Investigating Modulation of Neuropathic Pain by Transcranial Magnetic Stimulation: a Multimodal Imaging and Electrophysiological Approach

Neuropathic pain is pain arising from damage or disease of the somatosensory nervous system, affecting up to 10% of the general population. Common causes of neuropathic pain include diabetes, herpes zoster infections, chemotherapy, and trauma. Despite the employment of multi-line pharmacological treatment, 70~80% of neuropathic pain patients still remain refractory. The refractoriness of neuropathic pain may be attributed to the development of maladaptive plasticity in the brain following chronic neuropathic pain. The proposed project will combine functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) to identify neurobiological mechanisms underlying how repetitive transcranial magnetic stimulation (rTMS) applied to the primary motor cortex modulates maladaptive neuroplasticity following neuropathic pain. This combined fMRI-EEG approach will not only improve our understanding of mechanisms underlying neuropathic pain, the most suffering symptom in patients with peripheral neuropathy, but also provide non-invasive brain biomarkers that enable us to investigate the neuromodulatory effects of rTMS by (1) exploring how rTMS modulation is linked to changes in the functional connectivity of the motor cortex, (2) assessing rTMS modulation of the excitatory-inhibitory balance and excitability of the brain, and (3) applying machine-learning models to predict neuroimaging and neurophysiological changes by rTMS from baseline brain functional connectivity. Results from the current project will provide a new perspective to promote precision medicine for neuropathic pain, enabling the future exploration of non-invasive therapeutic targets for rTMS.

Inclusion criteria

• 1. Age 18 or older and 90 or younger. 2. Ability to give informed consent. 3. Independent in activity of daily living. 4. Neuropathic pain secondary to peripheral neuropathy (including hereditary neuropathies). The diagnosis of peripheral neuropathy is confirmed by a neurologist, based on clinical symptoms and at least one of the following objective criteria:

• Nerve conduction study: reduced compound muscle action potential (CMAP) or sensory nerve action potential (SNAP) (peroneal nerve: CMAP < 2 mV, tibial nerve: CMAP < 6.1 mV, and sural nerve: SNAP < 5 microV), or prolonged distal motor latencies (> 5.5 ms), or slowing of motor or sensory nerve conduction velocities (< 40 m/s), or prolonged minimal F latencies (> 50 ms) in two or more nerves in the lower limbs.
• Autonomic function test:

(i) absent sympathetic skin response (SSR); or (ii) reduced R-R interval variability (RRIV) during rest or forced deep breathing, below age-adjusted thresholds (rest/deep breathing: 12%/19% for age 20 ~ 29 years; 6%/9% for age 30 ~ 39 years; 6%/14% for age 40 ~ 49 years; 5%/11% for age 50 ~ 59 years; and 7%/8% for age not less than 60 years).

• Quantitative sensory test: abnormal warm or cold threshold at the foot (warm/cold thresholds: > 38.6 °C /< 27.5 °C for age < 40 years, > 40.1 °C/< 26.7 °C for age 40 ~ 59 years, and > 40.6 °C/< 27.0 °C for age not less than 60 years).
• Skin biopsy: reduced intraepidermal nerve fiber density at the distal leg (< 5.88 fibers/mm for age < 60 years, and < 2.50 fibers/mm for age not less than 60 years).

• Agree not to take caffeine, alcohol, tea and drugs with significant nervous system effects for 48 hours before each study session.

Exclusion criteria

• 1. Presence of severe systemic diseases, including severe heart disease, severe lung diseases with dyspnea, severe generalized edema, systemic infection, and uncontrolled migraines due to high intracranial pressure.

• Presence of major neurological disorders, including brain tumor, head trauma, and infection or inflammation of the nervous system.

• History of epilepsy or family history of seizure disorder. 4. Presence of neurodegenerative disorders involving the brain or spinal cord. 5. Patients suffering from multiple sclerosis. 6. Individuals with large areas of ischemic scarring. 7. Skin damage or lesions on the area of the body to be stimulated (the head). 8. Presence of psychiatric disorders diagnosed by a psychiatrist that may interfere with the subjective assessment of pain, including (i) major depressive disorder with a PHQ-9 score not less than 20 (indicating a severe episode; Kroenke et al. (2001)); (ii) anxiety disorder with a GAD-7 score not less than 15 (at a severe level; Spitzer et al. (2006)), or (iii) post-traumatic stress disorder with a PCL-5 score not less than 32 (exhibiting frequent flashbacks or hyperarousal symptoms; Zuromski et al. (2019)).

• Individuals with suicidal ideation within the past year. 10. Presence of implanted medical devices such as a cardiac pacemaker, implantable cardioverter-defibrillator (ICD), cochlear implant, implanted neurostimulator, implanted drug delivery pump, spinal or ventricular drainage device, aneurysm clips, or any metallic foreign object in the body, unless these devices are certified as compatible with MRI or TMS.

• Current use of any medication known to lower the seizure threshold. 12. History of sleep disorders during previous TMS sessions. 13. Pregnancy 14. Claustrophobia or any other contraindications to MRI 15. Inability to give informed consent. 16. Drug abuse and alcoholism