Deep brain stimulation (DBS) holds promise as a new option for patients suffering from treatment-resistant chronic pain, but current technology is unable to reliably achieve long-term pain symptom relief. A "one-size-fits-all" approach of continuous, 24/7 brain stimulation has helped patients with some movement disorders, but the key to reducing pain may be the activation of stimulation only when needed, as this may help keep the brain from adapting to stimulation effects. By expanding the technological capabilities of an investigative brain stimulation device, the investigators will enable the delivery of stimulation only when pain signals in the brain are high, and then test whether this more personalized stimulation leads to reliable symptom relief for chronic pain patients over extended periods of time.

Many pain syndromes are notoriously refractory to almost all treatment and pose significant costs to patients and society. Deep brain stimulation (DBS) for refractory pain disorders showed early promise but demonstration of long-term efficacy is lacking. Current DBS devices provide "open-loop" continuous stimulation and thus are prone to loss of effect owing to nervous system adaptation and a failure to accommodate natural fluctuations in chronic pain states. DBS could be significantly improved if neural biomarkers for relevant disease states could be used as feedback signals in "closed-loop" DBS algorithms that would selectively provide stimulation when it is needed. This approach may help avert the development of tolerance over time and enable the dynamic features of chronic pain to be targeted in a personalized fashion.

Optimizing the brain targets for both biomarker detection and stimulation delivery may also markedly impact efficacy. Recent imaging studies in humans point to the key role of frontal cortical regions in supporting the affective and cognitive dimensions of pain, which may be more effective DBS targets than previous targets involved in basic somatosensory processing. Pathological activity in the anterior cingulate (ACC) and orbitofrontal cortex (OFC) is correlated with the higher-order processing of pain, and recent clinical trials have identified ACC as a promising stimulation target for the neuromodulation of pain. In this study, the investigators will target ACC and OFC for biomarker discovery and closed-loop stimulation. The investigators will develop data-driven stimulation control algorithms to treat chronic pain using a novel neural interface device (Medtronic Activa PC+S) that allows longitudinal intracranial signal recording in an ambulatory setting. By building and validating this technological capacity in an implanted device, the investigators will empower DBS for chronic pain indications and advance personalized, precision methods for DBS more generally.

This study will enroll ten patients with post-stroke pain, phantom limb syndrome and spinal cord injury pain in our three-phase clinical trial. The investigators will first identify biomarkers of low and high pain states to define optimal neural signals for pain prediction in individuals (Aim 1). These pain biomarkers will then be used to develop closed-loop algorithms for DBS and test the feasibility and efficacy of performing closed-loop DBS for chronic pain in a single-blinded, sham controlled clinical trial (Aim 2). Our main outcome measures will be a combination of pain, mood and functional scores together with quantitative sensory testing. In the last phase, the investigators will assess the efficacy of closed-loop DBS algorithms against traditional open-loop DBS (Aim 3) and assess mechanisms of DBS tolerance in response to chronic stimulation. Successful completion of this study would result in the first algorithms to predict real-time fluctuations in chronic pain states for the delivery of analgesic stimulation and would prove the feasibility of closed-loop DBS for pain-relief by advancing implantable device technology.

Inclusion Criteria:

• Age ≥ 21 years
• Clinical diagnosis of post-stroke pain (thalamic pain), spinal cord injury or phantom limb pain with allodynia or dysesthesia with pinprick anesthesia or hypoesthesia on the affected hemibody or limb (anesthesia dolorosa).
• For Post-Stroke Pain: Stroke of ischemic etiology only. MRI done within one year of the first visit showing a lesion that involves the contralateral brainstem, thalamus or cortex. The lesion will involve cortical-subcortical areas in topography consistent with sensory thalamocortical connections. This will include patients with infarcts in the territory of the middle cerebral artery or those with cavernous malformations. A more recent MRI may be required if the patient's condition changed within the previous year.
• For Phantom limb pain: MRI done within one year not showing any contraindication to surgery such as mass, lesion, hemorrhage or other abnormality near target
• For Spinal Cord Injury pain: MRI done within one year not showing contraindication to surgery such as mass, lesion, hemorrhage or other abnormality near target
• One year or more of medically refractory severe pain (see below)
• Average daily pain for the past 30 days reported as >5 on a 0-10 numeric rating scale (NRS)
• Failure to respond adequately to at least one antidepressant, one anti-seizure medication and one oral narcotic with current stable doses of medications.
• Ability to speak / read English
• Capable of understanding and providing informed consent
• Stable doses of pain medications (e.g. anticonvulsant drug, anti-depressants, and opioids etc.)
• Women of childbearing age must be on regular use of an accepted contraceptive method(s).

Exclusion Criteria:

• Study subjects will be adults with refractory chronic neuropathic pain.
• Pregnancy or breast feeding
• Inability to speak and / or read English
• Inability to give informed consent
• Significant cognitive impairment or Dementia (MoCA < 25)
• Aphasia severe enough to limit the consent process or communication between the investigators and the patient. Patients with mild or recovering aphasia may be considered candidates at the discretion of the PI.
• Active depression (BDI > 20) or other untreated or uncontrolled psychiatric illness (active general anxiety disorder, schizophrenia, bipolar disorder, obsessive-compulsive disorder (OCD), or personality disorders (e.g. multiple personality disorder, borderline personality disorder, etc.) or other neuropsychiatric conditions that evaluating psychiatrist would recommend exclusion of patient after neuropsychiatric evaluation.
• Suicide attempt \

There is currently no plan to share IPD.

Chronic neuropathic pain with post stroke pain (3) or phantom limb pain (1)

2 years

There will be assigned active intervention and non-active intervention periods for each patient throughout phase 2 and 3 of the study. The participant will not know if he/she is in the active or non-active period of the phase.