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Deep Brain Stimulation of the Dorsal Anterior Cingulate Cortex for the Treatment of Chronic Neuropathic Pain

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Deep Brain Stimulation of the Dorsal Anterior Cingulate Cortex for the Treatment of Chronic Neuropathic Pain NEUROSURGICAL FOCUS Neurosurg Focus 38 (6):E11, 2015 Deep brain stimulation of the dorsal anterior cingulate cortex for the treatment of chronic neuropathic pain Jennifer F. Russo, BFA,1,2 and Sameer A. Sheth, MD, PhD2 1Columbia University College of Physicians and Surgeons and 2Department of Neurological Surgery, Columbia University Medical Center, New York, New York Chronic neuropathic pain is estimated to affect 3%–4.5% of the worldwide population. It is associated with significant loss of productive time, withdrawal from the workforce, development of mood disorders such as depression and anxiety, and disruption of family and social life. Current medical therapeutics often fail to adequately treat chronic neuropathic pain. Deep brain stimulation (DBS) targeting subcortical structures such as the periaqueductal gray, the ventral posterior lateral and medial thalamic nuclei, and the internal capsule has been investigated for the relief of refractory neuropathic pain over the past 3 decades. Recent work has identified the dorsal anterior cingulate cortex (dACC) as a new potential neuromodulation target given its central role in cognitive and affective processing. In this review, the authors briefly discuss the history of DBS for chronic neuropathic pain in the United States and present evidence supporting dACC DBS for this indication. They review existent literature on dACC DBS and summarize important findings from imaging and neurophysiological studies supporting a central role for the dACC in the processing of chronic neuropathic pain. The available neurophysiological and empirical clinical evidence suggests that dACC DBS is a viable therapeutic option for the treatment of chronic neuropathic pain and warrants further investigation. http://thejns.org/doi/abs/10.3171/2015.3.FOCUS1543 KEY WORDS deep brain stimulation; anterior cingulate cortex; chronic pain; neuropathic pain; ACC; dACC HRONIC pain affects approximately 100 million pain is associated with alterations in function of the pe- American adults each year and results in an an- ripheral, spinal, and central pain pathways, which result nual incremental health care cost of $560–$635 in abnormal activity, leading to the development of allo- Cbillion.66 The economic burden of chronic pain is multi- dynia, the experience of nonnociceptive stimuli as painful; plied when loss of productive work time is considered.143 hyperalgesia, an abnormally increased pain response to Chronic pain has been associated with impairment in cog- nociceptive stimuli; and spontaneous pain, which can be nition and attention,78 development of psychiatric comor- constant and debilitating.5,24,40,43,53,58,62 Chronic neuropath- bidities such as depression and anxiety,48 dependence on ic pain arising from aberrant nervous system activity is opioid analgesia, and decline in social functioning.59 Fur- particularly resistant to conventional medical therapies.18 ther, many chronic pain states, such as neuropathic pain, Additionally, many of the medications used to treat neuro- remain difficult if not impossible to treat with available pathic pain by modulating aberrant activity in the periph- therapeutics.159 For these reasons, the impact of chronic eral nervous system, such as carbamazepine, gabapentin, pain on public well-being cannot be overstated. tricyclic antidepressants, serotonin- and norepinephrine- Neuropathic pain is defined by the International Asso- selective reuptake inhibitors, are associated with signifi- ciation for the Study of Pain (IASP) as “pain arising as cant side effects, such as sedation and nausea.45 These a direct consequence of a lesion or disease affecting the treatments, which act peripherally, are unable to address somatosensory system.”78 When neuropathic pain extends pathologic changes in the central nervous system, which beyond the period of injury and healing, it becomes chron- are implicated in the development and maintenance of ic disease.45,70,74 The development of chronic neuropathic chronic pain. ABBREVIATIONS ACC = anterior cingulate cortex; dACC = dorsal ACC; DBS = deep brain stimulation; DTI = diffusion tensor imaging; fMRI = functional MRI; IASP = Inter- national Association for the Study of Pain; IC = internal capsule; LTP = long-term potentiation; MRS = MR spectroscopy; PAG = periaqueductal gray; PVG = periventricular gray; VAS = visual analog scale; VPL/VPM = ventral posterior lateral and medial thalamic nuclei. SUBMITTED February 1, 2015. ACCEPTED March 23, 2015. INCLUDE WHEN CITING DOI: 10.3171/2015.3.FOCUS1543. DISCLOSURE The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. ©AANS, 2015 Neurosurg Focus Volume 38 • June 2015 1 Unauthenticated | Downloaded 10/04/21 11:09 AM UTC J. F. Russo and S. A. Sheth Both internationally and in the United States, the use of only those patients who achieved a reduction in pain of ≥ deep brain stimulation (DBS) has been investigated for the 50% during a test stimulation period immediately postop- treatment of chronic neuropathic pain that is refractory to eratively with externalized leads went on to the next stage conventional medical therapy.14,21,28,30,46,60,63,79,81,115,116,137 In- for full device internalization. vestigations into the use of DBS targeting various areas For the first trial, 46.1% of patients reported ≥ 50% of the brain, including the periventricular gray (PVG), reduction in pain at 1 year and 17.8% at 24 months, and sensory thalamus, and the internal capsule (IC), have for the second trial, 16.2% had 50% reduction at 1 year yielded valuable information regarding patient selection, and 13.5% at 24 months. Neither study achieved the a stimulation parameters, operative technique, and outcome priori criteria for success. No major reduction in narcotic measurement.80 They have also served to highlight the medication usage was observed in either trial. Addition- complexity and burden associated with the management ally, withdrawals and dropouts accounted for 70%–73% of chronic pain. of patients at the 24-month outcome point, with a higher In this review, we briefly review the history of DBS for proportion of responders represented in this group. The chronic pain and present evidence supporting DBS of the weakness of these results led the device manufacturer to dorsal anterior cingulate cortex (dACC). We summarize reconsider pursuit of marketing approval for the treatment important findings from recent neuroimaging and neuro- of chronic pain. physiology studies supporting a central role for the dACC A number of limitations have been identified in the de- in the development of chronic neuropathic pain and review sign and execution of the studies described above. First, existent literature on DBS of the dACC for this indication. these studies consisted of a collection of prospective case series from participating centers. These series were nei- DBS for Chronic Pain: Subcortical Targets ther randomized nor case controlled. Subjects were drawn from a heterogeneous pain population, with a large variety The idea of using DBS to treat chronic pain has its ori- of syndrome types and etiologies. Interventions varied be- gins in the development of the gate control theory of pain 97,102 tween VPL/VPM and PAG stimulation in an uncontrolled as described by Melzack and Wall in 1965. This theo- manner, and no uniform stimulation parameters were em- ry, although now mostly supplanted by newer models such 96,98–100 ployed. Additionally, a variable number of electrodes were as the neuromatrix theory of pain, was instrumen- used per patient. Use of validated outcome measurement tal in establishing the central nervous system as an active tools was limited to the administration of the visual ana- partner in the development of chronic pain states. Over the log scale (VAS) score during the 3387 trial only. All other past 3 decades, multiple neural targets have been explored measurements of pain reduction upon which assessment for chronic stimulation, including the periaqueductal gray of efficacy was based were subjective and unblinded.113 (PAG) region, 57 the ventral posterior lateral and medial 114,123 1 As a result of these studies, DBS for chronic pain has thalamic nuclei (VPL/VPM), the IC, and, most re- remained “off-label” in the United States, and, as a result, cently, the dACC. very little additional formal study has been undertaken. Under the US Medical Device Amendment of 1976, Most of the current literature on DBS for chronic pain has which compelled the US Food and Drug Administration come from investigators in the United Kingdom, Europe, to require DBS device manufacturers to conduct studies and Canada. These more recent studies have benefited showing benefit of DBS for the treatment of chronic pain, from improved imaging techniques, updated DBS device 2 Medtronic-sponsored, open-label, multicenter trials design, and procedural refinement. In addition, continued were conducted. In the first of these trials, which enrolled work to determine which chronic pain etiologies are most 196 patients from 1989 to 1992, model 3380 DBS leads 29 responsive to this therapeutic intervention has led to im- were implanted into either the VPL/VPM or the PAG. provements in patient selection. Finally, advances in the This trial was supplanted by a second trial in 1992, utiliz- neuroscience of pain have opened up the possibility of new ing lead model 3387, which had replaced model 3380. This neural targets, such as the dACC, which hold promise for second trial enrolled 50 patients between 1992 and 1995. effective pain relief for some chronic pain pa tients.67,68,71, Both trials were closed early due to slow enrollment and 75–77,83,85,90,107,120,121,128,130,149,163–166, unexpectedly low efficacy, as determined by the limited reduction in pain scores postoperatively. The criterion for success for the model 3380 trial was The Role of the dACC in Pain Processing defined a priori as at least half of patients with internal- An extensive body of literature has been devoted to un- ized devices reporting ≥ 50% pain reduction at 1 year. For derstanding the role of the dACC in human cognition.
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