Invasive Neurostimulation for Poststroke Motor Recovery

Introduction

Approximately 795,000 people suffer a new or recurrent stroke annually in the United States, with 87% of strokes caused by cerebral ischemia ( ). Ischemic stroke (IS) is a leading cause of disability worldwide, and indirect costs resulting from lost productivity due to stroke are projected to increase from $25 billion in 2010 to $44 billion in 2030 in the United States alone ( ). Although stroke survivors suffer from a wide array of neurologic impairments, upper extremity motor deficits are associated with the worst limitations for executing activities of daily living (ADLs), leaving patients dependent upon caregivers ( ). As stroke mortality has continued to decline and the number of individuals with poststroke disability has increased, the need for effective rehabilitation strategies and treatments to augment rehabilitation has grown significantly. In the current review, we will briefly summarize the leading mechanistic hypotheses regarding poststroke functional recovery and describe current neurostimulation-based approaches to facilitate or enhance those processes ( Fig. 95.1 ).

Proposed Mechanisms Underlying Functional Recovery

Following IS, most patients experience some degree of recovery of lost motor function. This period of spontaneous recovery typically ceases, however, 3–6 months after stroke, at which point functional disability plateaus and remains stable ( ). Robust evidence supports the use of rehabilitation to improve neurologic function even beyond the window of spontaneous recovery ( ). Nevertheless, a large number of patients remain chronically disabled and incapable of independently performing ADLs, underscoring the need for new technologies and interventions aimed at promoting poststroke motor recovery.

Poststroke neuroplasticity is believed to be a primary contributor to functional recovery. Following ischemic injury, surviving neural circuits are able to subsume the function of damaged cortical regions, a process termed vicariation of function. Although regions of the contralesional hemisphere are also thought to play a role in the recovery of function, most attention is paid to changes in the perilesional cortex surrounding the ischemic core ( ). Cortical reorganization manifests as changes in the motor representation map following ischemia and subsequent rehabilitation ( ). This process has been further linked to changes in cortical excitability ( ), with enhanced excitability at the neuronal level thought to facilitate the plastic changes that contribute to cortical reorganization and functional recovery. Indeed, such changes, including map size, have been shown to correlate with improved recovery following stroke ( ). One of the key goals of neurostimulation in poststroke rehabilitation is to promote or redirect plasticity that is mediated by activity. While electrical stimulation is expected to cause effects at the cellular and synaptic levels, discussed later, it is unlikely that it can drive rehabilitation of specific neurological functions (i.e., movement, speech) without pairing with activity-dependent rehabilitation strategies. In other words, the clinical goal of neuromodulation is not to replace physical, occupational, or speech therapy but, rather, to augment their effect.

At the cellular level, functional reorganization is accompanied by axonal sprouting, synaptogenesis, and, to a lesser extent, neurogenesis ( ). Studies in a variety of animal models have extensively documented the widespread occurrence of axonal sprouting in the peri-infarct cortex as well as at sites distal to the infarct ( ). The process of axonal sprouting is regulated by a number of factors. NogoA, EphrinA5, and chondroitin sulfate proteoglycans act to confine the growing axon, while prosprouting factors including GDF10, GAP43, and a variety of other cellular adhesion, axonal guidance, and cytoskeletal molecules encourage the sprouting and growth of axons after injury ( ). In addition to axonal sprouting, new synapses are formed as indicated by elevated expression of synaptophysin in the perilesional cortex in animals ( ). The processes of angiogenesis and neurogenesis occur in tandem within a neurovascular niche. Growth factors and chemokines secreted by angiogenic vessels further stimulate the migration of endogenous, neuronal, stem cells from the subventricular zone to the infarct core ( ). The neurogenic response, however, is limited in scope, and there is mixed evidence supporting its occurrence and functionality in humans.

At the synaptic level, long-term potentiation (LTP) plays an important role in poststroke recovery ( ). In the mid-20th century, Donald Hebb proposed that when a given neuron repeatedly or consistently activates another neuron, metabolic or morphologic changes occur such that the first cell’s efficiency in activating the second cell is increased ( ), hence, LTP. Today, an extensive body of literature supports the phenomenon of activity-dependent changes in synaptic strength. The postsynaptic, N-Methyl-D-aspartic acid (NMDA) glutamate receptor is critical for LTP induction, while intracellular CaMKII and protein kinase C (PKC) also have been shown to play a role ( ). The changes in synaptic strength induced by LTP are critical for cortical reorganization, whether in the process of normal motor skill learning or in the recovery of motor function after stroke.

Neurostimulation-Based Approaches to Enhance Motor Poststroke Motor Recovery