Interhemispheric inhibition and gait adaptation associations in people with multiple sclerosis.

BACKGROUND: Multiple sclerosis is a neurodegenerative disease that damages the myelin sheath within the central nervous system. Axonal demyelination, particularly in the corpus callosum, impacts communication between the brain's hemispheres in persons with multiple sclerosis (PwMS). Changes in interhemispheric communication may impair gait coordination which is modulated by communication across the corpus callosum to excite and inhibit specific muscle groups. To further evaluate the functional role of interhemispheric communication in gait and mobility, this study assessed the ipsilateral silent period (iSP), an indirect marker of interhemispheric inhibition and how it relates to gait adaptation in PwMS. METHODS: Using transcranial magnetic stimulation (TMS), we assessed interhemispheric inhibition differences between the more affected and less affected hemisphere in the primary motor cortices in 29 PwMS. In addition, these same PwMS underwent a split-belt treadmill walking paradigm, with the faster paced belt moving under their more affected limb. Step length asymmetry (SLA) was the primary outcome measure used to assess gait adaptability during split-belt treadmill walking. We hypothesized that PwMS would exhibit differences in iSP inhibitory metrics between the more affected and less affected hemispheres and that increased interhemispheric inhibition would be associated with greater gait adaptability in PwMS. RESULTS: No statistically significant differences in interhemispheric inhibition or conduction time were found between the more affected and less affected hemisphere. Furthermore, SLA aftereffect was negatively correlated with both average percent depth of silent period (dSP%AVE) (r = -0.40, p = 0.07) and max percent depth of silent period (dSP%MAX) r = -0.40, p = 0.07), indicating that reduced interhemispheric inhibition was associated with greater gait adaptability in PwMS. CONCLUSION: The lack of differences between the more affected and less affected hemisphere indicates that PwMS have similar interhemispheric inhibitory capacity irrespective of the more affected hemisphere. Additionally, we identified a moderate correlation between reduced interhemispheric inhibition and greater gait adaptability. These findings may indicate that interhemispheric inhibition may in part influence responsiveness to motor adaptation paradigms and the need for further research evaluating the neural mechanisms underlying the relationship between interhemispheric inhibition and motor adaptability.

Propulsive Force Modulation Drives Split-Belt Treadmill Adaptation in People with Multiple Sclerosis.

Most people with multiple sclerosis (PwMS) experience significant gait asymmetries between their legs during walking, leading to an increased risk of falls. Split-belt treadmill training, where the speed of each limb is controlled independently, alters each leg's stepping pattern and can improve gait symmetry in PwMS. However, the biomechanical mechanisms of this adaptation in PwMS remain poorly understood. In this study, 32 PwMS underwent a 10 min split-belt treadmill adaptation paradigm with the more affected (MA) leg moving twice as fast as the less affected (LA) leg. The most noteworthy biomechanical adaptation observed was increased peak propulsion asymmetry between the limbs. A kinematic analysis revealed that peak dorsiflexion asymmetry and the onset of plantarflexion in the MA limb were the primary contributors to the observed increases in peak propulsion. In contrast, the joints in the LA limb underwent only immediate reactive adjustments without subsequent adaptation. These findings demonstrate that modulation during gait adaptation in PwMS occurs primarily via propulsive forces and joint motions that contribute to propulsive forces. Understanding these distinct biomechanical changes during adaptation enhances our grasp of the rehabilitative impact of split-belt treadmill training, providing insights for refining therapeutic interventions aimed at improving gait symmetry.

Using the Instrumented Sway System (ISway) to Identify and Compare Balance Domain Deficits in People With Multiple Sclerosis.

OBJECTIVE: To develop a multiple sclerosis (MS)-specific model of balance and examine differences between (1) MS and neurotypical controls and (2) people with MS (PwMS) with (MS-F) and without a fall history (MS-NF). DESIGN AND SETTING: A cross-sectional study was conducted at the Gait and Balance Laboratory at the University of Kansas Medical Center. Balance was measured from the instrumented sway system (ISway) assessment. PARTICIPANTS: In total, 118 people with relapsing-remitting MS (MS-F=39; MS-NF=79) and 46 age-matched neurotypical controls. INTERVENTION: Not applicable. OUTCOME MEASURES: A total of 22 sway measures obtained from the ISway were entered into an exploratory factor analysis to identify underlying balance domains. The model-derived balance domains were compared between (1) PwMS and age-matched, neurotypical controls and (2) MS-F and MS-NF. RESULTS: Three distinct balance domains were identified: (1) sway amplitude and velocity, (2) sway frequency and jerk mediolateral, and (3) sway frequency and jerk anteroposterior, explaining 81.66% of balance variance. PwMS exhibited worse performance (ie, greater amplitude and velocity of sway) in the sway velocity and amplitude domain compared to age-matched neurotypical controls (P=.003). MS-F also exhibited worse performance in the sway velocity and amplitude domain compared to MS-NF (P=.046). The anteroposterior and mediolateral sway frequency and jerk domains were not different between PwMS and neurotypical controls nor between MS-F and MS-NF. CONCLUSIONS: This study identified a 3-factor, MS-specific balance model, demonstrating that PwMS, particularly those with a fall history, exhibit disproportionate impairments in sway amplitude and velocity. Identifying postural stability outcomes and domains that are altered in PwMS and clinically relevant (eg, related to falls) would help isolate potential treatment targets.

Links between Neuroanatomy and Neurophysiology with Turning Performance in People with Multiple Sclerosis.

Multiple sclerosis is accompanied by decreased mobility and various adaptations affecting neural structure and function. Therefore, the purpose of this project was to understand how motor cortex thickness and corticospinal excitation and inhibition contribute to turning performance in healthy controls and people with multiple sclerosis. In total, 49 participants (23 controls, 26 multiple sclerosis) were included in the final analysis of this study. All participants were instructed to complete a series of turns while wearing wireless inertial sensors. Motor cortex gray matter thickness was measured via magnetic resonance imaging. Corticospinal excitation and inhibition were assessed via transcranial magnetic stimulation and electromyography place on the tibialis anterior muscles bilaterally. People with multiple sclerosis demonstrated reduced turning performance for a variety of turning variables. Further, we observed significant cortical thinning of the motor cortex in the multiple sclerosis group. People with multiple sclerosis demonstrated no significant reductions in excitatory neurotransmission, whereas a reduction in inhibitory activity was observed. Significant correlations were primarily observed in the multiple sclerosis group, demonstrating lateralization to the left hemisphere. The results showed that both cortical thickness and inhibitory activity were associated with turning performance in people with multiple sclerosis and may indicate that people with multiple sclerosis rely on different neural resources to perform dynamic movements typically associated with fall risk.

Split-Belt Treadmill Adaptation Improves Spatial and Temporal Gait Symmetry in People with Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease characterized by degradation of the myelin sheath resulting in impaired neural communication throughout the body. As a result, most people with MS (PwMS) experience gait asymmetries between their legs leading to an increased risk of falls. Recent work indicates that split-belt treadmill adaptation, where the speed of each leg is controlled independently, can decrease gait asymmetries for other neurodegenerative impairments. The purpose of this study was to test the efficacy of split-belt treadmill training to improve gait symmetry in PwMS. In this study, 35 PwMS underwent a 10 min split-belt treadmill adaptation paradigm, with the faster paced belt moving under the more affected limb. Step length asymmetry (SLA) and phase coordination index (PCI) were the primary outcome measures used to assess spatial and temporal gait symmetries, respectively. It was predicted that participants with a worse baseline symmetry would have a greater response to split-belt treadmill adaptation. Following this adaptation paradigm, PwMS experienced aftereffects that improved gait symmetry, with a significant difference between predicted responders and nonresponders in both SLA and PCI change (p < 0.001). Additionally, there was no correlation between SLA and PCI change. These findings suggest that PwMS retain the ability for gait adaptation, with those most asymmetrical at baseline demonstrating the greatest improvement, and that there may be separate neural mechanisms for spatial and temporal locomotor adjustments.

Inhibitory signaling as a predictor of leg force control in young and older adults.

As the populations of the United States and developed nations age, motor control performance is adversely impacted, resulting in functional impairments that can diminish quality of life. Generally, force control in the lower limb worsens with age, with older adults (OA) displaying more variable and less accurate submaximal forces. Corticospinal inhibitory signaling may influence force control, with those OA who maintain corticospinal inhibitory signaling capacity achieving steadier forces. This study aimed to assess the relationships between lower limb force control and transcranial magnetic stimulation (TMS) measures of corticospinal inhibition (i.e., cortical silent period (cSP) duration and depth). 15 OA and 14 young adults (YA) were recruited for this study. All subjects underwent a TMS protocol to elicit the cSP while maintaining 15% of their maximal force in their knee extensor muscles. OA and YA did not display differences in force control metrics or corticospinal inhibitory measures. However, in OA, maximal cSP depth (%dSP max) was associated with lower force variability. No other significant relationships existed in the YA or OA groups. Future studies will benefit from evaluating a range of target forces and target muscles to assess potential relationships between sensorimotor inhibitory capacity and control of muscle force output.

I Can Step Clearly Now, the TENS Is On: Transcutaneous Electric Nerve Stimulation Decreases Sensorimotor Uncertainty during Stepping Movements.

Transcutaneous electric nerve stimulation (TENS) is a method of electrical stimulation that elicits activity in sensory nerves and leads to improvements in the clinical metrics of mobility. However, the underlying perceptual mechanisms leading to this improvement are unknown. The aim of this study was to apply a Bayesian inference model to understand how TENS impacts sensorimotor uncertainty during full body stepping movements. Thirty healthy adults visited the lab on two occasions and completed a motor learning protocol in virtual reality (VR) on both visits. Participants were randomly assigned to one of three groups: TENS on first visit only (TN), TENS on second visit only (NT), or a control group where TENS was not applied on either visit (NN). Using methods of Bayesian inference, we calculated the amount of uncertainty in the participants' center of mass (CoM) position estimates on each visit. We found that groups TN and NT decreased the amount of uncertainty in the CoM position estimates in their second visit while group NN showed no difference. The least amount of uncertainty was seen in the TN group. These results suggest that TENS reduces the amount of uncertainty in sensory information, which may be a cause for the observed benefits with TENS.

White Matter Microstructure of the Cerebellar Peduncles Is Associated with Balance Performance during Sensory Re-Weighting in People with Multiple Sclerosis.

People with multiple sclerosis (PwMS) exhibit impaired balance during different sensory environments and poor cerebellar peduncle microstructure. We aimed to examine associations between microstructures of the superior, middle and inferior cerebellar peduncles (CP) with visual, vestibular, and proprioceptive-based balance in PwMS. Twenty-seven PwMS and twenty-nine healthy controls (HC) underwent MRI and balance assessments. We assessed CP microstructure with radial diffusivity (RD) and fractional anisotropy (FA) and balance with center of pressure-derived measures of path length and root mean square of sway during proprioceptive (C2), visual (C3), and vestibular (C4) balance conditions of the modified clinical test of sensory integration on balance (mCTSIB). PwMS exhibited significantly lower FA (p < 0.001) and greater RD (p < 0.001) across all CP and greater path length (p < 0.05) in the mCTSIB compared with HC. In PwMS, significant associations were detected between inferior CP white matter microstructure and proprioceptive-based balance control (rho = -0.43, p < 0.05) and middle CP white matter microstructure and visual-based balance control (rho = 0.39, p < 0.05). PwMS may rely more on cerebellar-regulated proprioceptive- and visual-based balance control than HC.

Relating Response Inhibition, Brain Connectivity, and Freezing of Gait in People with Parkinson's Disease.

OBJECTIVE: Freezing of gait (FoG) in Parkinson's disease (PD) has been associated with response inhibition. However, the relationship between response inhibition, neural dysfunction, and PD remains unclear. We assessed response inhibition and microstructural integrity of brain regions involved in response inhibition [right hemisphere inferior frontal cortex (IFC), bilateral pre-supplementary motor areas (preSMA), and subthalamic nuclei (STN)] in PD subjects with and without FoG and elderly controls. METHOD: Twenty-one people with PD and FoG (PD-FoG), 18 without FoG (PD-noFoG), and 19 age-matched controls (HC) completed a Stop-Signal Task (SST) and MRI scan. Probabilistic fiber tractography assessed structural integrity (fractional anisotropy, FA) among IFC, preSMA, and STN regions. RESULTS: Stop-signal performance did not differ between PD and HC, nor between PD-FoG and PD-noFoG. Differences in white matter integrity were observed across groups (.001 < p < .064), but were restricted to PD versus HC groups; no differences in FA were observed between PD-FoG and PD-noFoG (p > .096). Interestingly, worse FoG was associated with higher (better) mean FA in the r-preSMA, (ß = .547, p = .015). Microstructural integrity of the r-IFC, r-preSMA, and r-STN tracts correlated with stop-signal performance in HC (p ≤ .019), but not people with PD. CONCLUSION: These results do not support inefficient response inhibition in PD-FoG. Those with PD exhibited white matter loss in the response inhibition network, but this was not associated with FoG, nor with response inhibition deficits, suggesting FoG-specific neural changes may occur outside the response inhibition network. As shown previously, white matter loss was associated with response inhibition in elderly controls, suggesting PD may disturb this relationship.

The effect of shoe cushioning on gait and balance in females with multiple sclerosis.

Gait and balance deficits are significant concerns for people with multiple sclerosis (MS). Shoe cushioning can influence mobility and balance, but its effect on walking and balance remains unknown in MS. This study aimed to determine how shoe cushioning affects gait and balance in females with MS (FwMS). We hypothesized that extra cushioning would improve gait but reduce balance performance. FwMS performed gait (n = 18) and balance (n = 17) assessments instrumented using inertial sensors in two different shoe conditions: a standard-cushioned and an extra-cushioned shoe. Care was taken to ensure minimal differences between shoe types other than midsole cushioning, but shoe construction was not identical between conditions. Spatiotemporal gait parameters were assessed during a 2-min walk test, while postural sway measures were evaluated using the modified Clinical Test of Sensory Interaction and Balance. In the extra-cushioned shoe, FwMS spent less time in the double support and stance phase with more time in the single support and swing phase. No differences in stride length, gait speed, or elevation at midswing were observed between shoe conditions. Decreased path length, RMS sway, and sway velocity were observed in the extra-cushioned shoe. No differences were observed in the gait cycle's spatial composition between shoe conditions, but FwMS demonstrated improvements in the gait cycle's temporal parameters and postural sway in the extra-cushioned shoe. This may suggest a less cautious walking strategy and improved balance when wearing a shoe with extra cushioning.

Discriminative Mobility Characteristics between Neurotypical Young, Middle-Aged, and Older Adults Using Wireless Inertial Sensors.

Age-related mobility research often highlights significant mobility differences comparing neurotypical young and older adults, while neglecting to report mobility outcomes for middle-aged adults. Moreover, these analyses regularly do not determine which measures of mobility can discriminate groups into their age brackets. Thus, the current study aimed to provide a comprehensive analysis for commonly performed aspects of mobility (walking, turning, sit-to-stand, and balance) to determine which variables were significantly different and furthermore, able to discriminate between neurotypical young adults (YAs), middle-aged adults (MAAs), and older adults (OAs). This study recruited 20 YAs, 20 MAAs, and 20 OAs. Participants came into the laboratory and completed mobility testing while wearing wireless inertial sensors. Mobility tests assessed included three distinct two-minute walks, 360° turns, five times sit-to-stands, and a clinical balance test, capturing 99 distinct mobility metrics. Of the various mobility tests assessed, only 360° turning measures demonstrated significance between YAs and MAAs, although the capacity to discriminate between groups was achieved for gait and turning measures. A variety of mobility measures demonstrated significance between MAAs and OAs, and furthermore discrimination was achieved for each mobility test. These results indicate greater mobility differences between MAAs and OAs, although discrimination is achievable for both group comparisons.

Virtual time-to-contact identifies balance deficits better than traditional metrics in people with multiple sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease that negatively affects the quality of electrical signaling throughout the central nervous system. Although impaired postural control is one of the most common symptoms in people with MS (PwMS), commonly reported metrics such as center of pressure (CoP) path length and velocity have not been great predictors of fall risk. A relatively new metric, known as virtual time-to-contact (VTC), is a measurement that uses the instantaneous position, velocity and acceleration of the CoP, to predict how long it would take the CoP to reach the boundary of the base of support for every data point in a trial. While the VTC metric has shown promising results in PwMS, there are still inconsistencies in how VTC is reported. Thus, the purpose of this work was to compare VTC to commonly reported measures of postural balance control to identify the most appropriate metric(s) for assessing balance impairments unique to PwMS. A group of patients with MS and a group of neurologically healthy controls performed a static balance task with both eyes open and eyes closed. The VTC minimum values (minima) were the best at detecting balance performance differences between conditions and between study groups. In addition, VTC minima was the best at detecting proprioceptive weaknesses in PwMS, assessed via the Romberg ratio. These results suggest that the VTC minima may be better than traditional metrics at detecting balance impairments unique to PwMS as well as proprioceptive deficits within this population.

Cerebellar White Matter Damage Is Associated With Postural Sway Deficits in People With Multiple Sclerosis.

OBJECTIVE: To assess how postural sway deficits during eyes open and closed relate to the integrity of cerebellar peduncles in individuals with multiple sclerosis (MS). DESIGN: Cross-sectional study. SETTING: Laboratory based setting. PARTICIPANTS: Twenty-nine adults with MS (Expanded Disability Status Scale: 2-4) and 15 adults without MS were recruited (N=44). Inclusion criteria for all participants were ability to maintain balance independently by standing on toes for 3 seconds, and no known biomechanical conditions affecting balance. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Postural sway using body-worn, inertial sensors during quiet standing, integrity of cerebellar peduncles quantified using diffusion-tensor imaging and clinical assessment scales for ataxia and balance. RESULTS: Radial diffusivity of the inferior cerebellar peduncle was related to postural sway measures during both eyes open and closed. In contrast, radial diffusivity of the superior cerebellar peduncle was related to postural sway only in stance with eyes open. CONCLUSIONS: The inferior cerebellar peduncle, which carries somatosensory information to the cerebellum, contributes to control of standing balance with or without visual inputs, consistent with the high dependence on somatosensory information for posture. The superior cerebellar peduncle, which carries cortical information to the cerebellum, contributes to control of standing posture only when vision is available. Radial diffusivity of the inferior cerebellar peduncle was related to reactive balance control, whereas radial diffusivity of the superior cerebellar peduncle was related to the kinetic component of the ataxia rating scale.

Setting boundaries: Utilization of time to boundary for objective evaluation of the balance error scoring system.

Subjective evaluations of balance performance, like the modified Balance Error Scoring System (mBESS), are highly popular. Alternatively, quantitative measures may offer additional clarity in identifying balance dysfunction. A novel measure to define balance impairments is time to boundary (TTB), which represents the amount of time available to make corrective postural adjustments prior to the centre of pressure (CoP) reaching the edge of the base of support. The purpose of this investigation was to assess TTB and traditional measures of CoP displacement of young adults performing the mBESS on a BTrackS balance plate. Path length and TTB were calculated in anterior-posterior (AP) and medio-lateral (ML) directions, respectively. AP and ML path lengths were largest in Single stance (109.2 & 118.1 cm, respectively) and smallest in Dual stance (27.1 & 36.4 cm, respectively). The average AP and ML TTBs were higher in Dual (10.67 & 7.27 s, respectively) compared to Single (3.54 & 1.20 s, respectively) or Tandem (10.11 & 1.94 s, respectively) stances, and lower in Single stance compared to Tandem. Given the effect sizes for TTB were greater than those of path length in both directions, TTB more adequately differentiates these stance conditions than path length or subjective scores.

Merging Yoga and Occupational Therapy for Parkinson's Disease: A Feasibility and Pilot Program.

The purpose of this study was to assess feasibility and changes in outcome measures following the Merging Yoga and Occupational Therapy for Parkinson's Disease (MY-OT for PD) program: a 14-session program which combined community-based yoga for PD, and fall-risk focused group occupational therapy sessions. Seventeen participants completed an 8-week control period consisting of their normal participation, and an 8-week intervention period (14 MY-OT for PD sessions). There were fewer self-reported falls in the intervention (6) vs. control periods (10). One fall risk factor management scale (the Fall Prevention and Management Questionnaire, p=.02), and balance (p<.01) showed significant improvement between the control and intervention. The MY-OT for PD program is an encouraging occupational therapist-led program, which may improve balance and reduce self-reported falls.

Transcallosal Control of Bilateral Actions.

The corpus callosum is an important neural structure for controlling and coordinating bilateral movements of the upper limbs; however, there remains a substantial lack of knowledge regarding its association with lower limb control. We argue that transcallosal structure is an integral neural mechanism underlying control of the lower limbs and callosal degradation is a key contributor to mobility declines.

ADSTEP: Preliminary Investigation of a Multicomponent Walking Aid Program in People With Multiple Sclerosis.

OBJECTIVE: To evaluate the effect of the Assistive Device Selection, Training and Education Program (ADSTEP) on falls and walking and sitting activity in people with multiple sclerosis (PwMS). DESIGN: Randomized controlled trial. SETTING: Veterans affairs medical center. PARTICIPANTS: PwMS (N=40) using a walking aid at baseline who had fallen in the previous year. INTERVENTIONS: Participants were randomly assigned to ADSTEP or control. ADSTEP had 6 weekly, 40-minute, 1-on-1 sessions with a physical therapist, starting with walking aid selection and fitting, followed by task-oriented progressive gait training. Control was usual medical care with the option of ADSTEP after the study. MAIN OUTCOME MEASURES: The following were assessed at baseline, intervention completion, and 3 months later: falls, timed Up and Go, timed 25-foot walk, 2-minute walk, Four Square Step Test, International Physical Activity Questionnaire, Quebec User Evaluation of Satisfaction with Assistive Technologies, Multiple Sclerosis Walking Scale-12, Activities-Specific Balance Confidence Scale, and Multiple Sclerosis Impact Scale-29. Effect on these outcomes was estimated by a 2-by-2 repeated measures general linear model. RESULTS: Fewer ADSTEP than control participants fell (χ2=3.96, P<.05. number needed to treat =3.3). Time spent sitting changed significantly differently with ADSTEP than with control from baseline to intervention completion (F=11.16, P=.002. ADSTEP: reduced 87.00±194.89min/d; control: increased 103.50±142.21min/d; d=0.88) and to 3-month follow-up (F=9.25, P=.004. ADSTEP: reduced 75.79±171.57min/d; control: increased 84.50±149.23min/d; d=0.79). ADSTEP yielded a moderate effect on time spent walking compared to control at 3-month follow-up (P>.05. ADSTEP 117.53±148.40min/d; control 46.43±58.55min/d; d=0.63). CONCLUSIONS: ADSTEP prevents falls, reduces sitting, and may increase walking in PwMS.

Dual-task interference and brain structural connectivity in people with Parkinson's disease who freeze.

BACKGROUND: Freezing of gait in people with Parkinson's disease (PD) is likely related to attentional control (ie, ability to divide and switch attention). However, the neural pathophysiology of altered attentional control in individuals with PD who freeze is unknown. Structural connectivity of the pedunculopontine nucleus has been related to freezing and may play a role in altered attentional control; however, this relationship has not been investigated. We measured whether dual-task interference, defined as the reduction in gait performance during dual-task walking, is more pronounced in individuals with PD who freeze, and whether dual-task interference is associated with structural connectivity and/or executive function in this population. METHODS: We measured stride length in 13 people with PD with and 12 without freezing of gait during normal and dual-task walking. We also assessed asymmetry of pedunculopontine nucleus structural connectivity via diffusion tensor imaging and performance on cognitive tests assessing inhibition and set-shifting, cognitive domains related to freezing. RESULTS: Although stride length was not different across groups, change in stride length between normal and dual-task gait (ie, dual-task interference) was more pronounced in people with PD who freeze compared to non-freezers. Further, in people with PD who freeze, dual-task interference was correlated with asymmetry of pedunculopontine nucleus structural connectivity, Go-NoGo target accuracy (ability to release a response) and simple reaction time. CONCLUSIONS: These results support the hypothesis that freezing is related to altered attentional control during gait, and suggest that differences in pedunculopontine nucleus connectivity contribute to poorer attentional control in people with PD who freeze.

Altered organization of face-processing networks in temporal lobe epilepsy.

OBJECTIVE: Deficits in social cognition are common and significant in people with temporal lobe epilepsy (TLE), but the functional and structural underpinnings remain unclear. The present study investigated how the side of seizure focus impacts face-processing networks in temporal lobe epilepsy. METHODS: We used functional magnetic resonance imaging (fMRI) of a face-processing paradigm to identify face-responsive regions in 24 individuals with unilateral temporal lobe epilepsy (left = 15; right = 9) and 19 healthy controls. fMRI signals of face-responsive regions ipsilateral and contralateral to the side of seizure onset were delineated in TLE and compared to the healthy controls with right and left sides combined. Diffusion tensor images were acquired to investigate structural connectivity between face regions that differed in fMRI signals between the two groups. RESULTS: In TLE, activation of the cortical face-processing networks varied according to side of seizure onset. In temporal lobe epilepsy, the laterality of amygdala activation was shifted to the side contralateral to the seizure focus, whereas controls showed no significant asymmetry. Furthermore, compared to controls, patients with TLE showed decreased activation of the occipital face-responsive region on the ipsilateral side and an increased activity of the anterior temporal lobe in the side contralateral to the seizure focus. Probabilistic tractography revealed that the occipital face area and anterior temporal lobe are connected via the inferior longitudinal fasciculus, which in individuals with TLE showed reduced integrity. SIGNIFICANCE: Taken together, these findings suggest that brain function and white matter integrity of networks subserving face processing are impaired on the side of seizure onset, accompanied by altered responses on the side contralateral to the seizure.

Effect of augmenting cholinergic function on gait and balance.

BACKGROUND: Impaired mobility and falls are clinically important complications of Parkinson's disease (PD) and a major detractor from quality of life for which there are limited therapies. Pathological, neuroimaging and clinical evidence suggest that degeneration of cholinergic systems may contribute to impairments of balance and gait in PD. The proposed trial will examine the effects of augmentation of the cholinergic system on balance and gait. DESIGN: The study is a single-site, proof of concept, randomized, double-blind, cross-over trial in patients with PD. Each treatment period will be 6 weeks with a 6-week washout between treatments for a total of 18 weeks for each subject. Donepezil in 2.5 mg capsules or identical appearing placebo capsules will be increased from two per day (5 mg) to four capsules (10 mg) after 3 weeks, if tolerated. Subjects will have idiopathic Parkinson's disease, Hoehn and Yahr stages 2 to 4. We anticipate recruiting up to 100 subjects for screening to have 54 enrolled and 44 subjects complete both phases of treatment. Dropouts will be replaced. As this is a crossover trial, all subjects will be exposed to both donepezil and to placebo. The primary outcome measures will be the root mean square of the mediolateral sway when standing and the variability of the stride duration when walking for two minutes. Secondary outcomes will be the computerized Attention Network Test to examine three domains of attention and the Short-latency Afferent Inhibition (SAI), a physiological marker obtained with transcranial magnetic stimulation as a putative marker of cholinergic activity. DISCUSSION: The results of this study will be the most direct test of the hypothesized role of cholinergic neurotransmission in gait and balance. The study is exploratory because we do not know whether donepezil will affect gait, balance or attention, nor which measures of gait, balance or attention will be sensitive to drug manipulation. We hypothesize that change in cholinergic activity, as measured with SAI, will predict the relative effectiveness of donepezil on gait and balance. Our immediate goal is to determine the potential utility of cholinergic manipulation as a strategy for preventing or treating balance and gait dysfunction in PD. The findings of this trial are intended to lead to more sharply focused questions about the role of cholinergic neurotransmission in balance and gait and eventually to Phase II B trials to determine clinical utility of cholinergic manipulation to prevent falls and improve mobility. TRIAL REGISTRATION: This trial is registered at clinical trials.gov ( NCT02206620).