ABSOLUTELY FUCKING USELESS RESEARCH! Nothing here will get survivors recovered! You're all fired.
Testing spasticity mechanisms in chronic stroke before and after intervention with contralesional motor cortex 1 Hz rTMS and physiotherapy
Journal of NeuroEngineering and Rehabilitation volume 20, Article number: 150 (2023)
Abstract
Background
Previous studies showed that repetitive transcranial magnetic stimulation (rTMS) reduces spasticity after stroke. However, clinical assessments like the modified Ashworth scale, cannot discriminate stretch reflex-mediated stiffness (spasticity) from passive stiffness components of resistance to muscle stretch. The mechanisms through which rTMS might influence spasticity are also not understood.
Methods
We measured the effects of contralesional motor cortex 1 Hz rTMS (1200 pulses + 50 min physiotherapy: 3×/week, for 4–6 weeks) on spasticity of the wrist flexor muscles in 54 chronic stroke patients using a hand-held dynamometer for objective quantification of the stretch reflex response. In addition, we measured the excitability of three spinal mechanisms thought to be related to post-stroke spasticity: post-activation depression, presynaptic inhibition and reciprocal inhibition before and after the intervention. Effects on motor impairment and function were also assessed using standardized stroke-specific clinical scales.
Results
The stretch reflex-mediated torque in the wrist flexors was significantly reduced after the intervention, while no change was detected in the passive stiffness. Additionally, there was a significant improvement in the clinical tests of motor impairment and function. There were no significant changes in the excitability of any of the measured spinal mechanisms.
Conclusions
We demonstrated that contralesional motor cortex 1 Hz rTMS and physiotherapy can reduce the stretch reflex-mediated component of resistance to muscle stretch without affecting passive stiffness in chronic stroke. The specific physiological mechanisms driving this spasticity reduction remain unresolved, as no changes were observed in the excitability of the investigated spinal mechanisms.
Background
Besides paresis, post-stroke disability often arises from spasticity and soft tissue contractures which emerge weeks or months after the injury. Spasticity, which impacts 20–40% of survivors [1] can contribute to issues such as restricted range of motion (ROM), abnormal posture, and pain [2]. Lance's widely cited 1985 definition describes spasticity as a “velocity-dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex as part of the upper motor neuron syndrome” [3].
Many non-invasive and non-pharmacologic intervention options are emerging for treatment of spasticity [4, 5]. In particular, there is growing evidence to support the use of the non-invasive brain stimulation method, repetitive transcranial magnetic stimulation (rTMS), for reducing spasticity after stroke [6,7,8,9,10,11,12]. RTMS elicits an electric field within the brain, causing alterations in the excitability of neurons not only in the targeted brain areas at the stimulation site but also in distant brain areas, including the contralateral motor cortex and subcortical structures [13,14,15]. The precise mechanism by which rTMS might cause behavioral effects on spasticity is unclear. It is plausible that rTMS can modulate the activity of the spinal circuitry, implicated in spasticity observed in spastic stroke patients, by modifying the excitability of cortical centers that project to this circuitry [16,17,18].
A recent systematic review of randomized controlled trials concluded that the use of contralesional motor cortex 1 Hz rTMS has a positive effect on reducing spasticity as estimated from the modified Ashworth scale (MAS) [19]. The MAS [20] is performed by passively stretching a joint and simultaneously estimating the perceived resistance on a 6-point ordinal scale. Though widely used, the MAS suffers from poor reliability, sensitivity and objectivity [2, 21,22,23]. Importantly, the examiner perceiving the resistance cannot discriminate the velocity-dependent stretch reflex, i.e., true spasticity, from the passive stiffness that results from changes that occur in the muscle and the surrounding soft tissues after the injury [24,25,26,27,28,29]. Establishing therapeutic effects of rTMS on spasticity requires careful quantification of the reflex-mediated component of the resistance to muscle stretch and discriminating it from the passive stiffness components.
Significant progress has been achieved in recent years regarding the development and testing of devices that enable the objective quantification of spasticity and discrimination of the different components which contribute to the resistance to passive joint stretch [25, 30,31,32,33,34]. Using a hand-held dynamometer, which enables the simultaneous recording of biomechanical and muscle activity data [29, 33,34,35,36,37], we objectively measured the stretch reflex-mediated stiffness in the wrist joint in a cohort of chronic stroke patients [38].
Central to the pathophysiology of spasticity is the excitability of the monosynaptic Ia afferent-motoneurone (MN) pathway underlying the stretch reflex [39]. The excitability of the stretch reflex circuit is regulated by complex spinal circuitries, which themselves are modulated by supraspinal pathways descending from cortical and brainstem structures [40]. After an upper motor neuron injury, there is an imbalance in the cortical and subcortical regulatory input to the spinal cord, which triggers secondary changes in the excitability of the spinal circuitry over weeks and months [41,42,43]. As a result, reflex hyperexcitability emerges as a gradual adaptation in the spinal circuitry distal to the lesion [42, 44,45,46]. Changes in the excitability of certain pathways and their contribution to the clinical picture of spasticity has been the topic of many studies in humans and animal models in the last decades [40, 44, 47,48,49].
Multiple spinal inhibitory mechanisms have been found to be reduced in spastic stroke patients and identified as potentially contributing to stretch reflex hyperexcitability in both upper and lower limbs (for review see [44, 46]). These include (1) post-activation depression, a frequency-dependent reduction in the release of neurotransmitters from previously activated fibers. A mechanism that has consistently been found to be reduced on the affected but not the unaffected side in spastic patients after stroke, both in the lower [50,51,52] and upper limbs [50, 53]. The extent of the reduction in post-activation depression was also found to be related to the degree of spasticity measured clinically in the lower limb [50, 52] as well as in the upper limb [53]; (2) presynaptic inhibition of Ia terminals, a mechanism which modulates the synaptic transmission from Ia afferents before they reach the target neurons. Multiple studies have reported a significant reduction in presynaptic inhibition in the upper limb in the stroke population [54,55,56], but this reduction was found to be not exclusive to the affected side [53]; (3) reciprocal inhibition from muscle spindles of the antagonist muscle group. This disynaptic inhibition is mediated through Ia afferents and Ia inhibitory interneurons, which are normally controlled by excitatory descending pathways including the corticospinal tract [46]. At rest, a decrease in Ia reciprocal inhibition has been observed in spastic patients in the upper limb [55, 56] and even potentially converted into facilitation from flexors to extensors in the lower limb [57,58,59].
An intervention which causes clinical improvements in “spasticity” would be expected to interact with its central pathophysiological mechanisms i.e., the excitability of the stretch reflex and the spinal circuits involved in its modulation. In humans, corticospinal neurons project to a large group of spinal interneurons and modulate their activity [60,61,62,63,64]. It is likely that rTMS can change the excitability of the spinal circuitry by modulating the excitability of cortical centers that project to this circuitry [16,17,18]. In addition, rTMS can modify transmission in neuronal circuitries in deeper lying structures in the brain including the brain stem, which itself plays an important role in controlling the spinal reflex excitability through direct and indirect projections [40].
In this study we aimed to objectively quantify the effects of an rTMS and physiotherapy intervention on spasticity of the wrist flexors in chronic stroke patients. Additionally, we explored possible mechanisms through which the cortical effects of rTMS might interact with spinal mechanisms thought to be related to stretch reflex hyperexcitability.
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