Mechanisms of Action of Deep Brain Stimulation: A Review

Introduction

The modern history of the therapeutic application of high-frequency electrical stimulation to deep brain structures, now called deep brain stimulation (DBS), began in when Benabid et al. first described it as a treatment for intractable tremor. By the late 1990s and early 2000s, DBS had begun to replace surgical ablation or lesioning of the thalamus (thalamotomy) for essential tremor and lesioning of either the thalamus or the globus pallidus (pallidotomy) for the movement disorders associated with Parkinson disease (PD), which include tremor, bradykinesia (slowness), hypokinesia (difficulty initiating movement), and rigidity ( ). Significant progress in stereotactic neurosurgical techniques and neuroimaging has improved outcomes and fostered the expansion of DBS for other movement disorders, including dystonia and the tics associated with Tourette syndrome ( ). As of this writing, it is under consideration for applied off-label use for epilepsy ( ); chronic pain ( ); certain psychiatric conditions, such as obsessive–compulsive disorder ( ) and major depression ( ); and the memory disorders associated with dementing diseases ( ).

Over 40 stimulation targets have been explored, which include the globus pallidus interna (the entopeduncular nucleus homologue in rats, but referred to as GPi throughout this chapter), the subthalamic nucleus (STN), the dorsal STN (sensorimotor region), the ventral intermediate nucleus (VIM) of the thalamus ( ), the centromedian parafascicular nucleus ( ), and the pedunculopontine nucleus ( ).

As sometimes happens in medicine, rapid advances in treatment precede scientific understanding of mechanism. Such is the case with DBS. In-depth understanding of the underlying therapeutic action of DBS could not only improve outcomes and reduce adverse effects, but also add to our understanding of the disorders to which it is applied. Given its history of success for essential tremor and PD, it is not surprising that the vast majority of research on DBS mechanisms has focused on movement disorders associated with dysfunction of subcortical structures in the basal ganglia–thalamocortical circuitry (BGTC). Many of these investigations have been animal studies in which high-frequency stimulation (HFS) is applied. HFS is similar to clinical DBS in that, although not continuous, it involves electrical stimulation of cells at intensities (voltage amplitudes) and frequencies (hertz) comparable to those used in DBS. The experimental subjects in animal studies include healthy mammals as well as mammalian models of disease. The most common of these are parkinsonian models in which neurotoxins are applied to mimic some of the motor symptoms in PD. In rodents, 6-hydroxydopamine (6-OHDA), a hydroxylated analogue of dopamine, is used to lesion the nigrostriatal dopaminergic system. In the nonhuman primate (NHP), the application of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) also affects the nigrostriatal system, depleting dopamine and inducing parkinsonian movement disorders.

Early hypotheses were based primarily on the fact that the near-immediate reduction in tremor from DBS was similar to that seen in tissue ablation or lesioning of the thalamus or global pallidus ( ). The possible silencing of neurons in these surgical ablation targets for PD and essential tremor, did not, however, explain the symptom relief of other targets nor of DBS for other disorders, the effects of which are less immediate. Converging evidence from neuroanatomical, electrophysiological, neurochemical, and neuroimaging studies has revealed that the mechanisms of DBS are far more complex than originally thought.

Concurrent with the application of DBS to basal ganglia (BG) structures, the Albin and DeLong model of the functional anatomy of BG disorders provided a foundation for the understanding of the BGTC ( ). Research on the architecture of this neural network has uncovered new connections among the nuclei within it, especially the hyperdirect glutamatergic cortical to STN pathway ( ) ( Fig. 17.1 ). It was thought that the model’s afferent and efferent projections played a major role in the mechanisms of DBS, but it remained to be discovered whether DBS activated or inhibited these projections, as well as which neuronal elements were affected (i.e., local soma and axons or fibers of passage).

As data from clinical and preclinical studies continue to accumulate, multiple theories have been generated and reviewed ( ).

Five Hypotheses for Mechanism(s) of Action of Deep Brain Stimulation

The five hypotheses that have emerged as plausible explanations of DBS mechanisms involve the effects of DBS on local changes in neuronal activity (inhibition, excitation, and firing rates); modulation of neurochemical release, including neurotransmitters; astrocytic modulation of neurons within the stimulated brain structure; distal activation changes in nuclei to which the stimulated brain structure projects; and global activation changes across the entire BGTC network. The five hypotheses are the:

• 1.

  depolarization block hypothesis (inactivation of action potential generation in efferent outputs),

• 2.

  neural jamming hypothesis (antioscillatory action on the BGTC network),

• 3.

  synaptic depression hypothesis (depletion of neurotransmitters in terminals of efferent outputs),

• 4.

  synaptic modulation hypothesis (activation of neuronal terminals that inhibit and/or excite efferent outputs),

• 5.

  DBS–astrocyte hypothesis (extended astrocytic involvement in neurotransmitter release).

This chapter reviews the foundations and evidence for each of these hypotheses of DBS mechanisms.