional hemisphere. Thus, one rehabilitation strategy involves discouraging engagement of the contralesional hemisphere by only engaging the impaired upper limb with intensive unilateral activities. However, this premise has recently been debated and has been shown to be task specific and/or apply only to a subset of the stroke population. Bilateral rehabilitation, conversely, engages both hemispheres and has been shown to benefit motor recovery. To determine what neurophysiological strategies bilateral therapies may engage, we compared the effects of a bilateral and unilateral based therapy using transcranial magnetic stimulation. Methods. We adopted a peripheral electrical stimulation paradigm where participants received 1 session of bilateral contralaterally controlled functional electrical stimulation (CCFES) and 1 session of unilateral cyclic neuromuscular electrical stimulation (cNMES) in a repeated-measures design. In all, 15 chronic stroke participants with a wide range of motor impairments (upper extremity Fugl-Meyer score: 15 [severe] to 63 [mild]) underwent single 1-hour sessions of CCFES and cNMES. We measured whether CCFES and cNMES produced different effects on interhemispheric inhibition (IHI) to the ipsilesional hemisphere, ipsilesional corticospinal output, and ipsilateral corticospinal output originating from the contralesional hemisphere. Results. CCFES reduced IHI and maintained ipsilesional output when compared with cNMES. We found no effect on ipsilateral output for either condition. Finally, the less-impaired participants demonstrated a greater increase in ipsilesional output following CCFES. Conclusions. Our results suggest that bilateral therapies are capable of alleviating inhibition on the ipsilesional hemisphere and enhancing output to the paretic limb.

Transcranial direct current stimulation (tDCS) paired with massed practice training to promote adaptive plasticity and motor recovery in chronic incomplete tetraplegia: A pilot study.

OBJECTIVE: Our goal was to determine if pairing transcranial direct current stimulation (tDCS) with rehabilitation for two weeks could augment adaptive plasticity offered by these residual pathways to elicit longer-lasting improvements in motor function in incomplete spinal cord injury (iSCI). DESIGN: Longitudinal, randomized, controlled, double-blinded cohort study. SETTING: Cleveland Clinic Foundation, Cleveland, Ohio, USA. PARTICIPANTS: Eight male subjects with chronic incomplete motor tetraplegia. INTERVENTIONS: Massed practice (MP) training with or without tDCS for 2 hrs, 5 times a week. OUTCOME MEASURES: We assessed neurophysiologic and functional outcomes before, after and three months following intervention. Neurophysiologic measures were collected with transcranial magnetic stimulation (TMS). TMS measures included excitability, representational volume, area and distribution of a weaker and stronger muscle motor map. Functional assessments included a manual muscle test (MMT), upper extremity motor score (UEMS), action research arm test (ARAT) and nine hole peg test (NHPT). RESULTS: We observed that subjects receiving training paired with tDCS had more increased strength of weak proximal (15% vs 10%), wrist (22% vs 10%) and hand (39% vs. 16%) muscles immediately and three months after intervention compared to the sham group. Our observed changes in muscle strength were related to decreases in strong muscle map volume (r=0.851), reduced weak muscle excitability (r=0.808), a more focused weak muscle motor map (r=0.675) and movement of weak muscle motor map (r=0.935). CONCLUSION: Overall, our results encourage the establishment of larger clinical trials to confirm the potential benefit of pairing tDCS with training to improve the effectiveness of rehabilitation interventions for individuals with SCI. TRIAL REGISTRATION: NCT01539109.

Using theoretical models from adult stroke recovery to improve use of noninvasive brain stimulation for children with congenital hemiparesis.

Noninvasive brain stimulation has been widely used for adults with stroke to improve upper limb motor function. A recent study by Kirton and colleagues (Kirton A, Ciechanski P, Zewdie E, Andersen J, Nettel-Aguirre A, Carlson H, Carsolio L, Herrero M, Quigley J, Mineyko A, Hodge J, Hill M. Neurology 88: 259-267, 2017) applied noninvasive brain stimulation to children with congenital hemiparesis but found no significant effect of noninvasive brain stimulation on motor function. Here, we explore theories about cortical reorganization in both adult and children with hemiparesis and discuss how to improve the approaches of noninvasive brain stimulation to generate optimal motor improvement and development for children with congenital hemiparesis.

Inhibition versus facilitation of contralesional motor cortices in stroke: Deriving a model to tailor brain stimulation.

OBJECTIVE: The standard approach to brain stimulation in stroke is based on the premise that ipsilesional M1 (iM1) is important for motor function of the paretic upper limb, while contralesional cortices compete with iM1. Therefore, the approach typically advocates facilitating iM1 and/or inhibiting contralesional M1 (cM1). But, this approach fails to elicit much improvement in severely affected patients, who on account of extensive damage to ipsilesional pathways, cannot rely on iM1. These patients are believed to instead rely on the undamaged cortices, especially the contralesional dorsal premotor cortex (cPMd), for support of function of the paretic limb. Here, we tested for the first time whether facilitation of cPMd could improve paretic limb function in severely affected patients, and if a cut-off could be identified to separate responders to cPMd from responders to the standard approach to stimulation. METHODS: In a randomized, sham-controlled crossover study, fifteen patients received the standard approach of stimulation involving inhibition of cM1 and a new approach involving facilitation of cPMd using repetitive transcranial magnetic stimulation (rTMS). Patients also received rTMS to control areas. At baseline, impairment [Upper Extremity Fugl-Meyer (UEFMPROXIMAL, max=36)] and damage to pathways [fractional anisotropy (FA)] was measured. We measured changes in time to perform proximal paretic limb reaching, and neurophysiology using TMS. RESULTS: Facilitation of cPMd generated more improvement in severely affected patients, who had experienced greater damage and impairment than a cut-off value of FA (0.5) and UEFMPROXIMAL (26-28). The standard approach instead generated more improvement in mildly affected patients. Responders to cPMd showed alleviation of interhemispheric competition imposed on iM1, while responders to the standard approach showed gains in ipsilesional excitability in association with improvement. CONCLUSIONS: A preliminary cut-off level of severity separated responders for standard approach vs. facilitation of cPMd. SIGNIFICANCE: Cut-offs identified here could help select candidates for tailored stimulation in future studies so patients in all ranges of severity could potentially achieve maximum benefit in function of the paretic upper limb.

Transcranial Direct Current Stimulation Targeting Primary Motor Versus Dorsolateral Prefrontal Cortices: Proof-of-Concept Study Investigating Functional Connectivity of Thalamocortical Networks Specific to Sensory-Affective Information Processing.

The pain matrix is comprised of an extensive network of brain structures involved in sensory and/or affective information processing. The thalamus is a key structure constituting the pain matrix. The thalamus serves as a relay center receiving information from multiple ascending pathways and relating information to and from multiple cortical areas. However, it is unknown how thalamocortical networks specific to sensory-affective information processing are functionally integrated. Here, in a proof-of-concept study in healthy humans, we aimed to understand this connectivity using transcranial direct current stimulation (tDCS) targeting primary motor (M1) or dorsolateral prefrontal cortices (DLPFC). We compared changes in functional connectivity (FC) with DLPFC tDCS to changes in FC with M1 tDCS. FC changes were also compared to further investigate its relation with individual's baseline experience of pain. We hypothesized that resting-state FC would change based on tDCS location and would represent known thalamocortical networks. Ten right-handed individuals received a single application of anodal tDCS (1 mA, 20 min) to right M1 and DLPFC in a single-blind, sham-controlled crossover study. FC changes were studied between ventroposterolateral (VPL), the sensory nucleus of thalamus, and cortical areas involved in sensory information processing and between medial dorsal (MD), the affective nucleus, and cortical areas involved in affective information processing. Individual's perception of pain at baseline was assessed using cutaneous heat pain stimuli. We found that anodal M1 tDCS and anodal DLPFC tDCS both increased FC between VPL and sensorimotor cortices, although FC effects were greater with M1 tDCS. Similarly, anodal M1 tDCS and anodal DLPFC tDCS both increased FC between MD and motor cortices, but only DLPFC tDCS modulated FC between MD and affective cortices, like DLPFC. Our findings suggest that M1 stimulation primarily modulates FC of sensory networks, whereas DLPFC stimulation modulates FC of both sensory and affective networks. Our findings when replicated in a larger group of individuals could provide useful evidence that may inform future studies on pain to differentiate between effects of M1 and DLPFC stimulation. Notably, our finding that individuals with high baseline pain thresholds experience greater FC changes with DLPFC tDCS implies the role of DLPFC in pain modulation, particularly pain tolerance.

The effect of motor overflow on bimanual asymmetric force coordination.

Motor overflow, typically described in the context of unimanual movements, refers to the natural tendency for a 'resting' limb to move during movement of the opposite limb and is thought to be influenced by inter-hemispheric interactions and intra-cortical networks within the 'resting' hemisphere. It is currently unknown, however, how motor overflow contributes to asymmetric force coordination task accuracy, referred to as bimanual interference, as there is need to generate unequal forces and corticospinal output for each limb. Here, we assessed motor overflow via motor evoked potentials (MEPs) and the regulation of motor overflow via inter-hemispheric inhibition (IHI) and short-intra-cortical inhibition (SICI) using transcranial magnetic stimulation in the presence of unimanual and bimanual isometric force production. All outcomes were measured in the left first dorsal interosseous (test hand) muscle, which maintained 30% maximal voluntary contraction (MVC), while the right hand (conditioning hand) was maintained at rest, 10, 30, or 70% of its MVC. We have found that as higher forces are generated with the conditioning hand, MEP amplitudes at the active test hand decreased and inter-hemispheric inhibition increased, suggesting reduced motor overflow in the presence of bimanual asymmetric forces. Furthermore, we found that subjects with less motor overflow (i.e., reduced MEP amplitudes in the test hemisphere) demonstrated poorer accuracy in maintaining 30% MVC across all conditions. These findings suggest that motor overflow may serve as an adaptive substrate to support bimanual asymmetric force coordination.

Assessment of Vascular Stent Heating with Repetitive Transcranial Magnetic Stimulation.

OBJECTIVE: A high proportion of patients with stroke do not qualify for repetitive transcranial magnetic stimulation (rTMS) clinical studies due to the presence of metallic stents. The ultimate concern is that any metal could become heated due to eddy currents. However, to date, no clinical safety data are available regarding the risk of metallic stents heating with rTMS. METHODS: We tested the safety of common rTMS protocols (1 Hz and 10 Hz) with stents used commonly in stroke, nitinol and elgiloy. In our method, stents were tested in gelled saline at 2 different locations: at the center and at the lobe of the coil. In addition, at each location, stent heating was evaluated in 3 different orientations: parallel to the long axis of coil, parallel to the short axis of the coil, and perpendicular to the plane of the coil. RESULTS: We found that stents did not heat to more than 1°C with either 1 Hz rTMS or 10 Hz rTMS in any configuration or orientation. Heating in general was greater at the lobe when the stent was oriented perpendicularly. CONCLUSIONS: Our study represents a new method for ex vivo quantification of stent heating. We have found that heating of stents was well below the Food and Drug Administration standards of 2°C. Thus, our study paves the way for in vivo testing of rTMS (≤10 Hz) in the presence of implanted magnetic resonance imaging-compatible stents in animal studies. When planning human safety studies though, geometry, orientation, and location relative to the coil would be important to consider as well.

Post-exercise depression following submaximal and maximal isometric voluntary contraction.

It is well known that corticomotor excitability is altered during the post-exercise depression following fatigue within the primary motor cortex (M1). However, it is currently unknown whether corticomotor reorganization following muscle fatigue differs between magnitudes of force and whether corticomotor reorganization occurs measured with transcranial magnetic stimulation (TMS). Fifteen young healthy adults (age 23.8±1.4, 8 females) participated in a within-subjects, repeated measures design study, where they underwent three testing sessions separated by one-week each. Subjects performed separate sessions of each: low-force isometric contraction (30% maximal voluntary contraction [MVC]), high-force isometric contraction (95% MVC) of the first dorsal interosseous (FDI) muscle until self-perceived exhaustion, as well as one session of a 30-min rest as a control. We examined changes in corticomotor map area, excitability and location of the FDI representation in and around M1 using TMS. The main finding was that following low-force, but not high-force fatigue (HFF) corticomotor map area and excitability reduced [by 3cm(2) (t(14)=-2.94, p=0.01) and 56% respectively t(14)=-4.01, p<0.001)]. Additionally, the region of corticomotor excitability shifted posteriorly (6.4±2.5mm) (t(14)=-6.33, p=.019). Corticomotor output became less excitable particularly in regions adjoining M1. Overall, post-exercise depression is present in low-force, but not for HFF. Further, low-force fatigue (LFF) results in a posterior shift in corticomotor output. These changes may be indicative of increased sensory feedback from the somatosensory cortex during the recovery phase of fatigue.

Influence of Corticospinal Tracts from Higher Order Motor Cortices on Recruitment Curve Properties in Stroke.

BACKGROUND: Recruitment curves (RCs) acquired using transcranial magnetic stimulation are commonly used in stroke to study physiologic functioning of corticospinal tracts (CST) from M1. However, it is unclear whether CSTs from higher motor cortices contribute as well. OBJECTIVE: To explore whether integrity of CST from higher motor areas, besides M1, relates to CST functioning captured using RCs. METHODS: RCs were acquired for a paretic hand muscle in patients with chronic stroke. Metrics describing gain and overall output of CST were collected. CST integrity was defined by diffusion tensor imaging. For CST emerging from M1 and higher motor areas, integrity (fractional anisotropy) was evaluated in the region of the posterior limb of the internal capsule, the length of CST and in the region of the stroke lesion. RESULTS: We found that output and gain of RC was related to integrity along the length of CST emerging from higher motor cortices but not the M1. CONCLUSIONS: Our results suggest that RC parameters in chronic stroke infer function primarily of CST descending from the higher motor areas but not M1. RCs may thus serve as a simple, in-expensive means to assess re-mapping of alternate areas that is generally studied with resource-intensive neuroimaging in stroke.

Challenges in Recruitment for the Study of Noninvasive Brain Stimulation in Stroke: Lessons from Deep Brain Stimulation.

OBJECTIVE: Noninvasive brain stimulation (NIBS) can augment functional recovery following stroke; however, the technique lacks regulatory approval. Low enrollment in NIBS clinical trials is a key roadblock. Here, we pursued evidence to support the prevailing opinion that enrollment in trials of NIBS is even lower than enrollment in trials of invasive, deep brain stimulation (DBS). METHODS: We compared 2 clinical trials in stroke conducted within a single urban hospital system, one employing NIBS and the other using DBS, (1) to identify specific criteria that generate low enrollment rates for NIBS and (2) to devise strategies to increase recruitment with guidance from DBS. RESULTS: Notably, we found that enrollment in the NIBS case study was 5 times lower (2.8%) than the DBS trial (14.5%) (χ(2) = 20.815, P < .0001). Although the number of candidates who met the inclusion criteria was not different (χ(2) = .04, P < .841), exclusion rates differed significantly between the 2 studies (χ(2) = 21.354, P < .0001). Beyond lack of interest, higher exclusion rates in the NIBS study were largely due to exclusion criteria that were not present in the DBS study, including restrictions for recurrent strokes, seizures, and medications. CONCLUSIONS: Based on our findings, we conclude and suggest that by (1) establishing criteria specific to each NIBS modality, (2) adjusting exclusion criteria based on guidance from DBS, and (3) including patients with common contraindications based on a probability of risk, we may increase enrollment and hence significantly impact the feasibility and generalizability of NIBS paradigms, particularly in stroke.

Tailoring Brain Stimulation to the Nature of Rehabilitative Therapies in Stroke: A Conceptual Framework Based on their Unique Mechanisms of Recovery.

Despite showing early promise, several recent clinical trials of noninvasive brain stimulation (NIBS) failed to augment rehabilitative outcomes of the paretic upper limb. This article addresses why pairing NIBS with unilateral approaches is weakly generalizable to patients in all ranges of impairments. The article also addresses whether alternate therapies are better suited for the more impaired patients, where they may be more feasible and offer neurophysiologic advantages not offered with unilateral therapies. The article concludes by providing insight on how to create NIBS paradigms that are tailored to distinctly augment the effects of therapies across patients with varying degrees of impairment.

Reproducibility of transcranial magnetic stimulation metrics in the study of proximal upper limb muscles.

OBJECTIVE: Reproducibility of transcranial magnetic stimulation (TMS) metrics is essential in accurately tracking recovery and disease. However, majority of evidence pertains to reproducibility of metrics for distal upper limb muscles. We investigate for the first time, reliability of corticospinal physiology for a large proximal muscle - the biceps brachii and relate how varying statistical analyses can influence interpretations. METHODS: 14 young right-handed healthy participants completed two sessions assessing resting motor threshold (RMT), motor evoked potentials (MEPs), motor map and intra-cortical inhibition (ICI) from the left biceps brachii. Analyses included paired t-tests, Pearson's, intra-class (ICC) and concordance correlation coefficients (CCC) and Bland-Altman plots. RESULTS: Unlike paired t-tests, ICC, CCC and Pearson's were >0.6 indicating good reliability for RMTs, MEP intensities and locations of map; however values were <0.3 for MEP responses and ICI. CONCLUSIONS: Corticospinal physiology, defining excitability and output in terms of intensity of the TMS device, and spatial loci are the most reliable metrics for the biceps. MEPs and variables based on MEPs are less reliable since biceps receives fewer cortico-motor-neuronal projections. Statistical tests of agreement and associations are more powerful reliability indices than inferential tests. SIGNIFICANCE: Reliable metrics of proximal muscles when translated to a larger number of participants would serve to sensitively track and prognosticate function in neurological disorders such as stroke where proximal recovery precedes distal.

Implications of chronic daily anti-oxidant administration on the inflammatory response to intracortical microelectrodes.

OBJECTIVE: Oxidative stress events have been implicated to occur and facilitate multiple failure modes of intracortical microelectrodes. The goal of the present study was to evaluate the ability of a sustained concentration of an anti-oxidant and to reduce oxidative stress-mediated neurodegeneration for the application of intracortical microelectrodes. APPROACH: Non-functional microelectrodes were implanted into the cortex of male Sprague Dawley rats for up to sixteen weeks. Half of the animals received a daily intraperitoneal injection of the natural anti-oxidant resveratrol, at 30 mg kg(-1). The study was designed to investigate the biodistribution of the resveratrol, and the effects on neuroinflammation/neuroprotection following device implantation. MAIN RESULTS: Daily maintenance of a sustained range of resveratrol throughout the implantation period resulted in fewer degenerating neurons in comparison to control animals at both two and sixteen weeks post implantation. Initial and chronic improvements in neuronal viability in resveratrol-dosed animals were correlated with significant reductions in local superoxide anion accumulation around the implanted device at two weeks after implantation. Controls, receiving only saline injections, were also found to have reduced amounts of accumulated superoxide anion locally and less neurodegeneration than controls at sixteen weeks post-implantation. Despite observed benefits, thread-like adhesions were found between the liver and diaphragm in resveratrol-dosed animals. SIGNIFICANCE: Overall, our chronic daily anti-oxidant dosing scheme resulted in improvements in neuronal viability surrounding implanted microelectrodes, which could result in improved device performance. However, due to the discovery of thread-like adhesions, further work is still required to optimize a chronic anti-oxidant dosing regime for the application of intracortical microelectrodes.