Brett W. Fling

Asymmetric pedunculopontine network connectivity in parkinsonian patients with freezing of gait

Freezing of gait is one of the most debilitating symptoms in Parkinsons disease as it causes falls and reduces mobility and quality of life. The pedunculopontine nucleus is one of the major nuclei of the mesencephalic locomotor region and has neurons related to anticipatory postural adjustments preceding step initiation as well as to the step itself, thus it may be critical for coupling posture and gait to avoid freezing. Because freezing of gait and postural impairments have been related to frontal lesions and frontal dysfunction such as executive function, we hypothesized that freezing is associated with disrupted connectivity between midbrain locomotor regions and medial frontal cortex. We used diffusion tensor imaging to quantify structural connectivity of the pedunculopontine nucleus in patients with Parkinsons disease with freezing of gait, without freezing, and healthy age-matched controls. We also included behavioural tasks to gauge severity of freezing of gait, quantify gait metrics, and assess executive cognitive functions to determine whether between-group differences in executive dysfunction were related to pedunculopontine nucleus structural network connectivity. Using seed regions from the pedunculopontine nucleus, we were able to delineate white matter connections between the spinal cord, cerebellum, pedunculopontine nucleus, subcortical and frontal/prefrontal cortical regions. The current study is the first to demonstrate differences in structural connectivity of the identified locomotor pathway in patients with freezing of gait. We report reduced connectivity of the pedunculopontine nucleus with the cerebellum, thalamus and multiple regions of the frontal cortex. Moreover, these structural differences were observed solely in the right hemisphere of patients with freezing of gait. Finally, we show that the more left hemisphere-lateralized the pedunculopontine nucleus tract volume, the poorer the performance on cognitive tasks requiring the initiation of appropriate actions and/or the inhibition of inappropriate actions, specifically within patients with freezing. These results support the notion that freezing of gait is strongly related to structural deficits in the right hemispheres locomotor network involving prefrontal cortical areas involved in executive inhibition function.

Using the Wii Fit as a tool for balance assessment and neurorehabilitation: the first half decade of “Wii-search”

The Nintendo Wii Fit was released just over five years ago as a means of improving basic fitness and overall well-being. Despite this broad mission, the Wii Fit has generated specific interest in the domain of neurorehabilitation as a biobehavioral measurement and training device for balance ability. Growing interest in Wii Fit technology is likely due to the ubiquitous nature of poor balance and catastrophic falls, which are commonly seen in older adults and various disability conditions. The present review provides the first comprehensive summary of Wii Fit balance research, giving specific insight into the system’s use for the assessment and training of balance. Overall, at the time of the fifth anniversary, work in the field showed that custom applications using the Wii Balance Board as a proxy for a force platform have great promise as a low cost and portable way to assess balance. On the other hand, use of Wii Fit software-based balance metrics has been far less effective in determining balance status. As an intervention tool, positive balance outcomes have typically been obtained using Wii Fit balance games, advocating their use for neurorehabilitative training. Despite this, limited sample sizes and few randomized control designs indicate that research regarding use of the Wii Fit system for balance intervention remains subject to improvement. Future work aimed at conducting studies with larger scale randomized control designs and a greater mechanistic focus is recommended to further advance the efficacy of this impactful neurorehabilitation tool.

Functional Reorganization of the Locomotor Network in Parkinson Patients with Freezing of Gait

Freezing of gait (FoG) is a transient inability to initiate or maintain stepping that often accompanies advanced Parkinson’s disease (PD) and significantly impairs mobility. The current study uses a multimodal neuroimaging approach to assess differences in the functional and structural locomotor neural network in PD patients with and without FoG and relates these findings to measures of FoG severity. Twenty-six PD patients and fifteen age-matched controls underwent resting-state functional magnetic resonance imaging and diffusion tensor imaging along with self-reported and clinical assessments of FoG. After stringent movement correction, fifteen PD patients and fourteen control participants were available for analysis. We assessed functional connectivity strength between the supplementary motor area (SMA) and the following locomotor hubs: 1) subthalamic nucleus (STN), 2) mesencephalic and 3) cerebellar locomotor region (MLR and CLR, respectively) within each hemisphere. Additionally, we quantified structural connectivity strength between locomotor hubs and assessed relationships with metrics of FoG. FoG+ patients showed greater functional connectivity between the SMA and bilateral MLR and between the SMA and left CLR compared to both FoG− and controls. Importantly, greater functional connectivity between the SMA and MLR was positively correlated with i) clinical, ii) self-reported and iii) objective ratings of freezing severity in FoG+, potentially reflecting a maladaptive neural compensation. The current findings demonstrate a re-organization of functional communication within the locomotor network in FoG+ patients whereby the higher-order motor cortex (SMA) responsible for gait initiation communicates with the MLR and CLR to a greater extent than in FoG− patients and controls. The observed pattern of altered connectivity in FoG+ may indicate a failed attempt by the CNS to compensate for the loss of connectivity between the STN and SMA and may reflect a loss of lower-order, automatic control of gait by the basal ganglia.

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

Background Freezing of gait in people with Parkinsons 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.

Associations between Proprioceptive Neural Pathway Structural Connectivity and Balance in People with Multiple Sclerosis.

Mobility and balance impairments are a hallmark of multiple sclerosis (MS), affecting nearly half of patients at presentation and resulting in decreased activity and participation, falls, injuries, and reduced quality of life. A growing body of work suggests that balance impairments in people with mild MS are primarily the result of deficits in proprioception, the ability to determine body position in space in the absence of vision. A better understanding of the pathophysiology of balance disturbances in MS is needed to develop evidence-based rehabilitation approaches. The purpose of the current study was to (1) map the cortical proprioceptive pathway in vivo using diffusion-weighted imaging and (2) assess associations between proprioceptive pathway white matter microstructural integrity and performance on clinical and behavioral balance tasks. We hypothesized that people with MS (PwMS) would have reduced integrity of cerebral proprioceptive pathways, and that reduced white matter microstructure within these tracts would be strongly related to proprioceptive-based balance deficits. We found poorer balance control on proprioceptive-based tasks and reduced white matter microstructural integrity of the cortical proprioceptive tracts in PwMS compared with age-matched healthy controls (HC). Microstructural integrity of this pathway in the right hemisphere was also strongly associated with proprioceptive-based balance control in PwMS and controls. Conversely, while white matter integrity of the right hemisphere’s proprioceptive pathway was significantly correlated with overall balance performance in HC, there was no such relationship in PwMS. These results augment existing literature suggesting that balance control in PwMS may become more dependent upon (1) cerebellar-regulated proprioceptive control, (2) the vestibular system, and/or (3) the visual system.

Associations between mobility, cognition and callosal integrity in people with parkinsonism

Falls in people with parkinsonism are likely related to both motor and cognitive impairments. In addition to idiopathic Parkinsons disease (PD), some older adults have lower body parkinsonism (a frontal gait disorder), characterized by impaired lower extremity balance and gait as well as cognition, but without tremor or rigidity. Neuroimaging during virtual gait suggests that interhemispheric, prefrontal cortex communication may be involved in locomotion, but contributions of neuroanatomy connecting these regions to objective measures of gait in people with parkinsonism remains unknown. Our objectives were to compare the integrity of fiber tracts connecting prefrontal and sensorimotor cortical regions via the corpus callosum in people with two types of parkinsonism and an age-matched control group and to relate integrity of these callosal fibers with clinical and objective measures of mobility and cognition. We recruited 10 patients with frontal gait disorders, 10 patients with idiopathic PD and 10 age-matched healthy control participants. Participants underwent cognitive and mobility testing as well as diffusion weighted magnetic resonance imaging to quantify white matter microstructural integrity of interhemispheric fiber tracts. People with frontal gait disorders displayed poorer cognitive performance and a slower, wider-based gait compared to subjects with PD and age-matched control subjects. Despite a widespread network of reduced white matter integrity in people with frontal gait disorders, gait and cognitive deficits were solely related to interhemispheric circuitry employing the genu of the corpus callosum. Current results highlight the importance of prefrontal interhemispheric communication for lower extremity control in neurological patients with cognitive dysfunction.

Functional connectivity underlying postural motor adaptation in people with multiple sclerosis

A well-characterized neural network is associated with motor learning, involving several brain regions known to have functional and structural deficits in persons with multiple sclerosis (PwMS). However, it is not known how MS affects postural motor learning or the neural networks involved. The aim of this study was to gain a better understanding of the neural networks underlying adaptation of postural responses within PwMS. Participants stood on a hydraulically driven, servo-controlled platform that translated horizontally forward and backward in a continuous sinusoidal pattern across multiple trials over two consecutive days. Our results show similar postural adaptation between PwMS and age-matched control participants despite overall deficits in postural motor control in PwMS. Moreover, PwMS demonstrated better retention the following day. PwMS had significantly reduced functional connectivity within both the cortico-cerebellar and cortico-striatal motor loops; neural networks that subserve implicit motor learning. In PwMS, greater connectivity strength within the cortico-cerebellar circuit was strongly related to better baseline postural control, but not to postural adaptation as it was in control participants. Further, anti-correlated cortico-striatal connectivity within the right hemisphere was related to improved postural adaptation in both groups. Taken together with previous studies showing a reduced reliance on cerebellar- and proprioceptive-related feedback control in PwMS, we suggest that PwMS may rely on cortico-striatal circuitry to a greater extent than cortico-cerebellar circuitry for the acquisition and retention of motor skills.

Corpus Callosum Structural Integrity Is Associated with Postural Control Improvement in Persons with Multiple Sclerosis Who Have Minimal Disability

Background. Improvement of postural control in persons with multiple sclerosis (PwMS) is an important target for neurorehabilitation. Although PwMS are able to improve postural performance with training, the neural underpinnings of these improvements are poorly understood. Objective. To understand the neural underpinnings of postural motor learning in PwMS. Methods. Supraspinal white matter structural connectivity in PwMS was correlated with improvements in postural performance (balancing on an oscillating surface over 25 trials) and retention of improvements (24 hours later). Results. Improvement in postural performance was directly correlated to microstructural integrity of white matter tracts, measured as radial diffusivity, in the corpus callosum, posterior parieto-sensorimotor fibers and the brainstem in PwMS. Within the corpus callosum, the genu and midbody (fibers connecting the prefrontal and primary motor cortices, respectively) were most strongly correlated to improvements in postural control. Twenty-four-hour retention was not correlated to radial diffusivity. Conclusion. PwMS who exhibited poorer white matter tract integrity connecting the cortical hemispheres via the corpus callosum showed the most difficulty learning to control balance on an unstable surface. Prediction of improvements in postural control through training (ie, motor learning) via structural imaging of the brain may allow for identification of individuals who are particularly well suited for postural rehabilitation interventions.

Postural Motor Learning Deficits in People With MS in Spatial but Not Temporal Control of Center of Mass

Background: Multiple sclerosis (MS) is associated with balance deficits resulting in falls and impaired mobility. Although rehabilitation has been recommended to address these balance deficits, the extent to which people with MS can learn and retain improvements in postural responses is unknown. Aim: To determine the ability of people with MS to improve postural control with surface perturbation training. Methods: A total of 24 patients with mild MS and 14 age-matched controls underwent postural control training with a set pattern of continuous, forward-backward, sinusoidal, and surface translations provided by a force platform. Postural control was then tested the following day for retention. The primary outcome measures were the relative phase and center-of-mass (CoM) gain between the body CoM and the platform motion. Results: People with MS demonstrated similar improvements in acquiring and retaining changes in the temporal control of the CoM despite significant deficits in postural motor performance at the baseline. Both MS and control groups learned to anticipate the pattern of forward-backward perturbations, so body CoM shifted from a phase-lag (age-matched controls [CS] = −7.1 ± 1.3; MS = −12.9 ± 1.0) toward a phase-lead (CS = −0.7 ± 1.8; MS = −6.1 ± 1.4) relationship with the surface oscillations. However, MS patients were not able to retain the changes in the spatial control of the CoM acquired during training. Conclusions: People with MS have the capacity to improve use of a feed-forward postural strategy with practice and retain the learned behavior for temporal not spatial control of CoM, despite their significant postural response impairments.

Supraspinal control of automatic postural responses in people with multiple sclerosis.

The neural underpinnings of delayed automatic postural responses in people with multiple sclerosis (PwMS) are unclear. We assessed whether white matter pathways of two supraspinal regions (the cortical proprioceptive Broadmans Area-3; and the balance/locomotor-related pedunculopontine nucleus) were related to delayed postural muscle response latencies in response to external perturbations. 19 PwMS (48.8±11.4years; EDSS=3.5 (range: 2-4)) and 12 healthy adults (51.7±12.2years) underwent 20 discrete, backward translations of a support surface. Onset latency of agonist (medial-gastrocnemius) and antagonist (tibialis anterior) muscles were assessed. Diffusion tensor imaging assessed white-matter integrity (i.e. radial diffusivity) of cortical proprioceptive and balance/locomotor-related tracts. Latency of the tibialis anterior, but not medial gastrocnemius was larger in PwMS than control subjects (p=0.012 and 0.071, respectively). Radial diffusivity of balance/locomotor tracts was higher (worse) in PwMS than control subjects (p=0.004), and was significantly correlated with tibialis (p=0.002), but not gastrocnemius (p=0.06) onset latency. Diffusivity of cortical proprioceptive tracts was not correlated with muscle onset. Lesions in supraspinal structures including the pedunculopontine nucleus balance/locomotor network may contribute to delayed onset of postural muscle activity in PwMS, contributing to balance deficits in PwMS.