Exercise pressor reflex in Amyotrophic lateral sclerosis patients

Abstract

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by progressive loss of motor neurons that leads to a decrease in muscle strength and motor performance. It is still unclear whether acute exercise evokes circulatory responses in late-stage ALS patients, although it is well known that in healthy people, there is an increase in heart rate (HR) and blood pressure (BP). Therefore, we examined whether the sensory and autonomic nervous systems respond greatly sufficiently to evoke circulatory responses to acute movement in late-stage ALS patients. Late-stage ALS patients (age:55–92 yrs, five males, two females) on ventilators performed static passive forearm stretching and passive leg pedaling exercises. The intensity of stretching was lower than individual pain thresholds. The beat-to-beat BP was continuously recorded. HR, systolic blood pressure, diastolic blood pressure, and the mean arterial pressure significantly increased from rest with passive forearm stretching (p < 0.05), while no significant circulatory changes were observed during passive leg pedaling.These results are similar responses to those reported in healthy people, suggesting that the functions of sensory and autonomic nervous systems are intact to evoke circulatory responses in late-stage ALS patients.

Clinical trial registration : This study was registered at UMIN-CTR (R000069509) on February 25, 2026.

Introduction

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the progressive loss of motor neurons that decreases muscle strength and motor performance^1,2. ALS has a short prognosis of 3–5 years and there are few effective treatments^3–5. Pathologically, the motor neurons degenerate and fall off, resulting in upper and lower motor neurons disorders^5–8. In many cases, ALS progresses to breathing problems, requiring ventilation within a few years of onset^5,9,10. As the disease progresses, the strength of the limbs and facial muscles declines, and the remaining functions are localized to the movement of the fingertips, eyebrows, and eyes^9,10. The role of exercise in maintaining physical functionality in ALS patients is an ongoing debate⁵. Recent research has suggested that therapeutic exercise preserves physical function^1,2,5. For example, maintenance of lower limb motor function was observed in cybernic treatment for ALS⁵. In another study, therapeutic exercise exerted cardiopulmonary benefits by preventing the progression of limb weakness¹¹.

Autonomic responses to exercise in ALS patients are still unclear. Acute exercise induces an increase in heart rate (HR) and blood pressure (BP) in healthy individuals. These increases are primarily regulated by the autonomic nervous system. In turn, it was pointed out that different types of methods and measurements have led to different or contradictory results¹². The circulatory and autonomic responses to acute movement in ALS patients must be elucidated.

The acute circulatory responses to exercise are primarily evoked by nervous systems¹³. These originate from the central command¹⁴ and exercise pressor reflex, which includes the metaboreflex and mechanoreflex¹⁵. The central command is a leak out from motor commands that express muscle contraction to the cardiovascular center, which provides feed-forward regulation of circulation¹⁶. The exercise pressor reflex provides feedback regulation from the sensory receptors present in skeletal muscles through sensory neurons^15,16. Two types of reflexes are specified: these reflexes originate from the metabolic, and mechanical changes in the active muscles¹⁵.

Some ALS patients have shown sensory nerve impairments. Patients complained of sensory impairment in 32% of ALS patients, and nerve conduction tests showed a decrease in the action potential of the sensory nerve in 27% of patients¹⁷. The Awaji Diagnostic Criteria also indicate that mild abnormal changes in neurotransmission velocity are not grounds for ruling out ALS¹⁸. Recent study demonstrated that sensory dysfunction is a frequent and progressive feature of ALS, involving sensory fibers¹⁹. It is unclear whether these sensory nerve impairments affect the exercise pressor reflex and consequently alter the circulatory response to exercise.

ALS patients may have intact autonomic nervous systems. Similar circulatory responses in ALS patients and healthy people were reported in the Valsalva manoeuvre, isometric handgrip and diving reflex²⁰. The HR and BP responses to the orthostatic test were also similar to those of healthy participants. However, these data were obtained from early-stage ALS patients without a ventilator or gastrostomy. Autonomic functions in patients with late-stage disease remain unknown.

The mechanoreflex can be induced by passive movements and passive stretching²¹.The information related to mechanical change in the recruiting muscles is provided by group Ⅲ and group Ⅳ afferent fibers to the medulla, where sympathetic nerves are activated^13,15,16. Thus, we hypothesize that if the sensory and autonomic systems relevant to the mechanoreflex are intact in ALS patients, passive movements, which are used to evoke mechanoreflex in healthy individuals, increases circulation. To test this hypothesis, we observed circulatory responses to static passive forearm stretching and passive leg pedaling, which also evoke circulatory responses, in late-stage ALS patients on ventilator and gastrostomy. Static stretching and dynamic passive movement can exclude reflection by central command, and only muscle mechanoreflex can be stimulated. Observing the functions of the sensory and autonomic nervous systems during exercise may provide physiological and clinical comprehension in ALS patients.

Methods

Participants

ALS patients admitted to the neurology ward of the hospital were encouraged to participate in the present study. Nine ALS patients (age: 55–92 yrs, height 160 ± 8 cm, body mass 48 ± 11 kg; 5 males and 4 females) were recruited. The study participants are with late-stage ALS (Table 1). They were on mechanical ventilation under tracheostomy and fed via gastrostomy or nasal tube feeding. All participants are on tracheostomy positive pressure ventilator, and receiving nutrition through tube feeding. In Japan, 30% of ALS patients choose ventilator under tracheostomy, and ventilators include non-invasive ventilation and tracheostomy invasive ventilation²². None of the participants smoked or consumed alcohol. All participants are rehabilitated 2–3 days a week by physical therapists, occupational therapists, and speech therapists in units of 20 min. The purpose of rehabilitation is mainly to maintain cardiopulmonary function and muscle strength of the limbs, and to prevent contracture of joints. One participant provided a written informed consent, and eight participants provided eye-sign and oral informed consent to participate prior to the start of the study. One family member out of the eight participants provided written informed consent. To ensure that written records exist for all consents, we also obtained signatures from the nurses who confirmed the consent forms. These nurses were not involved in this study. The Waseda University Ethical Review Board approved the objectives, procedures, and risks associated with this study (Approval Number: 2022 − 423). The Ethical Review Committee of Neurology Hospital A, which was involved in a total of about 10% of ALS patients in Tokyo, also approved the present study. The study was conducted in accordance with the guidelines of the Declaration of Helsinki (1975).

Table 1.

The number of subjects classified by ALS Type, onset organ, limb involvement, ALS duration (years), duration of invasive ventilation, ALSFRS-R score and sensory symptoms of the participants. To avoid identifying individuals, details are not included

ALS type	ALS/MND, PBP to ALS-FTD	2
	ALS/MND	7
Onset organ	Bulbar	4
	Spinal	5
ALS duration	< 5yrs	2
	5 to 10 yrs	5
	10 to 15 yrs	2
TPPV duration	< 5yrs	3
	5 to 10 yrs	5
	10 to 15 yrs	1
ALSFRS-R	0 / 48	3
	1 / 48	4
	3 – 7 / 48	2
Sensory symptom	No	9

Sample size calculation

Sample size calculations is difficult as ALS is an incurable and rare disease with a prevalence of 9.9 (per 100,000 people)²³ and incidence of 2.2 (per 100,000 people/year)²³. In this study, we assumed that patients who had obtained consent at a single center would participate in the study based on their own free will. Randomization in studies is difficult in the selection of patients since the number of late ALS patients on mechanical ventilation is few.

Protocol

We observed the beat-to-beat HR and BP responses associated with passive forearm stretching and passive leg pedaling and examined the effects of the sensory and autonomic nervous system. Height, body mass, age, duration of ALS, and ALS functional rating scale-revised score (ALSFRS-R score) of the patients were recorded²⁴.

Passive forearm stretching

Stretching was performed for 1 min with the patient’s right or left forearm, which was not attached to the finger cuff for BP monitoring. Passive forearm stretching at two different intensities was performed: moderate intensity (MPS) and minimum painful intensity passive stretching (PPS), which was the minimum painful stretching, as described previously²¹. The intensity of MPS was immediately below the predetermined pain sensation, and that PPS was above the pain sensation²¹. BP was continuously recorded during 1 min resting, stretching and recovery periods.

Passive leg pedaling

Passive leg pedaling was performed on the patient’s right or left leg for 3 min (ALFITS, AFB3016, ALINCO Inc., Japan). The pedaling cadence was set at 35 rpm. BP were continuously recorded during 1-min resting, 3-min pedaling, and 1-min recovery periods.

Measurements

Hemodynamics

BP was recorded using a finger photoplethysmography (Finometer MIDI, Finapres Medical Systems, Amsterdam, The Netherlands). The probe was attached to a measurable finger from the first finger to the third finger of the participant’s hand because BP could not always be recorded from the second finger, which is best for measurement. The signal was converted from a force transducer to an analog-to-digital converter (PowerLab 4/25, AD Instruments, Australia) at a sampling rate of 1 kHz and recorded using a device connected to a personal computer (Dynabook, Toshiba, Japan).

In case Finapres could not be used for measurement, blood pressure was measured using an arm-cuff sphygmomanometer at rest, immediately before the end of passive stretch and exercise, and immediately after them (UA-704, AandD, Japan). The measurement immediately before exercise was not taken at a controlled time.

Force and range of motion of wrist joint angle

The force generated between the passively outstretched hand and the experimenter’s hand was controlled using a force transducer (MLT004/ST; AD Instruments, Australia). The force signal was converted from the force transducer to an analog-to-digital converter at a sampling rate of 1 kHz, and recorded using a device connected to a computer. The transducer was placed between the proximal interphalangeal joint and metacarpophalangeal joint of the contralateral hand to the attachment of the photoplethysmography device. The experimenter extended the participant’s forearm for 1 min, pushing perpendicular to the force transducer. The flexibility of the wrist joint angle in late ALS patients is similar to healthy people, while others have stiff joints. The angle and strength of force immediately before the onset of pain were recorded in advance.

Data analysis

HR was calculated from the BP waveforms. Mean arterial pressure (MAP) was calculated using the following equation: MAP = Diastolic blood pressure (DBP) + 1/3[Systolic blood pressure (SBP) - DBP]. The data were averaged for 10 s in the passive forearm stretching trial and by 30 s in the passive leg pedaling trial. Individual peak changes from baseline were used for statistical analysis. Statistical analyses were performed using SPSS Statistics for MAC (version 27.0; IBM Corp., Armonk, New York, USA). One-way analysis of variance (ANOVA) and Repeated Measures ANOVA were used to detect the effect of time on HR and BP. Student’s paired t-test was used to evaluate the differences in the peak absolute responses of HR, SBP, DBP, and MAP compared with baseline during MPS, PPS, and passive leg pedaling. Post-hoc (Bonferroni) tests were used to compare the value to resting value. Data are represented as mean ± SD. The significance level for all comparisons was set at p < 0.05.

Results

A participant no. 8 could not participate in the forearm stretching because one was isolated with infectious disease. Data was not successfully obtained from nos. 2 and 4 in stretching and leg pedaling, respectively, because of poor signal quality of Finapres probably due to low blood flow in fingers. Thus, beat-by-beat BP was measured in seven patients in both trials.

Supplemental BP data on arm was obtained from eight (except for no. 8) and nine participants in stretching and leg pedaling, respectively.

Duration of ALS

The duration of ALS in seven participants was a minimum duration of 2.5 years, and a maximum duration of 14.4 years. The mean duration was 7.1 years.

ALSFRS-R score

The ALSFRS-R score of nine participants was a minimum score of 0 points, and a maximum score of 7 points. The mean was 1.56 points.

Force

The minimum force of the MPS was 0.03 N, the maximum was 34.5 N, and the mean was 21.4 N. The minimum force of PPS was 0.04 N, the maximum value was 54.2 N, and the average value was 30.5 N

Circulatory responses to passive forearm stretching

The peak responses in HR, SBP, DBP, and MAP to passive forearm stretching are shown in Fig. 1. There were significant differences in the peak absolute responses of HR, SBP, DBP, and MAP compared with baseline during MPS (p < 0.05). No significant differences in HR, SBP, DBP, or MAP were observed during the PPS.

Fig. 1.

Peak circulatory responses to moderate-intensity passive forearm stretching in ALS patients. Heart rate (HR); (a), systolic blood pressure (SBP); (b), diastolic blood pressure (DBP); (c), and mean arterial pressure (MAP); (d) are shown. The bold line shows mean values, and other lines show individual values. Values are presented as mean ± SD. *: p < 0.05 vs. Rest.

The mean arterial pressure (MAP) measured by the arm cuff increased significantly from 81 ± 12 to 87 ± 11 mmHg (p < 0.05, n = 8), and recovered to 80 ± 7 mmHg during the recovery phase (p > 0.05 vs. rest).

Circulatory responses to passive leg pedaling

The responses of HR, SBP, DBP, and MAP to passive leg pedaling are shown in Fig. 2. No significant difference in HR, SBP, DBP or MAP were observed in passive leg pedaling.

Fig. 2.

Circulatory responses to passive leg pedaling in ALS patients. Time course of heart rate (HR); (a), systolic blood pressure (SBP); (b), diastolic blood pressure (DBP); (c), and mean arterial pressure (MAP); (d) are shown. The bold line shows mean values, and other lines show individual values. P means the onset of passive leg pedaling, R means the onset of recovery. No significant difference was shown.

The mean arterial pressure (MAP) measured by the arm cuff does not significantly change (88 ± 7, 85 ± 7, 86 ± 8 mmHg at rest, pedaling and recovery, respectively, n = 9).

Discussion

Late-stage ALS patients on ventilator and gastrostomy showed circulatory responses to static passive forearm stretching below the pain threshold, showing a mechanoreflex response similar to that of healthy participants. This suggests intact sensory and autonomic functions related to the mechanoreflex in the forelimbs, supporting our hypothesis. No responses were obtained for passive leg pedaling. These responses were similar to those in healthy people²¹. The presence of circulatory response to passive exercise may have clinical implication in ALS patients, since patients can only perform limited voluntary exercises, except for passive exercises.

The participants in the present study had late-stage ALS and were on ventilators and fed via gastrostomy or nasal tube, all of which are standard treatments in Japan. They could not perform voluntary limb exercises, whereas passive forearm stretching and passive leg pedaling were similar to those of the present methods. The ALSFRS-R score is a representative indicator of daily activity, functioning in ALS patients; a greater score indicates preservation of daily activity, and the 9-month survival rate is less than 25% when the ALSFRS-R score is less than 15 points²⁴. The present study showed the presence of mechanoreflex even in late-stage ALS patients.

The mechanoreflex was observed in the forearm stretching, whilst it was not in the dynamic passive leg pedaling in late-stage ALS patients. This was similar to the previous observation obtained in healthy subjects²¹. This was explained by the greater mechanoreflex originated from forearm than legs while the mechanism inducing different magnitude of mechanoreflex is still unclear.

The mechanoreflex has been observed in ALS patients, as well as in healthy people²¹, indicating that sensory nerve group Ⅲ and Ⅳ fibers and sympathetic nerve activities related to the exercise pressor reflex were intact in late-stage ALS patients. The magnitude of the exercise pressor reflex in the MAP was similar between patients with ALS and healthy participants. The response in healthy participants was 9 mmHg in MAP in a previous study recruiting the same methods, while the magnitude in the present study was 10 mmHg (MPS MAP)²¹.

A Similar magnitude in MAP response in ALS patients may have been delivered by disuse atrophy induced by ALS²⁰, despite smaller intensity of passive forearm stretching. The intensity of passive forearm stretching was much smaller in ALS patients than healthy participants in the previous study²¹. The intensity in the present study using the same method to evoke mechanoreflex was 21.4 N, whereas that in the previous study was 55.8 N. In turn, the atrophy of recruiting muscles may be related to a greater response in ALS patients. Disuse atrophy increases mechanoreflex in rats²⁵. This exaggerated response related to atrophy may compromise the decrease in smaller stimulation.

The sensory and autonomic nervous systems, relating to the mechanoreflex, were preserved in late-stage ALS patients. The mechanoreflex is induced by mechanical change in the recruiting muscles and conducted by group Ⅲ and group Ⅳ afferent fibers to the medulla, where sympathetic nerves are activated^13,15,16. The presence of the mechanoreflex in ALS patients suggests intact sensory and autonomic pathways and functions, including medulla. Circulatory responses in ALS patients similar to those of healthy people were reported in the Valsalva manoeuvre, isometric handgrip and diving reflex, though the patients were ambulatory and without a ventilator²⁰. A previous study showed similar HR response in healthy and ALS volunteers, indicating normal function of the vagal nerve²⁰. The HR and BP responses to an orthostatic test were also similar to those of healthy participants, showing preserved functions of the sympathetic nervous system²⁶. Taken together with the mechanoreflex presented in the present study, these results indicate that ALS patients have an intact a part of autonomic nervous system a specific reflex arc.

It should be noted that the findings of this study provide argument for intact nervous pathway solely in mechanoreflex, which reflects only a specific neural pathway involving muscle afferents, the medulla, and sympathetic vasomotor outflow. Autonomic dysfunction in ALS patients was reported, including cardiovagal, sympathetic, baroreflex components²⁷. Sensory dysfunction in both large and small fibers is reported to be a frequent and progressive feature in ALS patients¹⁹. Our findings indicate one component of autonomic regulation. We should not apply this finding to other neural circuits in ALS patients.

Considering the presence of the mechanoreflex, the functions of groups Ⅲ and Ⅳ were preserved in ALS patients. These preserved functions were also observed at lower pain thresholds in the present study. Some patients felt pain even when a small force was applied (e.g., 0.04 N in PPS trial). The force used in PPS (45.8 N) was equivalent to that used in the MPS of healthy participants in a previous study (44.0–59.2 N). In addition, pain was reported to be felt in greater parts of the body as the disease progressed in ALS patients²⁸. Based on the result of this previous study, the functions of groups Ⅲ and Ⅳ are preserved in ALS patients.

Limitation

We recruited patients having wide range of disease duration (2.5–14.4 years), implying that heterogeneous ALS phenotypes were pooled together. Recent evidence clearly demonstrates that ALS is not a single disorder but a spectrum of subtypes²⁹. The rate of disease progression is likely to influence whether sensory nerves and autonomic nerves are involved.

Only nine ALS patients were recruited, and that the study was not conducted in healthy people as an age- and sex- matched control group. Instead of a control group, we compared the data with circulatory responses in young healthy participants previously reported²¹. This was solely to confirm the presence or absence of the mechanoreflex and was not intended to compare whether the reflex magnitude was normal. If comparing the normality of reflex magnitude, comparison with age-matched healthy individuals would be necessary. It is necessary to track the sensory and autonomic nervous systems of functional changes in research that allows more ALS patients to participate.

Participants were under mechanical ventilation, which is known to induce cyclic changes in arterial blood pressure. Positive-pressure ventilation can modulate systolic and pulse pressure through heart–lung interactions, and these effects may overlap with or mask reflex-mediated circulatory responses Still, the observation of mechanoreflexes beyond these effects also constitutes a noteworthy result in this study.

Abbreviations

ALS

Amyotrophic lateral sclerosis

ALSFRS-R score

ALS functional rating scale-revised score

ANOVA

Analysis of variance

BP

Blood pressure

DBP

Diastolic blood pressure

HR

Heart rate

MAP

Mean arterial pressure

MPS

Moderate intensity passive stretching

PPS

Minimum painful intensity passive stretching

SBP

Systolic blood pressure

Author contributions

YS and NH conceived of and designed the study. YS and NN conducted the preliminary experiments. YS conducted the experiments. NN contributed to statistical analysis. YS, NN, and NH analyzed the data. YS wrote the manuscript. All authors have read and approved the final manuscript.

Data availability

The datasets acquired and analyzed during the current study are not publicly available since the small number of patients with the disease dealt in this study could lead to the identification of individuals. Still the datasets are available from the corresponding author on reasonable request.

Declarations

Competing interests

The authors declare no competing interests.