Effects of flexor reflex stimulation on gait aspects in stroke patients: randomized clinical trial.

BACKGROUND: Gait deficits are very common after stroke and therefore an important aspect in poststroke rehabilitation. A currently little used method in gait rehabilitation after stroke is the activation of the flexor reflex (FR) by electrical stimulation of the sole of foot while walking. The aim of this study was to investigate the effect of FR stimulation on gait performance and gait parameters in participants with stroke within a single session of flexor reflex stimulation using Incedo™. METHODS: Twenty-five participants with subacute (n = 14) and chronic (n = 11) stroke were enrolled in the study. Motor functions were tested with a 10-m walk test (10mWT), a 2-min walk test (2minWT), and a gait analysis. These tests were performed with and without Incedo™ within a single session in randomized order. RESULTS: In the 10mWT, a significant difference was found between walking with Incedo™ (15.0 ± 8.5 s) versus without Incedo™ (17.0 ± 11.4 s, p = 0.01). Similarly, the 2minWT showed a significant improvement with Incedo™ use (90.0 ± 36.4 m) compared to without Incedo™ (86.3 ± 36.8 m, p = 0.03). These results indicate that while the improvements are statistically significant, they are modest and should be considered in the context of their clinical relevance. The gait parameters remained unchanged except for the step length. A subgroup analysis indicated that participants with subacute and chronic stroke responded similarly to the stimulation. There was a correlation between the degree of response to electrostimulation while walking and degree of improvement in 2minWT (r = 0.50, p = 0.01). CONCLUSIONS: This study is the first to examine FR activation effects in chronic stroke patients and suggests that stimulation effects are independent of the time since stroke. A larger controlled clinical trial is warranted that addresses issues as the necessary number of therapeutical sessions and for how long stimulation-induced improvements outlast the treatment period. TRIAL REGISTRATION: The trial was retrospectively registered in German Clinical Trials Register. CLINICAL TRIAL REGISTRATION NUMBER: DRKS00021457. Date of registration: 29 June 2020.

Short­term effects of pregabalin plus exercise therapy on pain, emotional status, physical function and nociceptive responses in patients with fibromyalgia.

The aim of the present study was to investigate the effects of pregabalin plus exercise vs. pregabalin treatment alone on the electromyographic nociceptive flexion reflex (NFR) threshold in patients with fibromyalgia (FM). For this purpose, the present study included a total of 40 patients diagnosed with FM according to the American College of Rheumatology 2010 criteria. The patients were divided into two groups as follows: Group 1 received pregabalin treatment only and group 2 received exercise therapy in addition to pregabalin treatment. Assessments were made at baseline and at the 1st month using a visual analog scale (VAS) to measure pain, the Fibromyalgia Impact Questionnaire (FIQ) to measure the severity of FM, Beck's Depression Inventory (BDI) to measure depression and the NFR to measure the compressive forces on peripheral nerves. In both groups, the NFR threshold following treatment was significantly higher than that at the baseline results (P#x003C;0.001). There was no significant difference between the groups as regards the difference from pre- to post-treatment NFR threshold values (P=0.610 and P=0.555, respectively). There was a strong, negative correlation between the pre-treatment NFR threshold and VAS resting, VAS motion and FIQ scores (Rho=-0.62, Rho=-0.69 and Rho=-0.60, respectively). There was a moderate negative correlation between the pre-treatment NFR threshold and BDI scores (Rho=-0.35). On the whole, the present study demonstrates that in the treatment of FM, pregabalin improves the clinical scores and leads to an increase in the NFR threshold. Herewith, it should be noted that short-term exercise therapy does not appear to provide additional benefits.

Using the Flexor Reflex in a Chronic Stroke Patient for Gait Improvement: A Case Report.

The flexor reflex or withdrawal reflex can be elicited by electrical stimulation of the sole of the foot, which serves as a reflex to protect the stimulated limb against tissue damage and consists of flexion movements in the hip, knee, and ankle joint. Triggering this reflex might improve walking abilities in hemiparetic patients. We report the first case of a chronic stroke patient with the most severe impairment of walking. She was examined with and without flexor reflex activation by the Incedo® system. Tests included a 10-m walk and a 2-min walk at baseline, after 3 weeks of training with the Incedo® system and after a follow-up 3 weeks later. Moreover, a kinematic gait analysis was done before and after the training period. At baseline, activation of the flexor reflex induced an improved gait velocity. After the training period, the patient walked twice as fast compared with baseline. Her gait velocity without Incedo® was faster than the gait velocity with Incedo® at baseline. Examination at follow-up indicated that the improvements remained almost unchanged. The kinematic analysis showed an improved stride length and gait velocity during flexor reflex activation. Initially, the foot was elevated higher above the ground during flexor reflex activation. In conclusion, this first case report of a chronic stroke patient demonstrates that flexor reflex activation is feasible and improves gait parameters despite severe impairment of walking abilities.

Accuracy and Reliability of Single-Camera Measurements of Ankle Clonus and Quadriceps Hyperreflexia.

OBJECTIVE: To evaluate the accuracy and reliability of a simple, single-camera smartphone-based method, named the Reflex Tracker (RT) system, for measuring reflex threshold angles related to ankle clonus and quadriceps hyperreflexia. DESIGN: A prospective comparison study using a high-fidelity reference standard was constructed employing a 2 × 2 × 2 factorial design, with factors of rater (tester) type (student and experienced physical therapist), joint (ankle and knee), and repetition (2 per condition). SETTING: This multicenter study was conducted at 4 outpatient rehabilitation clinics. PARTICIPANTS: A convenience sample of 14 individuals with a neurologic condition presented with 20 lower limbs that exhibited ankle clonus and/or quadriceps hyperreflexia and were included in the study. Also participating in the study were 8 student and 8 experienced physical therapist raters (testers) (N=16). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The plantar flexor reflex threshold angle (PFRTA) related to ankle clonus and the quadriceps reflex threshold angle (QRTA) related to quadriceps hyperreflexia were quantified. RESULTS: PFRTA and QRTA results were compared between the smartphone RT method and synchronous 3-dimensional inertial measurement unit (IMU) sensor motion capture. Mean difference (bias) was minimal between RT and IMU measurements for PFRTA (bias≤0.2°) and QRTA (bias≤1.2°). Intrarater reliability for PFRTA ranged from 0.85-0.90 using RT and from 0.85-0.87 using IMU; QRTA ranged from 0.97-0.98 using RT and from 0.96-0.99 using IMU. Intersensor reliability for PFRTA and QRTA was 0.97 and 0.99, respectively. Minimum detectable change for PFRTA ranged from 7.1°- 8.7° and for QRTA ranged from 6.1°-8.3°. CONCLUSIONS: RT performed comparable to IMU for accurate and reliable measurement of PFRTA and QRTA to quantify ankle clonus and quadriceps hyperreflexia in clinical settings.

A Randomized Sham-Controlled Cross-Over Study on the Short-Term Effect of Non-Invasive Cervical Vagus Nerve Stimulation on Spinal and Supraspinal Nociception in Healthy Subjects.

OBJECTIVE: The aim of the present study was to test the effects of vagus nerve stimulation (VNS) on the descending pain inhibition, quantified by the nociceptive flexor (RIII) reflex and the conditioned pain modulation (CPM) paradigm, and on supraspinal nociceptive responses, assessed by pain intensity and unpleasantness ratings and late somatosensory evoked potentials (SEPs), in healthy subjects. BACKGROUND: Non-invasive vagus nerve stimulation (nVNS) showed promising effects on headache and pain treatment. Underlying mechanisms are only incompletely understood but may include the activation of the descending pain inhibitory system and/or the modification of emotional responses to pain. METHODS: Twenty-seven adult, healthy, and pain-free subjects participated in this double-blind cross-over study conducted at a university research center. They received 4 minutes of cervical nVNS or sham stimulation in randomized order. RIII reflexes, pain ratings, and SEPs were assessed before, during, and 5, 15, 30, and 60 minutes after nVNS/sham stimulation, followed by CPM testing. The primary outcome was the nVNS effect on the RIII reflex size. Three subjects were excluded after the preparatory session (before randomization), 1 subject was excluded after outlier analysis, leaving 23 for analysis. RESULTS: RIII reflex areas were 917.1 ± 563.8 µV × ms (mean ± SD) before, 952.4 ± 467.4 µV × ms during and 929.2 ± 484.0 µV × ms immediately after nVNS and 858.4 ± 489.2 µV × ms before, 913.9 ± 539.7 µV × ms during and 862.4 ± 476.0 µV × ms after sham stimulation, revealing no differences between the immediate effects of nVNS and sham stimulation (F [3,66]  = 0.67, P = .574). There also were no effects of nVNS over sham on RIII reflex areas up to 60 minutes after nVNS (F [1.7,37.4]  = 1.29, P = .283). Similarly, there was no statistically significant effect of nVNS on pain intensity ratings and thresholds, RIII reflex thresholds, late SEP amplitudes, and the CPM effect, compared to sham. Pain unpleasantness ratings statistically significantly decreased from 4.4 ± 2.4 (NRS 0-10) to 4.1 ± 2.5 during nVNS compared to sham stimulation (F [1,22]  = 8.74, P = .007), but there were no longer lasting effects (5-60 minutes after stimulation). CONCLUSIONS: The present study does not support an acute effect of nVNS on descending pain inhibition, pain intensity perception or supraspinal nociception in healthy adults. However, there was a small effect on pain unpleasantness during nVNS, suggesting that nVNS may preferentially act on affective, not somatosensory pain components.

Effect of phobic visual stimulation on spinal nociception.

To explore the role of strong negative emotions in spinal nociception, we evaluated the effect of fear-relevant videos of small animals on the nociceptive withdrawal reflex (NWR) and reflex-related pain perception in healthy subjects with a specific phobia of small animals. Twenty healthy subjects with a specific phobia of small animals diagnosed according to DSM-V criteria were included in this study. The NWR was evoked in the lower limb by stimulating the sural nerve and recording EMG activity in the biceps femoris. NWR pain-related perception was quantified on an 11-point numerical rating scale (NRS). Subjects were examined during 4 recording sessions. In the baseline session, no images were projected. In the other sessions, the subjects were invited to watch a video containing either neutral or phobic content. To evaluate neurovegetative responses, we measured heart rate using a pulse oximeter during each recording session. A series of clinical rating scales were administered to subjects to evaluate disgust, fear, and anxiety. The NWR amplitude was significantly increased during the phobic video session and was associated with the fear inventory scale scores. Women showed higher NWR amplitude values during the phobic video session and a lower recovery rate during the after-effect video session than did men. The NWR amplitude and related pain perception were dissociated from each other during the phobic video session, as the NRS score remained unchanged while the NWR increased in amplitude. Emotions induced by the viewing of phobic videos seem to enhance the activation of the spinal circuitries involved in nociception and the withdrawal reaction without interfering with pain processing pathways or dissociating the reflex response from related pain perception. This effect appears to differ by sex, as it was more intense and longer lasting in women than in men. Emotions induced by phobic video viewing increase the alertness devoted to the defensive reaction by emphasizing nociceptive responses independently from pain perception. The NWR may represent an interesting tool for exploring the interaction between strong negative emotions and spinal nociception. A better understanding of this mechanism may be a theoretical prerequisite for the optimization of pain management in several chronic pain syndromes.

Circadian variation of flexor withdrawal and crossed extensor reflexes in patients with restless legs syndrome.

An evening state of spinal hyperexcitability has been proposed to be a possible cause of evening increases in restless legs syndrome symptoms. Thus, the objective of the current study was to assess the circadian variation in spinal excitability in patients with restless legs syndrome based on flexor withdrawal reflex and crossed extensor reflex responses. The reflexes were elicited on 12 participants with restless legs syndrome and 12 healthy control participants in the evening (PM) and the morning (AM). Reflex response magnitudes were measured electromyographically and kinematically. Both the reflexes showed a circadian rhythm in participants with restless legs syndrome but not in control participants. Changes in ankle (median flexor withdrawal reflex PM: 16.0 ° versus AM: 2.8 °, P = 0.042; crossed extensor reflex PM: 0.8 ° versus AM: 0.2 °, P = 0.001) angle were significantly larger, and ankle angular velocity (median flexor withdrawal reflex PM: 38.8 ° s-1 versus AM: 13.9 ° s-1 , P = 0.049; crossed extensor reflex PM: 2.4 ° s-1 versus AM: 0.5 ° s-1 , P = 0.002) was significantly faster in the evening compared with the morning in participants with restless legs syndrome, for both reflexes. For participants with restless legs syndrome, evening change in hallux angle was significantly larger than morning responses (median PM: 5.0 ° versus AM: 1.3 °, P = 0.012). No significant differences for any of the electromyographic or kinematic variables were observed between participants with restless legs syndrome and controls. The flexor withdrawal reflex and the crossed extensor reflex show a circadian rhythm in participants with restless legs syndrome suggesting an evening increase in spinal excitability. We hypothesize the circadian variation in spinal excitability may be due to a possible nocturnal form of afferent circuitry central sensitization in the dorsal horn of the spinal cord in patients with restless legs syndrome.

Learned control over spinal nociception: Transfer and stability of training success in a long-term study.

OBJECTIVE: Healthy subjects can learn to use cognitive-emotional strategies to suppress their spinal nociception, quantified by the nociceptive flexor reflex (RIII reflex), when given visual RIII feedback. This likely reflects learned activation of descending pain inhibition. Here, we investigated if training success persists 4 and 8 months after the end of RIII feedback training, and if transfer (RIII suppression without feedback) is possible. METHODS: 18 and 8 subjects who had successfully completed feedback training were investigated 4 and 8 months later. RESULTS: At 4 months, RIII suppression during feedback and transfer was similar to that achieved at the final RIII feedback training session (to 50 ±â€¯22%, 53 ±â€¯21% and 52 ±â€¯21% of baseline, all differences n.s.). At 8 months, RIII suppression was somewhat (not significantly) smaller in the feedback run (to 64 ±â€¯17%) compared to the final training session (56 ±â€¯19%). Feedback and transfer runs were similar (to 64 ±â€¯17% vs. 68 ±â€¯24%, n.s.). Concomitant reductions in pain intensity ratings were stable at 4 and 8 months. CONCLUSIONS: RIII feedback training success was completely maintained after 4 months, and somewhat attenuated 8 months after training. Transfer was successful. SIGNIFICANCE: These results are an important pre-requisite for application of RIII feedback training in the context of clinical pain.

Lower limb flexor reflex: Comparisons between drug-induced akathisia and restless legs syndrome.

BACKGROUND AND OBJECTIVE: Akathisia is characterized by restlessness and crawling sensations similar to restless legs syndrome (RLS). Long latency flexor reflex (LLFR) which has helped to advance RLS pathophysiology has never been investigated in akathisia. Due to the clinical commonalities of akathisia and RLS, we investigated the behavior of LLFR in patients with akathisia aiming to understand pathophysiology of akathisia. PATIENTS AND METHODS: Seven patients with neuroleptic-induced akathisia, 12 drug-naïve patients with primary RLS and 17 healthy subjects were prospectively enrolled in the study. LLFR was recorded from unilateral tibialis anterior (TA) and long head of biceps femoris (BF) muscles after stimulating the sole by trains of electrical stimuli. We measured amplitude, latency, duration, presence of response and compared between three groups. RESULTS: One-way ANOVA showed mean durations of early and late responses recorded over TA were the longest in akathisia group compared to both RLS group and healthy subjects (p=0.012). The spatial spread of LLFR in akathisia patients was comparable to those of healthy subjects whereas presence of response on BF was significantly less in akathisia than RLS group. CONCLUSIONS: Our findings indicate increased excitability of LLFR pathway in akathisia group. These findings are probably due to lack of inhibition originated in regions other than those known to downregulate in RLS.

Convergence of flexor reflex and corticospinal inputs on tibialis anterior network in humans.

OBJECTIVE: Integration between descending and ascending inputs at supraspinal and spinal levels is a key characteristic of neural control of movement. In this study, we characterized convergence of the flexor reflex and corticospinal inputs on the tibialis anterior (TA) network in healthy human subjects. Specifically, we characterized the modulation profiles of the spinal TA flexor reflex following subthreshold and suprathreshold transcranial magnetic stimulation (TMS). We also characterized the modulation profiles of the TA motor evoked potentials (MEPs) following medial arch foot stimulation at sensory and above reflex threshold. METHODS: TA flexor reflexes were evoked following stimulation of the medial arch of the foot with a 30 ms pulse train at innocuous intensities. TA MEPs were evoked following TMS of the leg motor cortex area. RESULTS: TMS at 0.7 and at 1.2 MEP resting threshold increased the TA flexor reflex when TMS was delivered 40-100 ms after foot stimulation, and decreased the TA flexor reflex when TMS was delivered 25-110 ms before foot stimulation. Foot stimulation at sensory and above flexor reflex threshold induced a similar time-dependent modulation in resting TA MEPs, that were facilitated when foot stimulation was delivered 40-100 ms before TMS. The flexor reflex and MEPs recorded from the medial hamstring muscle were modulated in a similar manner to that observed for the TA flexor reflex and MEP. CONCLUSION: Cutaneomuscular afferents from the distal foot can increase the output of the leg motor cortex area. Descending motor volleys that directly or indirectly depolarize flexor motoneurons increase the output of the spinal FRA interneuronal network. The parallel facilitation of flexor MEPs and flexor reflexes is likely cortical in origin. SIGNIFICANCE: Afferent mediated facilitation of corticospinal excitability can be utilized to strengthen motor cortex output in neurological disorders.

Brainstem and spinal reflex studies in patients with primary progressive freezing of gait.

Our aim was to investigate the extent and pattern of involved pathways using brainstem and spinal reflexes by comparing primary progressive freezing of gait (PPFOG) progressive supranuclear palsy (PSP) with FOG. Seven patients with PPFOG and age and sex matched seven PSP patients and 16 healthy subjects were included in the study. All subjects underwent blink reflex (BR), trigemino-cervical reflex (TCR), auditory startle reflex (ASR) and long latency flexor reflex (LLFR) investigations under the same conditions. All three groups had normal BR latencies. ASR probability was lowest in the PSP group and was highest in PPFOG (p=0.005). The presence rate of TCR was lowest in PSP and it was highest in PPFOG (p=0.007 for SC and p=0.023 for SCM). The presence rate and amplitude of LLFR (R II) were decreased in the PSP group (p=0.010 and p=0.031, respectively) whereas it was in a continuous pattern in some of PPFOG patients. ASR, TCR and LLFR were all inhibited in PSP and we suggest that suppression of all three reflexes is probably related to degeneration of brainstem reticular formation and basal ganglia connections. However, interestingly, in PPFOG, excitabilities of ASR and TCR circuits are increased suggesting loss of pathways mediating suprasegmental control.

Analgesic effects of dyspnoea: "Air hunger" does not inhibit the spinal nociception reflex in humans.

Dyspnoea has distinct sensory modalities, including air hunger and the sensation of excessive breathing "work/effort". Both have analgesic properties. In the case of work/effort, spinal mechanisms have been documented (inhibitory effect on the spinal nociceptive flexor reflex, RIII). This mechanism involves C-fibres. As C-fibres are unlikely to play a major role in air hunger, we hypothesised that inducing this type of dyspnoea would not result in RIII inhibition. Eight healthy volunteers were exposed to a hypercapnic hyperoxic gas mixture (5% CO2 and 95% O2) and asked to voluntarily fight the corresponding ventilatory reflex response by reducing tidal volume below its spontaneous level. Ventilatory variables and dyspnoea intensity (ordinal scale) were measured. Electromyography of the biceps femoris was used to record the amplitude of RIII in response to painful electrical sural nerve stimulation. Air hunger failed to inhibit the RIII reflex. We conclude that the mechanisms of air hunger induced analgesia do not include a spinal contribution and are therefore mostly central.