Invited review
Uncovering the mechanism(s) of action of deep brain stimulation: activation, inhibition, or both

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Abstract

High-frequency deep brain stimulation (DBS) of the thalamus or basal ganglia represents an effective clinical technique for the treatment of several medically refractory movement disorders. However, understanding of the mechanisms responsible for the therapeutic action of DBS remains elusive. The goal of this review is to address our present knowledge of the effects of high-frequency stimulation within the central nervous system and comment on the functional implications of this knowledge for uncovering the mechanism(s) of DBS. Four general hypotheses have been developed to explain the mechanism(s) of DBS: depolarization blockade, synaptic inhibition, synaptic depression, and stimulation-induced modulation of pathological network activity. Using the results from functional imaging, neurochemistry, neural recording, and neural modeling experiments we address the general hypotheses and attempt to reconcile what have been considered conflicting results from these different research modalities. Our analysis suggests stimulation-induced modulation of pathological network activity represents the most likely mechanism of DBS; however, several open questions remain to explicitly link the effects of DBS with therapeutic outcomes.

Introduction

The modern era of deep brain stimulation (DBS) began in the late 1980s with the pioneering work of Benabid and colleagues at the University of Grenoble, France (Benabid et al., 1987, Benabid et al., 1991). Their realization that chronic high-frequency stimulation (HFS) results in clinical benefits analogous to those achieved by surgical lesioning transformed the use of functional neurosurgery for the treatment of movement disorders (Gross and Lozano, 2000). Thalamic DBS for intractable tremor has virtually replaced ablative lesions of the thalamus (Benabid et al., 1996). Moreover, DBS of the subthalamic nucleus (STN) or globus pallidus internus (GPi) has largely replaced pallidotomy in the treatment of the cardinal motor features of Parkinson's disease (PD) (resting tremor, rigidity, bradykinesia) (Obeso et al., 2001). In addition, multiple pilot studies have begun to examine the utility of DBS for dystonia (Coubes et al., 2000, Yianni et al., 2003), epilepsy (Hodaie et al., 2002), and obsessive-compulsive disorder (OCD) (Gabriels et al., 2003).

The general therapeutic stimulation parameters for DBS (monopolar cathodic; 1–5 V stimulus amplitude; 60–200 μs stimulus pulse duration; 120–180 Hz stimulus frequency) have been derived primarily by trial and error (Rizzone et al., 2001, Moro et al., 2002, Volkmann et al., 2002, O'Suilleabhain et al., 2003). This trial and error selection of the stimulation parameters has been effective because of the near immediate effects of DBS on the control of tremor and parkinsonian motor symptoms. However, new therapies utilizing DBS technology will not allow such ease of titration. The beneficial effects of stimulation can take weeks to months to manifest in dystonia and OCD, and it is unclear what stimulation amplitudes, pulse durations, and frequencies are most effective for these new therapeutic directions. Therefore, future advances in DBS technology are dependent on addressing fundamental questions on the therapeutic mechanism(s) of action (Montgomery and Baker, 2000, Dostrovsky and Lozano, 2002, Vitek, 2002, McIntyre and Thakor, 2002).

Four general modalities: neural modeling, neural recording, neurochemistry, and functional imaging, have been employed to address the effects of DBS within the central nervous system. Neural modeling experiments have been conducted to address action potential generation directly resulting from the stimulation (Grill and McIntyre, 2001, McIntyre et al., in press). Neural recording experiments have been conducted during and after HFS to address changes in neuronal activity (Dostrovsky and Lozano, 2002, Anderson et al., 2003, Hashimoto et al., 2003). Microdialysis experiments have been conducted to address changes in neurotransmitter levels (Bruet et al., 2001, Windels et al., 2000, Windels et al., 2003), and in situ hybridization histochemistry has been used to address changes in gene expression induced by HFS (Salin et al., 2002). Functional imaging experiments have been conducted to address the effects of DBS from a systems level perspective by examining changes in cortical activity induced by the stimulation (Zonenshayn et al., 2000). When considered individually the results from these different modalities have suggested mechanisms of action for DBS that would appear mutually exclusive (Vitek, 2002). However, when results from each modality are considered together a more complete understanding of the effects of DBS can be developed, with each line of study providing an integral piece of the puzzle.

Understanding the effects of DBS presents investigators with a paradox of how stimulation (traditionally thought to activate neurons) can result in similar therapeutic outcomes as lesioning target structures in the thalamus or basal ganglia. In turn, there exist two strongly debated general philosophies on the effects of DBS: (1) DBS generates a functional ablation by suppressing or inhibiting the stimulated nucleus or (2) DBS results in activation of the stimulated nucleus that is transmitted throughout the network. Based on these fundamental philosophies, 4 general hypotheses have been developed to explain the mechanisms of DBS. (1) Stimulation induced alterations in the activation of voltage-gated currents that block neural output near the stimulating electrode (Depolarization Blockade) (Beurrier et al., 2001). (2) Indirect regulation of neuronal output via activation of axon terminals that make synaptic connections with neurons near the stimulating electrode (synaptic inhibition) (Dostrovsky et al., 2000). (3) Synaptic transmission failure of the efferent output of stimulated neurons as a result of transmitter depletion (synaptic depression) (Urbano et al., 2002). (4) Stimulation-induced modulation of pathological network activity (Montgomery and Baker, 2000). While the therapeutic mechanisms that underlie DBS most likely represent a combination of several phenomena (Benabid et al., 2002, Vitek, 2002), the goal of this review is to address which of these general hypotheses best explains the available data from functional imaging, neurochemistry, neural recording, and neural modeling experiments.

Section snippets

Effects of DBS as revealed by neural modeling

Limitations in experimental techniques and the complex response of neurons to extracellular stimulation, has hampered our understanding of the effects of DBS. The use of multi-compartment cable models of neurons coupled to extracellular electric fields has provided the opportunity to study the effects of stimulation on neural activity in a highly controlled environment. The foundational principals of modeling extracellular stimulation date back to McNeal (1976) and have been used extensively in

Effects of DBS as revealed by neural recording

Due to the phenomenological similarity between the effects of DBS and lesioning, it appears logical to assume that DBS inactivates the structures being stimulated. However, the neural recording literature on the effects of DBS fall into two contradictory sets with one indicating that DBS inhibits the stimulated nucleus and the other indicating that DBS excites the stimulated nucleus. In vivo neural recordings made in the stimulated nucleus show decreased activity during and after HFS (Benazzouz

Effects of DBS as revealed by microdialysis and changes in gene expression

In vivo microdialysis and in situ hybridization histochemistry have recently been employed to investigate the cellular and molecular effects of DBS. High-frequency stimulation of the STN of rats with or without 6-hydroxydopamine-induced lesion of nigral dopamine (DA) neurons has been used to quantify changes in the DA, glutamatergic, and GABAergic systems of the basal ganglia. STN HFS has been reported to increase striatal DA release and metabolism in intact rats and in rats with partial lesion

Effects of DBS as revealed by functional imaging

DBS is ideally suited to functional imaging because it generates consistent and controllable stimulation of the brain that yields reproducible clinical effects. Over the last 10 years there have been several DBS-related PET studies, and more recently functional magnetic resonance imaging (fMRI) has also been employed (Zonenshayn et al., 2000, Jech et al., 2001). The great benefit of functional imaging is that data can be obtained from essentially the entire brain simultaneously, thus providing

DBS mechanisms of action

Presently, there exist 4 general hypotheses to explain the therapeutic mechanism(s) of DBS: Depolarization blockade (Beurrier et al., 2001); Synaptic inhibition (Dostrovsky et al., 2000); Synaptic depression (Urbano et al., 2002); and Stimulation-induced disruption of pathological network activity (Montgomery and Baker, 2000). Depolarization blockade and synaptic inhibition represent attractive hypotheses to explain the similarity between the therapeutic benefit of ablation and DBS for the

Acknowledgements

This work was supported by grants from the National Institute of Health (NS-37019), Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, European Community (Grant No. QLK6-1999-02173, Fifth Programme Cadre de Recherche et de Développement Technologique) and a post-doctoral fellowship supported by the Medtronic Corporation.

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