You can have your doctor get this to see if it
is useful. Assuming that your doctor does more than write E.T.(Evaluate
and Treat) prescriptions
Priming the Brain to Capitalize on Metaplasticity in Stroke Rehabilitation
Repetitive transcranial magnetic stimulation (rTMS) is emerging as a potentially valuable intervention to augment the effects of behavioral therapy for stroke. When used in conjunction with other therapies, rTMS embraces the concept of metaplasticity. Due to homeostatic mechanisms inherent to metaplasticity, interventions known to be in isolation to enhance excitability can interact when applied successively under certain timing conditions and produce enhanced or opposite effects. Similar to “muscular wisdom,” with its self-protective mechanisms, there also appears to be “synaptic wisdom” in neural networks with homeostatic processes that prevent over- and under-excitability. These processes have implications for both enhancing and suppressing the excitability effects from behavioral therapy. The purpose of this article is to relate the concept of metaplasticity, as derived from studies in humans who are healthy, to stroke rehabilitation and consider how it can be leveraged to maximize stroke outcomes.
Rehabilitation following stroke can follow the strategy of substitution or restitution. For the upper limb, substitution may involve activation of the contralesional hemisphere to direct movements with the nonparetic limb or use of adaptive maneuvers or devices to substitute for the impairments in the paretic limb. Restitution involves effort to reinstate function in the ipsilesional hemisphere to maximize recovery of the paretic limb. Depending on stroke size and location, a substitution strategy may be the only option. However, given that greater improvement in functional recovery is correlated with elevated excitability in the ipsilesional primary motor area (M1),1 whereas elevated excitability of contralesional M1 is associated with poorer prognosis for recovery of the affected hand,2 a restitution strategy is generally preferred. Repetitive transcranial magnetic stimulation (rTMS) is an emerging intervention in stroke rehabilitation used to condition the brain to make subsequent behavioral therapy more effective. As will be described, however, conditioning of neural networks is complex. Changes in brain plasticity resulting from the conditioning of neural networks may change the brain in unexpected ways—some more favorable and some less favorable for promoting recovery. Such changeable plasticity (ie, the plasticity of synaptic plasticity) is known as metaplasticity.3 The purpose of this article is to elucidate some of the principles of metaplasticity and how these principles can be used to synergize rTMS with behavioral therapy to optimize a return of ipsilesional excitability in M1 and promote recovery from stroke.
The Plastic Brain in Stroke
To understand the application of rTMS in stroke neurorehabilitation, it is first helpful to understand the adaptive and maladaptive factors that influence synaptic plasticity and recovery following stroke. In addition to neuronal death, stroke alters neurotransmitter activity, particularly gamma-aminobutyric acid-A (GABAA). GABAA is an inhibitory neurotransmitter known to decrease neuronal firing probability.4 During the acute phase of stroke recovery, the peri-infarct region demonstrates diminished excitability attributed to increased GABAA activity.5 This initial GABAA upregulation early in stroke may serve as a neuroprotective mechanism to minimize excitotoxicity and neuronal death. Yet, in the subacute stage, downregulation of GABAA signaling occurs.6 Related to stroke recovery, downregulation of GABAA is integral to both structural7 and electrophysiological8 reorganization in animals and reduced intracortical inhibition in humans.9,10
Interestingly, even with small strokes induced in animals, reduced GABAA inhibition is widespread to include not only the peri-infarct zone but also the contralesional hemisphere.6 Reduced intracortical inhibition in the contralesional hemisphere enhanced the use of and reliance on compensatory motor learning strategies in rodents.11 Indeed, studies in rats have shown that induced lesions to one sensorimotor cortex resulted in increased synaptogenesis and dendritic arborization in the contralesional sensorimotor cortex12,13 and were related to improved motor skill in the nonparetic forelimb.12,13 Hsu and Jones14 and Allred et al15 demonstrated similar results in rodents and cautioned that such early synaptic changes in the contralesional hemisphere, combined with motor training of the nonparetic limb, could diminish the recovery of the paretic limb. The corollary in humans is that such reorganization may facilitate substitutive motor relearning strategies involving contralesional hemispheric control of both nonparetic and paretic limbs. A reorganization scheme involving ipsilateral control of the paretic limb is detrimental to a restitution strategy because of an exaggeration of a phenomenon known as interhemispheric inhibition (IHI).
Interhemispheric Inhibition
Ferbert et al16 demonstrated IHI by applying a conditioning pulse of transcranial magnetic stimulation (TMS) to M1 of one hemisphere and a second TMS pulse, referred to as a test pulse, to contralateral M1 a short time later. Compared with unconditioned test pulse responses, Ferbert et al16 found reduced corticospinal excitability in response to the test pulse when a conditioning pulse preceded the test pulse. The effect, mediated through corpus callosum pathways, is thought to prevent mirror movements with the opposite hand during volitional unilateral movements.17 Following stroke, however, IHI becomes unbalanced, with contralesional M1 exerting exaggerated inhibition onto the ipsilesional M1.18 The imbalance of IHI may be a manifestation of contralesional M1 reorganization in response to a reduced GABAA environment. Over time, repetitive voluntary effort with the nonparetic hand, in an effort to compensate for the paretic hand, reinforces the reorganization in the contralesional M1. Thus, a consequence of persisting overactivity in the contralesional M1 from reduced GABAA inhibition is an abnormally strong IHI exerted on the ipsilesional M1.19–21 In this regard, the ipsilesional M1 becomes “doubly disabled”20 by the stroke itself and by the exaggerated IHI imparted from contralesional M1. Figures 1 and 2 illustrate balanced IHI in a healthy brain and unbalanced IHI in a brain following stroke, respectively.
Interhemispheric intervention (IHI): participant who is healthy. (A) Setup for measuring IHI with two 50-mm figure-8 coils over left and right primary motor areas (M1) of participant who is healthy and electromyography electrodes on bilateral first dorsal interosseous (FDI) muscles. (B) Mean (SD) values showing relatively balanced IHI in both directions, derived from multiple trials of left M1 inhibiting right M1 (left to right) (C–D) and right M1 inhibiting left M1 (right to left) (E–F). (C) Motor-evoked potential (MEP) in left FDI (upper trace) in response to unconditioned suprathreshold test stimulus to right M1. (D) MEP in right FDI (lower trace) in response to suprathreshold conditioning stimulus to left M1, followed by a MEP in left FDI in response to test stimulus to right M1 (interstimulus interval=10 ms). Interhemispheric intervention in the direction of left M1 inhibiting right M1 is demonstrated by reduction in conditioned test MEP (lower red circle) compared with unconditioned test MEP (upper red circle). (E–F) Interhemispheric intervention in the direction of right M1 to left M1 (compare yellow circles).
Interhemispheric intervention (IHI): participant with stroke. (A) Magnetic resonance images of brain of participant with stroke (red arrows). (B) Mean (SD) values showing exaggerated IHI in direction of contralesional primary motor area (M1) inhibiting ipsilesional primary motor areas (M1) (contralesional to ipsilesional), derived from multiple trials of C–D, compared with direction of ipsilesional M1 inhibiting contralesional M1 (ipsilesional to contralesional), derived from multiple trials of E–F. (C) Motor-evoked potential (MEP) in paretic first dorsal interosseous muscle (FDI) (upper trace) in response to unconditioned suprathreshold test stimulus applied to the ipsilesional M1. (D) Motor-evoked potential in nonparetic FDI (lower trace) in response to suprathreshold conditioning stimulus applied to the contralesional M1, followed by an MEP in paretic FDI in response to test stimulus applied to the ipsilesional M1 (interstimulus interval=10 ms). Interhemispheric intervention in the direction of the contralesional M1 inhibiting the ipsilesional M1 is demonstrated by reduction in conditioned test MEP (lower red circle) compared with unconditioned test MEP (upper red circle). (E–F) Interhemispheric intervention in the direction of ipsilesional to contralesional M1 (compare yellow circles).
Interhemispheric inhibition represents an important example of diaschisis following stroke. Diaschisis involves a decline in excitability and function in brain areas that are spatially distinct but functionally related to the stroke site.22 Neurons killed from the stroke cannot be salvaged by rehabilitation. However, neurons in diaschisis are salvageable, as evidence shows in some people with stroke that forced use of the paretic hand combined with forced nonuse of the nonparetic hand (ie, constraint-induced movement therapy) can adjust the unbalanced IHI and improve ipsilesional M1 excitability and functional recovery.23,24 Behavioral training alone, however, may not be sufficiently potent to trigger optimal brain reorganization. Growing evidence suggests that neuromodulation of the brain using rTMS can serve as an adjunctive modality in certain people with stroke to make accompanying behavioral therapy more effective.25–27
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