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School of Biological Sciences

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College of Sciences

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Center for the Study of Systems Biology

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Publication Search Results

Now showing 1 - 10 of 23

Chemotherapy Induced Sensory Neuropathy Depends on Non-Linear Interactions with Cancer

(Georgia Institute of Technology, 2020-03-30) Housley, Stephen N.

For the constellation of neurological disorders known as chemotherapy induced neuropathy, mechanistic understanding, and treatment remain deficient. In project one, I leveraged a multi-scale experimental approach to provide the first evidence that chronic sensory neuropathy depends on non-linear interactions between cancer and chemotherapy. Global transcriptional profiling of dorsal root ganglia revealed amplified differential expression, notably in regulators of neuronal excitability, metabolism and inflammatory responses, all of which were unpredictable from effects observed with either chemotherapy or cancer alone. Systemic interactions between cancer and chemotherapy also determined the extent of deficits in sensory encoding in vivo and ion channel protein expression by single mechanosensory neurons, with the potassium ion channel Kv3.3 emerging as candidate mechanisms explaining sensory neuron dysfunction. The sufficiency of this novel molecular mechanism was tested in an in silico biophysical model of mechanosensory function. Finally, validated measures of sensorimotor behavior in awake behaving animals confirmed that dysfunction after chronic chemotherapy treatment is exacerbated by cancer. Notably, errors in precise fore-limb placement emerged as a novel behavioral deficit unpredicted by our previous study of chemotherapy alone. These original findings identify novel contributors to peripheral neuropathy, and emphasize the fundamental dependence of neuropathy on the systemic interaction between chemotherapy and cancer across multiple levels of biological control. In project two, I extend study to multiple classes of mechanosensory neurons that are necessary for generating the information content (population code) needed for proprioception. I first tested the hypothesis that exacerbated neuronal dysfunction is conserved across multiple classes of mechanosensory neurons. Results revealed co-suppression of specific signaling parameters across all neuronal classes. To understand the consequences of corrupt population code, I employed a long-short-term memory neural network (LSTM), a deep-learning algorithm, to test how decoding of spatiotemporal features of movement are altered after chemotherapy treatment of cancer. Results indicate that spiking activity from the population of neurons in animals with cancer, treated by chemotherapy contain significantly less information about key features of movement including, e.g. timing, magnitudes, and velocity. I then modeled the central nervous systems (CNS) capacity to compensate for this information loss. Even under optimal learning conditions, the inability to fully restore predictive power suggests that the CNS would not be able to compensate and restore full function. Our results support our proposal that lasting deficits in mobility and perception experienced by cancer survivors can originate from sensory information that is corrupted and un-interpretable by CNS neurons or networks. Collectively, I present the first evidence that chronic cancer neuropathy cannot be explained by the effects of chemotherapy alone but instead depend on non-linear interactions with cancer. This understanding is a prerequisite for designing future studies and for developing effective treatments or preventative measures.
The influence of wheelchair mechanical parameters and human physical fitness on propulsion effort

(Georgia Institute of Technology, 2016-11-15) Lin, Jui-Te

The majority of wheelchair studies that attempt to evaluate propulsion efforts across wheelchair configurations examines long and steady propulsion. However, the results of these studies cannot represent performance during daily maneuvers, which include changes in speed and direction. Although each component of wheelchair configuration was widely studied, the knowledge has a limitation to describe the mechanical properties of wheelchairs systematically. Physical fitness was proved to be related to health status and exercise performance. In addition, the biomechanical characteristics of the user were shown to influence wheelchair maneuvers. However, it is still unknown how these human factors would influence wheelchair propulsions together. Therefore, the overall objective of the study is to define the relative influence of mechanical wheelchair parameters as well as individual physical and biomechanical variables on propulsion efforts during over-ground maneuvers. The first aim is to develop and validate a test that quantifies the impact of wheelchair configurations on frictional energy loss, particularly loss related to turning trajectories. The second aim is to develop and validate a testing protocol designed to measure maximum propulsion strength, which will test subjects in a realistic condition – while seated in their wheelchairs. The third aim is to identify the impact of the mechanical parameters of wheelchairs as well as the physical and biomechanical variables of operators on propulsion efforts during over-ground maneuvers. Mechanical parameters include both inertial and frictional measurements. Operator factors include shoulder position, propulsion strength, and aerobic capacity. To evaluate the performance of daily maneuvering, we designed a repeatable maneuver consisting of several momentum changes. Because of the breadth of wheelchair configurations and variance in user physical capacity, it is necessary to define the effects of wheelchair configurations and user fitness on propulsion with a systematic approach. The study results demonstrated that shoulder position and weight distribution had a significant influence on the frictional energy loss and propulsion efforts. However, aerobic capacity and muscle strength had less influence on daily wheelchair maneuver. Clinicians can use our finding, which covers wheelchair designs and human fitness, to select equipment and prescribe exercise to wheelchair users. Manufacturers can also improve their wheelchair design by understanding the importance of shoulder position and weight distribution.
Changes in leg and joint coordination during locomotor adaptation in amputees and able-bodied controls

(Georgia Institute of Technology, 2016-06-06) Selgrade, Brian Paul

Activities of daily life require humans to locomote in unfamiliar environments. We respond to these new environments through adaptation, a gradual change in movement parameters in response to a sensory error caused by altered environmental conditions. I investigated changes in coordination at the joint and leg level as subjects adapted to split-belt treadmill walking and altered visual feedback in hopping. As subjects adapted to increase leg force, they preferentially reduced deviations in joint torque that affected leg force. Once peak leg force reached a steady level, subjects reduced all joint torque deviations, regardless of relevance to leg force, suggesting that when subjects achieved the task goal, they switched from a minimal intervention strategy to a total noise reduction strategy. As subjects adapt to split-belt walking, they reduce hip work and shift to doing more ankle work in the step-to-step transition. Because ankle work in the step-to-step transition is more efficient, this ankle timing strategy likely contributes to the reduction in metabolic power during split-belt walking. Both amputees and controls gradually adapted step length symmetry in split-belt walking, demonstrating an aftereffect when the split-belt condition was removed. This result is consistent with previous studies of intact subjects and indicates that interlimb coordination is changed using feedforward control. Subjects also adapt to split-belt walking by moving farther backward in single support on the fast belt and less backward on the slow belt. This center of mass displacement strategy persists in amputees and controls, when the split-belt condition is introduced gradually or suddenly, and no matter which belt the prosthetic foot is on. This work suggests that mechanical changes that improve efficiency underlie the reduction in metabolic power during split-belt walking adaptation.
Mechanisms of coordination between one- and two-joint synergist muscles

(Georgia Institute of Technology, 2016-04-15) Mehta, Ricky

Major muscle groups (e.g. triceps surae, quadriceps, hamstrings, triceps brachii) contain synergist muscles that cross either one or two joints; they are called one- and two-joint muscles. The functional significance of this musculoskeletal design, extensively studied in the past, has been suggested to increase the economy and efficiency of movement. Much less attention has been paid to the mechanisms responsible for the differential activation, or coordination, between one- and two-joint synergists. The understanding of these mechanisms will not only add to the basic knowledge of neural control of movement but also contribute to prevention and therapeutic interventions of muscle injuries that often occur in two-joint muscles. Previous work has suggested that mechanical intermuscular interactions, resultant muscle moment requirements at the adjacent joints, movement speed, and muscle length-velocity related sensory feedback can affect this coordination. Additionally, the comparison of motoneuronal and muscle activity patterns between fictive and real locomotion in cats suggests a greater influence of motion related sensory feedback on activity of proximal two-joint muscles (i.e., rectus femoris and hamstrings) compared to one-joint muscles and distal two-joint muscles (medial and lateral gastrocnemius). Therefore, the first goal of this work was to test the possible contribution of mechanical intermuscular interactions between one- and two-joint ankle extensors in the cat. The second goal was to examine the role of joint moment requirements, movement speed and length-velocity related feedback in distinct activation of distal one- and two-joint muscles (soleus and gastrocnemius). The third goal was to investigate the effect of removal of length-velocity sensory feedback from proximal one- and two-joint muscles (vastii and rectus femoris) on coordination of these muscles. To address the above goals, an array of motor tasks with different speeds and combinations of joint moments were studied in cats and humans. The tasks included level, downslope and upslope walking and paw shake response in cats, as well as back and leg load lifting and jumping in humans. Motion capture and force plate data were recorded to analyze kinematics and joint moments, sonomicrometry was used to measure muscle fascicle length in cats, and electromyography (EMG) was used to quantify muscle activity. Length-velocity related sensory feedback was removed in cats by muscle self-reinnervation. Results show that mechanical intermuscular interactions via myofascial force transmission should be considered in the coordination between adjacent one- and two-joint synergist muscles in certain pathological conditions leading to increased muscle lengths. Coordination between distal and proximal one- and two-joint synergists depends on joint moment requirements, and the differential inhibition of soleus and excitation of gastrocnemius does not depend on movement speed or length-velocity related sensory feedback. Removal of length-velocity related sensory feedback has a strong effect on coordination between the studied proximal synergist pair (vastii and rectus femoris) but not on coordination of the distal synergist pair (soleus and gastrocnemius). Findings presented here expand on understanding the role of mechanical interactions, sensory feedback and feedforward control in the coordination between one- and two-joint muscles. These findings have potential implications for developing targeted rehabilitation strategies/treatment and implementation of new control strategies for robotics and prosthetics to improve movement efficiency.
Substrate-level control of glucose metabolism in C2C12 myotubes

(Georgia Institute of Technology, 2016-03-30) Hsu, Chia

Metabolic flexibility is critical for muscle to maintain proper function and overall health. Muscle adapts to metabolic stress with increasing ATP synthesis by enhancing the rate of glycolysis and mitochondrial respiration. The control of that rate is mediated by several glucose metabolites. This project is based on the conceptual model that AMP indicates the balance of ATP synthesis and degradation, and NADH indicates the balance of glucose delivery to oxygen delivery. AMP signaling facilitates all aspects of glucose metabolism, and NAD+ signaling facilitates oxidative metabolism and inhibits reductive metabolism. The overall hypothesis is that the distribution of glucose depends on AMP and NAD+ generated during energetic stress. The results suggest that glucose metabolism is highly sensitive to ATP homeostasis via AMPK activity. NADH oxidation alone is not sufficient to influence glucose oxidation, but require co-activation of AMPK. AMP and NAD+ signaling work independently in metabolic gene expression. The overall conclusion is that glucose metabolism depends on AMP signaling, but NAD signaling is unable to alter glucose disposal. AMP and NAD independently induced metabolic and differentiation adaptation. These findings suggest that other molecule may represent an additional gauge of aerobic and anaerobic metabolism.
Spatiotemporal patterns of parietofrontal activity and eye movements underlying the visual perception of complex human tool use

(Georgia Institute of Technology, 2015-11-16) Natraj, Nikhilesh

When watching a child learning to use a spoon, a mother is immediately able to recognize the error when the child grabs the bowl rather than the stem, or when the child uses the spoon to try and scoop paper. Recognizing proper tool grasp-postures and use-contexts is an ability vital for daily life and can be lost due to brain injury. A better understanding of how the brain encodes contextual and grasp-specific tool-use not only furthers basic neuroscience, but also has strong relevance to deficits arising from neural pathologies. However, the majority of research till date has studied the neural response to viewing tools in isolation or viewing simple tool-grasps. These studies have shown that the recognition of tools to be a complex visuomotor process, as not only was the visual cortex engaged but also parietal and frontal regions that underlie actual tool-use. The recognition of tools therefore involves automatically recalling their motor information (graspability and manipulability) via activation of parietofrontal motor regions, a property called action affordances. Yet, it is still unclear how parietofrontal regions encode the combination of contextual and grasp-specific tool-use scenes. In addition, parietofrontal regions are multifaceted and also underlie visuospatial attention and eye movements. It is possible a relationship might exist between eye movements, attention and tool-use understanding over parietofrontal regions. Therefore the overall goal of this thesis was to understand the spatiotemporal patterns of parietofrontal activity and eye movements underlying the perceptual of contextual and grasp-specific static tool use images. Electroencephalography (EEG) was used to measure neural activity, combined with eye tracking to measure fixation and saccades. Overall, results from this thesis present evidence that the affordances of non-functional grasp-postures perturbed an observer from understanding the contextual uses of tools, with corresponding unique patterns of parietofrontal activity and eye movements. This effect was most robust when the tool was placed in contexts that afforded a certain degree of tool-use. Results also revealed a relationship between attention, eye movements and action perception over parietofrontal regions. Specifically, saccades perturbed activity over frontal regions during the perception of non-functional grasp postures and in addition, there was greater engagement of the left precuneus in the superior parietal lobe if the observer had to quickly parse the scene information using peripheral vision and rely on short term memory. In contrast, there was greater engagement of the left middle temporal gyrus if the observer had the ability to parse scene information continuously using foveal attention. Results in this thesis shed light on the neural and visual mechanisms in understanding the affordances of non-functional grasp postures, and the relation between the two mechanisms. The automatic sensitivity in understanding the intent of non-functional grasp-postures may correspond to a lifetime of learning the affordances of grasp-specific action outcomes with tools. Such cognitive motor knowledge may be vital in navigating a human environment almost entirely constructed on advanced tool-use knowledge and findings from this thesis have many potential applications in the field of neuro-rehabilitation.
Neuromechanics of locomotion: Insights from the walk-to-run transition in amputees and pedaling in able-bodied individuals

(Georgia Institute of Technology, 2015-10-16) Norman, Tracy L.

Afferent feedback is important for modulating locomotion and maintaining stability. Studying locomotor extremes and applying perturbations to normal locomotion allows us to probe the effects of afferent feedback on the control of normal gait. Investigating the walk-to-run gait transition specifically provides a unique locomotor event to investigate the fundamental determinants of legged locomotion (walking or running) and identify the sensory inputs important to the ongoing neuromuscular control of walking and running. The first goal of this dissertation was to investigate the contributions of plantarflexor muscles during stance (Aim 1) and flexor muscles during swing (Aim 2) to the walk-to-run transition. To accomplish this I used unilateral, transtibial amputee subjects as a means to assess the affects of unilaterally eliminating plantarflexor propulsive force production and below-knee flexor activation on the walk-to-run transition speed. The main objective of Aim 1 was to determine the preferred gait transition speeds of unilateral, transtibial amputee subjects, and the influence of kinetics on the walk-to-run gait transition speed. Unilateral, transtibial amputee subjects transition between gaits at a lower speed than able-bodied controls and are still able to generate higher propulsive forces walking at speeds above their preferred gait transition speed. This finding indicates that their walk-to-run transition is not likely dictated by the force-length-velocity characteristics of the intact plantarflexor muscles. Thus, as an experimental model, unilateral, transtibial amputee subjects can provide unique insights for decoupling the previously identified performance limit of plantarflexor muscles from the preferred gait transition speed in order to probe other potential determinants. The main objective of Aim 2 was to quantify the muscle activation during walking and running gaits relative to the walk-to-run gait transition speed for unilateral, transtibial amputee subjects. The swing phase tibialis anterior muscle activation is a major determinant of the walk-to-run transitions in unilateral, transtibial amputee subjects. Swing phase dorsiflexion moments alone do not explain these results and additional work is necessary to probe potential mechanical and neural explanations. Furthermore, in unilateral, transtibial amputee subjects, swing-phase rectus femoris and biceps femoris long head activations and their respective joint moments are a function of changes in absolute speed and thus not indicative of their significantly lower gait transition speed. The second goal of this dissertation was to probe the potential contributions of afferent feedback to the underlying neuromuscular mechanism ultimately responsible for the transition (Aim 3). The main objective of Aim 3 was to evaluate the effects of contralateral sensory loss on the motor output of the ipsilateral leg. Unilateral below-knee, ischemic deafferentation has significant effects on both inter- and intra- limb motor output. The net effect of contralateral sensory loss below the knee is a significant decrease in ipsilateral flexor muscle activations during the transition from flexion to extension in pedaling (Q1). Due to the rapid time course of these responses, I speculate either i) contralateral below-knee afferents (most likely Ia and/or cutaneous) have a net excitatory effect on the ipsilateral flexor muscles or ii) contralateral above knee afferents (most likely Ib) have an inhibitory effect on the ipsilateral flexor muscles.
Altered intermuscular force feedback after spinal cord injury in cat

(Georgia Institute of Technology, 2015-07-24) Niazi, Irrum Fawad

Bipeds and quadrupeds are inherently unstable and their bodies sway during quiet stance and require complex patterns of muscle activation to produce direction-specific forces to control the body’s center of mass. The relative strength of length and force feedback within and across muscles collectively regulates the mechanical properties of the limb as a whole during standing and locomotion (Bonasera and Nichols 1994; Ross and Nichols 2009). Loss of posture control following spinal cord injury (SCI) is a major clinical challenge. While much is known about intermuscular force feedback during crossed extension reflex (XER) and locomotion in decerebrate cats, these have not been well characterized in animals with spinal cord injury. In this study, we mapped the distribution of heterogenic force feedback in hindlimb ankle extensor muscles using muscle stretch (natural stimulation) in intercollicular, non-locomoting, decerebrate cats with chronic lateral spinal hemisection (LSH). We also, determined the time of onset of redistribution of heterogenic force feedback following LSH by collecting force feedback data from cats with acute sci. In addition we revisited heterogenic force feedback between ankle extensors in decerebrate non-locomoting cats during mid-stance to ascertain whether these cats with intact spinal cord depict a certain pattern of force feedback. The goal was to ascertain whether the patterns and strength of feedback was different between the two states (cats with intact spinal cord and cats with SCI). We found that heterogenic feedback pathways remained inhibitory in non-locomoting decerebrate cats in two states. The latencies of inhibition also corresponded to those observed for force feedback from Golgi tendon organs. We observed variable patterns of force feedback between ankle extensors in decerebrate/control cats. On the other hand we observed consistent results in cats with chronic LSH exhibiting very strong distal to proximal pattern of inhibition from 2 weeks to 20 weeks following chronic LSH. The same results were obtained in acute LSH cats suggest that the change in neuromuscular system appears immediately after SCI and persists even after the animal start walking following SCI. The observed altered pattern of force feedback after spinal cord injury suggests either presence of a pattern intrinsic to the spinal cord or a unique pattern exhibited by the damaged spinal cord. The results are important clinically because even with vigorous rehabilitation attempts patients do not regain posture control after SCI even though they regain ability to walk. Therefore, to effectively administer treatment and therapy for patients with compromised posture control, a complete understanding of the circuitry is required.
Influencing motor behavior through constraint of lower limb movement

(Georgia Institute of Technology, 2015-04-29) Hovorka, Christopher Francis

Limited knowledge of the neuromechanical response to use of an ankle foot orthosis-footwear combination (AFO-FC) has created a lack of consensus in understanding orthotic motion control as a therapeutic treatment. Lack of consensus may hinder the clinician’s ability to target the motion control needs of persons with movement impairment (e.g., peripheral nerve injury, stroke, etc.). Some evidence suggests a proportional relationship between joint motion and neuromuscular activity based on the notion that use of lower limb orthoses that constrain joint motion may invoke motor slacking and decreasing levels of muscle activity. Use of AFO-FCs likely alters the biomechanical and neuromuscular output as the central control system gradually forms new movement patterns. If there is proportional relationship between muscle activation and joint motion, then it could be examined by quantifying joint motion and subsequent neuromuscular output. Considering principles of neuromechanical adjustment, my general hypothesis examines whether orthotic control of lower limb motion alters neuromuscular output in proportion to the biomechanical output as a representation of the limb’s dynamics are updated by the neural control system. The rationale for this approach is that reference knowledge of the neuromechanical response is needed to inform clinicians about how a person responds to walking with motion controlling devices such as ankle foot orthoses combined with footwear. In the first line of research, I hypothesize that a newly developed AFO which maximizes leverage and stiffness will constrain the talocrural joint and alter joint kinematics and ground reaction force patterns. To answer the hypothesis, I sampled kinematics and kinetics of healthy subjects’ treadmill walking using an AFO-FC in a STOP condition and confirmed that the AFO substantially limited the range of talocrural plantarflexion and dorsiflexion motion to 3.7° and in a FREE condition maintained talocrural motion to 24.2° compared to 27.7° in a CONTROL (no AFO) condition. A follow up controlled static loading study sampled kinematics of matched healthy subjects limbs and cadaveric limbs in the AFO STOP and FREE conditions. Findings revealed healthy and cadaveric limbs in the AFO STOP condition substantially limited their limb segment motion similar to matched healthy subjects walking in the STOP condition and in the AFO FREE condition healthy and cadaveric limbs maintained similar limb segment motion to matched healthy subjects walking in the FREE condition. In a second line of research, I hypothesize that flexibility of a newly developed footwear system will allow normal walking kinetics due to the shape and flexibility of the footwear. To answer the hypothesis, I utilized a curved-flexible footwear system integrated with an AFO in a STOP condition and sampled kinematics and kinetics of healthy subjects during treadmill walking. Results revealed subjects elicited similar cadence, stance and swing duration and effective leg-ankle-foot roll over radius compared to walking in the curved-flexible footwear integrated with the AFO in a FREE condition and a CONTROL (no AFO) condition. To validate rollover dynamics of the curved-flexible footwear system, a follow up study of healthy subjects’ treadmill walking in newly developed flat-rigid footwear system integrated with the AFO in a STOP condition revealed interrupted leg-ankle-foot rollover compared to walking in curved-flexible footwear in STOP, FREE and CONTROL conditions. In a third line of research, I hypothesize that use of an AFO that limits talocrural motion in a STOP condition will proportionally reduce activation of Tibialis Anterior, Soleus, Medial and Lateral Gastrocnemii muscles compared to a FREE and CONTROL condition due to alterations in length dependent representation of the limb’s dynamics undergoing updates to the central control system that modify the pattern of motor output. To answer the question, the same subjects and AFO-footwear presented in the first two lines of research were used in a treadmill walking protocol in STOP, FREE, and CONTROL conditions. Findings revealed the same subjects and ipsilateral AFO-footwear system presented in Aim 1 exhibited an immediate yet moderate 30% decline in EMG activity of ipsilateral Soleus (SOL), Medial Gastrocnemius (MG) and Lateral Gastrocnemius (LG) muscles in the STOP condition compared to the CONTROL condition. The reduction in EMG activity in ipsilateral SOL, MG and LG muscles continued to gradually decline during 15 minutes of treadmill walking. On the contralateral leg, there was an immediate yet small increase of 1% to 14% in EMG activity in SOL, MG, LG muscles above baseline. After 10 minutes of walking, the EMG activity in contralateral SOL, MG and LG declined to a baseline level similar to the EMG activity in the contralateral CONTROL condition. These collective findings provide compelling evidence that the moderate 30% reduction in muscle activation exhibited by subjects as they experience substantial (85%) constraint of total talocrural motion in the AFO STOP condition is not proportionally equivalent. Further, the immediate decrease in muscle activation may be due to a reactive feedback mechanism whereas the continued decline may in part be explained by a feedforward mechanism. The clinical relevance of these findings suggests that short term use of orthotic constraint of talocrural motion in healthy subjects does not substantially reduce muscle activation. These preliminary findings could be used to inform the development of orthoses and footwear as therapeutic motion control treatments in the development of motor rehabilitation protocols.
Understanding the neurophysiology of action interpretation in right and left-handed individuals

(Georgia Institute of Technology, 2015-04-08) Kelly, Rachel Louise

Investigating the neurophysiology behind our action encoding system offers a way of probing the underlying mechanisms regarding how we understand seen action. The ability to mentally simulate action (motor simulation) is a strong proposal to understand how we interpret others’ actions. The process of how we generate accurate motor simulations is proposed to be reliant on the context of the movement and sensory feedback from the limb. However, the neurophysiological mechanisms behind motor simulation are not yet understood. Known motor physiology for right-handed individuals show there is a left parietal-frontal network for the mental simulation of skilled movements; however, it remains unclear whether this is due to right limb dominance of the observer’s motor system because action simulation research has been focused primarily on right-handed individuals. The goal of this dissertation is to understand the underlying neurophysiology of the motor simulation process during action encoding. Generally, we propose different strategies of action simulation between right and left handed individuals. More specifically, we propose that right-handed individuals rely on their motor dominant left hemisphere for action encoding and motor simulation, while left-handed individuals will rely on their motor dominant right hemisphere. We will test this by evaluating neurobehavioral patterns of potential symmetry and asymmetry of motor simulation and action encoding based on patterns of limb dominance. We will also evaluate how impaired sensory feedback affects motor simulations, which can reveal how limb state affects the simulation process. The results of this series of studies will fill a void in our basic understanding of the motor simulation process and may generalize to populations with upper limb functional loss. Specifically, those with different hand dominance may require different rehabilitation programs in order to retrain an affected limb.