Arterio-venous metabolite and electrolyte responses to low-load training with and without blood flow restriction versus high-load training to failure.

ABSTRACTDespite growing interest in blood flow restriction (BFR) for enhancing training adaptations, its acute impacts on local and systemic physiological stress remain incompletely understood. This study compared the metabolic and perceptual responses of low‐intensity cycling (LI) with BFR (LI + BFR) to both LI and high‐intensity (HI) cycling without BFR, matched for time and external work. Ten males (26.9 ± 4.6 years) completed LI (20 min at 55% peak aerobic power output, PPO), LI + BFR (with 50% limb occlusion pressure), and HI (10 × 1 min at 90% PPO interspersed with 1‐min recovery at 20% PPO) protocols in a randomized cross‐over design. Interstitial metabolic responses were assessed via microdialysis in the vastus lateralis; systemic blood responses were evaluated via venous blood gas analysis. Cardiorespiratory responses, including heart rate, oxygen uptake, and ventilation, were continuously monitored during exercise. Serum creatine kinase (CK) and lactate dehydrogenase (LDH) were measured as indirect markers of muscle damage, and perceptual responses were documented. Muscle interstitial lactate and pyruvate were highest in HI, followed by LI + BFR, and lowest in LI (p < 0.05). Systemic blood and cardiorespiratory responses were comparable between LI + BFR and HI and exceeded LI (p < 0.05), while electrolyte shifts occurred across all conditions (p < 0.001) without between‐condition differences. All protocols increased CK and LDH 24–48 h post‐exercise, with the greatest increases in HI (p < 0.05). Perceived exertion and pain were higher in LI + BFR than in other conditions (p < 0.05). In conclusion, BFR intensifies local and systemic stress during LI and may be a potent strategy to promote muscle adaptive stimulus. However, when time and total external work are matched, high mechanical loading appears more effective in inducing local stress, which may be essential for further muscular adaptation processes.

Resistance training (RT) can improve functional outcomes among people with multiple sclerosis (PwMS) but is underutilized due to the use of heavy training loads. Low-load RT with blood flow restriction (RT + BFR) may provide an alternative. Therefore, the purpose of this study was to evaluate the effects of 12 wk of low-load RT + BFR and heavy-load RT on functional outcomes among PwMS. Seventeen PwMS (Expanded Disability Status Scale score, 0-6.5) completed 12 wk (2× a week) of heavy-load (65% of one-repetition maximum (1RM); n = 9) RT or low-load (30% of 1RM; n = 8) RT + BFR. Functional outcomes including gait speed (self-selected and fast 10-m Walk Test (10mWT)), walking endurance (6-Minute Walk Test (6MWT)), leg strength/transfers (Five Times Sit to Stand Test (5×STS), 30 Second Sit to Stand Test (30CST)), and fatigue (Modified Fatigue Impact Scale (MFIS)) were assessed every 4 wk. Improvements in 10mWT (fast) occurred earlier for low-load RT + BFR (1.31 ± 0.24 to 1.79 ± 0.53 m·s -1 from weeks 0 to 8; P = 0.005) than heavy-load RT (1.19 ± 0.31 to 1.63 ± 0.58 m·s -1 from weeks 4 to 12; P = 0.005). MFIS was lower for low-load RT + BFR (16.25 ± 15.59 au) compared with heavy-load RT (32 ± 13.63 au) after 4 wk ( P = 0.042). 6MWT only improved in heavy-load RT from baseline to week 12 (309.1 ± 97.5 to 390.5 ± 100.4 m; P = 0.001), although baseline walking distance was higher in the low-load RT + BFR group (429.3 ± 42.1 m; P = 0.006). Improvements in 5×STS and 30CST were similar for both groups. Low-load RT + BFR and heavy-load RT elicited comparable improvements among indices of strength, endurance, and walking speed with greater improvements in fatigue from low-load RT + BFR in PwMS. Thus, low-load RT + BFR may be a valuable modality to improve functional outcomes among PwMS in situations where heavy-load RT is intolerable.

BackgroundKnee osteoarthritis (KOA) is a common degenerative disease that causes pain, functional impairment, and reduced quality of life. Resistance training is considered as an effective approach to reduce the risk of muscle weakness in patients with KOA. Blood flow restriction (BFR) with low-load resistance training has better clinical outcomes than low-load resistance training alone. However, the degree of BFR which works more effectively with low-load resistance training has not been determined. The purpose of this study is to evaluate the effectiveness of different degrees of BFR with low-load resistance training in patients with KOA on pain, self-reported function, physical function performance, muscle strength, muscle thickness, and quality of life.MethodsThis is a study protocol for a randomized, controlled trial with blinded participants. One hundred individuals will be indiscriminately assigned into the following groups: two training groups with a BFR at 40% and 80% limb occlusion pressure (LOP), a training group without BFR, and a health education group. The three intervention groups will perform strength training for the quadriceps muscles twice a week for 12 weeks, while the health education group will attend sessions once a week for 12 weeks. The primary outcome is pain. The secondary outcomes include self-reported function, physical function performance, muscle strength of the knee extensors, muscle mass of the quadriceps, quality of life, and adverse events. Intention-to-treat analysis will be conducted for individuals who withdraw during the trial.DiscussionPrevious studies have shown that BFR with low-load resistance training is more effective than low-load resistance training alone; however, a high degree of BFR may cause discomfort during training. If a 40% LOP for BFR could produce similar clinical outcomes as an 80% LOP for BFR, resistance training with a low degree of BFR can be chosen for patients with KOA who are unbearable for a high degree of BFR.Trial registrationChinese Clinical Trial Registry ChiCTR2000037859 (http://www.chictr.org.cn/edit.aspx?pid=59956&htm=4). Registered on 2 September 2020

Despite accumulating evidence that blood flow restriction (BFR) training promotes muscle hypertrophy and strength gain, the underlying neurophysiological mechanisms have rarely been explored. The primary goal of this study is to investigate characteristics of cerebral cortex activity during BFR training under different pressure intensities. 24 males participated in 30% 1RM squat exercise, changes in oxygenated hemoglobin concentration (HbO) in the primary motor cortex (M1), pre-motor cortex (PMC), supplementary motor area (SMA), and dorsolateral prefrontal cortex (DLPFC), were measured by fNIRS. The results showed that HbO increased from 0 mmHg (non-BFR) to 250 mmHg but dropped sharply under 350 mmHg pressure intensity. In addition, HbO and functional connectivity were higher in M1 and PMC-SMA than in DLPFC. Moreover, the significant interaction effect between pressure intensity and ROI for HbO revealed that the regulation of cerebral cortex during BFR training was more pronounced in M1 and PMC-SMA than in DLPFC. In conclusion, low-load resistance training with BFR triggers acute responses in the cerebral cortex, and moderate pressure intensity achieves optimal neural benefits in enhancing cortical activation. M1 and PMC-SMA play crucial roles during BFR training through activation and functional connectivity regulation.

Blood flow restriction (BFR) training restricts arterial inflow and venous outflow from the extremity and can produce gains in muscle strength at low loads. Low-load training reduces joint stress and decreases cardiovascular risk when compared with high-load training, thus making BFR an excellent option for many patients requiring rehabilitation. Blood flow restriction has shown clinical benefit in a variety of patient populations including healthy patients as well as those with osteoarthritis, anterior cruciate ligament reconstruction, polymyositis/dermatomyositis, and Achilles tendon rupture. This video demonstrates BFR training in 3 clinical areas: upper extremity resistance training, lower extremity resistance training, and low-intensity cycling. All applications of BFR first require determination of total occlusion pressure. Upper extremity training requires inflating the tourniquet to 50% of total occlusion pressure, while lower extremity exercises use 80% of total occlusion pressure. Low-load resistance training exercises follow a specific repetition scheme: 30 reps followed by a 30-second rest and then 3 sets of 15 reps with 30-seconds rest between each. During cycle training, 80% total occlusion pressure is used as the patient cycles for 15 minutes without rest. Augmenting low-load resistance training with BFR increases muscle strength when compared with low-load resistance alone. In addition, low-load BFR has demonstrated an increase in muscle mass greater than low-load training alone and equivalent to high-load training absent BFR. A systematic review determined the safety of low-load training with BFR is comparable to traditional high-intensity resistance training. The most common adverse effects include exercise intolerance, discomfort, and dull pain which are also frequent in patients undergoing traditional resistance training. Severe adverse effects including deep vein thrombosis, pulmonary embolism, and rhabdomyolysis are exceedingly rare, less than 0.006% according to a national survey. Patients undergoing BFR rehabilitation experience less perceived exertion and demonstrate decreased pain scores compared with high-load resistance training. Blood flow restriction training is an effective alternative to high-load resistance training for patients requiring musculoskeletal rehabilitation for multiple disease processes as well as in the perioperative setting. Blood flow restriction has been shown to be a safe training modality when managed by properly trained physical therapists and athletic trainers.

It has been suggested that circulating hormones and cytokines are important in the adaptive response to low-load resistance training (LLRT) with blood flow restriction (BFR); however, their response following this type of training in older men is unclear. Seven healthy older men (age 71.0 ± 6.5 year, height 1.77 ± 0.05 m, body mass 80.0 ± 7.5 kg; mean ± SD) performed five sets of unilateral LLRT knee extensions (20 % 1-RM) of both limbs, with or without BFR in a counterbalanced order. For the BFR condition, a pressure cuff was applied on the upper thigh and inflated to ~110 mmHg. Venous blood samples were taken at rest and 30-, 60- and 120-min post-exercise and measured for plasma concentrations of growth hormone (GH), insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF), cortisol and interleukin-6 (IL-6). GH increased (P < 0.05) from rest to 30-min post-exercise and was greater (P < 0.05) during LLRT with BFR than without. VEGF was significantly (P < 0.05) elevated from resting levels at 30-, 60- and 120-min post-exercise following LLRT with BFR with no change seen following LLRT without BFR. IL-6 increased (P < 0.05) from 30- to 60-min post-exercise and remained elevated at 120-min post-exercise in both conditions. Cortisol and IGF-1 were unaffected following exercise. In conclusion, a single bout of LLRT with BFR increases the circulating concentrations of GH and VEGF in older men and may explain the skeletal muscle and peripheral vascular adaptations observed following training with BFR.

The response of calf muscle strength, resting (R (bf)) and post-occlusive (PO(bf)) blood flow were investigated following 4 weeks resistance training with and without blood flow restriction in a matched leg design. Sixteen untrained females performed unilateral plantar-flexion low-load resistance training (LLRT) at either 25% (n = 8) or 50% (n = 8) one-repetition maximum (1 RM). One limb was trained with unrestricted blood flow whilst in the other limb blood flow was restricted with the use of a pressure applied cuff above the knee (110 mmHg). Regardless of the training load, peak PO(bf), measured using venous occlusion plethysmography increased when LLRT was performed with blood flow restriction compared to no change following LLRT with unrestricted blood flow. A significant increase (P < 0.05) in the area under the blood time-flow curve was also observed following LLRT with blood flow restriction when compared LLRT with unrestricted blood flow. No changes were observed in R (bf) between groups following training. Maximal dynamic strength (1 RM), maximal voluntary contraction and isokinetic strength at 0.52 and 1.05 rad s(-1) also increased (P < 0.05) by a greater extent following resistance training with blood flow restriction. Moreover, 1 RM increased to a greater extent following training at 50% 1 RM compared to 25% 1 RM. These results suggest that 4 weeks LLRT with blood flow restriction provides a greater stimulus to increase peak PO(bf) as well as strength parameters than LLRT with unrestricted blood flow.

Blood flow restricted resistance training in older adults at risk of mobility limitations

BackgroundWhile the effects of blood-flow restriction (BFR) training on various performance outcomes have been widely studied, the combination of BFR with low-load (LL) resistance training for post-activation performance enhancement (PAPE), particularly in vertical jump performance, has not been fully explored. This study aimed to investigate whether combining BFR with LL resistance training can enhance vertical jump performance in male collegiate athletes.MethodsFifteen male strength trainers (mean ± standard deviation (SD): age 21.7 ± 1.4 years, body mass 77.2 ± 6.3 kg, and height 179.1 ± 5.7) with at least two years of resistance training experience participated in three experimental trials using a randomized crossover design with 72-hour intervals: (a) low-load resistance exercise at 30% one repetition maximum (1RM) back squat combined with BFR for four sets of 15 repetitions (BFR+LL); (b) low-load resistance exercise without BFR for 4 sets of 15 repetitions (LL); and (c) a control condition involving passive rest (CON). Countermovement jump (CMJ) performance , including vertical jump height (VJH), relative peak power output (RPP), force impulse (FI), and rate of force development (RFD), was assessed at baseline, immediately after, and at 3-, 6-, 9-, and 12-minutes post-protocol. Both peak and mean CMJ were measured to evaluate performance changes.ResultsThe repeated measures analysis of variance (ANOVA) revealed significant condition × time interactions (p < 0.001) for VJH, RPP, and FI. Post-hoc comparisons demonstrated that BFR+LL resulted in significant improvements in VJH, RPP, and FI at 12 minutes post-protocol relative to both the CON and LL conditions (p < 0.05). Specifically, VJH increased by 7.17% (effect size (ES) = 0.79), RPP by 2.26% (ES = 0.31), and FI by 3.21% (ES = 0.29) compared to CON at 12 minutes following the BFR+LL protocol. In contrast, a significant decline in performance (p < 0.05) was observed immediately after BFR+LL, with VJH decreasing by −9.1 ± 5.1% (ES = −1.12), RPP by −8.3 ± 4.3% (ES = −1.16), and FI by −5.0 ± 2.2% (ES = −0.44) compared to baseline. No significant changes in RFD or peak CMJ performance were observed across the three conditions (p > 0.05).ConclusionThe study suggests that BFR+LL resistance training may enhance acute vertical jump performance 12 minutes post-exercise, despite an initial decline in performance immediately following the protocol.

The main goal of musculoskeletal rehabilitation is to achieve the pre-injury and/or pre-surgery physical function level with a low risk of re-injury. Blood flow restriction (BFR) training is a promising alternative to conventional therapy approaches during musculoskeletal rehabilitation because various studies support its beneficial effects on muscle mass, strength, aerobic capacity, and pain perception. In this perspective article, we used an evidence-based progressive model of a rehabilitative program that integrated BFR in 4 rehabilitation phases: (1) passive BFR, (2) BFR combined with aerobic training, (3) BFR combined with low-load resistance training, and (4) BFR combined with low-load resistance training and traditional high-load resistance training. Considering the current research, we propose that a BFR-assisted rehabilitation has the potential to shorten the time course of therapy to reach the stage where the patient is able to tolerate resistance training with high loads. The information and arguments presented are intended to stimulate future research, which compares the time to achieve rehabilitative milestones and their physiological bases in each stage of the musculoskeletal rehabilitation process. This requires the quantification of BFR training-induced adaptations (eg, muscle mass, strength, capillary-to-muscle-area ratio, hypoalgesia, molecular changes) and the associated changes in performance with a high measurement frequency (≤1 week) to test our hypothesis. This information will help to quantify the time saved by BFR-assisted musculoskeletal rehabilitation. This is of particular importance for patients, because the potentially accelerated recovery of physical functioning would allow them to return to their work and/or social life earlier. Furthermore, other stakeholders in the health care system (eg, physicians, nurses, physical therapists, insurance companies) might benefit from that with regard to work and financial burden.

The present study aimed to evaluate whether blood flow restriction (BFR) can prevent exercise-induced muscle damage in resistance exercise (RE) performed until concentric muscle failure (CMF). Twenty healthy volunteers (25 ± 4 years, 80.4 ± 11.8 kg, 175 ± 8 cm) performed three sets of unilateral biceps curl exercise (40% of 1RM) with (RE + BFR) and without (RE) BFR until CMF. A third condition was to perform the same number of repetitions as RE + BFR without using BFR (matched). Performing fewer repetitions, RE + BFR caused muscle fatigue post-exercise as high as that caused by RE. In addition, the range of motion, upper arm circumference, pressure pain threshold, and maximal voluntary contraction were immediately affected by our exercise protocol with BFR, returning rapidly to basal values within 24 h, while in RE, muscle damage markers remained elevated until 48 h post-exercise. The same results were observed concerning serum creatine kinase and lactate dehydrogenase activity. Thus, BFR + RE performed until CMF attenuated muscle damage following similar metabolic stress to RE alone performed until CMF, with less work volume.

Blood flow restriction (BFR) training enhances muscular strength and hypertrophy in several populations including older adults and injured athletes. However, the efficacy of emerging BFR technologies on muscular adaptations, vascular health, and pain is unclear. The purpose of this study was to examine muscular performance, pain and vascular function in response to eight weeks of BFR compared to traditional resistance training and a control group. Randomized control trial. Thirty-one overtly healthy participants (age: 23 ± 4y, 65% female) underwent eight weeks of supervised high load resistance training (RES), low load resistance training with BFR (BFR) or no training (control, CON). RES and BFR (with pneumatic bands) performed seven upper and lower body exercises, two to three sessions per week at 60% and 30% of one-repetition maximum (1RM), respectively. Twenty-four hours post-exercise, general muscle soreness was assessed via a visual analog scale (VAS) and present pain intensity (PPI) of the McGill Pain Questionnaire. At baseline and after eight weeks, participants underwent one-repetition maximum (1RM), and flow-mediated dilation (FMD) testing. At baseline all groups exhibited similar muscle strength and endurance and vascular function. At the end of training, RES and BFR groups significantly increased muscle strength (1RM) to a similar magnitude as compared to the CON group (p < 0.0001), but did not alter body composition. FMD significantly increased in RES and BFR groups compared to CON group (p = 0.006). VAS and PPI were similar between RES and BFR groups throughout the exercise sessions until VAS decreased in the BFR group after the last session compared to the RES group (p = 0.02). Compared to RES, BFR resulted in similar muscular performance (strength and endurance) and vascular improvements at a lower exercise intensity, suggesting BFR is an effective alternative to high load resistance training. Further longitudinal studies may gain greater understanding regarding general muscle pain and soreness when using BFR. Therapy, Level 2.

PURPOSE: We assessed whether blood flow restriction (BFR) training with the addition of heat stress (BFRH) improves hypertrophy, muscle strength and sport-specific physical performance in rugby union players, compared to BFR training alone. METHODS: Nineteen elite U23 rugby union male players were randomly assigned to BFRH (n = 7), BFR (n = 6) or traditional high-load resistance training (CON, n = 6) groups. BFRH and BFR groups trained twice weekly for 3 weeks using BFR exercise (half squat, 4 sets of 30-15-15-15 repetitions at 30% 1 maximum repetition (1RM) with 30 s of passive recovery; 50% of resting arterial occlusion pressure) in hot (37°C) and cool (22°C) conditions, respectively. Before and after the intervention, thigh circumference, half squat 1RM, squat jump force-velocity profile, and performance in vertical jump, sprint and repeated-sprint ability (RSA) tasks were measured. Muscle damage marker (creatine kinase) was measured before and after (0.1-24 h) the first and last training session. RESULTS: Thigh circumference significantly increased (P<0.001) from pre- to post-training in both BFRH (+6%, P<0.001) and BFR (+4%, P<0.05). Significant time × group interaction revealed improvement in half squat 1RM (+12% and +19%, P<0.01) and maximal force component (+102% and +116%, P<0.001) of the force-velocity profile for BFRH and BFR. Vertical jump performance did not change. 10-m sprint (-5% and -3%, P<0.001) and RSA best and total times (both -2%, both P≤0.001) improved similarly in BFRH and BFR. Although not significant, muscle damage was lowered after the last session in BFRH only. No pre- to post-training changes occurred in CON. CONCLUSIONS: Combining BFR training with heat stress can potentially induce hypertrophy and improve rugby union-specific physical performance while also inducing lower muscle damage than BFR training alone. Such gains could be of benefit during competitive period or rehabilitative setting.

Blood flow restriction resistance training enhances athletic adaptations via distinct mechano-metabolic pathways. This review synthesizes evidence comparing three blood flow restriction resistance training modalities: Low-load resistance training with blood flow restriction (using 20%–30% of one-repetition maximum) prioritizes metabolic stress (lactate and hydrogen ion accumulation, cellular swelling), activating growth hormone (GH)/insulin-like growth factor 1 (IGF-1)/mechanistic target of rapamycin (mTOR) pathways to promote type I muscle fiber hypertrophy, making it suitable for joint-sparing rehabilitation scenarios. Supplemental blood flow restriction resistance training programs combine high-load tension (utilizing 75%–90% of one-repetition maximum) with additional blood flow restriction to produce an acute synergistic effect. This method enhances the recruitment of type IIa/x muscle fibers and prolongs mTOR phosphorylation. Combined blood flow restriction resistance training employs alternating cycles of high-load phases (70%–85% 1RM) and blood flow restriction phases (hypoxia-inducible factor 1-alpha (HIF-1α)-mediated angiogenesis), optimizing phosphocreatine resynthesis and neural drive to achieve specialization of type IIx muscle fibers. Periodized application requires matching modalities with training phases: combined blood flow restriction training for hypertrophy during the preparatory phase, supplemental blood flow restriction training for strength maintenance during the competitive phase, and low-load resistance training with blood flow restriction for active recovery. This mechanistic framework supports evidence-based blood flow restriction resistance training programming to maximize athletic adaptations while mitigating injury risk.

Acute blood flow restriction (BFR) by itself or in combination with low-intensity aerobic and/or low-load resistance exercise has been shown to result in favourable effects on skeletal muscle, namely increases in muscle size and strength (Loenneke et al. 2012). These positive muscular adaptations have been observed across a wide range of populations (e.g. athletes, elderly, diseased). Previous research indicates that BFR resistance exercise stimulates muscle protein synthesis (MPS) (Gundermann et al. 2012); however, little is known about the exact cellular mechanisms behind that response on muscle protein synthesis or muscle hypertrophy. Previous research suggests that the muscle hypertrophic effect may, in part, be related to the concomitant decrease in the mRNA gene expression of E3-ligases such as MURF-1 (8 h post-decrease; Manini et al. 2011) and atrogin (Manini et al. 2011). Furthermore, Laurentino et al. (2012) have observed decreased mRNA gene expression of myostatin, with an increased expression of the follistatin isoforms following low-load resistance exercise with BFR. In a recent issue of The Journal of Physiology, Nielsen et al. (2012) presented research that suggests that the proliferation of myogenic stem cells may be an additional mechanism involved in the muscle hypertrophic response to high-frequency low-load resistance exercise with BFR. Briefly, participants performed four sets of knee extensor exercise to failure at 20% of their concentric one repetition maximum. The researchers found that performing 23 sessions of low-load BFR exercise within 19 days resulted in marked increases in muscular strength and muscle fibre cross-sectional area when measured greater than 3 days post-training. It should be mentioned that there were transient increases in muscle fibre cross-sectional area after 5 days of the intervention in both groups; however, this was thought to be due to exercise-induced cell swelling and not a reflection of true muscle hypertrophy. This is supported by the post-training data which indicated increases in muscle size and strength only in the BFR group, while the work-matched control groups’ fibre cross-sectional area was equivalent to baseline levels. These positive muscular adaptations in the BFR group were accompanied by a substantial upregulation in myogenic stem cells, resulting in nuclear additions to the exercised muscle fibre. The data reported in the Nielsen et al. (2012) investigation provides valuable insight into the acute and chronic effects of high-frequency low-load resistance training with BFR. The increased proliferation of myogenic stem cells with BFR resistance training is significant as it is thought that the myonuclear donation is required in order to have substantial increases in human muscle fibre cross-sectional area. Further support of this notion comes from their data which show positive correlations between the change in myonuclei number per fibre and muscle fibre area as well as between the relative change in myogenic stem cells per fibre and muscle fibre area. The exact reason behind the large increase in myogenic stem cell proliferation is not known, but the authors speculated that the activation and proliferation of myogenic stem cells may be acutely stimulated by BFR-induced stretch-, hypoxia-, and/or contraction-induced nitric oxide secretion. In addition, they noted that it was unlikely that the increased proliferation was due to muscle cell membrane damage because the authors did not find any visible signs of damage to the basal lamina from their laminin stainings. This finding is consistent with previous BFR studies, which indicate minimal to no muscle damage with this type of exercise. It would be interesting if future research could expand on these findings and investigate whether or not there is proliferation of myogenic stem cells and a subsequent myonuclear addition in response to low-intensity aerobic exercise in combination with BFR. This type of study would be useful as low-intensity aerobic exercise with BFR has been observed to elicit significant increases in muscle size and strength (Loenneke et al. 2012). Currently it is unknown if the mechanisms behind that effect are different to that observed with low-load resistance training. Additionally, BFR in the absence of exercise has been shown to attenuate atrophy; however, it is unclear as to the exact mechanism involved with BFR in the absence of muscle contraction. Whether or not there is a relationship between the application of BFR in the absence of muscle contraction and myogenic stem cells is unknown but might be an interesting avenue of research to explore in the future.