Wrong goal! Survivors want spasticity cured not just analyzed. WILL YOU PLEASE FOR ONCE ACTUALLY SOLVE STROKE FOR SURVIVORS?
Examining the role of intrinsic and reflexive contributions to ankle joint hyper-resistance treated with botulinum toxin-A
Journal of NeuroEngineering and Rehabilitation volume 20, Article number: 19 (2023)
Abstract
Background
Spasticity, i.e. stretch hyperreflexia, increases joint resistance similar to symptoms like hypertonia and contractures. Botulinum neurotoxin-A (BoNT-A) injections are a widely used intervention to reduce spasticity. BoNT-A effects on spasticity are poorly understood, because clinical measures, e.g. modified Ashworth scale (MAS), cannot differentiate between the symptoms affecting joint resistance. This paper distinguishes the contributions of the reflexive and intrinsic pathways to ankle joint hyper-resistance for participants treated with BoNT-A injections. We hypothesized that the overall joint resistance and reflexive contribution decrease 6 weeks after injection, while returning close to baseline after 12 weeks.
Methods
Nine participants with spasticity after spinal cord injury or after stroke were evaluated across three sessions: 0, 6 and 12 weeks after BoNT-A injection in the calf muscles. Evaluation included clinical measures (MAS, Tardieu Scale) and motorized instrumented assessment using the instrumented spasticity test (SPAT) and parallel-cascade (PC) system identification. Assessments included measures for: (1) overall resistance from MAS and fast velocity SPAT; (2) reflexive resistance contribution from Tardieu Scale, difference between fast and slow velocity SPAT and PC reflexive gain; and (3) intrinsic resistance contribution from slow velocity SPAT and PC intrinsic stiffness/damping.
Results
Individually, the hypothesized BoNT-A effect, the combination of a reduced resistance (week 6) and return towards baseline (week 12), was observed in the MAS (5 participants), fast velocity SPAT (2 participants), Tardieu Scale (2 participants), SPAT (1 participant) and reflexive gain (4 participants). On group-level, the hypothesis was only confirmed for the MAS, which showed a significant resistance reduction at week 6. All instrumented measures were strongly correlated when quantifying the same resistance contribution.
Conclusion
At group-level, the expected joint resistance reduction due to BoNT-A injections was only observed in the MAS (overall resistance). This observed reduction could not be attributed to an unambiguous group-level reduction of the reflexive resistance contribution, as no instrumented measure confirmed the hypothesis. Validity of the instrumented measures was supported through a strong association between different assessment methods. Therefore, further quantification of the individual contributions to joint resistance changes using instrumented measures across a large sample size are essential to understand the heterogeneous response to BoNT-A injections.
Background
Botulinum neurotoxin-A (BoNT-A) injections are currently the most frequently used clinical intervention for focal spasticity [1,2,3]. Spasticity is a common symptom after various brain and neural injuries, such as spinal cord injury (SCI) or stroke, referring to an exaggerated stretch reflex, i.e. stretch hyperreflexia [4, 5]. Spasticity is perceived as an increased joint resistance to movement, i.e. joint hyper-resistance. BoNT-A injections are used clinically to reduce muscle activity and hence spasticity [1]. BoNT-A injections reduce muscle activity by inhibiting the release of acetylcholine at the neuromuscular junction, which chemically denervates the exposed muscle fibers. BoNT-A effects reduce after 2 to 4 months due to nerve sprouting and muscle re-innervation [1].
Clinical evaluation of BoNT-A injections has shown a significant reduction in joint resistance after 2–8 weeks using the modified Ashworth scale (MAS) [6,7,8]. With the MAS, currently a common clinical test, clinicians evaluate overall joint resistance, which can physiologically include tissue characteristics, and tonic and reflexive muscle activity [5, 9,10,11]. For the MAS, a single passive movement profile is repeatedly applied, whereas movements with varying characteristics, e.g. slow and fast velocities, are required to unravel joint resistance contributions. Therefore, the MAS can clinically only evaluate spasticity indirectly and cannot distinguish between spasticity and other symptoms as involuntary background activity, shortened soft tissue, contractures and muscle fibrosis [4, 12, 13]. Furthermore, the MAS has a questionable reliability, especially when applied at the lower limb [11, 14]. Hence, the clinical effect of BoNT-A injections on spasticity is poorly understood, while BoNT-A injections are a frequently used clinical intervention for spasticity.
Quantification of the intrinsic and reflexive contributions to joint hyper-resistance is essential to understand the beneficial and adverse effects of BoNT-A injections and support clinical decision making. BoNT-A injections can, for example, have side-effects and should ideally only be administered to patients who suffer from increased reflexive contributions to joint hyper-resistance [15]. Objective information on both intrinsic and reflexive joint resistance can support clinical decision making and help evaluate treatment effects [5]. The intrinsic resistance represents the combination of tissue-related non-neural and tonic neural contributions to joint resistance [10]. The reflexive resistance, representing the phasic neural contributions, can be used as measure for spasticity. Model-based processing of neuromechanical responses can be used to unravel and quantify the intrinsic and reflexive contributions [10, 16,17,18,19,20]. Furthermore, instrumentation and motorization using robotic devices can improve precision, consistency and objectivity of the applied movements and measurements [21,22,23].
Model-based evaluation of BoNT-A effects on joint hyper-resistance contributions have been applied using neuromechanical models [24,25,26,27]. These studies showed conflicting results on BoNT-A effects with either no change or a significant reduction of the reflexive resistance observed after injection. The neuromechanical modelling approaches used limited experimental datasets measured over the full passive range of motion (pROM), similar to current clinical measures. The subsequent joint resistance estimation primarily relies on a priori knowledge and simplifying assumptions. As a result, these methodologies are sensitive to incomplete model definitions and imperfect a priori knowledge [17, 18, 20]. Furthermore, the lack of a gold standard complicates interpretation of the reported conflicting results [5, 28, 29]. Besides the selected model, differences in reported BoNT-A effects may also be influenced by participant heterogeneity, the experimental setup, and the assessed joint. Given the conflicting results and lack of a gold standard, investigating fundamentally different approaches to assess joint hyper-resistance is of interest to improve understanding of BoNT-A effects.
An alternative approach to assess BoNT-A effects on joint hyper-resistance contributions is data-driven modelling. Data-driven modelling evaluation of BoNT-A effects on joint hyper-resistance contributions could be executed using system identification [10, 16, 30, 31]. For example, the parallel-cascade (PC) system identification technique has shown the ability to discriminate spastic participants from controls and paretic from non-paretic joints [30, 32]. The PC technique has also shown good group-level responsiveness during the evaluation of several clinical treatments, like functional electrical stimulation-assisted walking, Tizanidine and robot-assisted gait training [33,34,35]. Currently, no system identification results have been reported on BoNT-A effects. Contrary to neuromechanical modelling, the system identification techniques previously tested in a clinical setting used rich experimental datasets measured over only a limited portion of the pROM [30,31,32,33,34,35]. As intrinsic and reflexive joint resistance depend on joint angle, the obtained joint resistance estimates do not characterize the full pROM [36].
The goal of this paper was to distinguish the contribution of intrinsic and reflexive ankle joint resistance for participants treated with BoNT-A injections to reduce spasticity. We hypothesized that reflexive joint resistance decreases 6 weeks after injection, while returning close to baseline after 12 weeks [24, 25]. Due to the reduced reflexive joint resistance, we also expected the overall joint resistance to decrease 6 weeks after injection, while returning close to baseline after 12 weeks [6,7,8]. In absence of a gold standard, the joint resistance contributions were assessed using multiple joint resistance measures with different characteristics and limitations. Joint resistance contributions were estimated using clinical measures (MAS/Tardieu Scale) [9, 37], an instrumented spasticity test (SPAT) [22, 23] and a parallel-cascade (PC) system identification technique [10, 30]. To support validity of the measures used, the linear association between the various outcome measures was investigated.
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