Narayanan Krishnamurthi, PhD, studies the nervous system and how it is affected by Parkinson's disease and Spinal Cord Injury. As principal investigator and assistant research professor at the Center for Adaptive Neural Systems at Arizona State University, Dr. Krishnamurthi investigates the neuroprotective impact of exercise on Parkinson's disease, effects of deep-brain stimulation on posture and locomotion control in Parkinson's disease, improving balance control through real-time feedback of posture and gait performance, the effects of electrical stimulation of legs muscles on orthostatic hypotension in persons with spinal cord injury, etc. In addition, Dr. Krishnamurthi models cardiovascular physiology and applies nonlinear and linear signal processing techniques to electro- and neurophysiological systems.
Before ASU, Dr. Krishnamurthi completed postdoctoral research at Boston University/Harvard Medical School's Integrated Rehabilitation Engineering Training Program. He earned his PhD in nonlinear dynamics (theory of chaos and fractals) and its application to the human cardiac system from the Indian Institute of Technology in Madras, India
Assistant Research Professor
Center for Adaptive Neural Systems (ANS)
School of Biological and Health Systems Engineering (SBHSE)
Arizona State University (ASU)
1100 E. University Dr., Ste. 116, Tempe, AZ 85281
Program Manager, Parkinson Research
Muhammad Ali Parkinson Center (MAPC)
Barrow Neurological Institute (BNI)
St. Joseph’s Hospital and Medical Center (SJHMC)
240 West Thomas Road, Ste. 301
Neurorehabilitation, Parkinson’s disease, Spinal cord injury, Exercise training, Neural plasticity, Bioengineering, Neuromuscular electrical stimulation, Biomedical signal processing
Exercise training in Parkinson’s disease: Neural and functional benefits
Key Personnel: Narayanan Krishnamurthi, PhD (PI); ANS, SBHSE/ASU
James J. Abbas, PhD (ANS, SBHSE/ASU)
Wayne Willis, PhD (Kinesiology, ASU)
Holly Shill, MD (Sun Health Research Institute)
Kewei Chen, PhD (Banner Good Samaritan Medical Center)
Padma Mahant, MD (Banner Good Samaritan Medical Center)
Johan Samanta, MD (Banner Good Samaritan Medical Center)
Abraham Lieberman, MD (Barrow Neurological Institute)
Sponsor: NIH – National Center for Medical Rehabilitation Research
09/23/08 – 08/31/12, $495,525
Supplement: 09/01/2010-08/31/2012, 114,116
Parkinson’s disease (PD) is a complex progressive neurodegenerative disease in which the initial benefits of pharmacological therapy decline over time. Generally, individuals with PD suffer from motor symptoms such as tremor, bradykinesia (slowness of movement), akinesia (difficulty in initiating and/or maintaining movement), rigidity, and impaired balance and gait control. In addition, they also exhibit cardiovascular and respiratory dysfunction. The progression of debilitating conditions such as freezing of gait and falls during the later stages of the disease can severely compromise the quality of life. These conditions often lead to loss of independence and institutionalization, thus increasing health care costs and resulting in greater need for novel therapeutic interventions in PD.
Recently, the notion that physical exercise can produce favorable alterations in brain function has emerged. Many animal studies have demonstrated the ability of exercise and/or behavioral enrichment to increase neurogenesis, neurotrophic factors, and neuronal survival to promote brain vascularization, to enhance learning, and to improve cognitive function during aging. Specifically, animal models of PD have shown that intensive motor therapy can decrease the extent of dopaminergic degeneration. Even though earlier studies have indicated the possibility of changes in the brain due to regular physical activity in humans, it has not yet been shown whether regular exercise can induce favorable alterations in brain network activity in PD.
Therefore, given that there is no treatment available to stop or even to reduce the progression of PD, it is worthwhile to investigate the neuroprotective effects of regular physical exercise in people with PD. Also, the availability of many neuroimaging techniques to monitor the changes in the level and functioning of dopamine receptors due to the disease progression and possible recovery due to intervention encourage studies along these lines. This study investigates the effects of long-term polestriding (12-week training) on the functional benefits with respect to clinical symptoms and cardiovascular functioning, and neuroprotective effects with respect to changes in the brain metabolic network activity using FDG-PET imaging in individuals with PD. Of the many different forms of exercise, polestriding (walking with poles) has been chosen as the intervention for the following reasons: (1) it is more aerobic than normal walking and therefore may result in improved cardiovascular function which has been shown to have a positive relationship with brain functioning and (2) most importantly, polestriding provides better base of support and reduces the risk of falls (which is common in the advanced stages of the disease) and thereby facilitates regular participation in long-term exercise training.
A preliminary analysis of gait patterns obtained from the first group of 8 subjects (out of total 16 subjects) has shown significant increase in step and stride lengths and speed, and decrease in variability in step and stride time intervals due to participation in the 12-week polestriding intervention. In people with PD, stride length is generally reduced and stride time variability is increased and these alterations have shown to be related to falls and freezing of gait. Based on this, these results indicate the potential of regular polestriding to improve gait stability in PD.
If the anticipated benefits are observed, then regular practice of exercise can be developed as a non-pharmacological therapy to alleviate the symptoms of PD and also to slow or reverse the disease progression. Further, PD persons with lower income who cannot afford more expensive treatment can also benefit from regular practice of this low-cost and simple exercise training.
Improving orthostatic tolerance after spinal cord injury
Key Personnel: Narayanan Krishnamurthi, PhD (PI); ANS, SBHSE/ASU
James J. Abbas, PhD (ANS, SBHSE/ASU)
Sponsor: Paralyzed Veterans of America
There are approximately 250,000 Americans with SCI and about 11,000 new cases each year. The cardiovascular deconditioning following SCI due to autonomous nervous system (ANS) dysfunction and paralysis results in low resting blood pressure, profound orthostatic intolerance, lack of leg muscle pump activity, diminished blood volume, and decreased muscle or tissue pressure. In healthy individuals, the effects of gravity on blood volume distribution in the upright position are usually counteracted by the combined actions of sympathetically mediated vasoconstriction and leg muscle pump activity. The latter actively returns blood to the heart through compression of veins by muscle contraction. In contrast, in individuals with SCI, neither of these two mechanisms is strong enough to support blood volume redistribution, thus resulting in orthostatic hypotension (OH). OH is defined as a decrease in systolic blood pressure of 20 mmHg or more, or a reduction in diastolic blood pressure of 10 mmHg or more within three minutes, upon the change in body position from a supine position to an upright posture.
The usual decrease in the blood pressure during any standard SCI-related physiotherapy programs results in OH in 59% of SCI individuals, thus severely limiting the possibilities for participating in rehabilitation therapy targeting other injury-related issues. This leads to extension of the hospital stay, increases in the cost of rehabilitation, possibly limits on the effectiveness of other treatments, and affects many other aspects of their lives.
In this scenario, electrical stimulation (ES)-induced contraction of leg muscles may artificially restore the body’s ability to redistribute blood from the lower limbs to the heart. Recent studies in SCI persons have shown that intermittent ES-induced contractions of lower limb muscles produce a pumping mechanism of both the superficial and deep veins of the legs that effectively attenuate the orthostatic stress-induced reduction of systolic and diastolic blood pressures, stroke volume (SV), and/or cardiac output (CO). But these ES-induced cardiovascular benefits have been studied only in an acute setup and it is not known whether these benefits can be sustained for longer periods of time by regular application of electrical stimulation, such as participation in regular training over months.
In this study, an ES-based exercise training is being developed to increase the muscle pump activity of the lower legs and that can be readily and conveniently administered in a home environment. This research proposal tests the hypothesis that regular ES training (five 45-minute sessions per week for 12 weeks) can induce sustained increase in venous return (due to improved leg muscle pump activity) that may leads to sustained increases in SV and CO. This in turn may have a long-term impact on resting arterial blood pressure and/or its responses to orthostatic stress even in the absence of electrical stimulation. The study characterizes the effect of the intervention on the resting state cardiovascular function and cardiovascular responses to orthostatic stress. Any favorable changes may also affect long-term improvements in ANS functioning, skin perfusion (that can reduce the risk of pressure ulcers), and venous capacity in people with SCI.
The results from the initial experiments have demonstrated two new effects of ES on OH: (1) electrical stimulation while in a wheel chair seated position can acutely reduce OH and (2) participation in a long-term ES exercise program can improve orthostatic tolerance during orthostatic stress induced by head-up tilt procedure. To the best of our knowledge, this is the first demonstration of improved orthostatic tolerance using long-term ES of legs muscles in people with SCI.
Based on the possible benefits to be attained, this training has the potential to improve the cardiovascular and ANS function, which can lead to early and effective participation in rehabilitation protocols resulting in improvements in overall quality of life in individuals with SCI. Another appealing part of the proposed study is that the intervention itself does not require expensive instruments and it can be practiced daily even at home after an initial short training period. Depending on the benefits arising from this study, follow-up studies will be proposed to utilize this training during the acute phase of the injury in a clinical setup to promote early plasticity and participation in rehabilitation, which is crucial to achieve maximum recovery after SCI.
Improving mobility in Parkinson’s disease using dance-based movement program
Key Personnel: Prof. Claudia Murphey (PI); School of Dance/ASU
Narayanan Krishnamurthi, Ph.D.; ANS, SBHSE/ASU
Driver-Dunckley, M.D.; Mayo Clinic, Arizona.
Sponsor: ASU-Mayo Clinic Seed Grant Program
Recent studies have indicated that dance training can be beneficial in people with PD. Most of these studies have focused only on a certain type of dance called the Argentine Tango and are from only one particular research group. Moreover, it is not clear whether the dance training used in those studies was customized to suit the requirements of people with PD. Also, the confounding factors such as dancing with a partner and the effect of anti-parkinsonian medication were not addressed. The Movement and Motion (M&M) program proposed for the study involves an exploration of a wide range of physical activities that is designed to build strength and stability, expand gait stride and range of motion, enhance balance and posture, improve weight shifting and fluidity of motion and promote confidence and self-assurance. Each movement exploration is designed specifically for someone living with the challenges of PD.
Therefore, to clearly understand the benefits of this program in a systematic way, the proposed study will quantitatively and qualitatively investigate the effects of the M&M dance training (MMDT) on mobility in people with PD. The quantitative evaluation will include collection and characterization of neuromuscular variables that reflect posture and gait control, and range of motion, whereas the qualitative evaluation will involve clinical scores such as Unified Parkinson’s Disease Rating Scale (UPDRS) that indicates the severity of the disease and Parkinson’s Disease Questionnaire-39 that comprises of 39 items that provides information on quality of living.
The MMDT intervention is expected to provide the benefits based on the following rationale: (1) it is well known that external cues can improve gait initiation and help to achieve big movements in PD. The different types of cues involved in MMDT (auditory cues from music, visual cues from body movements of oneself and group members, and sensory cues from tapping) can help to produce big and fully embodied movements in PD; (2) MMDT would serve as a means of focusing conscious attention on balancing and walking, and with practice, movements may become more automatic resulting in improved performance; and (3) it is possible that MMDT may facilitate activation of the putamen, which plays a crucial role in the selection and organization of segments of action such as those involved in walking and whose activity is reduced in PD. If the anticipated benefits are observed, then regular practice of MMDT can be developed as a non-pharmacological therapy to alleviate symptoms of PD and can be carried out easily in an outpatient rehabilitation setting or even in a home environment.
The effect of whole body periodic acceleration (WBPA) on the disorders of balance, gait, and freezing of gait in Parkinson’s disease: A clinical study
Key Personnel: Abe Lieberman, MD (PI) (MAPC, BNI/SJHMC)
Narayanan Krishnamurthi, Ph.D. (ANS, SBHSE/ASU)
Sponsor: Non-Invasive Medical Systems, Miami, FL.
The goal of this study is to investigate whether whole body period acceleration (WBPA) provide a means of managing the symptoms of impaired balance and secondarily the symptoms of freezing of gait (FOG) in Parkinson’s disease individuals who are experiencing ‘wearing off’ defined as a dose of levodopa/carbidopa not lasting as long as it had in the past. The WBPA will be administered by a non-invasive, drug-free device called Exer-Rest®. The rationale for this study is that WBPA can mechanically stimulate endothelial cells to release beneficial mediators into the circulation, the chief one of which is nitric oxide. Also, it has been indicated that exposure to vibration (standing on a vibration platform) can lead to improved proprioception. Based on these, WBPA has the potential to improve balance through the above mechanisms. WBPA can serve as an alternative or supplement to exercise particularly in chronic debilitation diseases such as PD where exercise is recommended but difficult to carry-out.
Real-time feedback rehabilitation training to improve gait and posture in Parkinson’s disease
Key Personnel: Narayanan Krishnamurthi, Ph.D. (PI); (ANS, SBHSE/ASU)
Todd Ingalls, Associate Professor (Arts, Media, and Engineering, ASU)
James J. Abbas, Ph.D. (ANS, SBHSE/ASU)
Parkinson’s disease (PD) is a progressive neurodegenerative disease due to the loss of dopaminergic neurons in the substantia nigra part of the brain. Although tremor, bradykinesia, and rigidity are the cardinal symptoms of PD, degradation in balance control while walking is the critical factor that often leads to loss of independence. This gait impairment is usually resistant to the pharmacological treatment and worsens as the disease progresses resulting in hospitalization and increased mortality. People with PD are shown to suffer from perceptual difficulties due to deficiency in processing information related to movement initiation and execution. These deficiencies result in misperceptions of the actual effort necessary to perform a desired movement. During gait, these deficits lead to decreased step length, walking speed, arm swing, and rhythmicity. At the extreme, these deficiencies may lead to freezing of gait.
This study will develop and administer an intervention that utilizes real-time feedback to enhance the participant’s perception of their gait pattern and upright posture and encourages them to improve them. The specific design of the intervention has two key features: it focuses on step length and upright posture (stoopness) and it provides immediate feedback on a step-by-step basis with an indication of whether or not the step length is in the target step length range and whether the person is upright. The immediacy of the feedback is intended to improve perception of gait patterns and upright in a manner that will transfer the improvements during therapy to overground walking, thus leading to improvements of gait and posture in PD.
Effect of Deep Brain Stimulation on Motor Impairments in Parkinson’s Disease
Key Personnel: James Abbas, PhD (ANS, SBHSE/ASU)
Narayanan Krishnamurthi, PhD (ANS, SBHSE/ASU)
Johan Samantha, MD (ANS/Banner Good Samaritan Medical Center)
Padma Mahant, MD (ANS/Banner Good Samaritan Medical Center)
This study investigates the effects of deep brain stimulation (DBS) intensity (amplitude of stimulation) on various motor impairments in PD. The long-term goal of this work is to develop quantitative indicators to improve selection of stimulation parameters in the clinic in order to obtain maximum benefits from DBS systems.
The clinical presentation of PD is typically a combination of various symptoms such as tremor, muscular rigidity, bradykinesia, and posture and gait instability. These impairments can have a significant deleterious impact on independence in activities of daily living. Although medication is often effective in treating the early stages of PD, surgical lesioning of basal ganglia structures has often been used to alleviate symptoms as the disease progresses. More recently, DBS, which uses implanted electrodes to activate certain basal ganglia structures (subthalamic nucleus - STN, globus pallidus interna - GPi), has emerged as a reversible and safer alternative to surgical lesions for the treatment of PD and other movement disorders.
Even though brain stimulators have been successfully implanted in about 30,000 people around the world, currently there is no quantitative methodology available to characterize the effects of DBS on motor symptoms and to select the appropriate stimulation parameters. Clinicians primarily depend on a clinical score called Unified Parkinson’s Disease Rating Scale (UPDRS) that is qualitative and subjective, to evaluate the changes in the symptoms severity for different stimulation parameters. Often only brief observation of the patient or a small subset of the UPDRS battery is used in the clinic. Furthermore, most studies of the efficacy of DBS have been limited to comparing stimulation on/off conditions using a small set of clinical outcomes measures, providing a very restricted view of the effects of DBS.
In this study, the effects of changing deep brain stimulation amplitude (STN stimulation) on different motor impairments such as posture and locomotion control, tremor, and rigidity are being investigated. Among the different stimulation parameters, we choose to alter the stimulation amplitude since this variable is the most critical factor to obtain adequate alteration in subthalamic nucleus activity and capable of inducing significant clinical benefits even for small changes.
Preliminary analyses on gait patterns indicate that stride-time variability (time from heel strike to the subsequent heel strike on the same side) is significantly increased during altered (reduced from clinically determined settings) or no stimulation conditions compared to that of clinically determined stimulation (CDS) conditions in five out of eight subjects. This change in stride-time variability may be of clinical importance since increased stride-time variability has been shown to be associated with falls.
With respect to posture control during dynamical posture shifts, velocity during initiation and movement and peak velocity were consistently affected during reduced DBS amplitude settings. The changes observed in these measures are likely to be related to effects of DBS on different symptoms of PD. For example, the decrease in initiation velocity was mostly due to decrease in pathlength during movement initiation and may be attributed to deteriorated akinesia. The reductions in mean movement velocity and peak velocity were mostly due to increase in time taken and may be due to increased bradykinesia, decreased ankle strength, and abnormal electromyographic patterns during altered stimulation conditions.
The quantitative measures listed above can potentially be efficiently obtained in the clinic and can be utilized for rapid assessment and iterative optimization of DBS settings. These techniques have the potential to overcome the current limitation of depending on qualitative clinical scores and may be able to improve clinical outcomes of DBS programming procedures. The quantitative characterization of the effects of DBS on many motor symptoms of PD can also lead to better understanding of the differential effects of DBS.