Electric Field Navigated 1-Hz rTMS for Poststroke Motor Recovery: The E-FIT Randomized Controlled Trial.

BACKGROUND: To determine if low-frequency repetitive transcranial magnetic stimulation targeting the primary motor cortex contralateral (M1CL) to the affected corticospinal tract in patients with hemiparetic stroke augments intensive training-related clinical improvement; an extension of the NICHE trial (Navigated Inhibitory rTMS to Contralesional Hemisphere Trial) using an alternative sham coil. METHODS: The present E-FIT trial (Electric Field Navigated 1Hz rTMS for Post-stroke Motor Recovery Trial) included 5 of 12 NICHE trial outpatient US rehabilitation centers. The stimulation protocol remained identical (1 Hz repetitive transcranial magnetic stimulation, M1CL, preceding 60-minute therapy, 18 sessions/6 wks; parallel arm randomized clinical trial). The sham coil appearance mimicked the active coil but without the weak electric field in the NICHE trial sham coil. Outcomes measured 1 week, and 1, 3, and 6 months after the end of treatment included the following: upper extremity Fugl-Meyer (primary, 6 months after end of treatment), Action Research Arm Test, National Institutes of Health Stroke Scale, quality of life (EQ-5D), and safety. RESULTS: Of 60 participants randomized, 58 completed treatment and were included for analysis. Bayesian analysis of combined data from the E-FIT and the NICHE trials indicated that active treatment was not superior to sham at the primary end point (posterior mean odds ratio of 1.94 [96% credible interval of 0.61-4.80]). For the E-FIT intent-to-treat population, upper extremity Fugl-Meyer improvement ≥5 pts occurred in 60% (18/30) active group and 50% (14/28) sham group. Participants enrolled 3 to 6 months following stroke had a 67% (31%-91% CI) response rate in the active group at the 6-month end point versus 50% in the sham group (21.5%-78.5% CI). There were significant improvements from baseline to 6 months for both active and sham groups in upper extremity Fugl-Meyer, Action Research Arm Test, and EQ-5D (P<0.05). Improvement in National Institutes of Health Stroke Scale was observed only in the active group (P=0.004). Ten serious unrelated adverse events occurred (4 active group, 6 sham group, P=0.72). CONCLUSIONS: Intensive motor rehabilitation 3 to 12 months after stroke improved clinical impairment, function, and quality of life; however, 1 Hz-repetitive transcranial magnetic stimulation was not an effective treatment adjuvant in the present sample population with mixed lesion location and extent. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03010462.

Randomized Sham-Controlled Trial of Navigated Repetitive Transcranial Magnetic Stimulation for Motor Recovery in Stroke.

Background and Purpose- We aimed to determine whether low-frequency electric field navigated repetitive transcranial magnetic stimulation to noninjured motor cortex versus sham repetitive transcranial magnetic stimulation avoiding motor cortex could improve arm motor function in hemiplegic stroke patients when combined with motor training. Methods- Twelve outpatient US rehabilitation centers enrolled participants between May 2014 and December 2015. We delivered 1 Hz active or sham repetitive transcranial magnetic stimulation to noninjured motor cortex before each of eighteen 60-minute therapy sessions over a 6-week period, with outcomes measured at 1 week and 1, 3, and 6 months after end of treatment. The primary end point was the percentage of participants improving ≥5 points on upper extremity Fugl-Meyer score 6 months after end of treatment. Secondary analyses assessed changes on the upper extremity Fugl-Meyer and Action Research Arm Test and Wolf Motor Function Test and safety. Results- Of 199 participants, 167 completed treatment and follow-up because of early discontinuation of data collection. Upper extremity Fugl-Meyer gains were significant for experimental ( P<0.001) and sham groups ( P<0.001). Sixty-seven percent of the experimental group (95% CI, 58%-75%) and 65% of sham group (95% CI, 52%-76%) improved ≥5 points on 6-month upper extremity Fugl-Meyer ( P=0.76). There was also no difference between experimental and sham groups in the Action Research Arm Test ( P=0.80) or the Wolf Motor Function Test ( P=0.55). A total of 26 serious adverse events occurred in 18 participants, with none related to the study or device, and with no difference between groups. Conclusions- Among patients 3 to 12 months poststroke, goal-oriented motor rehabilitation improved motor function 6 months after end of treatment. There was no difference between the active and sham repetitive transcranial magnetic stimulation trial arms. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02089464.

Associative Recognition Memory Awareness Improved by Theta-Burst Stimulation of Frontopolar Cortex.

Neuroimaging and lesion studies have implicated specific prefrontal cortex locations in subjective memory awareness. Based on this evidence, a rostrocaudal organization has been proposed whereby increasingly anterior prefrontal regions are increasingly involved in memory awareness. We used theta-burst transcranial magnetic stimulation (TBS) to temporarily modulate dorsolateral versus frontopolar prefrontal cortex to test for distinct causal roles in memory awareness. In three sessions, participants received TBS bilaterally to frontopolar cortex, dorsolateral prefrontal cortex, or a control location prior to performing an associative-recognition task involving judgments of memory awareness. Objective memory performance (i.e., accuracy) did not differ based on stimulation location. In contrast, frontopolar stimulation significantly influenced several measures of memory awareness. During study, judgments of learning were more accurate such that lower ratings were given to items that were subsequently forgotten selectively following frontopolar TBS. Confidence ratings during test were also higher for correct trials following frontopolar TBS. Finally, trial-by-trial correspondence between overt performance and subjective awareness during study demonstrated a linear increase across control, dorsolateral, and frontopolar TBS locations, supporting a rostrocaudal hierarchy of prefrontal contributions to memory awareness. These findings indicate that frontopolar cortex contributes causally to memory awareness, which was improved selectively by anatomically targeted TBS.

Transcranial direct current stimulation and aphasia: the case of mr. C.

PURPOSE: To illustrate the ethical challenges that arose from investigating a novel treatment procedure, transcranial direct current stimulation (tDCS), in a research participant with aphasia. METHOD: We review the current evidence supporting the use of tDCS in aphasia research, highlighting methodological gaps in our knowledge of tDCS. Then, we examine the case of Mr. C, a person with chronic aphasia who participated in a research protocol investigating the impact of tDCS on aphasia treatment. We describe the procedures that he underwent and the resulting behavioral and neurophysiological outcomes. Finally, we share the steps that were taken to balance beneficence and nonmaleficence and to ensure Mr. C's autonomy. RESULTS: The objective data show that while Mr. C may not have benefitted from participating in the research, neither did he experience any harm. CONCLUSION: Researchers must consider not only the scientific integrity of their studies, but also potential ethical issues and consequences to the research participants.

A paradox: after stroke, the non-lesioned lower limb motor cortex may be maladaptive.

What are the neuroplastic mechanisms that allow some stroke patients to regain high-quality control of their paretic leg, when others do not? One theory implicates ipsilateral corticospinal pathways projecting from the non-lesioned hemisphere. We devised a new transcranial magnetic stimulation protocol to identify ipsilateral corticospinal tract conductivity from the non-lesioned hemisphere to the paretic limb in chronic stroke patients. We also assessed corticospinal tract degeneration by diffusion tensor imaging, and used an ankle tracking task to assess lower limb motor control. We found greater tracking error during antiphase bilateral ankle movement for patients with strong conductivity from the non-lesioned hemisphere to the paretic ankle than for those with weak or no conductivity. These findings suggest that, instead of assisting motor control, contributions to lower limb motor control from the non-lesioned hemisphere of some stroke survivors may be maladaptive.

Posture-Dependent Corticomotor Excitability Differs Between the Transferred Biceps in Individuals With Tetraplegia and the Biceps of Nonimpaired Individuals.

BACKGROUND: Following biceps transfer to enable elbow extension in individuals with tetraplegia, motor re-education may be facilitated by greater corticomotor excitability. Arm posture modulates corticomotor excitability of the nonimpaired biceps. If arm posture also modulates excitability of the transferred biceps, posture may aid in motor re-education. OBJECTIVE: Our objective was to determine whether multi-joint arm posture affects corticomotor excitability of the transferred biceps similar to the nonimpaired biceps. We also aimed to determine whether corticomotor excitability of the transferred biceps is related to elbow extension strength and muscle length. METHODS: Corticomotor excitability was assessed in 7 arms of individuals with tetraplegia and biceps transfer using transcranial magnetic stimulation and compared to biceps excitability of nonimpaired individuals. Single-pulse transcranial magnetic stimulation was delivered to the motor cortex with the arm in functional postures at rest. Motor-evoked potential amplitude was recorded via surface electromyography. Elbow moment was recorded during maximum isometric extension trials, and muscle length was estimated using a biomechanical model. RESULTS: Arm posture modulated corticomotor excitability of the transferred biceps differently than the nonimpaired biceps. Elbow extension strength was positively related and muscle length was unrelated, respectively, to motor-evoked potential amplitude across the arms with biceps transfer. CONCLUSIONS: Corticomotor excitability of the transferred biceps is modulated by arm posture and may contribute to strength outcomes after tendon transfer. Future work should determine whether modulating corticomotor excitability via posture promotes motor re-education during the rehabilitative period following surgery.

Neurophysiological measurements of affected and unaffected motor cortex from a cross-sectional, multi-center individual stroke patient data analysis study.

OBJECTIVES: Transcranial magnetic stimulation (TMS) has been used to measure cortical excitability as a functional measurement of corticomotor pathways. Given its potential application as an assessment tool in stroke, we aimed to analyze the correlation of TMS parameters with clinical features in stroke using data from 10 different centers. METHODS: Data of 341 patients with a clinical diagnosis of stroke were collected from studies assessing cortical excitability using TMS. We used a multivariate regression model in which the baseline cortical excitability parameter "resting Motor Threshold (rMT)" was the main outcome and the demographic, anatomic and clinical characteristics were included as independent variables. RESULTS: The variable "severity of motor deficit" consistently remained significant in predicting rMT in the affected hemisphere, with a positive ß coefficient, in the multivariate models after sensitive analyses and adjusting for important confounders such as site center. Additionally, we found that the correlations between "age" or "time since stroke" and the rMT in the affected hemisphere were significant, as well as the interaction between "time since stroke" and "severity of motor deficit". CONCLUSIONS: We have shown that severity of motor deficit is an important predictor for rMT in the affected hemisphere. Additionally, time since stroke seems to be an effect modifier for the correlation between motor deficit and rMT. In the unaffected motor cortex, these correlations were not significant. We discuss these findings in the context of stroke rehabilitation.

Corticomotor excitability of arm muscles modulates according to static position and orientation of the upper limb.

OBJECTIVE: We investigated how multi-joint changes in static upper limb posture impact the corticomotor excitability of the posterior deltoid (PD) and biceps brachii (BIC), and evaluated whether postural variations in excitability related directly to changes in target muscle length. METHODS: The amplitude of individual motor evoked potentials (MEPs) was evaluated in each of thirteen different static postures. Four functional postures were investigated that varied in shoulder and elbow angle, while the forearm was positioned in each of three orientations. Posture-related changes in muscle lengths were assessed using a biomechanical arm model. Additionally, M-waves were evoked in the BIC in each of three forearm orientations to assess the impact of posture on recorded signal characteristics. RESULTS: BIC-MEP amplitudes were altered by shoulder and elbow posture, and demonstrated robust changes according to forearm orientation. Observed changes in BIC-MEP amplitudes exceeded those of the M-waves. PD-MEP amplitudes changed predominantly with shoulder posture, but were not completely independent of influence from forearm orientation. CONCLUSIONS: Results provide evidence that overall corticomotor excitability can be modulated according to multi-joint upper limb posture. SIGNIFICANCE: The ability to alter motor pathway excitability using static limb posture suggests the importance of posture selection during rehabilitation aimed at retraining individual muscle recruitment and/or overall coordination patterns.

Posture-dependent changes in corticomotor excitability of the biceps after spinal cord injury and tendon transfer.

Following tendon transfer of the biceps to triceps after cervical spinal cord injuries (SCI), individuals must learn to activate the transferred biceps muscle to extend the elbow. Corticomotor excitability of the transferred biceps may play a role in post-operative elbow extension strength. In this study, we evaluated whether corticomotor excitability of the transferred biceps is related to an individuals' ability to extend the elbow, and whether posture and muscle length affects corticomotor excitability after SCI and tendon transfer similarly to the nonimpaired biceps. Corticomotor excitability was assessed in twelve nonimpaired arms and six arms of individuals with SCI and biceps-to-triceps transfer using transcranial magnetic stimulation (TMS) delivered at rest. Maximum isometric elbow extensor moments were recorded in transferred arms and the fiber length of the transferred biceps was estimated using a musculoskeletal model. Across the SCI subjects, corticomotor excitability of the transferred biceps increased with elbow extension strength. Thus, rehabilitation to increase excitability may enhance strength. Excitability of the transferred biceps was not related to fiber length suggesting that similar to nonimpaired subjects, posture-dependent changes in biceps excitability are primarily centrally modulated after SCI. All nonimpaired biceps were most excitable in a posture in the horizontal plane with the forearm fully supinated. The proportion of transferred biceps in which excitability was highest in this posture differed from the nonimpaired group. Therefore, rehabilitation after tendon transfer may be most beneficial if training postures are tailored to account for changes in biceps excitability.

Targeted enhancement of cortical-hippocampal brain networks and associative memory.

The influential notion that the hippocampus supports associative memory by interacting with functionally distinct and distributed brain regions has not been directly tested in humans. We therefore used targeted noninvasive electromagnetic stimulation to modulate human cortical-hippocampal networks and tested effects of this manipulation on memory. Multiple-session stimulation increased functional connectivity among distributed cortical-hippocampal network regions and concomitantly improved associative memory performance. These alterations involved localized long-term plasticity because increases were highly selective to the targeted brain regions, and enhancements of connectivity and associative memory persisted for ~24 hours after stimulation. Targeted cortical-hippocampal networks can thus be enhanced noninvasively, demonstrating their role in associative memory.

The effects of paired associative stimulation on knee extensor motor excitability of individuals post-stroke: a pilot study.

OBJECTIVE: Paired associative stimulation (PAS) modulates bilateral distal lower limb motor pathways during walking. We assessed the effects of inhibitory PAS applied to the vastus medialis (VM) motor pathways of chronic stroke patients. METHODS: PAS consisted of 120 electrical stimuli applied to the femoral nerve paired with transcranial magnetic stimulation (TMS) of the lower limb primary motor cortex so that the estimated arrival of the afferent volley occurred 8 ms after delivery of the magnetic stimulus. Stimulus pairs were delivered to the non-paretic VM motor system of 11 chronic stroke patients and the right limb motor system of 11 non-impaired subjects at 0.19 Hz. The effects of PAS on VM motor pathway excitability and muscle activity were assessed during pedaling. TMS-induced motor evoked potential (MEP) amplitudes and the percent of VM activity in the flexion phase of active pedaling (% FLEXVM) was examined before and after PAS. RESULTS: Inhibitory PAS reduced VM MEP amplitudes in the target limb (p<0.05) of both groups, while post-PAS paretic VM MEP amplitudes increased for some patients and decreased for others. Group mean paretic limb % FLEXVM was not altered by inhibitory PAS. CONCLUSIONS: These results indicate PAS can be used to manipulate motor cortical excitability in proximal lower limb representations, however the sign of induced modulation was unpredictable and cyclic muscle activity was not modified. SIGNIFICANCE: The study has important implications for the development of therapies involving non-invasive brain stimulation to modify abnormal motor behavior following stroke.

Descending control to the nonparetic limb degrades the cyclic activity of paretic leg muscles.

During anti-phased locomotor tasks such as cycling or walking, hemiparetic phasing of muscle activity is characterized by inappropriate early onset of activity for some paretic muscles and prolonged activity in others. Pedaling with the paretic limb alone reduces inappropriate prolonged activity, suggesting a combined influence of contralesional voluntary commands and movement-related sensory feedback. Five different non-target leg movement state conditions were performed by 15 subjects post-stroke and 15 nonimpaired controls while they pedaled with the target leg and EMG was recorded bilaterally. Voluntary engagement of the non-lesioned motor system increased prolonged paretic vastus medialis (VM) activity and increased phase-advanced rectus femoris (RF) activity. We suggest bilateral descending commands are primarily responsible for the inappropriate activity in the paretic VM during anti-phase pedaling, and contribute to the dysfunctional motor output in the paretic RF. Findings from controls suggest that even an undamaged motor system can contribute to this phenomenon.

Direction of foot force for pushes against a fixed pedal: role of effort level.

Control of the force exerted by the foot on the ground is critical to human locomotion. During running on a treadmill and pushing against a fixed pedal, humans increased foot force in a linear manner in sagittal plane force space. However, for pushes against a moving pedal, force output was linear for some participants but slightly curved for others. A primary difference between the static and dynamic pedaling studies was that the dynamic study required participants to push with varying peak effort levels, whereas a constant peak effort level was used for the fixed pedal pushes. The present study evaluated the possibility that force direction varied with level of effort. Seated humans pushed against a fixed pedal to a series of force magnitude targets. The force direction varied systematically with effort level consistent with the force path curvature observed for dynamic pedaling.

Direction of foot force for pushes against a fixed pedal: variation with pedal position.

The force that healthy humans generated against a fixed pedal was measured and compared with that predicted by four models. The participants (n = 11) were seated on a stationary bicycle and performed brief pushing efforts against an instrumented pedal with the crank fixed. Pushes were performed to 10 force magnitude targets and at 12 crank angles. The increasing magnitude portion of the sagittal-plane force path for each push effort was fitted with a line to determine the direction of the muscle component of the foot force. Those directions varied systematically with the position of the pedal (crank angle) such that the force path lines intersected a common region superior and slightly anterior to the hip. The ability of four models to predict force path direction was tested. All four models captured the general variation of direction with pedal position. Two of the models provided the best performance. One was a musculoskeletal model consisting of nine muscles with parameters adjusted to provide the best possible fit. The other model was derived from (a) observations that the lines-of-action of the muscle component of foot force tended to intersect in a common region near the hip, and (b) the corresponding need for foot force to intersect the center-of-mass during walking. Thus, this model predicted force direction at each pedal position as that of a line intersecting the pedal pivot and a common point located near the hip (divergent point). The results suggest that the control strategy employed in this seated pushing task reflects the extensive experience of the leg in directing force appropriately to maintain upright posture and that relative muscle strengths have adapted to that pattern of typical activation.