Review
Mechanisms of action of deep brain stimulation (DBS)

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Abstract

Deep brain stimulation (DBS) is remarkably effective for a range of neurological and psychiatric disorders that have failed pharmacological and cell transplant therapies. Clinical investigations are underway for a variety of other conditions. Yet, the therapeutic mechanisms of action are unknown. In addition, DBS research demonstrates the need to re-consider many hypotheses regarding basal ganglia physiology and pathophysiology such as the notion that increased activity in the globus pallidus internal segment is causal to Parkinson's disease symptoms. Studies reveal a variety of apparently discrepant results. At the least, it is unclear which DBS effects are therapeutically effective. This systematic review attempts to organize current DBS research into a series of unifying themes or issues such as whether the therapeutic effects are local or systems-wide or whether the effects are related to inhibition or excitation. A number of alternative hypotheses are offered for consideration including suppression of abnormal activity, striping basal ganglia output of misinformation, reduction of abnormal stochastic resonance effects due to increased noise in the disease state, and reinforcement of dynamic modulation of neuronal activity by resonance effects.

Introduction

Despite of the fact that there is no clear understanding of the therapeutic mechanisms of action of deep brain stimulation (DBS), it is highly effective in the treatment of an increasing array of neurological and psychiatric disorders. Already considered standard and accepted treatment for Parkinson's disease (Deep Brain Stimulation in Parkinson's Disease Group, 2001), Essential tremor (Koller et al., 1997), dystonia (Yianni et al., 2003), and cerebellar outflow tremor (Montgomery et al., 1999), clinical trials are underway for epilepsy (Loddenkemper et al., 2001), depression (Stefurak et al., 2003), obsessive-compulsive disorder (Abelson et al., 2005), and minimally conscious states (Yamamoto et al., 2005). Clearly, clinical developments in the past did not require a detailed knowledge of the neuronal mechanisms of DBS but at the minimum, notions as to the mechanisms have inspired or given confidence to pursuing new clinical applications. For example, the early notion that DBS inhibits the stimulated target nucleus thereby, reducing what was considered overactivity in the target, had considerable heuristic value. Thus, DBS of the globus pallidus interna (GPi) has replaced pallidotomy. Extending this notion further, DBS of the anterior limb of the internal capsule may replace capsulotomy for obsessive-compulsive disorder.

The remarkable effectiveness of DBS must be saying something about the underlying neuronal pathophysiology. For example, DBS for Parkinson's disease is effective when all manner of medications (Deep Brain Stimulation in Parkinson's Disease Group, 2001) and indeed, when brain fetal dopamine cell transplantation fails (Olanow et al., 2003). Clearly, DBS must be addressing neuronal pathophysiological mechanisms not addressed by pharmacological or cellular replacement of dopamine. The success of DBS in the face of pharmacological and cellular transplant failure and the expansion of DBS to other clinical conditions give considerable confidence that a greater understanding of the therapeutic mechanisms of action will lead to even more effective therapies for a wider array of neurological and psychiatric disorders.

Expanding use of DBS has resulted in a number of inconsistencies and paradoxes that may require a fundamental reconsideration of current hypotheses of DBS mechanisms of action and suggests benefit in considering a wider range of perspectives, which is the purpose of this review. Contrary to earlier notions that only high frequency DBS was clinically effective, recent studies demonstrate that low frequency DBS, in some circumstances such as the pedunculopontine (PPN) nucleus for gait disorders (Stefani et al., 2007) or of the STN for speech (Wojtecki et al., 2006) in Parkinson's disease. The same high frequency DBS of the GPi is effective for both hypokinetic disorders, such as chorea (Montgomery, 2004a, Montgomery, 2004b), as well as hypokinetic disorders such as Parkinson's disease (Deep-Brain Stimulation for Parkinson's Disease Study Group, 2001). This is inconsistent with current theories that hold that the mechanisms underlying hypo- and hyperkinesia are reciprocal. DBS of nearly every nuclei in the basal ganglia-thalamic-cortical (BG-Th-Ctx) system is effective for at least some symptoms of Parkinson's disease, for example GPi (Deep-Brain Stimulation for Parkinson's Disease Study Group, 2001), STN (Deep-Brain Stimulation for Parkinson's Disease Study Group, 2001), ventrolateral thalamus (VL) (Koller et al., 1997), globus pallidus external segment (GPe) (Vitek et al., 2004), and motor cortex (Canavero et al., 2002). The putamen (Pt) is not listed only because the authors are unaware of any attempts at putamenal DBS, not that it has been shown not to work. Either there are as many different DBS mechanisms as there are effective targets or there is some common mechanism that is not unique to any particular target. This suggests that it may be profitable to view DBS from a “systems” perspective rather than just its local effects, an approach that here-to-fore has not been received much consideration.

At the minimum, a better understanding of how DBS works may shed considerable light on the neuronal pathophysiology of diseases such as Parkinson's disease and perhaps illuminate our understanding of normal brain physiology. In this regard, the current interest in DBS mechanisms is timely because current notions of basal ganglia pathophysiology, particularly as it relates to Parkinson's disease, are in a state of flux. First, as will be discussed, therapeutic high frequency DBS of GPi and STN directly increases GPi output (Hasmimoto et al., 2001; Anderson et al., 2003; Montgomery, 2006), which is inconsistent with current theories positing GPi overactivity as causal to Parkinson's disease (Albin et al., 1989; DeLong, 1990). Second, GPi activity does not solely inhibit VL neurons, many demonstrate post-inhibitory rebound increased excitability sometimes causing net increases in neuronal activity over baseline with GPi DBS (Montgomery, 2006). In addition, GPi DBS probably antidromically activates VL neurons that result in orthodromic activation of cortical neurons. Third, recent studies demonstrate that the pattern of DBS and not just the frequency is important for its therapeutic effect (Ma and Wichmann, 2004; Montgomery, 2005). Thus, a better understanding of DBS mechanisms of action increases it utility as a probe to study brain function.

Demonstration of the importance of the pattern of DBS is particularly interesting in view of recent interest in abnormal oscillations within the basal ganglia as a potential pathophysiological mechanism, particularly in Parkinson's disease. Basal ganglia oscillations in local field potentials in the 11–30-Hz range are thought antikinetic (Brown, 2006; Brown and Williams, 2005; Hutchison et al., 2004) as evidenced by reductions in STN oscillations in this frequency range are correlated with improvement (Kuhn et al., 2006). DBS in this frequency range worsens motor performance (Fogelson et al., 2005a, Fogelson et al., 2005b). Oscillations in the range of 70 Hz are thought to be prokinetic, because they are lost in PD (Hutchison et al., 2004; Pogosyan et al., 2006) and restored with levodopa treatment (Fogelson et al., 2005a, Fogelson et al., 2005b).

The relevance of oscillators in Parkinson's disease to DBS is illustrated in the following case report of a single human undergoing DBS demonstrating the importance of DBS patterns (unpublished observations). This patient had a STN DBS lead placed but required revision of the DBS lead because of previous placement of the extension connector in the neck which was subsequently shown to increase the risk of DBS lead fractures. During the surgery, it was possible to connect the lead to an external stimulator (Grass Instruments S88 with dual SIU7 stimulus isolation units) under computer control. This experiment received prior Institutional Review Board (IRB) approval and informed consent by the patient.

Constant current and charge-balanced stimulation with pulse width for each phase of 0.9 ms were delivered under computer control. The authors evaluated motor function of the contralateral upper extremity while blinded to the pattern of stimulation. Five different patterns were used all at the same overall frequency of 130 (pulses per second) pps. There was 130 pps regular and 130 pps irregular with the inter-stimulus intervals drawn randomly from a Gaussian distribution. Another set of stimulation patterns was modulated stimulation were the instantaneous stimulation frequencies varied regularly from 6 to 256 pps. The rates of these variations were 2, 5 and 10 Hz for different stimulation periods.

Fig. 1 shows the effects of these stimulation patterns on finger tapping in the ipsilateral and contralateral hand as measured by the motor examination of the unified Parkinson rating scales (UPDRS). The graph in Fig. 1 shows the change in finger tapping scores from the pre-stimulation baseline. The order of the different stimulation patterns was randomized. As can be seen, DBS at 130 pps resulted in an improvement in the finger tapping performance, while stimulation with 130 pps irregular caused a worsening of finger tapping performance. However, DBS at 130 pps modulated at 2 Hz produced the greatest worsening of motor performance followed by 130 pps modulated at 5 Hz and then 130 pps modulated at 10 Hz. While this is only a single case, the results are intriguing and hopefully this study will be expanded by future research. But it does raise the question about what kind of effect is inherent in the 130 pps DBS modulated at 2 Hz compared to the 130 pps irregular DBS.

Given the state of uncertainty as to the pathophysiological mechanism, the importance of a better understanding of the pathophysiology for the development of new treatments, and the potential insights that DBS research may contribute, a critical review of the current state of understanding of DBS mechanisms is important as this paper attempts. However, perhaps more important at this stage of understanding, or lack thereof, is the necessity to consider a wide variety of hypotheses and possibilities, if for no other reason than to stimulate debate and subsequent research. Such hypotheses, given the current state of knowledge, necessarily will be speculative and often based on “work in progress” and indulgences are appropriate. The premature windowing of possibilities and considerations seems unwise.

DBS and its mechanisms of action have captured the imagination of many scientists as evidence by the abundance of papers published. It is not feasible to recognize all the important contributions by these scientists in this review. Further, our goal in this review was not to catalogue the many contributions but rather to synthesize the important themes. Consequently, we have cited only a limited number of studies that represent or typify certain themes. In addition, our laboratory has focused on relatively novel themes. These are the effects of DBS throughout the basal ganglia-thalamic-cortical (BG-Th-Ctx) system and the importance of the DBS pulse train rather than the response to individual pulses. Most other laboratories examine the effects of individual DBS pulses and assume that these responses generalize to the effects of a DBS pulse train. Much of the work from our laboratory is preliminary and in need of repetition, verification, and extension. However, the uniqueness of those observations, their contrast to much of the current published work, and timeliness of these issues justifies their presentation.

The central themes to be addressed include: (1) whether DBS inhibits or excites the stimulated target; (2) whether the therapeutic DBS mechanisms of action are local or attributable to the basal ganglia-thalamic-cortical system (BG-Th-Ctx); and (3) whether the effects follow from responses to a single pulse or a collective of pulses. Possible therapeutic mechanisms, from the review of the literature and data, have been distilled and synthesized into key hypotheses which include: (1) Direct Inhibition Hypothesis; (2) Indirect Inhibition of Pathological Activity Hypothesis; (3) Increased Regularity of GPi and Reduced Miss-information Hypothesis; and (4) Resonance and Carrier Signal Effect Hypothesis. Which of these or their variations or some entirely novel hypothesis emerges as the most plausible awaits further research.

Section snippets

Inhibition or Excitation

One of the first controversies, which persist, is whether high frequency DBS inhibits the stimulated target. Originally, the hypothesis of inhibition was based on the similarity of clinical efficacy with ablation and high frequency DBS. Just as thalamotomy and pallidotomy improved parkinsonian symptoms so did thalamic and pallidal DBS, respectively. Unfortunately, this analogy constitutes a logical fallacy. If curare and stroke equals paralysis, this does not mean that curare and stroke have

Local versus Systems Effects.

The large majority of other laboratories have focused on the DBS effects at the site of stimulation (Anderson et al., 2006; Bar-Gad et al., 2004; Dostrovsky et al., 2000; Filali et al., 2004; Garcia et al., 2003; Kiss et al., 2002; Kita et al., 2005; Magarinos-Ascone et al., 2002; Tai et al., 2003) or the first order neurons immediately downstream of the stimulated target (Anderson et al., 2003; Hashimoto et al., 2003; Iremonger et al., 2006; Kita et al., 2005; Maurice et al., 2003; Tai et al.,

Effects from single DBS pulse or a collective of DBS pulses

Much of neurophysiological research at the neuronal level as focused on the effects of individual stimulation pulses (Anderson et al., 2003; Bar-Gad et al., 2004; Beurrier et al., 2001; Dostrovsky et al., 2000; Garcia et al., 2003; Hashimoto et al., 2003; Kiss et al., 2002; Kita et al., 2005; Magarinos-Ascone et al., 2002; Maurice et al., 2003; Tai et al., 2003; Wu et al., 2001) rather than interactions between sequential pulses (Kita et al., 2005; Montgomery, 2004b). However, Baker et al.

Hypotheses of DBS Therapeutic Mechanisms

The currently popular hypothesis that STN and GPi DBS directly reduce GPi inhibition of VL, the Direct Inhibition Hypothesis, is unlikely to be true as discussed above. There are at least three viable alternative hypotheses for the therapeutic effect of DBS. First, there may be indirect inhibition of pathologic GPi activity. Second, high frequency and regular STN and GPi DBS induces regularity of GPi activity (Hashimoto et al., 2003) thereby reducing miss-information in the pathologically noisy

Implications of DBS for Theories of Physiology and Pathophysiology

It is safe to say that as yet it is not known how DBS exerts its therapeutic effect. However, DBS research as reduced the probability of some early notions such as inhibition of the stimulated target. Further, there are now a number of hypotheses that can compete and provide direction of future research. However, DBS research at the neuronal level has been successful because it has forced reconsideration of how the basal ganglia functions normally and in disease.

The demonstration that

Future DBS research at the Neuronal Level

DBS research also illustrates the categorical logical error that has dominated current approaches to studying basal ganglia pathophysiology, particularly related to parkinsonism. A categorical logical error (Ryle, 2000) is where findings in one category or context are extrapolated to a different category or context. In this case, the error is extrapolating from changes in neuronal activities at rest in studies of diseases or models of disease to what may occur during behavior. The limited

Acknowledgments

The authors thank He Huang for his assistance. This work was supported by an American Parkinson Disease Association Advanced Center for Research Grant, the Roger Duvoisin Fellowship of the American Parkinson Disease Association (EBM), and in part by Grant number P51 RR000167 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), to the Wisconsin National Primate Research Center, University of Wisconsin-Madison. This research was conducted

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