Brain-controlled neuromuscular stimulation to drive neural plasticity and functional recovery
Introduction
Brain machine interfaces (BMIs) hold great promise for improving the lives of patients with motor disabilities caused by stroke or spinal cord injury (SCI). Over the last 15 years, BMI users, mostly non-human primates, have controlled computer cursors [1, 2, 3] or robotic devices [4] directly from their thoughts. For a small number of human patients with neurological disorders, a BMI has actually replaced lost motor function [5, 6••]. These neuroprostheses typically rely on ‘decoders’ that map neural activity into the desired control signals, for example, cursor or robot motion.
A much larger number of patients with SCI or stroke have benefited from functional electrical stimulation (FES), electrical stimuli applied to muscles or nerves, used to restore both arm and leg function [7]. The most common application addresses foot drop by stimulating the common peroneal nerve to generate ankle dorsiflexion at the onset of swing (Figure 1a). Current FES neuroprostheses that restore grasp rely on preprogrammed stimulation patterns that the patient can initiate by residual proximal limb movements (Figure 1c).
Recently, in experiments with monkeys, BMIs have been used to supply the control signals for FES, thereby overcoming the need to rely on residual movement [8, 9, 10••, 11]. Our group demonstrated the potential of this approach by restoring grasp in monkeys temporarily paralyzed by peripheral nerve block. We used the combined activity of nearly 100 cortical neurons to predict forearm flexor EMGs, which served as control signals driving stimulation of five electrodes [10••].
There is an intriguing potential additional benefit of BMI-controlled FES: its use in patients recovering from SCI or stroke may lead to recovered function beyond that of standard therapy. In a small number of patients with a variety of motor disorders, the use of FES to assist movement has led to recovered function that persisted after FES was discontinued in both walking (Figure 1b) [12, 13] and use of the hands (Figure 1d) [14, 15, 16]. The functional recovery resulted from neural plasticity, probably including long-term potentiation (LTP) and depression (LTD) of existing synapses, axonal sprouting, and synaptogenesis and neurogenesis, among other mechanisms [17, 18]. Numerous studies involving single-neuron trigger sources have demonstrated the importance of timing of presynaptic and postsynaptic activity in the generation of these plastic changes [19, 20] (see Figure 2a and Box 1). However, the importance of precise timing is less clear when numerous, continuously modulated neural pathways are involved.
Neurological injury triggers widespread changes across the CNS and increases its plasticity, opening a window for therapeutic intervention soon after injury [21, 22•]. Unfortunately, all plasticity is not necessarily beneficial; it can also lead to maladaptive reorganization [22•, 23•, 24, 25•, 26]. Potentially, the most effective way to guide adaptive plasticity would be by using a BMI to assist the patient's attempted movements through control of a powered orthosis, or by artificially activating their own muscles through FES. The conjunction of cortical activity generated voluntarily, and movement-related afferent feedback may lead to adaptive plastic changes and improved functional recovery [11, 26, 27•, 28, 29•, 30•, 31••].
Section snippets
In vivo, spike-triggered stimulation to induce plastic changes
Intracortical microstimulation (ICMS) triggered by naturally occurring action potentials has been used to induce neural plasticity in behaving animals, probably evoking mechanisms like those observed in vitro (Box 1). Following one or more days of spike-triggered stimulation in primary motor cortex (M1) of monkeys, test ICMS trains at the ‘trigger’ site began to activate some of the same muscles as the conditioned site, provided the trigger/target delay was less than 50 ms [32] (Figure 2b). In a
Associating stimulation and voluntary effort
Paired stimulation techniques such as PAS have been shown to induce cortical and spinal plasticity, with some evidence of functional recovery after SCI [43] and stroke [39•] as well. There is also evidence that FES, using preprogrammed stimulus trains timed to coincide with voluntary effort and designed to effect movement, may accelerate recovery in both SCI and stroke [12, 13, 14, 15, 16, 28, 44]. Likewise, even continuous stimulation combined with voluntary effort has led to improved motor
Conclusion
Interventions that facilitate activity-dependent plasticity by associating motor intent with artificially generated movement and afferent activity using electrical stimulation constitute a promising avenue for promoting recovery after neurological injury. However, we still have an incomplete understanding of the principles underlying stimulus-driven neural plasticity, and how to apply it optimally to promote adaptive forms of plasticity while suppressing maladaptive changes. We know that timing
Conflict of interest
The authors confirm that there are no known conflicts of interest.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported in part by Grant #NS053603 from the National Institute of Neurological Disorder and Stroke (L Miller), and by Grant # FP7-PEOPLE-2013-IOF-627384 from the European Commission (J Gallego).
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These authors contributed equally to this work.