HHS Public Access

Author manuscript
Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
Author Manuscript

Published in final edited form as:

Arch Phys Med Rehabil. 2021 May ; 102(5): 865–873. doi:10.1016/j.apmr.2020.11.002.

Impact of different forms of activity-based recovery training on

bladder, bowel and sexual function following spinal cord injury
Charles H. Hubscher, Ph.D.1,2, Jennifer Wyles, M.Sc.2,3, Anthony Gallahar, B.Sc.2,3, Kristen
Johnson, R.N., B.S.N.2,3, Andrea Willhite, B.A.2,3, Susan Harkema, Ph.D.2,3, April N. Herrity,
Ph.D.2,3
1Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY;
Author Manuscript

2Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY;
3Department of Neurological Surgery, University of Louisville, Louisville, KY

Abstract
Objective: To investigate whether the urogenital and bowel functional gains previously
demonstrated post-locomotor step training after chronic spinal cord injury could have been derived
due to weight-bearing alone or from exercise in general.

Study Design: Prospective cohort study; pilot trial with small sample size.

Setting: Urogenital and Bowel Scientific Core Facility at a Rehabilitation Institute and Spinal
Cord Injury Research Center in the United States.
Author Manuscript

Participants: Twenty-two males and females with spinal cord injury (ASIA Impairment Scale
grades of A-D) participated in this study.

Interventions: Approximately eighty daily one-hour sessions of either stand training or non-
weight bearing arm crank ergometry. Comparisons are made with previously published locomotor
training data (step; N=7).

Main Outcome Measures: Assessments at both pre-and post-training time-points included

cystometry for bladder function and International Data Set Questionnaires for bowel and sexual
functions.

Results: Cystometry measurements revealed a significant decrease in bladder pressure and

limited improvement in compliance with non-weight bearing exercise but not with standing.
Author Manuscript

Although International Data Set questionnaires revealed profound bowel dysfunction and marked

Corresponding author: Charles H. Hubscher, Ph.D., 511 South Floyd Street, MDR Building, Room 111, Louisville, KY 40202
chhubs01@louisville.edu; (502)852-3058.
Publisher's Disclaimer: 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.
No conflicts of interest.
Trial Registration: ClinicalTrials.gov ID: NCT03036527
Suppliers
 Hubscher et al. Page 2

deficits in sexual function pre-training, no differences were identified post-stand or after non-
Author Manuscript

weight bearing exercise.

Conclusion: These pilot trial results suggest that although stand/weight-bearing alone does not
benefit pelvic organ functions after spinal cord injury, exercise in general may contribute at least
partially to the lowering of bladder pressure and the increase in compliance that was seen
previously with locomotor training, potentially through metabolic, humoral and/or cardiovascular
mechanisms. Thus, in order to maximize activity-based recovery training benefits for storage and
emptying related functions, an appropriate level of sensory input to the spinal cord neural
circuitries controlling bladder and bowel requires task-specific stepping.

Keywords
Locomotor Training; Arm Crank; Bladder; Bowel; Sexual Function; SCI
Author Manuscript

Urogenital and bowel complications affect daily living, well-being and quality of life after
SCI1–5, with bladder and bowel related deficits in both storage and emptying, and sexual
dysfunctions related to arousal, desire, satisfaction and orgasm. Management strategies
target maintenance but not recovery of function, leaving a tremendous need for a more
comprehensive targeted non-invasive rehabilitation type of approach and intervention6.

Through activity-based rehabilitation with locomotor training (LT) after spinal cord injury
(SCI), neuromuscular activation below the level of lesion is an effective intervention for
motor deficits with many known systemic benefits (cardiovascular and respiratory function,
strength, and mobility)7–12. Motor patterns, limb loading and stepping rate provide sensory
information to spinal cord inter-neuronal networks to improve locomotion13–17. In both our
pre-clinical SCI animal model and human clinical studies involving one hour per day task-
Author Manuscript

specific LT, we demonstrated with cystometry (a recommended outcome measure18, 19)

significant improvements in bladder capacity, bladder pressure/compliance, detrusor
contraction time, and voiding efficiency post-training relative to baseline and reduced
polyuria/nocturia20–22. In addition, time for defecation and sexual desire were positively
impacted20. Although these LT benefits could be due to sensory inputs provided to the
lumbosacral cord, other possibilities include weight-bearing alone, as added pressure is
exerted on the pelvis when in the upright position. Also, exercise in general may contribute
to LT benefits through potential changes in blood flow to pelvic/visceral organs and/or
indirect humoral/metabolic effects23.

The goal of the current study was to narrow potential contributors toward the LT benefits on
urogenital/bowel to guide future mechanistic studies and identify the most impactful
therapeutic approaches. Note that in our pre-clinical SCI rodent model, significant
Author Manuscript

improvements in some but not all aspects of urinary tract function were found in a non-
weight-bearing general exercise group (forelimb-only stepping)21.

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
 Hubscher et al. Page 3

Methods
Author Manuscript

Study Research Participants

Twenty-two individuals with chronic SCI, who were either enrolled in a stand training study
between 2015 and 2018 (n=12) or were enrolled for upper extremity training (arm crank
ergometry) for the current study (n=10) during the same time-frame, were directly recruited
to participate in this pilot trial. A summary of their characteristics is provided in Table 1.
Inclusion criteria include: 1) minimum age of 18 years; 2) non-progressive supra-sacral SCI;
3) urogenital and bowel dysfunctions due to SCI; 4) stable medical condition without
cardiopulmonary disease or dysautonomia that would contraindicate training; 5) no painful
musculoskeletal dysfunction, unhealed fracture, contracture, pressure injury or urinary tract
infection that might interfere with training; 6) no untreated psychiatric disorders or ongoing
drug abuse; 7) clear indications that the period of spinal shock is concluded determined by
Author Manuscript

presence of muscle tone, deep tendon reflexes or muscle spasms and discharged from
standard inpatient rehabilitation.

All procedures were conducted in compliance with NIH guidelines. Study protocols were
reviewed and approved by the local Institutional Review Board Committee. An informed
consent was signed by all participants.

Clinical Evaluations
To ensure safety, a physical examination was performed by a clinician for medical clearance.
Also, two clinicians independently performed the International Standards for Neurological
Classification of Spinal Cord Injury24, 25. Injuries were classified prior to the start of the
study using the American Spinal Injury Association (ASIA) Impairment Scale (AIS).
Author Manuscript

Stand Training
As part of two other research studies, participants received approximately 80 daily sessions
of standing in a body-weight support system (BWSS; 3 of 12 participants) or a custom
designed frame comprised of horizontal bars anterior and lateral to the participant for upper
extremity support. Two of the individuals that started stand training in the BWSS were
progressed to the frame to increase weight-bearing on their legs and provide more
challenging balance and independent standing goals. Balance assistance was provided as
needed as previously described20 including manual facilitation by a trainer or with elastic
cords. For better perception of body position, mirrors were placed in front of and lateral to
the participant, who were encouraged to maintain standing for 60 minutes with the least
amount of manual facilitation. Seated rest periods occurred if requested. Note that each of
the two primary stand studies included individuals randomly assigned to two training
Author Manuscript

intervention groups: Stand Retraining (SRT-only) and SRT with neuromuscular electrical
stimulation (NMES). NMES was applied per established protocols26 via bifurcated leads
and self-adhesive electrodes placed bilaterally on multiple leg muscles. One of the studies
also included daily administration of testosterone replacement therapy (TRT), AndroGel®
1.62% (40.5 to 80 mg per day), or placebo to the shoulders and upper arms during the 20-
week intervention period.

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
 Hubscher et al. Page 4

Upper Extremity Training

Author Manuscript

Non-weight bearing arm crank was conducted using a Scientific Solutions for Fitness unita
with an adjustable wheelchair platform for proper posture and desired angle for training.
Each participant self-determined a comfortable amount of revolutions per minute and
resistance adjusted accordingly (200 levels of output resistances adjustable in 0.1
increments). Participants were seated in their wheelchair and attempted to propel the arm
crank at similar speeds to that of the LT intervention20. For participants with limited
dexterity, padded general purpose gripping aides were used. One hour monitored arm crank
sessions were conducted 4–5 times per week. Resistance levels were gradually increased
while cycling based on endurance and proficiency throughout the course of the 80 training
sessions. Short rest and water breaks were implemented based on the participants’ tolerance
and fatigue. Sessions were concluded when the participant became fatigued (often in the
beginning as participants built up endurance to achieve 60 minutes), if session continuation
Author Manuscript

compromised participants’ health and safety (never occurred in the current study), or an hour
of arm cycling was achieved.

Urodynamic Study (UDS)

Assessments were performed by the same registered nurse at pre-/post-training time-points
using methodology compliant with recommendations of the International Continence
Society (ICS)27–29. For consistency, all research participants were asked to refrain from
taking any bladder medication at least 24 hours prior to UDS testing. Cystometry was
performed as previously described20 using the Aquarius LT Urodynamic systemb. The
bladder was emptied with a 12 French (Fr) straight catheter and a urine sample tested to
confirm absence of bacterial infection using a urinary reagent dipstick testc. Filling
cystometry via a 7 Fr single sensor dual channel catheterd was conducted at a fixed rate of
Author Manuscript

20 mL/min with sterile room temperature water. Fill volume and bladder pressure were
recorded, as was abdominal pressure via a rectal sensor cathetere and pelvic floor
electromyography (EMG) with surface patch electrodesf. Blood pressure (BP) and heart rate
(HR) were also recorded during UDS every minute using an automated
sphygmomanometerg.

Participants were instructed to communicate bladder sensations (sensation, desire, urgency)

and any symptoms of autonomic dysreflexia (AD; headache and/or chills, for example).
Filling was ceased upon 1) spontaneous urine leakage, 2) infused volume ≥ 600 mL, 3)
sustained intravesical pressure ≥ 40 cmH2O or 4) AD as evidenced by a sustained systolic
blood pressure recording ≥ 20 mm Hg from baseline and/or intolerable symptoms. At the
end of filling, the bladder was drained with a catheter for measurement of residual volume.
If AD persisted beyond emptying, established guidelines were followed30. No research
Author Manuscript

aInclusive Fitness PRO1 Upper Body Model from SCIFIT (Scientific Solutions for Fitness), Tulsa, OK, USA.
bAquarius LT Urodynamic Investigation system, Laborie Medical Technologies ULC, Mississauga, ON, Canada.
cMultistix PRO 10LS, Siemans Healthcare Diagnostics Inc., Tarrytown, NY, USA.
d7 Fr, T-DOC® Air-Charged™ catheter, Laborie Medical Technologies Corp, Williston, VT, USA.
eT-DOC®−7FA Air-Charged™ abdominal sensor catheter, Laborie Medical Technologies Corp, Williston, VT, USA.
fNeotrode II surface patch EMG electrodes, Laborie Medical Technologies Corp, Williston, VT, USA.
gDinamapV100, GE Medical Systems, Fairfield, CT, USA.

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
 Hubscher et al. Page 5

participants required the use of an antihypertensive agent to manage their AD post-UDS

Author Manuscript

assessment.

Patient Reported Outcomes: Questionnaires

At the time of UDS, participants were asked to estimate the average number of daily
catheterizations during the past week (waking and sleep hours) per The International SCI
Data Set for lower urinary tract function31. The International SCI Data Set for bowel
function32, 33 was also administered at pre-/post-training time-points. Numeric values
associated with each question contribute to an overall Neurogenic Bowel Dysfunction
(NBD) score, with ranges clinically interpreted as either very minor (1–6), minor (7–9),
moderate (10–13) or severe (14 or more).

Either the 15-item International Index of Erectile Function (IIEF)34, 35 or the 19-item
Female Sexual Function Index (FSFI)36, 37 were also administered at pre-/post-training time-
Author Manuscript

points. The IIEF, which includes five domains, yields an overall IIEF score range of 5.0–
75.0 with a total score of 61.8 indicative of normal35. The FSFI is divided into six domains
with a total scoring range of 2.0–36.0. An overall score below the threshold value of 26 is
considered at risk for sexual dysfunction38.

Data Analysis and Statistics

Acquired volume and pressure data during filling cystometry at pre-/post-training time-
points were used to calculate bladder capacity (volume of leaked or voided water plus
residual), voiding efficiency (VE; spontaneous leak or void volume voided / (volume voided
+ residual) × 100), and compliance (change in volume [ΔV] / change in detrusor pressure
[ΔPdet])39 per our published protocol20. Compliance is considered low below 20 cm/H2O40,
although this threshold value is still a subject of debate within the neurourology field.
Author Manuscript

Maximum detrusor pressure (MDP) was identified as the highest intravesical pressure just
prior to the void in the cystometrogram.

All statistical analyses were performed using SigmaStat v3.5 (Systat Software). The
Student’s paired t-test was used to analyze pre/post training differences. One-way analysis of
variance was used to compare data between the different training groups. Pairwise multiple
comparison procedure (Holm-Sidak method) was used for post-hoc analyses. Significance
value was at p ≤ 0.05. Standard errors of the mean are reported.

Results
Clinical Characteristics
Author Manuscript

A summary of the twenty-two (91% male) participant attributes is provided in Table 1.

Characteristics include an average age of 32.6 years with an average time since injury of 5.3
years. Clean intermittent catheterization (CIC) was performed by 81.2% of participants
(including one via Monti procedure41). The four participants having indwelling suprapubic
(SP) catheters were all part of the stand group and thus are not included in the comparative
analyses between groups. The average pre-training baseline capacity value for the SP
individuals was 141.8 ± 47.3 ml (n=4) versus 540.2 ± 65.5 ml (n=18) for those using CIC

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
 Hubscher et al. Page 6

(significant difference; p=0.011). Individuals with indwelling catheters (about 1/3 of the SCI
population42) tend to have low bladder capacities due to continuous drainage and higher
Author Manuscript

incidences of bacteriuria42.

The baseline capacities for the stand group using CIC ranged from 395 ml to 950 ml,
reflecting over-distended bladders (>600 ml) for a subset of participants. Note that some
capacities exceeded the maximum 600 ml volume infused, which is likely due to urine
production during the fill cycle (individual differences in diuresis and variations based upon
intake). A comparison between groups revealed significantly higher capacities for the stand
group at baseline (Table 2), necessitating the presentation of data both as raw values as well
as % change pre-/post-training. Note that the inclusion/exclusion criteria for the studies that
recruited these individuals (arm crank and stand) were similar (inclusion criteria include
“bladder dysfunction” with no further a priori criteria).
Author Manuscript

For upper extremity ergometry training, resistance values averaged over the 80 sessions were
6.9 ± 1.6. For the last 20 sessions, the resistances levels were significantly higher (8.3 ± 1.6;
significant, p=0.003), indicating a progression to more vigorous levels of activity over time.
One of the 10 upper extremity group participants were withdrawn from the study prior to
completion due to non-compliance.

Lower Urinary Tract Assessments

UDS data for the stand and arm crank groups (those using CIC, n=17) is provided in Figure
1. Our previous LT data20 for the 7 of 8 participants using CIC is included for comparison.
There were no significant urologic benefits with weight-bearing alone (stand) regardless of
emptying method (SP stand group values [n=4] were 141.8 ± 47.3 ml versus 118.5 ± 20.6 ml
pre-/post-training for capacity and 50.8 ± 13.6 cmH2O versus 47.0 ± 10.8 cmH2O pre-/post-
Author Manuscript

training for bladder pressure; p>0.05) or additional treatments (see Table 1). There was a
slight overall significant decrease in capacity post-stand training. There were no significant
differences between those using the stand frame (n=9) versus BWSS (n=3).

For the arm crank group, a significant improvement was found for bladder pressure
(reduction; Figure 1) and compliance (increase; see Table 2), but not bladder capacity or
voiding efficiency, which differs from previous LT data where benefits were found for all
parameters. Of clinical relevance is that while most of the upper extremity training group
was below the 20 ml/cmH2O threshold at baseline, indicative of poor compliance, several
participants had compliances values shift this threshold post-training (Table 2), with an
average group increase of 6.6 ± 2.5 ml/cmH2O.

No difference was found pre-/post-training for the average number of daily catheterizations
Author Manuscript

(during waking hours, 4.75 ± 0.53 / 5.0 ± 0.19 for the stand group and 4.89 ± 0.82 / 4.56 ±
0.80 for the upper extremity group). No changes were found during sleep hours, with 70.6%
reporting the need to awaken once or twice a night. The prevalence of nocturia in this
sample group increases to 88.2% when those who report restricting fluid intake prior to
bedtime are included.

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
 Hubscher et al. Page 7

Patient Reported Outcomes for Bowel and Sexual Functions:

Author Manuscript

The overall NBD score did not change pre-/post-training for any of the three training groups
examined. A summary of the combined score distribution from the data collected at baseline
(N of 29 includes the data collected from the LT group of 7) is provided in Figure 2A. The
results indicate that most of the scores fall within the ranges clinically interpreted as
moderate to severe levels of dysfunction. Although we have previously found a significant
decrease in time required for defecation after LT20, no significant pre-/post-training
differences (p>0.05) for either stand or arm crank were found (Figure 2B).

The IIEF (N of 24 males includes data from LT group20) data reveal no overall significant
differences pre-/post-training. The mean overall IIEF score was 32.6 pre-training and 26.2
post-training (not significant; p>0.05). The domain of sexual desire, shown to significantly
improve after LT20, was not significantly different for either the stand or upper extremity
Author Manuscript

groups. A summary of the combined score distribution from the baseline data across each
domain is presented in Figure 3A. The distribution of overall scores (Figure 3B) reveals
many with moderate to severe levels of dysfunction. For the five females that completed the
FSFI, the mean baseline score was 8.32 ± 4.3 (15.76 ± 4.1 post-training; not significant
p>0.05). All scores were within the range for classification as sexual dysfunction (i.e., total
scores below 26.0).

Discussion
A review of 82 studies involving some form of activity-based recovery training post-SCI
provided strong evidence for the positive benefits of exercise, performed 2–3 times per week
at moderate-to-vigorous intensity, for physical activity and muscular strength43. Our novel
studies have focused on the potential benefits of activity-based recovery upon various pelvic
Author Manuscript

visceral organ systems. UDS performed pre-/post-training in the current study revealed a
significant decrease in bladder pressure as well as increased compliance for some of the
participants receiving non-weight bearing exercise, but no benefits for stand training.
Although questionnaires revealed profound bowel dysfunction and marked deficits in sexual
function pre-training, no differences were identified post-stand or after non-weight bearing
exercise. The current findings differ from our previous LT findings20 which significantly
benefited 1) bladder capacity and voiding efficiency in addition to pressure and compliance
and 2) time required for defecation and sexual desire ratings.

Elevated intravesical pressure during storage above 10 cmH2O and detrusor leak point
pressures above 40 cmH2O during emptying can cause vesico-ureteral reflux and thus are
risk factors for damage to the upper urinary tract, including hydronephrosis, which
Author Manuscript

ultimately could lead to renal failure44–46. Thus, a reduction in elevated bladder pressure
with upper extremity training would be beneficial to the SCI population and can be done at
home. The unknown mechanisms involved are likely multifactorial. The finding that both LT
and upper extremity non-weight bearing exercise affected bladder pressure and compliance
in some participants supports the involvement of non-spinal mechanisms. Previous arm
crank studies after chronic SCI, for example, have shown a reduction in plasma levels of
inflammatory cytokines (TNF-α and IL-6) and leptin47, lipid and protein oxidation48 and
plasminogen activator inhibitor 1, as well as biometric measures, including systolic blood

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
 Hubscher et al. Page 8

pressure, peak oxygen uptake, body mass and waist circumference49. Note that spinal
Author Manuscript

mechanisms may still be a contributing factor, as residual intact long propriospinal inter-
limb enlargement pathways that mediate coordination for locomotor function could induce
adaptive changes to neural networks within the lumbosacral cord, including those
controlling other systems such as the bladder. Some facilitation of lower extremity muscles
has been shown during walking with reciprocal arm swing versus walking while holding
onto parallel bars50, 51.

The finding that weight bearing with standing and exercise in general fail to explain the
bladder storage/emptying improvements previously shown with LT20 supports a spinal
mechanism, whereby sensory inputs derived from stepping activate the lumbosacral
networks involved. Multiple human and large/small animal studies have documented vesico-
somatic interactions of lower limb musculature with the bladder and its sphincter52–58
whereby flexor and extensor reflexes can be modulated by the state of bladder filling and
Author Manuscript

voiding in both normal individuals and those with CNS damage.

Although we previously found a significant decrease in time needed for defecation with LT,
a lack of effect with either stand training or general exercise also likely relates to underlying
mechanisms involving vesico-somatic interactions within lumbosacral networks. Note that
pre-clinical studies indicate a high degree of viscero-somatic convergence in the lumbosacral
cord that includes the distal colon, rectum and somatic territories supplying the feet and
legs59. Further mechanistic insights into more specific pathophysiologic features of
defecation that could have benefited from LT will require use of more physiological
outcome measures such as anorectal manometry60, 61. Note that the NBD questionnaires
total score did not reveal any significant changes in overall function for any of the three
training interventions. The NBD questionnaire is a valid measure with good test/retest and
Author Manuscript

inter-rater reliability and validity for evaluating symptoms and management19. Several
clinical trials impacting symptoms and/or management detected significant improvements
based upon NBD scoring (trials involving ether trans-anal irrigation or sacral anterior root
stimulation62–64).

No improvements were detected for male/female sexual function following either stand
training or general arm crank exercise, including the sexual desire domain which was found
to improve with LT20. These questionnaires, validated as good general screening tools, are
not specifically designed for the SCI population. Use as an endpoint in clinical trials has not
to our knowledge been validated. Future therapeutic approach studies, including those
involving rehabilitation, should incorporate more physiological measures such as blood
flow65, 66.
Author Manuscript

Study Limitations
Limitations include the small sample size and potential lack of sensitivity of bowel and
sexual function questionnaires to detect potential physiological changes in colonic and rectal
activity and pressure, firmness of erection, or vaginal blood flow that could be beneficial to
pelvic organ health and function.

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
 Hubscher et al. Page 9

Conclusions
Author Manuscript

These pilot trial results suggest that although stand/weight-bearing alone does not benefit
pelvic organ functions after SCI, exercise in general may contribute at least partially to the
lowering of bladder pressure and the increase in compliance that is seen with LT20,
potentially through metabolic, humoral and/or cardiovascular mechanisms. However, an
appropriate level of sensory input to the spinal cord neural circuitries controlling bladder and
bowel requires task-specific stepping in order to maximize activity-based recovery training
benefits for storage and emptying related functions.

Acknowledgements:
We would like to thank the research volunteers and advocates for their valuable contributions to this study. The
authors also thank Dr. Ahmad Mohamed and Carolyn Williams, A.P.R.N., for urological support and Dr. Steven
Kirshblum for his input and edits. Supported by the NICHHD (R01HD080205), the Leona M. and Harry B.
Author Manuscript

Helmsley Charitable Trust, and the Christopher & Dana Reeve Foundation.

Abbreviations
AD Autonomic Dysreflexia

AIS ASIA Impairment Scale

ASIA American Spinal Injury Association

BP Blood Pressure

BWSS Body-weight support system

CIC Clean Intermittent Catheterization

Author Manuscript

EMG Electromyography

Fr French

FSFI Female Sexual Function Index

HR Heart Rate

ICS International Continence Society

IIEF International Index of Erectile Function

LT Locomotor Training
Author Manuscript

MDP Maximum detrusor pressure

NBD Neurogenic Bowel Dysfunction

NMES Neuromuscular Electrical Stimulation

SCI Spinal Cord Injury

SP Suprapubic Catheter

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
 Hubscher et al. Page 10

SRT Stand Retraining

Author Manuscript

UDS Urodynamic Study

Upper Ext Upper Extremity

References
1. Anderson KD. Targeting recovery: priorities of the spinal cord-injured population. J Neurotrauma
2004;21(10):1371–83. [PubMed: 15672628]
2. Anderson KD, Borisoff JF, Johnson RD, Stiens SA, Elliott SL. The impact of spinal cord injury on
sexual function: concerns of the general population. Spinal Cord 2007;45(5):328–37. [PubMed:
17033620]
3. Anderson KD, Borisoff JF, Johnson RD, Stiens SA, Elliott SL. Long-term effects of spinal cord
injury on sexual function in men: implications for neuroplasticity. Spinal Cord 2007;45(5):338–48.
[PubMed: 17016492]
Author Manuscript

4. Ditunno PL, Patrick M, Stineman M, Ditunno JF. Who wants to walk? Preferences for recovery after
SCI: a longitudinal and cross-sectional study. Spinal Cord 2008;46(7):500–6. [PubMed: 18209742]
5. Glickman S, Kamm MA. Bowel dysfunction in spinal-cord-injury patients. Lancet
1996;347(9016):1651–3. [PubMed: 8642958]
6. Wheeler TL, de Groat W, Eisner K, Emmanuel A, French J, Grill W et al. Translating promising
strategies for bowel and bladder management in spinal cord injury. Exp Neurol 2018;306:169–76.
[PubMed: 29753647]
7. Harkema SJ. Neural plasticity after human spinal cord injury: application of locomotor training to
the rehabilitation of walking. The Neuroscientist : a review journal bringing neurobiology,
neurology and psychiatry 2001;7(5):455–68.
8. Dietz V, Harkema SJ. Locomotor activity in spinal cord-injured persons. J Appl Physiol (1985)
2004;96(5):1954–60. [PubMed: 15075315]
9. Dietz V, Colombo G, Jensen L, Baumgartner L. Locomotor capacity of spinal cord in paraplegic
patients. Annals of neurology 1995;37(5):574–82. [PubMed: 7755351]
Author Manuscript

10. Edgerton VR, Roy RR, Hodgson JA, Prober RJ, de Guzman CP, de Leon R. A physiological basis
for the development of rehabilitative strategies for spinally injured patients. J Am Paraplegia Soc
1991;14(4):150–7. [PubMed: 1683668]
11. Edgerton VR, Tillakaratne NJ, Bigbee AJ, de Leon RD, Roy RR. Plasticity of the spinal neural
circuitry after injury. Annu Rev Neurosci 2004;27:145–67. [PubMed: 15217329]
12. Harkema SJ, Hillyer J, Schmidt-Read M, Ardolino E, Sisto SA, Behrman AL. Locomotor training:
as a treatment of spinal cord injury and in the progression of neurologic rehabilitation. Archives of
physical medicine and rehabilitation 2012;93(9):1588–97. [PubMed: 22920456]
13. Harkema SJ, Hurley SL, Patel UK, Requejo PS, Dobkin BH, Edgerton VR. Human lumbosacral
spinal cord interprets loading during stepping. Journal of Neurophysiology 1997;77(2):797–811.
[PubMed: 9065851]
14. Forssberg H, Grillner S, Halbertsma J. The locomotion of the low spinal cat. I. Coordination within
a hindlimb. Acta physiologica Scandinavica 1980;108(3):269–81. [PubMed: 7376922]
15. Dietz V, Colombo G, Jensen L. Locomotor activity in spinal man. Lancet 1994;344(8932):1260–3.
[PubMed: 7967986]
Author Manuscript

16. Dietz V, Quintern J, Sillem M. Stumbling reactions in man: significance of proprioceptive and pre-
programmed mechanisms. The Journal of physiology 1987;386:149–63. [PubMed: 3681704]
17. Harkema SJ. Plasticity of interneuronal networks of the functionally isolated human spinal cord.
Brain Research Reviews 2008;57(1):255–64. [PubMed: 18042493]
18. Holmes GM, Hubscher CH, Krassioukov A, Jakeman LB, Kleitman N. Recommendations for
evaluation of bladder and bowel function in pre-clinical spinal cord injury research. J Spinal Cord
Med 2020;43(2):165–76.

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
 Hubscher et al. Page 11

19. Tate DG, Wheeler T, Lane GI, Forchheimer M, Anderson KD, Biering-Sorensen F et al.
Recommendations for evaluation of neurogenic bladder and bowel dysfunction after spinal cord
Author Manuscript

injury and/or disease. J Spinal Cord Med 2020;43(2):141–64.

20. Hubscher CH, Herrity AN, Williams CS, Montgomery LR, Willhite AM, Angeli CA et al.
Improvements in bladder, bowel and sexual outcomes following task-specific locomotor training in
human spinal cord injury. PLoS One 2018;13(1):e0190998. [PubMed: 29385166]
21. Hubscher CH, Montgomery LR, Fell JD, Armstrong JE, Poudyal P, Herrity AN et al. Effects of
exercise training on urinary tract function after spinal cord injury. Am J Physiol Renal Physiol
2016;310(11):F1258–68. [PubMed: 26984956]
22. Ward PJ, Herrity AN, Smith RR, Willhite A, Harrison BJ, Petruska JC et al. Novel multi-system
functional gains via task specific training in spinal cord injured male rats. Journal of neurotrauma
2014;31(9):819–33. [PubMed: 24294909]
23. Galea MP. Spinal cord injury and physical activity: preservation of the body. Spinal Cord
2012;50(5):344–51. [PubMed: 22158253]
24. Marino RJ, Barros T, Biering-Sorensen F, Burns SP, Donovan WH, Graves DE et al. International
standards for neurological classification of spinal cord injury. The journal of spinal cord medicine
Author Manuscript

2003;26 Suppl 1:S50–6. [PubMed: 16296564]

25. Waring WP 3rd, Biering-Sorensen F, Burns S, Donovan W, Graves D, Jha A et al. _ 2009 review
and revisions of the international standards for the neurological classification of spinal cord injury.
J Spinal Cord Med 2010;33(4):346–52. [PubMed: 21061894]
26. Canton S, Momeni K, Ramanujam A, Garbarini E, Forrest GF. Neuromotor response of the leg
muscles following a supine, stand retraining with/without neuromuscular electrical stimulation
training intervention for individuals with SCI: A case series. Conf Proc IEEE Eng Med Biol Soc
2016;2016:3143–6.
27. Schafer W, Abrams P, Liao L, Mattiasson A, Pesce F, Spangberg A et al. Good urodynamic
practices: uroflowmetry, filling cystometry, and pressure-flow studies. Neurourology and
urodynamics 2002;21(3):261–74. [PubMed: 11948720]
28. Blaivas JG, Awad SA, Bissada N, Khanna OP, Krane RJ, Wein AJ et al. Urodynamic procedures:
Recommendations of the Urodynamic Society. I. Procedures that should be available for routine
urologic practice. Neurourology and urodynamics 1982;1(1):51–5.
29. Gammie A, Clarkson B, Constantinou C, Damaser M, Drinnan M, Geleijnse G et al. International
Author Manuscript

Continence Society guidelines on urodynamic equipment performance. Neurourol Urodyn

2014;33(4):370–9. [PubMed: 24390971]
30. Krassioukov A, Warburton DE, Teasell R, Eng JJ. A systematic review of the management of
autonomic dysreflexia after spinal cord injury. Arch Phys Med Rehabil 2009;90(4):682–95.
[PubMed: 19345787]
31. Biering-Sorensen F, Kennelly M, Kessler TM, Linsenmeyer T, Pannek J, Vogel L et al.
International Spinal Cord Injury Lower Urinary Tract Function Basic Data Set (version 2.0).
Spinal cord series and cases 2018;4:60. [PubMed: 30002915]
32. Krogh K, Emmanuel A, Perrouin-Verbe B, Korsten MA, Mulcahey MJ, Biering-Sorensen F.
International spinal cord injury bowel function basic data set (Version 2.0). Spinal Cord
2017;55(7):692–8. [PubMed: 28195229]
33. Krogh K, Perkash I, Stiens SA, Biering-Sorensen F. International bowel function basic spinal cord
injury data set. Spinal Cord 2009;47(3):230–4 [PubMed: 18725887]
34. Alexander MS, Biering-Sorensen F, Elliott S, Kreuter M, Sonksen J. International spinal cord
Author Manuscript

injury male sexual function basic data set. Spinal Cord 2011;49(7):795–8. [PubMed: 21283085]
35. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of
erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology
1997;49(6):822–30. [PubMed: 9187685]
36. Alexander MS, Biering-Sorensen F, Elliott S, Kreuter M, Sonksen J. International spinal cord
injury female sexual and reproductive function basic data set. Spinal Cord 2011;49(7):787–90.
[PubMed: 21383760]

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
 Hubscher et al. Page 12

37. Alexander MS, Brackett NL, Bodner D, Elliott S, Jackson A, Sonksen J. Measurement of sexual
functioning after spinal cord injury: preferred instruments. J Spinal Cord Med 2009;32(3):226–36.
Author Manuscript

[PubMed: 19810624]
38. Wiegel M, Meston C, Rosen R. The female sexual function index (FSFI): cross-validation and
development of clinical cutoff scores. J Sex Marital Ther 2005;31(1):1–20. [PubMed: 15841702]
39. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U et al. The standardisation of
terminology of lower urinary tract function: report from the Standardisation Sub-committee of the
International Continence Society. Neurourology and urodynamics 2002;21(2):167–78. [PubMed:
11857671]
40. Pannek J, Kennelly M, Linsenmeyer T, Wyndaele JJ, Biering-Sorensen F. International spinal cord
injury urodynamic basic data set (version 2.0). Spinal Cord Ser and Cases 2018;4:98.
41. Monti PR, Lara RC, Dutra MA, de Carvalho JR. New techniques for construction of efferent
conduits based on the Mitrofanoff principle. Urology 1997;49(1):112–5. [PubMed: 9000197]
42. Jamil F. Towards a catheter free status in neurogenic bladder dysfunction: a review of bladder
management options in spinal cord injury (SCI). Spinal Cord 2001;39(7):355–61. [PubMed:
11464308]
Author Manuscript

43. Hicks AL, Martin Ginis KA, Pelletier CA, Ditor DS, Foulon B, Wolfe DL. The effects of exercise
training on physical capacity, strength, body composition and functional performance among
adults with spinal cord injury: a systematic review. Spinal Cord 2011;49(11):1103–27. [PubMed:
21647163]
44. Adriaansen JJ, van Asbeck FW, Tepper M, Faber WX, Visser-Meily JM, de Kort LM et al.
Bladder-emptying methods, neurogenic lower urinary tract dysfunction and impact on quality of
life in people with long-term spinal cord injury. J Spinal Cord Med 2017;40(1):43–53. [PubMed:
26446581]
45. Lane TM, Shah PJ. Leak-point pressures. BJU Int 2000;86(8):942–9. [PubMed: 11069431]
46. Panicker JN, de Seze M, Fowler CJ. Rehabilitation in practice: neurogenic lower urinary tract
dysfunction and its management. Clin Rehabil 2010;24(7):579–89. [PubMed: 20584864]
47. Rosety-Rodriguez M, Camacho A, Rosety I, Fornieles G, Rosety MA, Diaz AJ et al. Low-grade
systemic inflammation and leptin levels were improved by arm cranking exercise in adults with
chronic spinal cord injury. Archives of physical medicine and rehabilitation 2014;95(2):297–302.
[PubMed: 24060491]
Author Manuscript

48. Ordonez FJ, Rosety MA, Camacho A, Rosety I, Diaz AJ, Fornieles G et al. Arm-cranking exercise
reduced oxidative damage in adults with chronic spinal cord injury. Archives of physical medicine
and rehabilitation 2013;94(12):2336–41. [PubMed: 23811316]
49. Horiuchi M, Okita K. Arm-Cranking Exercise Training Reduces Plasminogen Activator Inhibitor 1
in People With Spinal Cord Injury. Arch Phys Med Rehabil 2017;98(11):2174–80. [PubMed:
28286201]
50. Behrman AL, Harkema SJ. Locomotor training after human spinal cord injury: a series of case
studies. Physical therapy 2000;80(7):688–700. [PubMed: 10869131]
51. Visintin M, Barbeau H. The effects of parallel bars, body weight support and speed on the
modulation of the locomotor pattern of spastic paretic gait. A preliminary communication.
Paraplegia 1994;32(8):540–53. [PubMed: 7970859]
52. Denny-Brown D, Robertson E. The state of the bladder and its sphincter in complete transverse
lesions of the spinal cord and cauda equina. Brain 1933;56:397–469.
53. Jolesz FA, Cheng-Tao X, Ruenzel PW, Henneman E. Flexor reflex control of the external sphincter
Author Manuscript

of the urethra in paraplegia. Science 1982;216(4551):1243–5. [PubMed: 7200635]

54. Mai J, Pedersen E. Clonus depression by propranolol. Acta neurologica Scandinavica
1976;53(5):395–8. [PubMed: 1266577]
55. Pedersen E, Petersen T, Schroder HD. Relation between flexor spasms, uninhibited detrusor
contractions and anal sphincter activity. Journal of neurology, neurosurgery, and Psychiatry
1986;49(3):273–7.
56. Sato A, Sato Y, Sugimoto H, Tervi N. Reflex changes in the urinary bladder after mechanical and
thermal stimulation of the skin at various segmental levels in cats. Neuroscience 1977;2(1):111–7.
[PubMed: 917270]

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
 Hubscher et al. Page 13

57. Tai C, Roppolo JR, de Groat WC. Spinal reflex control of micturition after spinal cord injury.
Restorative Neurology and Neuroscience 2006;24(2):69–78. [PubMed: 16720943]
Author Manuscript

58. Thor KB, Roppolo JR, deGroat WC. Naloxone induced micturition in unanesthetized paraplegic
cats. J Urol 1983;129(1):202–5. [PubMed: 6681849]
59. Berkley KJ, Hubscher CH, Wall PD. Neuronal responses to stimulation of the cervix, uterus, colon,
and skin in the rat spinal cord. J Neurophysiol 1993;69(2):545–56. [PubMed: 8459285]
60. MacDonagh R, Sun WM, Thomas DG, Smallwood R, Read NW. Anorectal function in patients
with complete supraconal spinal cord lesions. Gut 1992;33(11):1532–8. [PubMed: 1452079]
61. Valles M, Mearin F. Pathophysiology of bowel dysfunction in patients with motor incomplete
spinal cord injury: comparison with patients with motor complete spinal cord injury. Dis Colon
Rectum 2009;52(9):1589–97. [PubMed: 19690487]
62. Christensen P, Bazzocchi G, Coggrave M, Abel R, Hulting C, Krogh K et al. Outcome of transanal
irrigation for bowel dysfunction in patients with spinal cord injury. J Spinal Cord Med
2008;31(5):560–7. [PubMed: 19086714]
63. Christensen P, Bazzocchi G, Coggrave M, Abel R, Hultling C, Krogh K et al. A randomized,
controlled trial of transanal irrigation versus conservative bowel management in spinal cord-
Author Manuscript

injured patients. Gastroenterology 2006;131(3):738–47. [PubMed: 16952543]

64. Rasmussen MM, Kutzenberger J, Krogh K, Zepke F, Bodin C, Domurath B et al. Sacral anterior
root stimulation improves bowel function in subjects with spinal cord injury. Spinal Cord
2015;53(4):297–301. [PubMed: 25600307]
65. Vardi Y, Dayan L, Apple B, Gruenwald I, Ofer Y, Jacob G. Penile and systemic endothelial
function in men with and without erectile dysfunction. European urology 2009;55(4):979–85.
[PubMed: 18692305]
66. Allers KA, Richards N, Sultana S, Sudworth M, Dawkins T, Hawcock AB et al. I. Slow oscillations
in vaginal blood flow: alterations during sexual arousal in rodents and humans. The journal of
sexual medicine 2010;7(3):1074–87. [PubMed: 19732310]
Author Manuscript
Author Manuscript

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
 Hubscher et al. Page 14
Author Manuscript
Author Manuscript

Figure 1.
Comparison of pre/post-training data for each of the three activity-based training groups (A)
and percent change post- versus pre-training (B) on bladder function. In A, significant
training benefits can be seen for the LT group of participants for capacity (increased volume)
and for both the LT and arm crank groups for pressure (decrease). In B, the embedded
histograms reflect means of the individual plotted data. Whereas capacity (far left plot)
Author Manuscript

increased significantly above baseline (zero = no change) with locomotor training (LT; step
and stand20) and differed significantly from stand (Y), standing (weight-bearing) on its own
and upper extremity training did not significantly change for capacity. Regardless of the
group effect, one can notice that capacity more than doubled for many individuals receiving
LT and for several undergoing arm crank training. There were no changes between groups
for either bladder pressure or voiding efficiency, although mean pressure did significantly
change (decrease) post-training relative to baseline (reflected in middle graph) for both the
LT and arm crank groups. X=significant relative to baseline. *=significant relative to
baseline.
Author Manuscript

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
 Hubscher et al. Page 15
Author Manuscript
Author Manuscript

Figure 2.
A. Summary of the score distribution from the data collected at baseline indicates that most
of the scores fall within the ranges clinically interpreted as moderate to severe levels of
dysfunction (NBD range 1–6 very minor; 7–9 minor; 10–13 moderate; 14 or more severe).
B. As time for defecation is clinically important and impactful with respect to quality of life,
these data were collected as well. A significant improvement (*; shorter duration) post- vs
pre- training was found for only the LT group of study participants.
Author Manuscript
Author Manuscript

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
 Hubscher et al. Page 16
Author Manuscript
Author Manuscript

Figure 3.
A. Summary of the baseline IIEF score distribution for the various domains related to male
sexual function are shown for all training groups. The corresponding clinically interpreted
categories based upon numerical ranges of the scores for each domain is plotted for all 24
male study participants. B. The distribution of the plotted scores overall reveals many of the
scores within the moderate to severe levels, indicating a high degree of sexual dysfunction in
the SCI population.
Author Manuscript
Author Manuscript

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
 Hubscher et al. Page 17

Table 1:

Summary of Participant Characteristics

Author Manuscript

Group Participant ID # Age (Years) Sex Time Since Neuro Level of AIS Grade Bladder Emptying
Injury (Years) Injury Method
SRT+NMES A61 48 M 2.0 T8 A CIC

SRT-only C44 39 M 1.6 T4 B CIC

SRT+NMES A55 38 M 8.1 T9 C CIC

SRT+NMES A94 35 M 4.8 T7 A CIC

SRT-only* B38 19 M 1.3 C4 B CIC

SRT+NMES* B41 25 M 7.5 C8 B CIC

SRT-only* A99 19 M 2.3 C4 A CIC

SRT+NMES C53 38 M 9.4 T10 C CIC

SRT+NMES C40 34 M 9.8 C4 C SP

Author Manuscript

SRT+NMES* A82 34 M 5.4 C5 A SP

SRT+NMES A96 26 F 2.0 C4 A SP

SRT-only* A100 50 M 15.9 C4 A SP

Upper Ext. A37 30 M 7.6 C4 A CIC

Upper Ext. A83 26 M 2.1 T9 A CIC

Upper Ext. A84 31 M 8.4 T11 A CIC

Upper Ext. A57 29 F 6.8 T3 A Monti

Upper Ext. B37 40 M 16.3 T4 B CIC

Upper Ext. B38 19 M 1.0 C4 B CIC

Upper Ext. B39 22 M 1.2 T8 B CIC

Upper Ext. D48 62 M 1.1 C3 D CIC

Author Manuscript

Upper Ext. A125 22 M 0.7 C4 A CIC

Upper Ext. B40 32 M 1.0 C4 B CIC

*
Daily administration of TRT or placebo gel during intervention period
Author Manuscript

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.
 Hubscher et al. Page 18

Table 2:

Summary of Compliance Data

Author Manuscript

Compliance Values Training Group

ml/cmH2O
Locomotor** Upper Extremity Stand

Group Mean Pre-Training 6.9 ± 2.0 10.5 ± 5.5 44.4 ± 14.5

Post-Training 17.5 ± 6.4 17.0 ± 5.8* 33.8 ± 12.5

P Value p=0.07 p=0.03 p=0.25

Group Median Pre-Training 5.5 4.6 33.3

Post-Training 12.5 12.4 19.8

Pre/Post Change 10.6 ± 4.9 6.6 ± 2.5 −10.5 ± 6.4

% Compliance Pre-Training 0% 11.1% 62.5%

> 20 ml/cmH2O
Post-Training 28.6% 33.3% 50.0%
Author Manuscript

*
significant difference pre- versus post-training (Paired t-test); ± SEM.
**
Data from our previously published locomotor training study20.
Author Manuscript
Author Manuscript

Arch Phys Med Rehabil. Author manuscript; available in PMC 2022 May 01.