For over half a century, neurosurgeons have attempted to treat pain from a diversity of causes using acute and chronic intracranial stimulation. Targets of stimulation have included the sensory thalamus, periventricular and periaqueductal gray, the septum, the internal capsule, the motor cortex, posterior hypothalamus, and more recently, the anterior cingulate cortex. The current work focuses on presenting and evaluating the evidence for the efficacy of these targets in a historical context while also highlighting the major challenges to having a double-blind placebo-controlled clinical trial. Considerations for pain research in general and use of intracranial targets specifically are included.
Key points
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For more than half a century, neurosurgeons have attempted to treat pain from a diversity of causes using acute and chronic intracranial stimulation.
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Targets of stimulation have included the sensory thalamus, periventricular and periaqueductal gray, the septum, the internal capsule, the motor cortex, posterior hypothalamus, and more recently, the anterior cingulate cortex.
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The current work focuses on presenting and evaluating the evidence for the efficacy of these targets in a historical context while also highlighting the major challenges to having a double-blind placebo-controlled clinical trial.
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Considerations for pain research in general and use of intracranial targets specifically are included.
Introduction
The use of electrical stimulation as a neurosurgical tool is rooted firmly in the history of treating hypokinetic and hyperkinetic disorders. Its emergence was directly related to the use of neurosurgical interventions that included lesions to the thalamus and fibers projecting to and from the thalamus as a treatment of motor signs like rigidity, bradykinesia, and tremor. Although promising, these results were overshadowed by the introduction of l -Dopa as a method for treating Parkinson disease. The use of chronic intracranial stimulation for the treatment of neurologic disorders would remain nearly quiescent for nearly 2 decades until 1987, when Benabid and colleagues reintroduced thalamic stimulation for Parkinson patients who had emerging symptoms after a unilateral thalamotomy. The renaissance of intracranial chronic stimulation further flourished after Parkinson patients on chronic l -Dopa developed adverse side effects. From there, the 1990s through the present would see a strong reemergence of the use of chronic stimulation in hyperkinetic and hypokinetic disorders with targets including the subthalamic nucleus, globus pallidus internus, and ventral intermediate thalamus (Vim).
Embedded within the success story of deep brain stimulation (DBS) for movement disorders is the use of chronic intracranial stimulation as an intervention for pain. The work of Heath and Mickle in the 1950s is often thought of as the birth of intracranial stimulation for pain control. Their observation that septal stimulation acutely alleviated intractable pain would lead to the birth of the field. From there, DBS targets for pain control would expand to include the internal capsule (IC), the ventral posterolateral nucleus (VPLP) and the ventral posteromedial nucleus (VPM) of the sensory thalamus (STH), the centro-median parafasicular region (CM-Pf) of the thalamus, the periaqueductal/paraventricular gray (PAG/PVG), the posterior hypothalamus (PH), the motor cortex, the nucleus accumbens (NAcc), and the anterior cingulate cortex. The following sections highlight the past, present, and future DBS targets used to treat various types of pain.
Introduction
The use of electrical stimulation as a neurosurgical tool is rooted firmly in the history of treating hypokinetic and hyperkinetic disorders. Its emergence was directly related to the use of neurosurgical interventions that included lesions to the thalamus and fibers projecting to and from the thalamus as a treatment of motor signs like rigidity, bradykinesia, and tremor. Although promising, these results were overshadowed by the introduction of l -Dopa as a method for treating Parkinson disease. The use of chronic intracranial stimulation for the treatment of neurologic disorders would remain nearly quiescent for nearly 2 decades until 1987, when Benabid and colleagues reintroduced thalamic stimulation for Parkinson patients who had emerging symptoms after a unilateral thalamotomy. The renaissance of intracranial chronic stimulation further flourished after Parkinson patients on chronic l -Dopa developed adverse side effects. From there, the 1990s through the present would see a strong reemergence of the use of chronic stimulation in hyperkinetic and hypokinetic disorders with targets including the subthalamic nucleus, globus pallidus internus, and ventral intermediate thalamus (Vim).
Embedded within the success story of deep brain stimulation (DBS) for movement disorders is the use of chronic intracranial stimulation as an intervention for pain. The work of Heath and Mickle in the 1950s is often thought of as the birth of intracranial stimulation for pain control. Their observation that septal stimulation acutely alleviated intractable pain would lead to the birth of the field. From there, DBS targets for pain control would expand to include the internal capsule (IC), the ventral posterolateral nucleus (VPLP) and the ventral posteromedial nucleus (VPM) of the sensory thalamus (STH), the centro-median parafasicular region (CM-Pf) of the thalamus, the periaqueductal/paraventricular gray (PAG/PVG), the posterior hypothalamus (PH), the motor cortex, the nucleus accumbens (NAcc), and the anterior cingulate cortex. The following sections highlight the past, present, and future DBS targets used to treat various types of pain.
Intracranial targets
Within each target section is a brief review of the history behind stimulating the area for pain, the current literature surrounding its use as a target, and the current clinical standing of that area. Tables present a summarized account for the literature on each region. Each entry is based on the information reported in the article with no attempts to standardize terminology across studies. In other words, independent criteria for “successful treatment” (most reports will define this as >50% improvement of their outcome measure), “side effects” (listed side effects only pertain to stimulation, not due to the surgery or postoperative care), or “pain type” (details of patients conditions and source of pain) have not been defined. Several reports included stimulation to multiple targets for pain (eg, a patient will have electrodes placed in the VPLP/VPM and PVG/PAG). These articles are listed once in the table corresponding to the target used for most patients but are noted in the charts for the other brain areas. The notes section of the table contains an abbreviated accounting of other areas stimulated and any additional aspects of the article that should be considered.
Septal Interventions
The stimulation of the septal region of the human brain ( Table 1 ) was first initiated by Heath and Mickle likely based on the rewarding (or “pleasurable”) effects seen in rats. In their work, Heath and Mickle noted that most patients with septal stimulation were more alert and spoke more rapidly. In addition, a few patients were also acutely relieved of their chronic pain (pain due to either rheumatoid arthritis or advanced carcinoma). Later work stimulating the medial forebrain bundle in patients with terminal carcinoma also echoed these results. In particular, Ervin and colleagues stimulated the medial forebrain bundle, among many other areas, and noted an amelioration of the pain reported in their patients with cancer. Because the medial forebrain bundle is part of the mesolimbic pathway, including ventral tegmentum, and NAcc, and also connects to septal nuclei, it is not clear what part of the “pleasure system” could be generating these results. More directly, Gol attempted to study the effects of septal stimulation on pain further and showed some success in a few patients but not the majority (2 of 6 patients). Given these early challenges and only moderate success, it appears that the septum has fallen out of favor. However, it should be noted that 2 works have been published by Schvarcz that suggest a nearly 60% success rate of intractable pain relief with septal stimulation. Currently, septal targeting is not common and there is not a double-blind, randomized, placebo-controlled trial to evaluate it efficacy.
| Study, Year | Study Type | Pain Type | Total-(Implanted)-Success | Electrode and Stimulation Parameters | Side Effects |
|---|---|---|---|---|---|
| Heath & Mickle, 1960 | CS | RA/CP | 6-NFS | 4 Strand, silver-plated copper wire, plastic insulation, silver ball tip | Rapid speech, alert, acute relief of pain |
| Ervin et al, 1969 | CS | CP | NFS | NFS | Mild euphoria, acute relief of pain |
| Gol, 1967 | CS | CP/BP | 6-1 | Heavy, single-lead electrode, 6 terminal, silver ball tip, 2000–5000 c/s, 0–12 V | More cheerful, alert |
| Schvarcz, 1985 | CS | CP/DP | 10-10-6 | Standard DBS electrode | Feeling of warmth, well-being, relaxation |
| Schvarcz, 1993 | CS | CP/DP | 19-19-12 | Bipolar or tetrapolar electrode | Feeling of warmth, well-being |
IC Interventions
The idea of stimulating the internal capsule as a therapeutic option for treating intractable pain ( Table 2 ) started in 1974 when Fields and Adams reported efficacy in a case report. Their results would later expand to a case series. These results would be further bolstered by other groups in the late 1970s to mid-1980s. Interestingly, the notion of stimulating the IC for pain would remain dormant for more than 2 decades until Franzini and colleagues reported a case study in 2008. As of late, Plow and colleagues have published their clinical trial design for stimulation of the ventral striatum and anterior limb of the internal capsule. Although the proposal by Plow and colleagues is not the first clinical trial for the treatment of pain with DBS, it does hold a great deal of promise because it improves several limitations of older clinical trials (discussed later in the Consideration for Trial Design Section).
| Study, Year | Study Type | Pain Type | Total-(Implanted)-Success | Electrode and Stimulation Parameters | Side Effects | Notes |
|---|---|---|---|---|---|---|
| Fields & Adams, 1974 | CR | SH | 1-1-1 | Medtronic, 30–150 Hz, 0.25–0.45 ms, 0.7 mA | Paresthesias | F-U: 12 mo |
| Adams et al, 1974 | CS | SH, PSP, SCI | 6-5-5 | Medtronic, 30–150 Hz, 0.25–0.45 ms, 0.7 mA | Paresthesias | STH electrodes; bilateral pain, patient shifted electrode position = lost unilateral therapeutic effect. VPLP stimulation led to worse pain |
| Hosobuchi et al, 1975 | Please see entry in the STH Section | |||||
| Boethius et al, 1976 | CS | AD, TPS, PI, PLP | 5-5-4 | Medtronic, 10–100 Hz, 0.1–0.3 ms, 0.15–7 mA | Motor responses, visual phenomena | Pulvinar, CM-Pf, STH, PAG electrodes; Pulvinar, STH, IC successful |
| Hosobuchi et al, 1979 | Please see entry in the PV(A)G Section | |||||
| Tsubokawa et al, 1982 | Please see entry in the STH Section | |||||
| Tsubokawa et al, 1984 | Please see entry in the STH Section | |||||
| Namba et al, 1984 | CS | PSP, TPS | 7-6-5 | Medtronic, 50 Hz, 0.2–1.0 ms, 2–8 V | Feeling of warmth | F-U: 9–31 mo |
| Namba et al, 1985 | CS | PSP, TPS, MS | 11-11-8 | Medtronic, 50 Hz, 0.6 ms, 2–3 V | Paresthesias; muscle contraction (putamen involvement) | STH electrodes; most medial/posterior IC past the posterior commissure level |
| Young et al, 1985 | Please see entry in the PV(A)G Section | |||||
| Kumar et al, 1997 | Please see entry in the PV(A)G Section | |||||
| Farnzini et al, 2008 | CR | TS | 1-1-1 | Medtronic, 3389, 100 Hz, 60 ms, 1 V | Paresthesias, contralateral motor responses | Pain/spasticity reduction; F-U 60+ mo |
| Plow et al, 2013 | Write up of design of clinical trial NCT01072656 | |||||
STH, VPM/Lateral Nucleus Interventions
Primary literature focusing on the treatment of intractable pain with STH stimulation ( Table 3 ) dates to the early 1970s. Inspired by the results of VPM lesions, the gate control theory of pain, and the paresthesias noted by Ervin, the often cited paper by Hosobuchi and colleagues would involve the treatment of facial anesthesia dolorosa with stimulation of the VPM nucleus of the thalamus. They noted success in 4 of 5 patients. That year and a year later, Mazars and colleagues published their work (started in the early 1960s) on treating intractable pain with thalamic stimulation with 13 of 17 patients showing benefit. Expanding more broadly to chronic neuropathic pain in general, Turnbull and colleagues showed complete or partial success in 14 of 18 patients (including cases of complex regional pain syndrome, lumbar arachnoiditis, phantom limb pain, and plexus avulsion) when stimulating the ventral posterior portion of the thalamus. During these early studies, it was noted that some patients showed an acute relief of pain with VPM/VPLP stimulation, but that the pain would recur gradually. Several attempts would be made to prevent stimulation tolerance. In the peri(aqueductal)ventricular gray (PV[A]G) literature, Hosobuchi would propose the use of l -tryptophan, and Meyerson and colleagues would propose the use l -Dopa to prevent the reduction of the DBS effect. Tsubokawa would pay particular attention to this phenomenon as he further explored VPLP stimulation over several studies. He would introduce the use of l -Dopa and l -Tryptophan supplements in thalamic stimulation to help mitigate the appearance of “stimulation tolerance,” although this practice would not continue because of the lack of evidence for efficacy. Interestingly, stimulation tolerance is still a very real concern and is only further compounded with current work that has suggested that there is also an insertional effect (benefit with electrode insertion but no stimulation, as opposed to a developing tolerance to stimulation ).
| Study, Year | Study Type | Pain Type | Total-(Implanted)-Success | Electrode and Stimulation (F, PW, V) | Side Effects | Notes |
|---|---|---|---|---|---|---|
| Hosobuchi et al, 1973 | CS | AD | 5-4 | 7 Intertwined, insulated, platinum wires. 0–4.5 V, 0.4-ms pulse, 60–125 Hz | Paresthesias | F-U: 3–24 mo |
| Mazars et al, 1973 | CS | PLP, PHP, AD, DP | 14-13 | Monopolar or bipolar gold/copper electrodes, 0.6–1.8 V, 20–50 Hz, 2-ms pulse | NFS | NFS |
| Mazars et al, 1974 | CS | PLP, AD, TPS, PHP | 25-18 | Monopolar or bipolar gold/copper electrodes, 0.6–1.8 V, 20–50 Hz, 2-ms pulse | NFS | First cohort of 17 patients: external stimulators; second cohort of 8 patients: implantable stimulators |
| Adams et al, 1974 | Please see entry in the IC Section | |||||
| Hosobuchi et al, 1975 | CS | AD, TPS, PP | 11-9 | 7 Intertwined, insulated, platinum wires. 0–4.5 V, 0.4-ms pulse, 60–125 Hz | NFS | IC electrodes; 2 patients who failed, medullary syndrome |
| Mazars, 1975 | CS | PLP, AD, TPS, PHP, PP, PI, CP | 44-29 | Monopolar or bipolar gold/copper electrodes, 0.6–1.8 V, 20–50 Hz, 2 ms | NFS | NFS |
| Boethius et al, 1976 | Please see entry in the IC Section | |||||
| Schvarcz, 1980 | CS | TPS, PCD, SCI | 6-6-4 | Medtronic, 20 Hz, 0.25 ms, 0.5 mA | Sensation of well-being and relaxation | Medial posterior inferior thalamic stimulation, F-U: 6–42 mo |
| Turnbull et al, 1980 | CS | LA, PI, CRPS | 18-14-12 | Medtronic, 75–100 Hz, NFS | Paresthesias | PV(A)G electrodes |
| Plotkin, 1982 | Please see entry in the PV(A)G Section | |||||
| Siegfried, 1982 | CS | PHP | 10-8 | Platinum electrode, monopolar, 33–195 Hz, NFS | NFS | F-U: 8–17 mo |
| Roldan et al, 1982 | CS | AD | 2-2-2 | Medtronic, 80–120 Hz, NFS | NFS | F-U: 5–11 mo |
| Tsubokawa et al, 1982 | CS | CP, TPS, PP | 5-5-4 | Medtronic, 50 Hz, 200 μs, 0.1–2.0 V | Stimulation tolerance | PV(A)G, IC electrodes; l -Dopa supplement |
| Tsubokawa et al, 1982 | CS | SCI, STP, PLP | 6-6-5 | Medtronic, 25–100 Hz, NFS | Rapid stimulation tolerance noted | Used l -Dopa and l -Tryptophan for stimulation tolerance, F-U: 12 mo |
| Hosobuchi, 1983 | Please see entry in the PV(A)G Section | |||||
| Tsubokawa et al, 1984 | CS | CP, PLP | 14-14-13 | Platinum electrode, NFS | Stimulation tolerance noted | PV(A)G, IC electrodes; no clear relationship between STH stimulation and β-Endorphin/pain levels |
| Tsubokawa et al, 1985 | CS | PLP, PHP, CP | 24-24-24 | Medtronic, NFS | PV(A)G electrodes | |
| Namba et al, 1985 | Please see entry in the IC Section | |||||
| Schvarcz, 1985 | Please see entry in Septal Section | |||||
| Young et al, 1985 | Please see entry in the PV(A)G Section | |||||
| Kumar & Wyant, 1985 | Please see entry in the PV(A)G Section | |||||
| Hosobuchi, 1986 | Please see entry in the PV(A)G Section | |||||
| Young & Brechner, 1986 | Please see entry in the PV(A)G Section | |||||
| Siegfried, 1987 | CS | PHP, AD, TSP, PI, PLP, STP, PP, DP | 112-112-89 | Medtronic, 33–100 Hz, 0.5–2 ms, 0.5–3 V | Paresthesias | F-U: 6–72 mo |
| Levy et al, 1987 | CS | TPS, PN, AD, PP, PCD, PLP, CP, BP | 141-141-84I, 42LT | Medtronic, STH, 20–100 Hz, 3–8 V; PV(A)G, 5–15 Hz, 1–5 V | PV(A)G: diplopia, nausea, vertical gaze palsies, blurred vision, horizontal nystagmus, persistent oscillopsia; STH, paresthesias, local pain | PV(A)G electrodes; review of literature, differentiated deafferentation and nociceptive pain, F-U: 24–169 mo |
| Young & Chambi, 1987 | Please see entry in the PV(A)G Section | |||||
| Kumar et al, 1990 | Please see entry in the PV(A)G Section | |||||
| Gybels & Kupers, 1990 | CS | PHP, TPS, PLP, FBS, PI, AD, SCI | 36-36-22I, 11LT | NFS | NFS | F-U: up to 120 mo, 48 mo avg |
| Kuroda et al, 1991 | CR | CM | 1-1-1 | Medtronic, NFS | NFS | Histologic analysis of placement medial lemniscus and VIM |
| Schvarcz, 1993 | Please see entry in the Septal Section | |||||
| Hariz & Bergenheim, 1995 | CS | PLP, DP, TPS, CP | 14-9 | Monopolar ISSAL, NFS | Paresthesias | Comparison to ablative procedures, F-U: 1–72 mo |
| Taira et al, 1998 | CR | FP | 1-1-1 | Medtronic 3387, 200 Hz, 100 μs, NFS | NFS | Patient cotreated for pain/movement disorder, F-U: 10 mo |
| Katayama et al, 2001 | CS | PLP | 19-10-6 | Medtronic, NFS | NFS | 10 STH electrodes after spinal cord stimulation failed |
| Katayama et al, 2001 | CS | PSP | 45-12-7 | Medtronic, NFS | NFS | 12 STH electrodes after spinal cord stimulation failed |
| Coffey, 2001 | CT MC P | LBP, LP, TPS, PI, PHP, TMJ, AD, MS, FBS | 194-169-90I, 30LT for the 3380 trial; 50-37-8I, 5LT for the 3387 trial | Medtronic, 3380/3387, NFS | NFS | Data not parsed for analysis of target location |
| Nandi et al, 2002 | Please see entry in the PV(A)G Section | |||||
| Nandi et al, 2003 | Please see entry in the PV(A)G Section | |||||
| Marchand et al, 2003 | CS PC Pseudo-DB | TN, FP, LP, PI | 6-6-6 | NFS | NFS | Small, significant effect of stimulation vs control |
| Green et al, 2004 | Please see entry in the PV(A)G Section | |||||
| Romanelli & Heit, 2004 | CR | PSP | 1-1-1 | Medtronic 3387, 31–130 Hz, 60 μs, 0–3.0 V | Stimulation tolerance | Patient tolerance at 29 mo, autonomous control of stimulation mitigated tolerance |
| Bittar et al, 2005 | Please see entry in the PV(A)G Section | |||||
| Yamamoto et al, 2006 | CS | PLP, STP | 18-18-14 | Medtronic 3387, 20–135 Hz, 0.15–0.21 ms, NFS | NFS | NFS |
| Hamani et al, 2006 | CS R | PSP, FP, PLP, MS, SCI | 21-13-5 | Medtronic 3387, 25–125 Hz, 60–250 μs, 0–10 V | Insertional effect of 45% | PV(A)G electrodes |
| Owen et al, 2006 | Please see entry in the PV(A)G Section | |||||
| Owen et al, 2006 | Please see entry in the PV(A)G Section | |||||
| Green et al, 2006 | Please see entry in the PV(A)G Section | |||||
| Rasche et al, 2006 | Please see entry in the PV(A)G Section | |||||
| Owen et al, 2007 | Please see entry in the PV(A)G Section | |||||
| Boccard et al, 2013 | Please see entry in the PV(A)G Section | |||||
| Pereira et al, 2013 | CS P | PLP, PI | 12-11-11 | Medtronic 3387, 5–50 Hz, 200–450 μs, 0.5–5 V | Unremarkable | F-U at 1, 3, 6, and 12 mo |
The late 1980s and early 1990s would show the first attempts by neurosurgeons to summarize their cases with DBS of the VPLP/VPM and PVG/PAG. These results would, for the first time, cast some doubt on the efficacy of DBS for pain (eg, previous reports had success rates in the 60%–80% range, and reports in this era would document long-term success in the 30%–40% range). They would also come at a time when the US Food and Drug Administration (FDA) ruled that DBS devices must be undergo evaluation for safety and efficacy with chronic pain. To add further complication, this ruling would come out at nearly the same time as the retirement of older-generation Medtronic 4 contact platinum electrodes (3380); hence, the appearance of a newer model (thinner diameter and more narrowly spaced contacts) in the literature (3387). Therefore, 2 clinical trials were conducted to evaluate the use of DBS electrodes for the treatment of chronic, intractable pain (1993 was the final report on model 3380, 1999 for 3387). Summarized years later in 2001, Coffey and colleagues would evaluate the new and older electrodes (3380 and 3387) across 2 centers with 246 patients in a prospective clinical trial. The results for VPLP/VPM and PVG/PAG stimulation were disappointing. In the case of the model 3380 electrode trial, only 46.1% of patients showed greater than 50% improvement at 12 months, which dropped to 17.8% at 24 months. The 3387 numbers were even more disheartening with only 16.2% showing greater than 50% pain relief at 12 months and only 13.5% at 24 months (note that withdrawals were counted as failures with these calculations).
Fortunately, despite Medtronic not pursuing FDA approval for DBS electrode use for intractable pain patients, several studies have been published in the interim showing some efficacy of STH stimulation in specific situations. Currently, the STH is often co-targeted with the PVG/PAG areas as first studied by Hosobuchi. The most recent work for DBS stimulation of the STH for pain control suggests that the VPLP/VPM should be considered a second-line treatment target if PAG/PVG stimulation should fail. A well-powered, double-blind, randomized, placebo-controlled trial has yet to occur.
CM-Pf Interventions
The CM-Pf intralaminar complex of the thalamus has a small history of stimulation for the control of pain ( Table 4 ). A comprehensive review of the potential for the CM-Pf is provided by Weigel and Krauss, while the evidence in patients was mostly driven by Andy, with a more recent interest by Krauss and colleagues. Given the recent resurgence of exploring different neurosurgical targets for intractable, chronic pain control, this area may be of future interest.
| Study, Year | Type of Study | Type of Patient | Total-(Implanted)-Success | Electrode and Stimulation Parameters | Side Effects | Notes |
|---|---|---|---|---|---|---|
| Boethius et al, 1976 | Please see the IC Section | |||||
| Ray & Burton, 1980 | CS | FBS, CP, SCI, PSP, TSP, PLP | 28-26-23 | Medtronic, NFS | Feeling of warmth, visual effects | F-U: 1–33 mo |
| Andy, 1980 | CS | PAD | 4-4-4 | Bipolar platinum electrode. 25–125 Hz, 0.1–0.5 ms, 6–20 V | NFS | 4 Patients with dyskinesia, 1 without pain but stimulation treated dyskinesia |
| Andy, 1983 | CS | TPS, HA | 5-5-5 | Electrode NFS, 50 Hz, 200 ms, 0.1–5.0 V | NFS | Stimulation of the CM-Pf with concurrent EEG recordings |
| Krauss et al, 2001 | CS P | NFS | 11-10-10 | Quadripolar electrodes, NFS | NFS | CM-Pf was compared with STH stimulation and was found more efficacious |
| Krauss et al, 2002 | CS P | — | 3-2-2 | Medtronic 3387, NFS | NFS | Part of a larger case series, this paper focused on movement disorders |
Related posts:
Introduction to Neuropathic Pain Syndromes
Intracranial Ablative Procedures for the Treatment of Chronic Pain
Microvascular Decompression for Trigeminal Neuralgia
Neurolysis, Neurectomy, and Nerve Repair/Reconstruction for Chronic Pain
Nerve Blocks for Chronic Pain
Transcranial Magnetic Stimulation for Chronic Pain
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