Targeting plasticity with vagus nerve stimulation to treat neurological disease

Abstract

Pathological neural activity in a variety of neurological disorders could be treated by directing plasticity to specifically renormalize aberrant neural circuits, thereby restoring normal function. Brief bursts of acetylcholine and norepinephrine can enhance the neural plasticity associated with coincident events. Vagus nerve stimulation (VNS) represents a safe and effective means to trigger the release of these neuromodulators with a high degree of temporal control. VNS-event pairing can generate highly specific and long-lasting plasticity in sensory and motor cortex. Based on the capacity to drive specific changes in neural circuitry, VNS paired with experience has been successful in effectively ameliorating animal models of chronic tinnitus, stroke, and posttraumatic stress disorder. Targeted plasticity therapy utilizing VNS is currently being translated to humans to treat chronic tinnitus and improve motor recovery after stroke. This chapter will discuss the current progress of VNS paired with experience to drive specific plasticity to treat these neurological disorders and will evaluate additional future applications of targeted plasticity therapy.

Keywords: acetylcholine; cortical plasticity; neuromodulators; norepinephrine; recovery; targeted plasticity; vagus nerve stimulation (VNS).

FIGURE 1

Model of targeted plasticity therapy driving specific changes in neural circuits and not in other areas. (A) (i) Presentation of an 8 kHz tone drives circuit activity in the auditory cortex (green). (ii) Temporally precise release of neuromodulators (blue), such as that induced by VNS, paired with this activity drives plasticity. (iii) After targeted plasticity, the map reorganization results in an increase in representation of the paired tone (Engineer et al., 2011). Previously subthreshold inputs (yellow) drive activity (green) after pairing with VNS. (B) (i) Activity within neurons of the motor cortex results in movement of the shoulder. (ii) Diffuse release of neuromodulators paired with movement drives plasticity in the motor cortex. (iii) After targeted plasticity, the number of circuits representing the shoulder movement is increased (Porter et al., 2011). The large rectangles represent topographical organization of the auditory and motor cortices, and the activity of neurons is represented within each individual box. Green denotes suprathreshold action potential firing, yellow denotes subthreshold depolarization, and gray denotes no response.

FIGURE 2

Model of VNS paired with experience driving therapeutic plasticity in neural circuits. (A) (i) In tinnitus, the auditory neurons are hyperactive and the map of sound frequency is distorted. (ii) Presentation of high and low tones (black arrows) is insufficient to drive plasticity. (iii) However, high and low tones paired with VNS (blue) drive plasticity within the auditory system. (iv) After targeted plasticity therapy, activity within the auditory system is renormalized, demonstrating that VNS paired with experience can reverse maladaptive plasticity (Engineer et al., 2011). (B) (i) Following a stroke, circuits previously controlling the forelimb are destroyed (black), resulting in impaired function. (ii) Physical rehabilitation (black arrows) drives some reorganization and partially restores function. (iii) Physical rehabilitation paired with VNS drives robust and specific neural plasticity by increasing subthreshold activity (yellow). (iv) VNS paired with physical rehabilitation can drive robust and specific changes to enhance recovery limited by insufficient plasticity (Khodaparast et al., 2013; Khodaparast et al., submitted).

FIGURE 3

Vaccination and targeted plasticity therapy are based on similar principles. (A) Injection of an antigen alone causes a generally weak immunologic response. Injection of an adjuvant alone causes a nonspecific inflammatory response. Many different compounds can act as adjuvants, including aluminum salts, virosomes, or saponins (Cox and Coulter, 1997). Concurrent presentation of the antigen and adjuvant results in a significantly enhanced immunologic response beyond that evoked by either element alone, resulting in specific and long-lasting immunity. (B) Targeted plasticity therapy is based on similar principles of synergism. Experience alone drives activity within circuitry but does not result in plasticity. Neuromodulators alone have generalized neuronal effects, but do not drive lasting changes. A variety of factors can cause release of neuromodulators, including attention, pain, or VNS. When bursts of neuromodulators correspond with experience, specific and long-lasting plasticity results.