- Email: [email protected]
Neuromuscular rate of force development deficit in Parkinson disease
Accepted Manuscript Neuromuscular rate of force development deficit in Parkinson disease
Kelley G. Hammond, Ronald F. Pfeiffer, Mark S. LeDoux, Brian K. Schilling PII: DOI: Reference:
S0268-0033(17)30092-X doi: 10.1016/j.clinbiomech.2017.04.003 JCLB 4313
To appear in:
Clinical Biomechanics
Received date: Accepted date:
18 August 2016 10 April 2017
Please cite this article as: Kelley G. Hammond, Ronald F. Pfeiffer, Mark S. LeDoux, Brian K. Schilling , Neuromuscular rate of force development deficit in Parkinson disease. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jclb(2017), doi: 10.1016/j.clinbiomech.2017.04.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 NEUROMUSCULAR RATE OF FORCE DEVELOPMENT DEFICIT IN PARKINSON DISEASE Kelley G. Hammonda,1, Ronald F. Pfeifferb,2, Mark S. LeDouxb, Brian K. Schillinga,3 a
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The University of Memphis School of Health Studies 106 Elma Roane Fieldhouse 495 Zach Curlin St Memphis, TN 38152, USA [email protected] (corresponding author) [email protected]
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The University of Tennessee Health Science Center College of Medicine 855 Monroe Ave Suite 415 Link Building Memphis, TN 38163, USA [email protected] [email protected]
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Word Count: 220 (abstract); 2368 (main text)
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The University of Alabama at Birmingham, Department of Physical Therapy, 1720 2 nd Ave S, SHPB 360X, Birmingham, AL 35294, USA (Permanent address) 2 Oregon Health and Science University, School of Medicine, 3181 S.W. Sam Jackson Park Rd, Portland, OR 97239, USA (Present address) 3 The University of Nevada at Las Vegas, 4505 S Maryland Pkwy, BHS 329, Las Vegas, NV 89154, USA (Permanent address)
ACCEPTED MANUSCRIPT 2 ABSTRACT Background: Bradykinesia and reduced neuromuscular force exist in Parkinson disease. The interpolated twitch technique has been used to evaluate central versus peripheral manifestations of neuromuscular strength in healthy, aging, and athletic populations, as well as moderate to advanced Parkinson disease, but this
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method has not been used in mild Parkinson disease. This study aimed to evaluate quadriceps femoris rate of
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force development and quantify potential central and peripheral activation deficits in individuals with Parkinson
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disease.
Methods: Nine persons with mild PD (Hoehn & Yahr ≤2, Unified Parkinson Disease Rating Scale total score =
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mean 19.1 (SD 5.0)) and eight age-matched controls were recruited in a cross-sectional investigation. Quadriceps femoris voluntary and stimulated maximal force and rate of force development were evaluated
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using the interpolated twitch technique.
Findings: Thirteen participants satisfactorily completed the protocol. Individuals with early Parkinson disease
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(n=7) had significantly slower voluntary rate of force development (p = 0.008; d=1.97) and rate of force
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development ratio (p = 0.004; d=2.18) than controls (n=6). No significant differences were found between groups for all other variables.
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Interpretations: Persons with mild-to-moderate Parkinson disease display disparities in rate of force
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development, even without deficits in maximal force. The inability to produce force at a rate comparable to
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controls is likely a downstream effect of central dysfunction of the motor pathway in Parkinson disease.
Key Words: skeletal muscle; weakness; central activation; rate of force development
ACCEPTED MANUSCRIPT 3 Parkinson disease (PD) is a progressive neurological disorder affecting more than one million people in the United States. PD is characterized by tremor, muscle rigidity, bradykinesia, and reduced neuromuscular force production. 1, 2 Although neuropathology is widespread in the majority of post-mortem PD brains, major difficulties in motor control can be ascribed to loss of dopaminergic neurons within the substantia nigra. Moreover, bradykinesia is directly correlated with striatal dopamine deficiency. 3 A complex battery of factors
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aside from specific PD symptoms, including balance, muscle synergies and co-contraction, body weight, and
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ability to generate force, can cause difficulty in performing activities of daily living such as moving from a
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seated to standing position. 4 Although force deficits are widely accepted as an effect of PD, specific
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mechanisms for decreased neuromuscular force production have not been identified. Aging adults typically demonstrate loss of muscle mass5 and reduced voluntary neuromuscular force
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capability. 6 However, several studies have shown a severe decline in maximal neuromuscular force in PD compared with healthy, age-matched individuals. 2 In non-PD older adults, time to achieve peak force in the
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quadriceps femoris typically takes less than one second, while persons with PD and moderate bradykinesia
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can take 3-4 seconds to achieve peak force. 7, 8 Several studies report reduced rate of force development (RFD) and strength (maximal force) in persons with PD following withdrawal from dopaminergic therapy. 7, 8
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This suggests that the weakness and reduction in RFD is a direct result of the disease (dopaminergic denervation of the striatum), and at least partly central in nature. Consequently, persons with PD experience
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age-related muscle changes at a greater magnitude than their age-matched peers (as reviewed2). The
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compromised ability to rapidly produce force (reduced RFD) can be observed in the prevalence of falls in aging adults. 9 Similarly, muscle power (force x velocity) greatly affects walking velocity, and has a stronger association with falling in PD than muscle strength alone. 10 This indicates that the rate (velocity) at which force can be produced is as important, if not more important, than the maximum force of muscle contraction. The interpolated twitch technique (ITT) is an effective method of evaluating and quantifying voluntary versus involuntary muscle contraction, 11 but only recently has been used in PD. 12 By electrically stimulating a relaxed muscle, a wealth of information can be acquired, including the absolute ability of the muscle to produce force (torque) as well as RFD. Specifically, the muscle’s contractility can be examined without central input in
ACCEPTED MANUSCRIPT 4 two important ways. First, involuntary RFD (iRFD) can be compared with vRFD to evaluate RFD proficiency (RFD ratio = vRFD/ iRFD). The RFD ratio is a novel way to identify a central mechanism of dysfunction in muscle performance. Based on the assumption that iRFD establishes the maximal mechanical capability of a muscle to rapidly produce force, a ratio equal to one would indicate that voluntary effort in a maximal contraction (with instruction to contract “as fast and hard as possible”) elicits central descending drive equal to
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the electrical stimulation applied. A ratio <1 would suggest that central input during voluntary effort is not
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evoking adequate neural drive to achieve maximal RFD. Additionally, an evoked twitch can be added to a
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maximal voluntary contraction, and the difference in force output can provide a quantitative value of central activation. One method of calculating this is the central activation ratio (CAR = maximal voluntary
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contraction/(maximal voluntary contraction + stimulated force)). 13 Similar to the RFD ratio, the CAR can
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identify central deficits reflected in decreased maximal voluntary force production. Although deficits in strength are reasonably accepted as result of PD progression, the current literature
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is equivocal regarding measures of strength in various stages of PD. One investigation of individuals with PD
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who exhibit prominent motor impairment (Unified Parkinson’s Disease Rating Scale motor score ≥ 31.7; UPDRS) displayed decreased leg muscle torque and central activation (CAR) compared with those with less
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severe motor impairment (UPDRS <31.7) and non-PD controls, 12 and another found no differences in maximal voluntary strength or leg power in those with PD (UPDRS motor score mean 35.8 (SD 2.9)) compared to age-
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matched controls. 14 The results of these studies indicate that further examination is warranted on voluntary vs.
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involuntary neuromuscular performance in persons with PD. The first aim of this study was to quantify central and peripheral neuromuscular force and RFD deficits in persons with early stages of PD. Secondly, the study sought to examine the usability of ITT for examining central versus peripheral mechanisms of neuromuscular dysfunction in PD. METHODS Participants
ACCEPTED MANUSCRIPT 5 Seventeen participants (M = 11, F = 6) were recruited to participate in the study, and the size of the sample was based on the magnitude of effects from similar studies in persons with PD. The nine persons in the PD group (M = 6, F = 3) were diagnosed with idiopathic PD by a neurologist with subspeciality expertise in movement disorders. Individuals with orthostatic hypotension, dementia (Mini-Mental State Examination Scores <24), or other significant co-morbidities (i.e., stroke, severe degenerative osteoarthritis) were excluded.
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Individuals with other causes of Parkinsonism, such as progressive supranuclear palsy, vascular
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Parkinsonism, and multiple system atrophy were also excluded from the study. A board-certified neurologist
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examined each PD participant and performed the UPDRS within two months of testing. Eight neurologically healthy, similarly-aged individuals (M=5, F=3) were recruited from the local
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university faculty and staff as a control group. These participants were of good general health based on self-
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report, and were free of neurological impairment. All procedures were approved by the local Institutional Review Board. Participants completed a health history, drug usage, and fitness activity questionnaire and
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provided written informed consent prior to data collection. Height, weight, and thigh skinfold and circumference were measured (right leg). Skinfold and circumference were used to estimate quadriceps femoris cross-
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sectional area according to the equation by Housh et al. ([2.52 x mid-thigh circumference in cm] – [1.25 x
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anterior thigh skinfold in mm] – 45.13). 15 Cross-sectional area was measured as a possible variable to adjust quadriceps force in the statistical analysis, as larger muscles typically produce more force. All testing was done
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with PD participants in an optimally medicated state (carbidopa/levodopa, n=4; dopamine agonists, n=4; MAO-
ITT Testing
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B inhibitors, n=2), which was determined by the participants as their “on state” earliest in the day.
Participants were seated in a customized chair that provided back support and placed in an upright position (Fig. 1). Seatbelt restraints were placed across the participant’s trunk and lap to minimize movement of the torso. Rubber stimulating electrodes (7.5 x 13 cm) were secured with tape over the femoral triangle (cathode) and just proximal to the superior border of the patella (anode). Stimulation was supplied by an external stimulator (Digitimer® DS7AH, Hertfordshire, United Kingdom). The participant’s right ankle was inserted into a padded sleeve and cuff, which was attached via steel cable to the load cell (Transducer
ACCEPTED MANUSCRIPT 6 Techniques® MLP-1K load cell, Temecula, CA, USA) with enough tension to eliminate slack. This fixed the knee at 90°flexion and hips at 100° extension. Participants were instructed to cross their arms over their chest during testing. For the first trial, they were instructed to relax prior to being given a 200µs16 triplet pulse of 50mA at 400V17 to the quadriceps femoris. 18 The amperage was then increased in 50mA increments for subsequent trials16 until the peak
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stimulated force reached a plateau (less than 5% change19). The plateau typically occurred between 200-
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400mA. 20 An octet pulse was then administered at the previously determined maximal parameters to identify maximal iRFD. 21 Participants were given up to one minute to rest between trials.18, 19
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Participants were instructed to contract the knee extensors of their restrained leg maximally in order to practice maximal voluntary contractions (MVC). Two MVCs were then performed with one-minute rest between
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trials, or when the individual being tested was ready to continue. Participants then performed a trial where the
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predetermined triplet pulse (same maximal parameters) was applied after voluntary force plateaued. 22 The MVC with stimulation trial was repeated23 after a one-minute break. The higher force of two trials was used for
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analysis. The reliability of this protocol has been established. 11
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The force signal was acquired via analog/digital conversion (Measurement Computing, DAS1200JR, Norton, MA, USA), and Datapac5 software was used for application of pulses, data acquisition, and
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processing. The force signal was filtered through a fourth-order Butterworth low-pass filter with a cutoff
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frequency of 30Hz. The RFD during interpolated twitch (iRFD) and maximal voluntary contraction (vRFD) were calculated as the maximum velocity of the signal (N/s) during the rise phase. Start of the action was defined as the point at which the first derivative of the filtered force signal crossed zero for the last time. The RFD ratio was calculated as the vRFD divided by iRFD, and the CAR was determined using the voluntary and interpolated (involuntary) twitch force data as indicated previously. Statistical Analysis Independent one-sample t-tests (P <0.05) were used to compare MVC, interpolated isometric twitch force, vRFD, iRFD, CAR, and RFD ratio between the group with PD and the control group. Effect sizes (d)
ACCEPTED MANUSCRIPT 7 were calculated to determine the magnitude of differences between groups using the pooled SD adjusted for sample size. Data are reported as mean (SD). RESULTS Seventeen participants volunteered for testing. Two participants from the control group (M=1, F=1) did
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not finish the protocol due to discomfort. Data from one male PD participant and one male control participant
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were not useable due to impact artifact in the force channel that was not detected at the time of testing.
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Estimated cross-sectional area was not associated with force in our sample, thus we report the non-adjusted forces only. In the final analysis (PD=7, control=6; Table 1), we found that unimpaired individuals had
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significantly higher vRFD (P < 0.05, d=1.97) and larger RFD ratio (P < 0.05, d=2.18) than the PD participants (Fig. 2). No significant differences were found (p> 0.634, d< 0.47) between PD and controls for all other
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notable variables, including iRFD, interpolated isometric twitch force, voluntary force, and CAR. The η2 values
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indicated that grouping was responsible for ~49% of the variance in vRFD.
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DISCUSSION
This study is only the second investigation using ITT to determine involuntary neuromuscular activation
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and CAR in PD. Despite an absence of maximal force differences, the results demonstrate large deficits in
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vRFD and the RFD ratio of the quadriceps femoris in PD compared with healthy, similarly-aged controls. No meaningful difference existed in iRFD between groups, indicating that the mechanism responsible for the
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deficit in vRFD, even in mild to moderate PD, likely is central in nature. Since the effect sizes were all less than 0.47, it is unlikely that the differences were undetectable only due to our small sample size. Other investigations of neuromuscular force measures have reported similar findings of reduced vRFD in PD, 7, 8, 25 but the present study is the first to examine iRFD using ITT. Our data provide practical insight to the effects of PD neuromuscular performance. For persons with mild motor symptoms of PD, such as the participants in this study (UPDRS = mean 19.1 (5.0)), the mechanical ability of the quadriceps femoris remains intact (no difference in iRFD between groups). However, a large difference in RFD exists when maximal contraction is performed voluntarily (vRFD). At least 50% of dopaminergic neurons in the substantia nigra are compromised
ACCEPTED MANUSCRIPT 8 prior to the appearance of motor symptoms, 26 and this extensive cell death may affect RFD prior to decline in strength or manifestation of other symptoms. This hypothesis may provide awareness of the effects of PD in the early stages of diagnosis, when great damage has occurred in the brain, but obvious signs are minimal. The PD group’s CAR scores and peak force measures were similar to the control group in the present study, even when adjusted for quadriceps femoris cross-sectional area. Full activation of the quadriceps
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femoris has been reported in unimpaired individuals, 21 so our finding of CAR outcomes near 1.0 in controls
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was not unfounded. Because strength deficits were expected in this investigation, CARs for PD participants were also expected to be lower than controls. Absence of differences in maximal voluntary force translated to
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no differences in CAR. The lack of differences in maximal strength in our investigation conflicts with several earlier studies reporting decreased strength in individuals with PD compared with controls (as reviewed 2, 27),
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though recently no differences in maximal voluntary strength or leg power has been reported. 14 Our hypothesis included strength deficits in the PD group, but the absence of differences between groups in our study can
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likely be explained by the nominal motor impairment (UPDRS = mean 15.7 (SD 5.0); Hoehn & Yahr = mean
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1.9 (SD 0.20)) of our PD participants and minimal presence of symptoms in these individuals when optimally
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medicated (as during testing).
Neuromuscular deficits in persons with PD are a potential target for exercise interventions. Individuals
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who are early in their disease course may be able to slow neurodegeneration and symptom progression by implementing a moderate to high-load resistance training regimen, but further investigation is necessary to
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examine the effects of interventions early in treatment. Robust physiological adaptations in the skeletal muscle of persons with moderate PD (UPDRS motor score mean 35.8 (SD 2.9)) were accompanied by gains in functional performance following 16 weeks of a high-intensity exercise training intervention. 14 Kelly et al. (2013) demonstrated that a high-intensity training paradigm elicited post-training improvements in the PD group beyond the performance of untrained age-matched controls; the substantial gains by individuals with more advanced PD provides exciting grounds for further research into the effects of high-intensity exercise training on individuals with mild PD, such as those in the present study. Additionally, voluntary and involuntary
ACCEPTED MANUSCRIPT 9 performance testing similar to the protocol herein may be able to partial out central vs. peripheral gains in performance. CONCLUSION We demonstrated that ITT can be used to assess central activation and RFD in PD and older adults,
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ITT for initial assessment and to examine exercise-training responses in PD.
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and provided practical insight into early motor deficits in PD. Future investigations may be well-served to utilize
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ACKNOWLEDGEMENTS
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The authors would like to thank Susan Silverman for her assistance in manuscript preparation.
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Funding: This work was supported by the National Strength and Conditioning Association. MSL was supported, in part, by the Dorothy/Daniel Gerwin Parkinson’s Research Fund.
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Conflicts of interest: none
ACCEPTED MANUSCRIPT 10 REFERENCES
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2. Falvo MJ, Schilling BK, Earhart GM. Parkinson's disease and resistive exercise: rationale, review, and
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5. Doherty TJ. Invited review: Aging and sarcopenia. J Appl Physiol. 2003;95:1717-1727.
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balance, gait, and posture in Parkinson's disease: a pilot study. Am J Phys Med Rehabil. 2004;83:898-908.
8. Corcos DM, Chen CM, Quinn NP, McAuley J, Rothwell JC. Strength in Parkinson's disease: relationship to rate of force generation and clinical status. Ann Neurol. 1996;39:79-88.
9. Orr R, Raymond J, Fiatarone Singh M. Efficacy of progressive resistance training on balance performance in older adults : a systematic review of randomized controlled trials. Sports Med. 2008;38:317-343.
ACCEPTED MANUSCRIPT 11 10. Allen NE, Sherrington C, Canning CG, Fung VS. Reduced muscle power is associated with slower walking velocity and falls in people with Parkinson's disease. Parkinsonism Relat Disord. 2010.
11. Bulow PM, Norregaard J, Danneskiold-Samsoe B, Mehlsen J. Twitch interpolation technique in testing of maximal muscle strength: influence of potentiation, force level, stimulus intensity and preload. Eur J Appl
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Physiol Occup Physiol. 1993;67:462-466.
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12. Stevens-Lapsley J, Kluger BM, Schenkman M. Quadriceps muscle weakness, activation deficits, and
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13. Kent-Braun JA, Le Blanc R. Quantitation of central activation failure during maximal voluntary contractions
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15. Housh DJ, Housh TJ, Weir JP, Weir LL, Johnson GO, Stout JR. Anthropometric estimation of thigh muscle
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16. Bampouras TM, Reeves ND, Baltzopoulos V, Maganaris CN. Muscle activation assessment: effects of
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18. Knight CA, Kamen G. Relationships between voluntary activation and motor unit firing rate during maximal voluntary contractions in young and older adults. Eur J Appl Physiol. 2008;103:625-630.
19. Kendall TL, Black CD, Elder CP, Gorgey A, Dudley GA. Determining the extent of neural activation during maximal effort. Med Sci Sports Exerc. 2006;38:1470-1475.
ACCEPTED MANUSCRIPT 12 20. de Ruiter CJ, Kooistra RD, Paalman MI, de Haan A. Initial phase of maximal voluntary and electrically stimulated knee extension torque development at different knee angles. J Appl Physiol. 2004;97:1693-1701.
21. de Ruiter CJ, Vermeulen G, Toussaint HM, de Haan A. Isometric knee-extensor torque development and jump height in volleyball players. Med Sci Sports Exerc. 2007;39:1336-1346.
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22. Suter E, Herzog W, Huber A. Extent of motor unit activation in the quadriceps muscles of healthy subjects.
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24. Hopkins WG, Marshall SW, Batterham AM, Hanin J. Progressive statistics for studies in sports medicine
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25. Paasuke M, Mottus K, Ereline J, Gapeyeva H, Taba P. Lower limb performance in older female patients
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26. Fearnley JM, Lees AJ. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain.
27. Cruickshank TM, Reyes AR, Ziman MR. A systematic review and meta-analysis of strength training in
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individuals with multiple sclerosis or Parkinson disease. Medicine (Baltimore). 2015;94:e411.
ACCEPTED MANUSCRIPT 13 Figure Legends
FIGURE 1. Participant orientation for interpolated twitch technique testing.
FIGURE 2. Maximal involuntary and voluntary rate of force development in. (A) Force signal during data collection of a control (CNTL) participant. (B) Maximal involuntary rate of force development (MIRFD) and (C)
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maximal voluntary rate of force development (MVRFD) in PD versus controls . *Different from CNTL, P < 0.05.
ACCEPTED MANUSCRIPT 14 TABLE 1. Descriptive statistics and outcome data Effect PD (n = 7)
CONTROL (n = 6)
P -value size
M = 6, W = 1
M = 4, W = 2
N/A
N/A
UPDRS (total)
19.1 (SD 5.0)
N/A
N/A
N/A
Hoehn and Yahr Staging
HY1.5, n=1; HY2, n=6
N/A
N/A
N/A
Disease Duration
7.9 (SD 5.01)
N/A
N/A
N/A
Age (yr)
65.4 (SD 7.3)
60.5 (SD 4.9)
0.189
0.84
Height (cm)
177.7 (SD 8.7)
174.6 (SD 6.8)
0.503
0.43
Weight (kg)
84.9 (SD 6.5)
81.1 (SD 14.2)
0.561
0.39
Estimated Thigh CSA (cm2)
56.3 (SD 19.7)
59.3 (SD 7.8)
0.717
0.21
Maximum Voltage (mV)
283.3 (SD 25.8)
0.549
0.30
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Sex
271.4 (SD 56.7)
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UPDRS = Unified Parkinson’s Disease Rating Scale; CSA = cross-sectional area
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Figure 1
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ACCEPTED MANUSCRIPT 17 Highlights Strength and rate of force development deficits have been reported in Parkinson disease.
The interpolated twitch technique is used to calculate a central activation ratio.
Voluntary rate of force development is reduced compared to controls.
Central activation ratio may change with disease progression and serve as an indicator of decline.
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Kelley G. Hammond, Ronald F. Pfeiffer, Mark S. LeDoux, Brian K. Schilling PII: DOI: Reference:
S0268-0033(17)30092-X doi: 10.1016/j.clinbiomech.2017.04.003 JCLB 4313
To appear in:
Clinical Biomechanics
Received date: Accepted date:
18 August 2016 10 April 2017
Please cite this article as: Kelley G. Hammond, Ronald F. Pfeiffer, Mark S. LeDoux, Brian K. Schilling , Neuromuscular rate of force development deficit in Parkinson disease. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jclb(2017), doi: 10.1016/j.clinbiomech.2017.04.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 NEUROMUSCULAR RATE OF FORCE DEVELOPMENT DEFICIT IN PARKINSON DISEASE Kelley G. Hammonda,1, Ronald F. Pfeifferb,2, Mark S. LeDouxb, Brian K. Schillinga,3 a
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The University of Memphis School of Health Studies 106 Elma Roane Fieldhouse 495 Zach Curlin St Memphis, TN 38152, USA [email protected] (corresponding author) [email protected]
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The University of Tennessee Health Science Center College of Medicine 855 Monroe Ave Suite 415 Link Building Memphis, TN 38163, USA [email protected] [email protected]
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Word Count: 220 (abstract); 2368 (main text)
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The University of Alabama at Birmingham, Department of Physical Therapy, 1720 2 nd Ave S, SHPB 360X, Birmingham, AL 35294, USA (Permanent address) 2 Oregon Health and Science University, School of Medicine, 3181 S.W. Sam Jackson Park Rd, Portland, OR 97239, USA (Present address) 3 The University of Nevada at Las Vegas, 4505 S Maryland Pkwy, BHS 329, Las Vegas, NV 89154, USA (Permanent address)
ACCEPTED MANUSCRIPT 2 ABSTRACT Background: Bradykinesia and reduced neuromuscular force exist in Parkinson disease. The interpolated twitch technique has been used to evaluate central versus peripheral manifestations of neuromuscular strength in healthy, aging, and athletic populations, as well as moderate to advanced Parkinson disease, but this
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method has not been used in mild Parkinson disease. This study aimed to evaluate quadriceps femoris rate of
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force development and quantify potential central and peripheral activation deficits in individuals with Parkinson
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disease.
Methods: Nine persons with mild PD (Hoehn & Yahr ≤2, Unified Parkinson Disease Rating Scale total score =
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mean 19.1 (SD 5.0)) and eight age-matched controls were recruited in a cross-sectional investigation. Quadriceps femoris voluntary and stimulated maximal force and rate of force development were evaluated
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using the interpolated twitch technique.
Findings: Thirteen participants satisfactorily completed the protocol. Individuals with early Parkinson disease
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(n=7) had significantly slower voluntary rate of force development (p = 0.008; d=1.97) and rate of force
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development ratio (p = 0.004; d=2.18) than controls (n=6). No significant differences were found between groups for all other variables.
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Interpretations: Persons with mild-to-moderate Parkinson disease display disparities in rate of force
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development, even without deficits in maximal force. The inability to produce force at a rate comparable to
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controls is likely a downstream effect of central dysfunction of the motor pathway in Parkinson disease.
Key Words: skeletal muscle; weakness; central activation; rate of force development
ACCEPTED MANUSCRIPT 3 Parkinson disease (PD) is a progressive neurological disorder affecting more than one million people in the United States. PD is characterized by tremor, muscle rigidity, bradykinesia, and reduced neuromuscular force production. 1, 2 Although neuropathology is widespread in the majority of post-mortem PD brains, major difficulties in motor control can be ascribed to loss of dopaminergic neurons within the substantia nigra. Moreover, bradykinesia is directly correlated with striatal dopamine deficiency. 3 A complex battery of factors
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aside from specific PD symptoms, including balance, muscle synergies and co-contraction, body weight, and
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ability to generate force, can cause difficulty in performing activities of daily living such as moving from a
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seated to standing position. 4 Although force deficits are widely accepted as an effect of PD, specific
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mechanisms for decreased neuromuscular force production have not been identified. Aging adults typically demonstrate loss of muscle mass5 and reduced voluntary neuromuscular force
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capability. 6 However, several studies have shown a severe decline in maximal neuromuscular force in PD compared with healthy, age-matched individuals. 2 In non-PD older adults, time to achieve peak force in the
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quadriceps femoris typically takes less than one second, while persons with PD and moderate bradykinesia
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can take 3-4 seconds to achieve peak force. 7, 8 Several studies report reduced rate of force development (RFD) and strength (maximal force) in persons with PD following withdrawal from dopaminergic therapy. 7, 8
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This suggests that the weakness and reduction in RFD is a direct result of the disease (dopaminergic denervation of the striatum), and at least partly central in nature. Consequently, persons with PD experience
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age-related muscle changes at a greater magnitude than their age-matched peers (as reviewed2). The
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compromised ability to rapidly produce force (reduced RFD) can be observed in the prevalence of falls in aging adults. 9 Similarly, muscle power (force x velocity) greatly affects walking velocity, and has a stronger association with falling in PD than muscle strength alone. 10 This indicates that the rate (velocity) at which force can be produced is as important, if not more important, than the maximum force of muscle contraction. The interpolated twitch technique (ITT) is an effective method of evaluating and quantifying voluntary versus involuntary muscle contraction, 11 but only recently has been used in PD. 12 By electrically stimulating a relaxed muscle, a wealth of information can be acquired, including the absolute ability of the muscle to produce force (torque) as well as RFD. Specifically, the muscle’s contractility can be examined without central input in
ACCEPTED MANUSCRIPT 4 two important ways. First, involuntary RFD (iRFD) can be compared with vRFD to evaluate RFD proficiency (RFD ratio = vRFD/ iRFD). The RFD ratio is a novel way to identify a central mechanism of dysfunction in muscle performance. Based on the assumption that iRFD establishes the maximal mechanical capability of a muscle to rapidly produce force, a ratio equal to one would indicate that voluntary effort in a maximal contraction (with instruction to contract “as fast and hard as possible”) elicits central descending drive equal to
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the electrical stimulation applied. A ratio <1 would suggest that central input during voluntary effort is not
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evoking adequate neural drive to achieve maximal RFD. Additionally, an evoked twitch can be added to a
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maximal voluntary contraction, and the difference in force output can provide a quantitative value of central activation. One method of calculating this is the central activation ratio (CAR = maximal voluntary
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contraction/(maximal voluntary contraction + stimulated force)). 13 Similar to the RFD ratio, the CAR can
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identify central deficits reflected in decreased maximal voluntary force production. Although deficits in strength are reasonably accepted as result of PD progression, the current literature
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is equivocal regarding measures of strength in various stages of PD. One investigation of individuals with PD
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who exhibit prominent motor impairment (Unified Parkinson’s Disease Rating Scale motor score ≥ 31.7; UPDRS) displayed decreased leg muscle torque and central activation (CAR) compared with those with less
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severe motor impairment (UPDRS <31.7) and non-PD controls, 12 and another found no differences in maximal voluntary strength or leg power in those with PD (UPDRS motor score mean 35.8 (SD 2.9)) compared to age-
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matched controls. 14 The results of these studies indicate that further examination is warranted on voluntary vs.
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involuntary neuromuscular performance in persons with PD. The first aim of this study was to quantify central and peripheral neuromuscular force and RFD deficits in persons with early stages of PD. Secondly, the study sought to examine the usability of ITT for examining central versus peripheral mechanisms of neuromuscular dysfunction in PD. METHODS Participants
ACCEPTED MANUSCRIPT 5 Seventeen participants (M = 11, F = 6) were recruited to participate in the study, and the size of the sample was based on the magnitude of effects from similar studies in persons with PD. The nine persons in the PD group (M = 6, F = 3) were diagnosed with idiopathic PD by a neurologist with subspeciality expertise in movement disorders. Individuals with orthostatic hypotension, dementia (Mini-Mental State Examination Scores <24), or other significant co-morbidities (i.e., stroke, severe degenerative osteoarthritis) were excluded.
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Individuals with other causes of Parkinsonism, such as progressive supranuclear palsy, vascular
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Parkinsonism, and multiple system atrophy were also excluded from the study. A board-certified neurologist
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examined each PD participant and performed the UPDRS within two months of testing. Eight neurologically healthy, similarly-aged individuals (M=5, F=3) were recruited from the local
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university faculty and staff as a control group. These participants were of good general health based on self-
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report, and were free of neurological impairment. All procedures were approved by the local Institutional Review Board. Participants completed a health history, drug usage, and fitness activity questionnaire and
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provided written informed consent prior to data collection. Height, weight, and thigh skinfold and circumference were measured (right leg). Skinfold and circumference were used to estimate quadriceps femoris cross-
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sectional area according to the equation by Housh et al. ([2.52 x mid-thigh circumference in cm] – [1.25 x
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anterior thigh skinfold in mm] – 45.13). 15 Cross-sectional area was measured as a possible variable to adjust quadriceps force in the statistical analysis, as larger muscles typically produce more force. All testing was done
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with PD participants in an optimally medicated state (carbidopa/levodopa, n=4; dopamine agonists, n=4; MAO-
ITT Testing
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B inhibitors, n=2), which was determined by the participants as their “on state” earliest in the day.
Participants were seated in a customized chair that provided back support and placed in an upright position (Fig. 1). Seatbelt restraints were placed across the participant’s trunk and lap to minimize movement of the torso. Rubber stimulating electrodes (7.5 x 13 cm) were secured with tape over the femoral triangle (cathode) and just proximal to the superior border of the patella (anode). Stimulation was supplied by an external stimulator (Digitimer® DS7AH, Hertfordshire, United Kingdom). The participant’s right ankle was inserted into a padded sleeve and cuff, which was attached via steel cable to the load cell (Transducer
ACCEPTED MANUSCRIPT 6 Techniques® MLP-1K load cell, Temecula, CA, USA) with enough tension to eliminate slack. This fixed the knee at 90°flexion and hips at 100° extension. Participants were instructed to cross their arms over their chest during testing. For the first trial, they were instructed to relax prior to being given a 200µs16 triplet pulse of 50mA at 400V17 to the quadriceps femoris. 18 The amperage was then increased in 50mA increments for subsequent trials16 until the peak
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stimulated force reached a plateau (less than 5% change19). The plateau typically occurred between 200-
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400mA. 20 An octet pulse was then administered at the previously determined maximal parameters to identify maximal iRFD. 21 Participants were given up to one minute to rest between trials.18, 19
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Participants were instructed to contract the knee extensors of their restrained leg maximally in order to practice maximal voluntary contractions (MVC). Two MVCs were then performed with one-minute rest between
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trials, or when the individual being tested was ready to continue. Participants then performed a trial where the
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predetermined triplet pulse (same maximal parameters) was applied after voluntary force plateaued. 22 The MVC with stimulation trial was repeated23 after a one-minute break. The higher force of two trials was used for
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analysis. The reliability of this protocol has been established. 11
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The force signal was acquired via analog/digital conversion (Measurement Computing, DAS1200JR, Norton, MA, USA), and Datapac5 software was used for application of pulses, data acquisition, and
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processing. The force signal was filtered through a fourth-order Butterworth low-pass filter with a cutoff
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frequency of 30Hz. The RFD during interpolated twitch (iRFD) and maximal voluntary contraction (vRFD) were calculated as the maximum velocity of the signal (N/s) during the rise phase. Start of the action was defined as the point at which the first derivative of the filtered force signal crossed zero for the last time. The RFD ratio was calculated as the vRFD divided by iRFD, and the CAR was determined using the voluntary and interpolated (involuntary) twitch force data as indicated previously. Statistical Analysis Independent one-sample t-tests (P <0.05) were used to compare MVC, interpolated isometric twitch force, vRFD, iRFD, CAR, and RFD ratio between the group with PD and the control group. Effect sizes (d)
ACCEPTED MANUSCRIPT 7 were calculated to determine the magnitude of differences between groups using the pooled SD adjusted for sample size. Data are reported as mean (SD). RESULTS Seventeen participants volunteered for testing. Two participants from the control group (M=1, F=1) did
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not finish the protocol due to discomfort. Data from one male PD participant and one male control participant
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were not useable due to impact artifact in the force channel that was not detected at the time of testing.
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Estimated cross-sectional area was not associated with force in our sample, thus we report the non-adjusted forces only. In the final analysis (PD=7, control=6; Table 1), we found that unimpaired individuals had
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significantly higher vRFD (P < 0.05, d=1.97) and larger RFD ratio (P < 0.05, d=2.18) than the PD participants (Fig. 2). No significant differences were found (p> 0.634, d< 0.47) between PD and controls for all other
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notable variables, including iRFD, interpolated isometric twitch force, voluntary force, and CAR. The η2 values
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indicated that grouping was responsible for ~49% of the variance in vRFD.
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DISCUSSION
This study is only the second investigation using ITT to determine involuntary neuromuscular activation
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and CAR in PD. Despite an absence of maximal force differences, the results demonstrate large deficits in
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vRFD and the RFD ratio of the quadriceps femoris in PD compared with healthy, similarly-aged controls. No meaningful difference existed in iRFD between groups, indicating that the mechanism responsible for the
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deficit in vRFD, even in mild to moderate PD, likely is central in nature. Since the effect sizes were all less than 0.47, it is unlikely that the differences were undetectable only due to our small sample size. Other investigations of neuromuscular force measures have reported similar findings of reduced vRFD in PD, 7, 8, 25 but the present study is the first to examine iRFD using ITT. Our data provide practical insight to the effects of PD neuromuscular performance. For persons with mild motor symptoms of PD, such as the participants in this study (UPDRS = mean 19.1 (5.0)), the mechanical ability of the quadriceps femoris remains intact (no difference in iRFD between groups). However, a large difference in RFD exists when maximal contraction is performed voluntarily (vRFD). At least 50% of dopaminergic neurons in the substantia nigra are compromised
ACCEPTED MANUSCRIPT 8 prior to the appearance of motor symptoms, 26 and this extensive cell death may affect RFD prior to decline in strength or manifestation of other symptoms. This hypothesis may provide awareness of the effects of PD in the early stages of diagnosis, when great damage has occurred in the brain, but obvious signs are minimal. The PD group’s CAR scores and peak force measures were similar to the control group in the present study, even when adjusted for quadriceps femoris cross-sectional area. Full activation of the quadriceps
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femoris has been reported in unimpaired individuals, 21 so our finding of CAR outcomes near 1.0 in controls
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was not unfounded. Because strength deficits were expected in this investigation, CARs for PD participants were also expected to be lower than controls. Absence of differences in maximal voluntary force translated to
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no differences in CAR. The lack of differences in maximal strength in our investigation conflicts with several earlier studies reporting decreased strength in individuals with PD compared with controls (as reviewed 2, 27),
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though recently no differences in maximal voluntary strength or leg power has been reported. 14 Our hypothesis included strength deficits in the PD group, but the absence of differences between groups in our study can
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likely be explained by the nominal motor impairment (UPDRS = mean 15.7 (SD 5.0); Hoehn & Yahr = mean
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1.9 (SD 0.20)) of our PD participants and minimal presence of symptoms in these individuals when optimally
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medicated (as during testing).
Neuromuscular deficits in persons with PD are a potential target for exercise interventions. Individuals
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who are early in their disease course may be able to slow neurodegeneration and symptom progression by implementing a moderate to high-load resistance training regimen, but further investigation is necessary to
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examine the effects of interventions early in treatment. Robust physiological adaptations in the skeletal muscle of persons with moderate PD (UPDRS motor score mean 35.8 (SD 2.9)) were accompanied by gains in functional performance following 16 weeks of a high-intensity exercise training intervention. 14 Kelly et al. (2013) demonstrated that a high-intensity training paradigm elicited post-training improvements in the PD group beyond the performance of untrained age-matched controls; the substantial gains by individuals with more advanced PD provides exciting grounds for further research into the effects of high-intensity exercise training on individuals with mild PD, such as those in the present study. Additionally, voluntary and involuntary
ACCEPTED MANUSCRIPT 9 performance testing similar to the protocol herein may be able to partial out central vs. peripheral gains in performance. CONCLUSION We demonstrated that ITT can be used to assess central activation and RFD in PD and older adults,
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ITT for initial assessment and to examine exercise-training responses in PD.
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and provided practical insight into early motor deficits in PD. Future investigations may be well-served to utilize
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ACKNOWLEDGEMENTS
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The authors would like to thank Susan Silverman for her assistance in manuscript preparation.
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Funding: This work was supported by the National Strength and Conditioning Association. MSL was supported, in part, by the Dorothy/Daniel Gerwin Parkinson’s Research Fund.
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Conflicts of interest: none
ACCEPTED MANUSCRIPT 10 REFERENCES
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ACCEPTED MANUSCRIPT 11 10. Allen NE, Sherrington C, Canning CG, Fung VS. Reduced muscle power is associated with slower walking velocity and falls in people with Parkinson's disease. Parkinsonism Relat Disord. 2010.
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15. Housh DJ, Housh TJ, Weir JP, Weir LL, Johnson GO, Stout JR. Anthropometric estimation of thigh muscle
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19. Kendall TL, Black CD, Elder CP, Gorgey A, Dudley GA. Determining the extent of neural activation during maximal effort. Med Sci Sports Exerc. 2006;38:1470-1475.
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ACCEPTED MANUSCRIPT 13 Figure Legends
FIGURE 1. Participant orientation for interpolated twitch technique testing.
FIGURE 2. Maximal involuntary and voluntary rate of force development in. (A) Force signal during data collection of a control (CNTL) participant. (B) Maximal involuntary rate of force development (MIRFD) and (C)
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maximal voluntary rate of force development (MVRFD) in PD versus controls . *Different from CNTL, P < 0.05.
ACCEPTED MANUSCRIPT 14 TABLE 1. Descriptive statistics and outcome data Effect PD (n = 7)
CONTROL (n = 6)
P -value size
M = 6, W = 1
M = 4, W = 2
N/A
N/A
UPDRS (total)
19.1 (SD 5.0)
N/A
N/A
N/A
Hoehn and Yahr Staging
HY1.5, n=1; HY2, n=6
N/A
N/A
N/A
Disease Duration
7.9 (SD 5.01)
N/A
N/A
N/A
Age (yr)
65.4 (SD 7.3)
60.5 (SD 4.9)
0.189
0.84
Height (cm)
177.7 (SD 8.7)
174.6 (SD 6.8)
0.503
0.43
Weight (kg)
84.9 (SD 6.5)
81.1 (SD 14.2)
0.561
0.39
Estimated Thigh CSA (cm2)
56.3 (SD 19.7)
59.3 (SD 7.8)
0.717
0.21
Maximum Voltage (mV)
283.3 (SD 25.8)
0.549
0.30
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Sex
271.4 (SD 56.7)
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UPDRS = Unified Parkinson’s Disease Rating Scale; CSA = cross-sectional area
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Figure 1
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ACCEPTED MANUSCRIPT 17 Highlights Strength and rate of force development deficits have been reported in Parkinson disease.
The interpolated twitch technique is used to calculate a central activation ratio.
Voluntary rate of force development is reduced compared to controls.
Central activation ratio may change with disease progression and serve as an indicator of decline.
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