Deep Brain Stimulation

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Chapter 22 Deep Brain Stimulation

Chapter Overview

Chapter Synopsis: Most applications of electrical stimulation for the treatment of intractable pain are delivered at the spinal cord or in the periphery, but deep brain stimulation (DBS) at central brain structures can also be effective. DBS is indicated for several types of neuropathic pain, including pain after amputation or stroke; plexopathies; and head and face pain, including anesthesia dolorosa. DBS for pain should be undertaken only when all other therapies have failed. The technique is performed at a limited number of centers and would benefit from multicenter studies. Although the spinal cord first- and second-order neuronal hierarchy is well understood, the more central structures involved in pain processing are not, including the targets of DBS for pain, the sensory thalamus and periaqueductal gray. Still-unanswered questions include whether pain processing through these and other brain structures is “top-down” or “bottom-up” and whether endogenous opiates play a role in DBS-induced analgesia. Perhaps it is these unanswered questions that make DBS one of the most fascinating uses of electrical stimulation for intractable pain. Also intriguing is the retention of a somatotopic homunculus in both these centers. This map can provide guidance for electrode implantation; but final placement is determined by an awake, sensing patient who confirms sensations of paresthesias and analgesia with stimulation. These sensations can lend clues as to the complex processing interplay between multiple brain centers that contributes to the overall experience of pain.

Important Points:

Clinical Pearls: Although not a new therapy, DBS has metamorphosed considerably over the last decade, concomitant with advances in both stimulator technology and neuroimaging techniques and by corollary improvements in efficacy and reductions in complications. Few centers have published detailed studies of patients treated during the last decade. Our results suggest that DBS gives analgesia most consistently to patients with pain after amputation, either phantom or stump; and cranial and facial pain, including anesthesia dolorosa and plexopathies. Our greater experience of pain after stroke reveals greatest efficacy for stroke patients complaining of burning hyperesthesia.1,2 Therefore our stroke case series illustrates how important patient selection is to outcome. To improve selection and thus efficacy, objective adjuncts to current pain assessments are desirable. Subjective patient preference for PVG/PAG stimulation over VPL/VPM in stroke together with correlations revealed between cardiovascular effects, analgesic efficacy of DBS and burning hyperesthesia point toward autonomical measures as potential objective markers.3

Sustained analgesia by DBS has been shown for myriad indications; our own experience includes multiple sclerosis and genital pain. Each case must be considered individually rather than relying on dogmatic distinctions between neuropathic and nociceptive pain. Consistent with the notion that chronic pain states confer specific central neuropathic changes are results showing poor DBS efficacy for spinal cord–related pain (e.g., from failed back surgery). Predominantly spinal injuries and hence spinal neuropathic changes are unlikely to respond favorably to central brain stimulation. Conversely, causes of chronic pain not traditionally treated by DBS (e.g., visceral pain in which PVG/PAG changes are described using functional neuroimaging) 4,5 have potential for amelioration by DBS worthy of further study.

Investigations both into the mechanisms of DBS and using deep brain recording to elucidate pain processing mechanisms have yielded considerable advances. Future insights will arise from complementary information gathered using new technologies. Diffusion tensor imaging (DTI) using MRI to trace neuronal connections has shown connectivity between PVG/PAG and thalamic structures and may elucidate differential somatotopic connections6,7; it also has clinical use to aid targeting in functional neurosurgery.8 MEG enables whole brain changes to be mapped, with spatial resolution comparable to functional MRI yet temporal resolution of the order of milliseconds, in contrast to functional neuroimaging technique.9 Our initial investigations have revealed activation of pain-processing neocortical areas during analgesic DBS after filtering out artifactual interference from stimulation.10,11 Therefore global MEG measurements combined with local deep brain recording holds promise for revealing much about pain processing and DBS-related mechanisms beyond wider neurosurgical applications,12 toward identifying predictors of efficacy and enhancing treatments. Nevertheless, complimentary functional neuroimaging modalities such as SPECT have roles in characterizing whole brain changes with DBS with excellent deep brain structure penetration compared to present MEG studies, albeit with more limited temporal resolution and characterization of metabolic correlates of neuronal function.13

Clinical Pitfalls: The large variability of results in case series of DBS for pain to date reflects not just limitations in pain assessment tools and study design and execution, but individual differences among patients as to what constitutes success. A positive outcome may be the removal of a particular component of pain (e.g., burning hyperesthesia) without quantitative reduction in pain scores. Such pain relief may serve to unmask other types or components of pain elsewhere such as muscular allodynia, as has been described after stroke.14 Conversely, complete pain eradication by DBS may even accompany unease, motor complications, or other sequelae precipitating intolerance of stimulation. Thus clinicians must characterize patients’ pain qualitatively and quantitatively, and investigators should endeavor to include quality of life measures in outcome assessment to overcome the limitations of using pain questionnaires alone.

Other contemporary case series suggest that between one third and one half of patients successful during trial stimulation do not experience long-term success beyond 1 year after surgery. To address the predicament and to improve case selection, further challenges are to identify predictors of long-term efficacy and investigate the putative phenomenon of tolerance. Progressive increases of stimulus amplitude or insertion of a second electrode have proven unhelpful.15 Our experience2 and that of others16 is that tolerance is often overcome by subtle alterations of either pulse width by 30 to 90 µs, frequency by 5 to 15 Hz, or both, and by either cycling stimulation or having stimulation breaks (i.e., periods off DBS lasting from days to months as required). Such experience is in contrast to DBS for movement disorders in which it has been established that rebound of tremor with time can be overcome by ramping up thalamic stimulation parameters.17 It is possible that the unmasking of other discomfort such as muscular allodynia by relief of burning hyperesthesia can be overcome by “deramping” DBS. A positive correlation found between frequency and amplitude in long-term follow-up of poststroke pain DBS and reduction in both amplitudes and frequencies of stimulation over time in patients achieving pain relief supports such a hypothesis.2

At present our experience guides us broadly toward whom to offer DBS, which targets to select, and tentatively toward prognostication. For both thalamic and PVG/PAG DBS targets for pain, the relative contributions of local interactions and wider functional neuroanatomical circuitry are yet to be fully elucidated. In addition, research attention should turn to focus on improving patient selection. When successful, results from DBS for intractable pain are frequently spectacular and life transforming. DBS should only be performed in experienced, specialist centers willing to carefully study their patients and publish their results. The intensive experimental study of small groups of patients generates hypotheses that create opportunity for larger randomized controlled, clinical trials.

Introduction

The pioneer neurosurgeon Lauri Laitinen once commented that “when one sets out to make a historical survey of surgical attempts to relieve the tremor and rigor in Parkinson disease, one cannot help feeling that it would have been a far easier task to list those nervous structures which have not been attacked.”18,19 Neurosurgical attempts to relieve intractable pain mirror his wry observation; all structures from peripheral nerve through dorsal root, spinal cord, midbrain, and thalamus to cingulate cortex have been first lesioned and later electrically stimulated or perfused with analgesics or anesthetics (Fig. 22-1). Yet chronic pain continues to present a considerable burden to society, transcending many debilitating medical diseases, including cancer, stroke, trauma, and failed surgery.20 Its prevalence may be over 20%.21

The concept of ameliorating persistent pain by deep brain stimulation (DBS) originates from clinical studies over half a century ago. On the basis of septal self-stimulation experiments in rodents22 and reports of analgesia in patients receiving septal DBS for psychiatric disorders,23,24 Heath and Mickle25 postulated that stimulating the same area that produced pleasure might relieve pain. They successfully reduced a patient’s cancer pain over several weeks with intermittent stimulation. The findings were replicated by a case series using improved equipment a decade later.26

Further impetus for DBS was provided in the mid-1960s by the theoretical paradigm shift initiated by Melzack and Wall’s gate control theory27 and advances in stimulator technology. The gate control theory was translated first into implantable peripheral nerve stimulators28 and then into spinal cord stimulation (SCS),29 developed by Medtronic (Minneapolis, Minn) into a commercially available permanently implantable device.30,31

Identification of the periventricular and periaqueductal gray (PVG/PAG) regions as a target for DBS has its origins in animal research. Mayer and associates32 and Reynolds and others33 were able to perform major surgery in awake rodents using analgesia induced by PAG stimulation alone. Pain relief by PVG/PAG DBS was first reported in patients by Richardson and Akil3436 and then Hosobuchi, Adams, and Linchitz.37 Evidence supporting ventroposterolateral and ventroposteromedial (VPL/VPM) thalamic nuclei and adjacent structures as putative targets for DBS came from ablative surgery,3841 leading Hosobuchi, Adams, and Rutkin42 to treat anesthesia dolorosa with VPM thalamic DBS. Several others pioneered thalamic DBS, including Mazars, Merienne, and Cioloca,43,44 Mazars,45 Mazars, Roge, and Mazars46 and Adams and Fields who, along with Hosobuchi,4749 also targeted the internal capsule. Observations from inadvertent localization errors and investigations into current spread from the PVG/PAG led others to target more medial thalamic nuclei, including the centromedian-parafascicular complex (Cm-Pf).5053

The rapid diffusion of electrical stimulation treatments for multifarious clinical indications by the mid-1970s led the U.S. Food and Drug Administration (FDA) to sponsor a symposium to evaluate their merits.54 Only pain treatments were documented to be both safe and effective,55,56 albeit in an era when the long-term complications of the then recently discovered levodopa on Parkinson disease were yet to be revealed. Crucial primate investigations elucidating basal ganglia functions and presaging a renaissance in DBS for movement disorders had also not yet been undertaken.19,57

Despite the consensus, the U.S. Medical Device Amendments of 1976 compelled the FDA to request DBS manufacturers to conduct further studies to show the benefits of DBS for pain, and an additional ruling in 1989 required clinical trials to demonstrate safety and efficacy. Two multicenter trials were conducted, first in 1976 using the Medtronic Model 3380 electrode (196 patients) and then in 1990 with the Model 3387 (50 patients) that superseded it.58 The two studies were an amalgam of prospective case series from participating neurosurgical centers, neither randomized nor case controlled, and both suffered from poor enrollment and high attrition. Other shortcomings included heterogeneous case mixes with underspecified patient selection criteria and subjective and unblinded assessment of patient outcomes. Confounds arose from inconsistencies in deep brain sites stimulated, numbers of electrodes used per patient, and stimulation parameters chosen. Improvements made to the later Model 3387 trial included limiting deep brain sites stimulated to two per patient and using visual analog scores (VASs) to rate pain intensity for outcome assessment; but its included cases per center were tiny, with a mean of five and median of three patients treated.

Neither trial satisfied study criteria for efficacy of at least half of patients reporting at least 50% pain relief 1 year after surgery. Therefore U.S. FDA approval for analgesic DBS was not sought by the device manufacturer. However, intriguingly, the large numbers of patients lost to follow-up resulted in a steady increase with time in the proportion of patients with at least 50% pain relief; 2 years after implantation they comprised 18 out of the 30 remaining patients (60%) followed up in the Model 3380 trial and 5 out of the 10 in the Model 3387 trial (50%). Nonetheless, the trials resulted in the U.S. FDA giving DBS for pain “off-label” status, thus precluding its approval by medical insurers.5860 As a consequence, few clinical investigations into DBS for pain using current technology and techniques have been reported.

In the last decade to our knowledge only five centers, three European and two Canadian, have published case series of more than six patients.1,6169 In contrast, both other centrally implantable neurostimulation treatments for pain, SCS and motor cortex stimulation (MCS), have continued to yield research publications, albeit mostly of uncontrolled case series,7075 with small randomized controlled, clinical trials in SCS emerging.7678 Over 1300 recipients of DBS for pain have been reported63,64,68,69,79,80 compared to nearly 400 patients with MCS73,81 and nearly 4000 with SCS.74,75

Our experience is that DBS is superior to MCS for selected refractory pain syndromes.82 Similarly we find DBS more appropriate than SCS for certain pain etiologies, although little published data exists comparing treatments by the same surgeon in the same group of patients. Two retrospective studies from the same group have compared all three modalities of central neurostimulation, but the results are obfuscated first by different treatments trialed both between and sequentially within patients and second by limited outcome information.83,84 A recent review has compared the three neurostimulatory therapies but did not include all contemporary DBS case series in its analysis.85 Over the last decade we have treated over 70 patients with analgesic DBS, regularly publishing results for many implanted and amenable to follow-up.1,62,65,67,68 Our experience is described, and results reviewed alongside other current studies to clarify the current status of DBS for pain.

Establishing Diagnosis and Indications/Contraindications

Historically, clinical approaches to DBS have sought to categorize patients first by cause of pain and second by dichotomizing the pain into such categories as nociceptive or deafferentation, epicritic or protopathic, peripheral or central. Such distinctions are largely unhelpful to patient selection since a gathering body of human functional neuroimaging and electrophysiological evidence confirms that chronic pain arises concomitant with centrally mediated changes related to neuronal plasticity, regardless of etiology.8691 Thus it can be assumed that chronic pain refractory to medical treatment is largely central pain and thus neuropathic. The challenges to patient selection for DBS then become twofold: (1) the confirmation that the patient’s pain is neuropathic and neither factitious nor psychogenic, and (2) the selection of those with neuropathic pain who are likely to derive benefit from DBS.

Essential to the patient selection process is assessment by a multidisciplinary team consisting at a minimum of a pain specialist, neuropsychologist, and neurosurgeon. Comprehensive neuropsychological evaluation provides best practice in patient selection for DBS to exclude psychoses, addiction, and medically refractory psychiatric disorders and ensure minimal cognitive impairment.9295 Quantitative assessment of the pain and health-related quality of life should be a requirement of the preoperative patient selection process. Our preference is to use both VAS (scale of 0 to 10) to rate pain intensity and the McGill Pain Questionnaire (MPQ) for pain evaluation,96,97 the latter giving additional qualitative information and including a quality of life assessment. We also assess quality of life using the Short Form 36 (SF-36) and VAS part of the Euroqol five-dimensional assessment tool (EQ-5D).98100 The patient records his or her VAS twice daily in a pain diary over a period of 12 days. The 24 VAS scores are reviewed to ensure consistency and clarified with the patient if inconsistent. The EQ-5D, SF-36, and MPQ are administered by the pain specialist before surgery. The MPQ is repeated on a separate occasion independently by the neuropsychologist and scored using the ranked pain rating index. Our experience is that certain items of the MPQ can predict a positive response to DBS. In particular, over 80% of our patients who describe burning pain have found benefit from DBS, regardless of whether VPL/VPM, PVG/PAG or both are stimulated. We have published patient data linking resolution of burning pain with blood pressure reduction and long-term PVG/PAG DBS analgesia implicating cardiovascular changes in this type of pain3 and found heart rate variability changes consistent with sympathetic suppression and/or parasympathetic augmentation by PVG/PAG DBS101; but further multivariate analysis of other MPQ items, other brain targets, and other measurable cardiovascular parameters are required to elucidate further the phenomenon.

The specific etiology of the chronic pain appears less important to efficacy than its symptom history, which may involve hyperalgesia, allodynia, and hyperpathia. The pain must have a definable organic origin with the patient refractory to or poorly tolerant of pharmacological treatments. Surgical treatments may have been attempted (e.g., peripheral neuroablative or decompressive procedures for trigeminal neuralgia); however, we do not consider failure of other neurostimulatory therapies a prerequisite for DBS. Our preference is to trial DBS rather than SCS or MCS in carefully selected patients wherever the etiologies of chronic pain are consistent with neuronal reorganization at multiple levels of the central neuromatrix.

The greater body of clinical studies of SCS,71,72 coupled with ours and others’ lack of success with DBS for spinal injuries,63,65 favors SCS over DBS as a more appropriate first-line neurostimulatory intervention for spinal cord injury when central reorganization is likely to be mostly at a spinal level. However, our experience of DBS for pain after limb or plexor injury65,67 encourages us to consider DBS rather than SCS as first-line treatment for complex regional pain syndromes (CRPS). A 100% success rate in 13 implanted patients to date, together with a recent paradigm shift toward central brain reorganization with autonomic dysfunction as the mechanism underlying CRPS,102106 supports the treatment both for brachial and lumbar plexus injuries and stump pain after amputation and for phantom limb pain.

Other pain etiologies for which we and others have obtained positive outcomes using DBS are stroke1,2; facial and head pain, including postherpetic trigeminal neuralgia and anesthesia dolorosa62,107; multiple sclerosis63; genital pain; and malignancy.65,68 These are listed for reference by etiology with implantation success rates shown in Fig. 22-2; however, we reiterate our position that to select patients for DBS primarily by etiology rather than by findings on history and examination and use of assessment tools is to oversimplify their chronic pain and risk poor outcomes. Rather than using inflexible selection criteria, our preference in patient selection is expert opinion after multidisciplinary assessment demonstrating quantitatively severe pain refractory to medication for at least 1 year, with significantly impaired quality of life and qualitative pain suggestive of neuropathic changes without predominantly spinal involvement. We find little merit in opiate or naloxone administration to determine suitability for DBS, although an historical literature exists.80 Medical contraindications to DBS include uncorrectable coagulopathy obviating neurosurgery and ventriculomegaly sufficient to preclude direct electrode passage to the surgical target.

Considering cephalalgias, we have also successfully treated cluster headache with DBS of the posterior hypothalamic nuclei and investigated it using multiple translational methods as for chronic pain.108110 As we review comprehensively elsewhere,111 this debilitating condition has responded impressively to DBS in our initial experience and others’ and is worthy of multicenter, randomized controlled clinical trials. Further consideration of cluster headache is beyond the scope of this review.

Anatomy

DBS targets are contralateral to the painful side of the body. Currently used sites for DBS can be divided anatomically first into somesthetic regions of the ventrobasal thalamus (VPL/VPM) and second into more medial regions surrounding the third ventricle and aqueduct of Sylvius, including the gray matter (PVG/PAG) and medial thalamic Cm-Pf nuclei. Further anatomical distinction is redundant since accuracy of DBS placement for most practitioners is limited to ±2 mm at best by magnetic resonance imaging (MRI) and computerized tomography (CT) slice thickness.

Moreover, our ultimate adjustment of intracerebral electrode position is directed by awake patient reports of somesthetic localization during intraoperative stimulation. Such subjective information may alter the final electrode site by up to several millimeters from preoperative target coordinates. A guiding principle is the established somatotopic organization of the somesthetic thalamic and PVG/PAG regions. Human microelectrode studies reveal a mediolateral somatotopy in the contralateral ventroposterior thalamus, the head of the homunculus being medial and the feet lateral.112 Subjective observation of a rostrocaudally inverted sensory homunculus in contralateral PVG/PAG113 has been confirmed objectively by our human macroelectrode recordings of somatosensory evoked potentials.114 The PVG/PAG target is found at a point 2 to 3 mm lateral to the third ventricle at the level of the posterior commissure, 10 mm posterior to the midcommissural point. Its pertinent anatomical boundaries in the midbrain include the medial lemniscus laterally, the superior colliculus inferoposteriorly, and the red nucleus inferoanteriorly. Sensory thalamic targets are found 10 to 13 mm posterior to the midcommissural point and from 5 mm below to 2 mm above it. The VPM is targeted for facial pain only and found midway between the lateral wall of the third ventricle and the internal capsule; the arm area of VPL is 2 to 3 mm medial to the internal capsule and the leg area of VPL 1 to 2 mm medial to the internal capsule. The sensory thalamus is bordered by Cm-Pf nuclei medially; the internal capsule laterally; the thalamic fasciculus, zona incerta, and subthalamic nucleus inferiorly; the thalamic nucleus ventralis intermedius anteriorly; and the pulvinar thalamic nucleus posteriorly.

Basic Science

A wealth of electrophysiological, anatomical, and radiological evidence in humans and animals, reviewed elsewhere, establishes both PVG/PAG and ventrobasal thalamus as structures important to pain perception and the pathophysiology of chronic pain syndromes.9,115122 The subtleties of hierarchical position and behavioral function of individual brain structures, whether sensory-discriminative, attentional, motivational-affective, or hedonic, are much debated. However, the consensus is toward a pain neuromatrix also involving spinal cord; posterior hypothalamus; amygdala; and neocortical structure, including somatosensory, insular, anterior cingulate, and prefrontal cortex. Whether pain control is top-down or bottom-up in its hierarchy is unresolved and often depends on the experimental paradigm used. Our human electrophysiological studies of neuronal coherence have used somatosensory-evoked potentials and Granger causality predictive modeling to suggest that PVG/PAG exerts ascending modulation on VPM/VPL in a bottom-up model of pain processing,114 a finding that functional MRI would be unable to confirm because of insufficient temporal resolution.9,123125

Central to the rationale for DBS is the concept of aberrant neuronal firing at the target sites concomitant with the chronic pain. Human and animal electrophysiological experiments show increased thalamic neuronal firing in pain.126 Comprehensive reviews of electrophysiological studies conclude that the mechanisms of analgesic stimulation are not clearly delineated.80,127131 From insights revealed by basal ganglia microelectrode recordings and DBS for movement disorders reviewed elsewhere,132134 we postulate that altered rhythmic activity in VPL/VPM and PVG/PAG neurons is likely to play an important role in the pathophysiology of central pain. At either target our clinical experience is that in general DBS at lower frequencies (≤50 Hz) is analgesic and at higher frequencies (>70 Hz) hyperalgesic,2,135,136 supporting a dynamic model whereby synchronous oscillations in discrete neuronal populations centrally modulate chronic pain perception. Therefore analgesic DBS may either disrupt pathological high-frequency synchronous oscillations or, more likely, augment pathologically diminished low-frequency synchronous oscillations in the thalamic and reticular components of a reticulothalamocorticofugal pain neuromatrix. We have shown a positive correlation between analgesic efficacy at either DBS site and the amplitude of slow frequency (<1 Hz) VPL/VPM local field potentials (LFPs),61,137 allowing for physiologically modulated artifact.138 We now also have early evidence that patients off DBS have characteristically enhanced low-frequency (8 to14 Hz) power spectra of both PVG/PAG and VPL/VPM LFPs when in pain.139 Further research is required to elucidate if such neuronal signatures could aid patient selection, in particular if combined with technical advances in noninvasive functional neuroimaging and electrophysiological techniques such as single photon emission computed tomography (SPECT) and magnetoencephalography (MEG) to characterize functional neuronal connectivity.10,11,

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