Brett Fling | Colorado State University (original) (raw)

Papers by Brett Fling

Journal of neurology, neurosurgery, and psychiatry, Jan 15, 2014

Freezing of gait in people with Parkinson's disease (PD) is likely related to attentional con... more 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. 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 cogn...

Epilepsia, Jan 30, 2015

Deficits in social cognition are common and significant in people with temporal lobe epilepsy (TL... more 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. 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. In TLE, activation of the cortical face-processing networks varied according to side of seizure onset. In temporal lobe epilepsy, the latera...

NeuroImage. Clinical, 2015

A well-characterized neural network is associated with motor learning, involving several brain re... more 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 th...

BACKGROUND: Freezing of gait in people with Parkinson's disease (PD) is likely related to attenti... more 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.

J Neuroeng Rehabil

Goble DJ, Cone BL, Fling BW. The Nintendo Wii Fit was released just over five years ago as a m... more Goble DJ, Cone BL, Fling BW.

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.

Mobility and balance impairments are a hallmark of multiple sclerosis (MS), affecting nearly half... more 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. 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 healthy controls, 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.

Freezing of gait (FoG) is a transient inability to initiate or maintain stepping that often accom... more 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 FoG2 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 FoG2 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.

Journal of NeuroEngineering and Rehabilitation, 2014

The Nintendo Wii Fit was released just over five years ago as a means of improving basic fitness ... more 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.

Brain : a journal of neurology, 2013

Freezing of gait is one of the most debilitating symptoms in Parkinson’s disease as it causes fal... more Freezing of gait is one of the most debilitating symptoms in Parkinson’s 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 connect-
ivity between midbrain locomotor regions and medial frontal cortex. We used diffusion tensor imaging to quantify structural
connectivity of the pedunculopontine nucleus in patients with Parkinson’s 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 hemisphere’s locomotor network involving prefrontal
cortical areas involved in executive inhibition function.

Adv Exp Med Biol, 2013

During the initial stages of skill learning, motor performance is cognitively demanding and uncoo... more During the initial stages of skill learning, motor performance is cognitively demanding and uncoordinated. Understanding how an individual progresses to the exquisite and automatic processes of proficient performance has not been a trivial process. Here, we review the role that error detection and correction plays in skill learning. We make a distinction between within trial error corrections, or performance adjustments made during the course of a movement that is not achieving its intended goal, and across trial error corrections, or cumulative adjustments that reflect ongoing learning. We review recent debates regarding whether skill learning is a purely implicit or subconscious process, or if it can benefit from explicit instruction.

NeuroImage, 2013

Healthy aging is marked by declines in a variety of cognitive and motor abilities. A better under... more Healthy aging is marked by declines in a variety of cognitive and motor abilities. A better understanding of the aging brain may aid in elucidating the neural substrates of these behavioral effects. Investigations of resting state functional brain connectivity have provided insights into pathology, and to some degree, healthy aging. Given the role of the cerebellum in both motor and cognitive behaviors, as well as its known volumetric declines with age, investigating cerebellar networks may shed light on the neural bases of age-related functional declines. We mapped the resting state networks of the lobules of the right hemisphere and the vermis of the cerebellum in a group of healthy older adults and compared them to those of young adults. We report disrupted cortico-cerebellar resting state network connectivity in older adults. These results remain even when controlling for cerebellar volume, signal-to-noise ratio, and signal-to-fluctuation noise ratio. Specifically, there was consistent disruption of cerebellar connectivity with both the striatum and the medial temporal lobe. Associations between connectivity strength and both sensorimotor and cognitive task performances indicate that cerebellar engagement with the default mode network and striatal pathways is associated with better performance for older adults. These results extend our understanding of the resting state networks of the aging brain to include cortico-cerebellar networks, and indicate that age differences in network connectivity strength are important for behavior.

Numerous studies have identified age differences in brain structure and function that correlate w... more Numerous studies have identified age differences in brain structure and function that correlate with declines in motor performance. While these investigations have typically focused on activity in isolated regions of the brain, resting state functional connectivity magnetic resonance imaging (MRI) and diffusion tensor imaging allow for more integrative assessments of spatially disparate neural networks. The novel contribution of the current study is to combine both resting state functional connectivity and diffusion tensor imaging to examine motor corticocortical circuits in young and older adults. We find that relatively greater functional connectivity between the primary motor cortices was strongly associated with decreased structural connectivity and poorer motor performance solely in older adults. We suggest that greater functional connectivity in older adults may be reflective of a release from the normally predominantly inhibitory interhemispheric communication associated with the primary motor cortices.

"Bimanual actions involve coordinated motion but often rely on the movements performed with each ... more "Bimanual actions involve coordinated motion but often rely on the movements performed with each hand to be different. Older adults exhibit differentially greater variability for bimanual actions in which each hand has an independent movement goal. Such actions rely on interhemispheric communication via the corpus callosum, including both facilitatory and inhibitory interactions. Here, we investigated whether age differences in callosal structure and interhemispheric function contribute to this selective movement difficulty. Participants performed 3 force production tasks: 1) unimanual, 2) bimanual simultaneous, and 3) bimanual independent. Older adults had significantly greater interhemispheric facilitation during voluntary muscle activation. We also report a fundamental shift with age in the relationship between callosal tract microstructural integrity and interhemispheric inhibition (IHI). Specifically, older adults with relatively greater callosal tract microstructural integrity have less IHI. Furthermore, greater IHI was related to poorer bimanual
performance (assessed by dominant hand force variability) in older adults on all tasks, whereas this relationship was only observed in young adults for the bimanual independent condition. These findings indicate changes in interhemispheric communication with advancing age such that older adults may rely on bilateral cortical cooperation to a greater extent than young adults for manual actions."

Recent studies have demonstrated neuroanatomically selective relationships among white matter tra... more Recent studies have demonstrated neuroanatomically selective relationships among white matter tract microstructure, physiological function, and task performance. Such findings suggest that the microstructure of transcallosal motor fibers may reflect the capacity for interhemispheric inhibition between the primary motor cortices, although full characterization of the transcallosal inhibitory sensorimotor network is lacking. Thus, the goal of this study was to provide a comprehensive description of transcallosal fibers connecting homologous sensorimotor cortical regions and to identify the relationship(s) between fiber tract microstructure and interhemispheric inhibition during voluntary cortical activity. To this end, we assessed microstructure of fiber tracts connecting homologous sensorimotor regions of the cortex with diffusion tensor imaging. We also assessed interhemispheric inhibition by eliciting the ipsilateral silent period (iSP) within the same participants. We mapped mutually exclusive transcallosal connections between homologous sensorimotor regions and computed quantitative metrics of each fiber tract. Paralleling work in non-human primates, we found the densest interhemispheric sensorimotor connections to be between the medial motor areas. Additionally, we provide a midsagittal callosal atlas in normalized Montreal Neurological Institute (MNI) space for future studies to use when investigating callosal fiber tracts connecting primary and secondary sensorimotor cortices. Finally, we report a strong, positive relationship (r = 0.76) between strength of interhemispheric inhibition (iSP) and microstructure of interhemispheric fibers that is specific to tracts connecting the primary motor cortices. Thus, increased fiber microstructure in young adults predicts interhemispheric inhibitory capacity.

Interhemispheric communication consists of a complex balance of facilitation and inhibition that ... more Interhemispheric communication consists of a complex balance of facilitation and inhibition that is modulated in a task-dependent manner. However, it remains unclear how individual differences in interhemispheric interactions relate to motor performance. To assess interhemispheric inhibition, we utilized the ipsilateral silent period technique (iSP; evoked by suprathreshold transcranial magnetic stimulation), which elicits inhibition of volitional motor activity. Participants performed three force production tasks: (1) unimanual (right hand) constant force, (2) bimanual constant force, (bimanual simultaneous) and (3) bimanual with right hand constant force and left hand sine wave tracking (bimanual independent). We found that individuals with greater IHI capacity demonstrated reduced mirror EMG activity in the left hand during unimanual right hand contraction. However, these same individuals demonstrated the poorest performance during the bimanual independent force production task. We suggest that a high capacity for IHI from one motor cortex to another can effectively prevent “motor overflow” during unimanual tasks, but it can also limit interhemispheric cooperation during independently controlled bimanual tasks.

There is a fundamental gap in understanding how brain structural and functional network connectiv... more There is a fundamental gap in understanding how brain structural and functional network connectivity are interrelated, how they change with age, and how such changes contribute to older adults’ sensorimotor deficits. Recent neuroimaging approaches including resting state functional connectivity MRI (fcMRI) and diffusion tensor imaging (DTI) have been used to assess brain functional (fcMRI) and structural (DTI) network connectivity, allowing for more integrative assessments of distributed neural systems than in the past. Declines in corpus callosum size and microstructure with advancing age have been well documented, but their contributions to age deficits in unimanual and bimanual function are not well defined. Our recent work implicates age-related declines in callosal size and integrity as a key contributor to unimanual and bimanual control deficits. Moreover, our data provide evidence for a fundamental shift in the balance of excitatory and inhibitory interhemispheric processes that occurs with age, resulting in age differences in the relationship between functional and structural network connectivity. Training studies suggest that the balance of interhemispheric interactions can be shifted with experience, making this a viable target for future interventions.

In many cases bilateral cortical activation in older adults has been associated with better task ... more In many cases bilateral cortical activation in older adults has been associated with better task performance, suggesting that a greater reliance on interhemispheric interactions aids performance. Interhemispheric communication is primarily mediated via the corpus callosum (CC), however with advancing age the anterior half of the CC undergoes significant atrophy. Here we determine whether there are age differences in the relationship between cross-sectional area of the CC and performance on cognitive tests of psychomotor processing speed and working memory. We found that older adults had significantly smaller callosal area in the anterior and mid-body of the CC than young adults. Furthermore, older adults with larger size in these callosal areas performed better on assessments of working memory and processing speed. Our results indicate that older adults with larger size of the anterior half of the CC exhibit better cognitive function, although their performance was still poorer than young adults with similar CC size. Thus, while the capability for interhemispheric interactions, as inferred from callosal size, may provide performance benefits for older adults, this capacity alone does not assure protection from general performance decline.

Neuroscience & …, Jan 1, 2010

Journal of neuroscience …, Jan 1, 2007

Journal of Neuroscience, Jan 1, 2008