History of DBS for Treatment of Chronic Pain

DBS traces its roots back to the mid-20th century. Heath¹ looked to DBS to provide effective treatment for patients afflicted with intransigent psychiatric symptoms. Failure of more established treatments such as electric shock therapy and contemporary pharmacologic regimens prompted Heath to implant electrodes in various subcortical targets. Initial reports of successful diminution of psychotic symptoms in schizophrenics prompted Heath to continue utilizing DBS. During one incident, Heath and Mickle unexpectedly observed analgesic effects following septal stimulation in a young woman.^1,2 Over the ensuing years, other studies reported analgesia following intracranial stimulation in humans.^3–5 Then in 1969, Reynolds was able to produce analgesia in rats following electric stimulation of the brain.⁶ By precise stimulation of the lateral margin of the periaqueductal gray (PAG) matter, Reynolds inhibited nociceptive responses in rats undergoing abdominal surgery. This prompted further research into DBS-related analgesia. Shortly after Reynold’s work, several other studies reported consistent results in similar experiments with rats^7–10 and in cats.¹¹ Following this research, DBS for pain relief began to be used in clinical trials.

Clinical trials utilizing DBS for the treatment of acute and chronic somatogenic pain of various origins can be categorized into different periods depending on the specific target stimulation. The first period took place between the late 1970s and the late 1990s. Clinical trials utilizing DBS for the treatment of somatogenic pain principally targeted the central gray matter, or periaqueductal gray and periventricular gray (PAG/PVG) matter, and the sensory thalamus (ST).¹² The PAG/PVG matter was predominantly stimulated to treat nociceptive pain, while neuropathic pain was primarily treated with stimulation of the ST alone or in combination with PAG/PVG matter stimulation.¹² Furthermore, although more infrequent, the internal capsule was stimulated for treatment of somatogenic pain by a number of studies.^13–15 Long-term relief of chronic pain symptoms following ST stimulation was first reported by Mazars et al.,¹⁶ and such relief following PAG/PVG matter stimulation was reported by Richardson and Akil¹⁷ and by Hosobuchi et al.¹⁸ During the early 1990s, researchers sought to identify other areas of the brain that could be used as targets for stimulation to relieve chronic pain symptoms.

Another important period for DBS treatment of chronic, intractable pain began in the early 2000s. Cluster headache (CH) is a syndrome that is characterized by severe episodic primary neurovascular headaches.¹⁹ Prior to the 21st century, standard treatments for CH were ineffective. Then utilization of positron emission tomography (PET) studies demonstrated to researchers increased cerebral blood flow to the posterior hypothalamus during an acute CH attack.^20–22 Taking these findings into account, Leone et al. hypothesized that electric stimulation to the posterior hypothalamus may prevent and/or relieve pain symptoms from a CH attack. Thus, in 2001, Leone et al. applied DBS to the posterior hypothalamus of a 39-year-old man suffering chronic CH.²³ The patient experienced reduced pain for 13 months following the procedure. Subsequently, stimulation of the hypothalamus became a highly researched method for the treatment of chronic CH pain. This was not the first time the hypothalamus was targeted for DBS treatment of pain. Heath stimulated the hypothalamus of a pain patient in 1954, reporting one of the first cases of acute pain relief following stimulation. However, the circumstances were much different.¹ Soon after Leone et al.’s success, Franzini et al. assembled the first important clinical trial for this procedure.²⁴

In summary, intensive research and clinical trials for DBS in the treatment of chronic pain began primarily with the stimulation of the central gray matter and the ST. More recently, application of DBS to the motor cortex has developed into its own field of stereotactic neurosurgery, remaining highly researched. Lastly, treatment for pain arising from CH via stimulation of the hypothalamus represents the latest and currently most heavily researched applications of DBS.

Types of Pain and Targets

Pain is a common symptom of illness and disease. The International Association for the Study of Pain’s classification of pain elucidates pain as a “negative sensory or emotional experience linked with actual or potential tissue damage or that which is described in terms of such damage.”²⁵ Chronic pain is classified as pain experienced daily for 6 months or longer. Pain is usually categorized as either somatogenic or psychogenic. Somatogenic pain, or “organic pain,” arises from somatogenic lesions resulting from trauma, infection, or other external factors.²⁶ By contrast, the origin of psychogenic is psychological. Often, it is difficult to assign a patient’s pain to a particular category. Although DBS has also been utilized for psychogenic disorders such as tremors, Parkinson’s disease, and epilepsy, this chapter focuses on DBS treatment for somatogenic pain.

Somatogenic pain is divided into two main categories, nociceptive and neuropathic pain. Nociceptive pain refers to pain originating via stimulation of peripheral nociceptors, or pain receptors. Nociceptive stimulation then transmits signals to the central nervous system through integral somatosensory pain pathways, causing a person to experience pain.²⁷ DBS treatment for pain of nociceptive origin predominately entails stimulation of the central gray matter, both the PAG matter and the PVG matter. The central gray matter, residing within the tegmentum of the midbrain, surrounds the cerebral aqueduct.²⁸ Neuronal pathways traversing the central gray matter have demonstrated roles in reproduction, defensive behavior, and analgesia.²⁸ Nonetheless, DBS of the central gray matter has proved to elicit analgesic responses.

Neuropathic pain, or deafferentation pain, refers to pain following direct damage to the nervous system. Neuropathic pain can be classified as either peripheral or central.²⁹ Peripheral neuropathic pain originates from damage to the peripheral nervous system. Types of peripheral neuropathic pain include dysesthesia dolorosa, phantom-limb pain, and diabetic neuropathy. Central neuropathic pain originates from damage to the central nervous system, that is, the brain and spinal cord. Specific types of central pain include spinal cord injury, poststroke pain, postherpetic neuralgia, and other forms of neuralgia.²⁹ The ST has been the principal target region for DBS treatment of neuropathic pain. The thalamus, a large, paired mass of gray matter, resides in the diencephalon. It is located in the center of the brain, along the midline, and sits right above the brain stem. The thalamus’s functions include motor control and transmission of sensory stimuli.³⁰ Stimulation of the lateral nuclei, specifically the ventral posterolateral (VPL) nucleus and the ventral posteromedial (VPM) nucleus, has been shown to reduce pain symptoms of neuropathic origin.

CH is a severe primary neurovascular headache disorder causing 10% to 20% of patients with the disorder to experience debilitating headaches.³¹ Pain arising from this syndrome is indicated by attacks of intense unilateral periorbital pain, often jointly experienced with ipsilateral cranial autonomic disturbance. Through utilization of PET studies, increased blood flow to the posterior hypothalamic region was observed in patients amid an acute CH attack. The hypothalamus, forming the ventral aspect of the diencephalon and located beneath the thalamus, is linked with endocrine and pituitary function.³⁰ DBS of the posterior hypothalamic region was introduced to treat pain arising from acute CH attacks.²³

Mechanism of Action (of A DBS Device)

The mechanism by which DBS treats pain symptoms is not fully understood. The most common sites of electric stimulation are the PAG/PVG matter and the ST. More recently, targeted sites have included the posterior hypothalamus and the motor cortex. The original studies of Reynolds in rats showed that stimulation of the lateral margin of the PAG matter inhibited nociceptive responses.⁶ Further research indicated that this effect was reversible with administration of opioids antagonists.³² Other research studies also reported reverses in pain relief after administration of naloxone.^17,18 Two additional studies showed that endogenous opioid levels were elevated in the third ventricle following electric stimulation of the PAG/PVG matter.^33,34 Elevated levels of endogenous opioids following PAG/PVG matter stimulation may be critical in producing analgesic effects. However, it is still open to debate whether opioid release is a direct result of PAG/PVG matter stimulation or is a secondary effect.

Although electric stimulation of both the PAG matter and the PVG matter leads to increased levels of endogenous opioids, research has shown that other mechanisms are likely to accompany this stimulation. Specific to PAG matter stimulation, an additional mechanism involves spinal cord stimulation. Although PAG matter neurons do not usually extend directly to the spinal cord, they normally connect with the medullary nucleus raphe magnus (NRM).²⁷ Following stimulation via PAG matter neurons, the NRM projects to the dorsal horn of the spinal cord. Considering that the PAG matter, NRM, and dorsal horn of the spinal cord all contain high levels of opiates, analgesic effects via stimulation are likely to be mediated by these structures. Furthermore, analgesic effects following PAG matter stimulation are terminated if descending pathways to the spinal cord are incised. Because analgesia is produced when opiates permeate the subarachnoid space of the spinal cord and the interventricular space of the brain,³⁵ this action strongly suggests that a signal cascade from the PAG matter to the NRM to the dorsal root of the spinal cord, subsequent to PAG matter stimulation, causes those structures to mediate and possibly sequester opiates to specific areas, inducing pain relief.²⁷

Similar to stimulation of PAG matter, stimulation of PVG matter leads to increased levels of endogenous opiates. However, it is thought that other mechanisms, together with increased opiate levels, result in analgesic effects following PVG matter stimulation.¹² One such mechanism involves signaling along ascending pathways from the PVG matter. One study noted that following PVG matter stimulation, there was increased activity in the medial dorsal nucleus of the thalamus. This region is associated with the limbic system and has strong links to the amygdala and cingulated cortex.³⁶ More simply, stimulation of PVG matter may alter a patient’s psychogenic response to pain.¹² To summarize, evidence suggests that rising opiate levels, together with an altered psychological response to pain, give rise to analgesic effects.

The mechanism by which analgesia is produced following stimulation of the somatosensory thalamus is not completely understood.¹² Studies by Benabid and colleagues on induced analgesia following ST stimulation in rats experiencing deafferentation pain provided evidence that the mechanism does not involve rises in endogenous opioid levels.^27,37 In experiments with rats, Benabid et al. found that stimulation of the VPL nucleus of thalamus, the ventral caudal thalamus in humans, prevented binding of noxious agonists to their respective receptors in the thalamic intralaminar nucleus, or the nucleus parafascicularis (Pf), through an opioid-independent process.³⁷ Furthermore, Benabid et al.’s findings suggested that dorsal horn neurons were not involved in neural pathways responsible for suppression of Pf pain reception following VPL stimulation. Moreover, the neural pathways involved were not monosynaptic. Some believe that analgesia via ST stimulation occurs due to activation of inhibitory corticofugal fibers following stimulation.^38,39 Activation of these fibers would inhibit the sequestration of foreign pain agonists. Gerhart et al. performed experiments with ST stimulation in monkeys to address this hypothesis.⁴⁰ These experiments focused on the inhibitory effects of lamina I to V spinothalamic tract (STT) neurons following thalamic stimulation. Gerhart et al. sought to observe which neuronal pathways led to activation of inhibitory STT neurons following ST stimulation. They observed that inhibitory effects, subsequent to ST stimulation, of lamina I cells contained within the dorsal horn of the spinal cord were terminated when lesions were made to the dorsolateral funiculi and the ventral funiculus of the ipsilateral funiculus. However, when lesions were applied solely to the dorsolateral funiculus, substantial STT inhibition remained. Gerhart et al. concluded that although neurons projecting through the dorsal lateral funiculus have involvement in STT inhibition following ST stimulation, much of the inhibition is mediated through pathways projecting through the ventral spinal cord. This strongly suggests an inhibitory thalamocortical–corticofugal pathway.¹² Also, increases in extracellular serotonin concentrations have been observed in monkeys undergoing VPL stimulation.⁴¹ Serotonin is involved in mediation of nociceptive signaling and thus may be involved in pain relief subsequent to ST stimulation. Finally, in some neuropathic pain patients, thalamic bursting is observed, which may be associated with feelings of chronic pain.^42–44 ST stimulation may inhibit this bursting, resulting in analgesic effects. Thus, several possible mechanisms could account for the analgesic effects following ST stimulation.

Targeting the posterior hypothalamus for stimulation for treatment of CH is a relatively new practice. Hypothesized mechanisms of action are activation or inhibition of neuronal pathways traversing the posterior hypothalamus. These neuronal pathways include ascending catecholaminergic and descending pathways from the hypothalamus to the brain stem and spinal cord. The posterior hypothalamus also contains cells concentrated with melatonin and opiate peptides.⁴⁵ Traversing autonomic neuronal pathways through the targeted area led to theories that the induction of analgesia following electric stimulation includes a hormonal mechanism. However, this hypothesis was disproved through close patient assessment following chronic DBS stimulation. Schoenen et al. utilized DBS for hypothalamic stimulation of a small number of patients suffering from chronic CH.⁴⁶ One week following DBS, two patients showed small decreases in urinary secretion of melatonin but no other hormonal abnormalities. Schoenen et al. concluded that the induced hypoalgesia was independent of a reduction in sensitivity or perception of pain. They also concluded that the mechanism was more complex than any simple pathway leading to hypoalgesia. This idea is in accord with earlier predictions by May and Leone, who suggested that various central pathways are involved.¹⁹ Lastly, it was observed that amid a CH attack, there is increased blood flow localized to the hypothalamus.⁴⁶ Electric stimulation of the hypothalamus could mediate CH attacks by suppressing the surge of blood to the hypothalamus.

To summarize, mechanisms of pain relief following DBS stimulation of particular areas of the brain are not completely understood, but there is sufficient evidence to support a number of hypotheses.

Patient Selection and Indications

Criteria for patients receiving DBS vary from one clinical trial to another, although similarities are present. The most common sites stimulated in clinical trials have been the PAG/PVG matter and the somatosensory thalamus. In a thorough review, Bittar et al. stated that patients chosen for DBS stimulation were selected based on three main criteria: the patient’s pain was diagnosed as somatogenic, prior treatment had failed to provide relief, and the patient did not present any psychogenic disorders and/or severe depression.¹² Levy et al. stated that between 1972 and 1984, 304 patients who received DBS stimulation had debilitating, chronic, and intractable pain that was untreatable by conventional methods.¹⁴ Generally, patients were chosen for PAG/PVG matter stimulation if their pain was nociceptive and for ST stimulation if their pain was neuropathic. Young et al. discussed their selection criteria for 48 patients receiving DBS over a 5-year period, from 1978 to 1983.¹⁵ Patients selected for DBS had suffered chronic pain for a mean duration of 4.5 years. Patients were subjected to more established means of treatment prior to receiving DBS. They also received a thorough psychological analysis, and their therapeutic responses to morphine, naloxone, and a placebo were monitored closely. In our study, electrodes were implanted into the PAG/PVG matter, the ST, and the internal capsule. In accordance with Levy et al., the placement of electrodes was based on the pathogenesis of pain (i.e., nociceptive or neuropathic).

Patients receiving posterior hypothalamic stimulation suffered from chronic CH. Patients diagnosed with CH generally displayed increased vascular perfusion to the posterior hypothalamic region during a spontaneous or nitroglycerin-induced CH attack from PET scanning utilizing a H₂¹ marker.^21,22 Franzini et al. composed one of the first teams of neurosurgeons to observe the therapeutic effects of hypothalamic stimulation on CH patients. They arranged a multidisciplinary team of neurologists to select patients for clinical trials. Neurologists chose patients presenting symptoms of chronic CH in accordance with the International Headache Society. Patients had to have suffered CH for at least 1 year with no response to prior medical treatment, including corticosteroids, lithium, methysergide, ergotamine, calcium channel blockers, beta-blocking agents, tricyclic antidepressants, melatonin, and nonsteroidal anti-inflammatory drugs.²⁴ Potential subjects also underwent psychological screening and were informed of alternative neurosurgical treatments. A more recent clinical trial undertaken by Starr et al. at the University of California at San Francisco chose four patients for hypothalamic stimulation under similar guidelines. Trial patients were diagnosed with chronic CH via the criteria presented by the International Headache Society, had chronic CH episodes for at least 6 months in the previous 2 years, had at least seven unbearable headaches (6 on visual analogue scale of 1-10), and did not respond to several prophylactic and abortive therapies.³¹

Classifying Pain (Patient Screening)

Patients who took part in clinical trials utilizing DBS for the treatment of chronic pain received thorough physical and psychological evaluations, as described previously. If initial evaluations deemed patients were qualified to participate in the clinical trials, they were screened into two groups based on the etiology of their pain (i.e., nociceptive vs. neuropathic). Nociceptive pain patients principally received DBS in the PAG/PVG matter, and neuropathic pain patients received DBS in the ST. Research by Hosobuchi et al. provided the key method for localizing patients into the aforementioned groups. In one of their early clinical trials, Hosobuchi et al. noted that analgesia invoked via electric stimulation of the central gray matter was reversed following administration of naloxone, an opioid antagonist.³⁴ Combining this knowledge with the finding that levels of endogenous opioids were increased in the third ventricle subsequent to PAG matter stimulation,^33,34 it was concluded that PAG/PVG matter stimulation produced analgesia through an opioid-dependent mechanism. However, other research found that stimulation of the ST worked through an opioid-independent mechanism.³⁷ Although contradictory, reports published by Young and Chambi demonstrated conflicting results concerning stimulation of the PAG/PVG matter. Within their findings, they suggested that nonopioid-dependent mechanisms accounted for the majority of analgesia produced via PAG/PVG matter stimulation.⁴⁷ However, most clinical studies followed research demonstrating that nociceptive pain responded more strongly to PAG/PVG matter stimulation. Thus, a principal screening test performed to discriminate patients based of etiology of pain was the morphine saturation test.¹²