Low Intensity Focused Ultrasound Modulation of Thalamic Nuclei for Central Neuropathic Pain.

Chronic pain (CP) is highly prevalent worldwide and has been identified as a major public health problem in many countries (1), being one of the ten leading causes of years lived with disability. CP has recently been identified as even more prevalent in countries with low human development indices (2-3). Pain affects 20-40% of the general population in Latin America and constitutes a major public health challenge (4-7). CP has known associations with depressed mood, fatigue, and catastrophic thinking. It is also widely recognized that even for CP directly triggered by peripheral structures, such as joints and muscles, there is a wide range of central changes (spinal cord, brain) occurring in CP, leading to a series of central modifications that will allow perpetuation and maintenance of the CP status (8-10). Pain is linked to maladaptive plasticity in the central nervous system (CNS) (8, 11-16), and structural and functional changes observed in the CNS during CP are related to symptom severity.

Central neuropathic pain (CNP) is caused by injury or disease of the somatosensory pathways in the CNS. CNP is a secondary complication of common diseases such as stroke (i.e., central post-stroke pain [CPSP]) and spinal cord injury (SCI) secondary to traumatic, inflammatory, or demyelinating diseases. CPSP occurs in 2% to 8% of stroke survivors and is present in up to 18% of those with somatosensory deficits and in up to 50% of those with lesions affecting only the spinothalamic pathways (20). Pain is also among the most debilitating complications of traumatic SCI (21), affecting more than 80% of patients within 5 years of trauma and leading to CNP in up to 59% of individuals. SCI It can also be caused by inflammatory insults that occur in demyelinating disorders such as multiple sclerosis (MS) or neuromyelitis optica spectrum disorders. These conditions affect more than 2 million individuals worldwide, leading to a lifetime prevalence of CNP of at least 28%. Unfortunately, attempts to control CNP have been marked by refractoriness and failure. For example, CPSP failed to respond satisfactorily to levetiracetam (22), pregabalin (23), duloxetine (24), morphine, and carbamazepine (25); while IBS-CNP did not respond to venlafaxine (26), levetiracetam (27), or dronabinol (28). MS-related CNP did not respond to cannabinoids (11) and duloxetine (29). In the rare positive trials that have existed, the magnitude of the analgesic effect has often been small, such as the response of CPSP/SCI-related CNP to duloxetine or pregabalin (30), or the response to opioids (31) in SCI-CNP. In other cases, positive results have been derived from very small studies. Thus, the treatment of CNP remains a major unmet need and has been the focus of several new treatment options, such as noninvasive neuromodulation.

The hallmark of CNP is the presence of pain with neuropathic descriptors in an area of impaired somatosensory function, often affecting thermal sensations (32). It has been proposed that damage to the spinothalamic projections would lead to plastic changes in brain areas implicated in pain processing; differentiation of insular pain receptors, leading to isolated functional disinhibition; and increased activity, causing increased processing of ascending stimuli by mesial pain pathways, including those targeting the parabrachial nucleus, anterior cingulate cortex (ACC) (33), and amygdala.

Although some aspects of this model have been questioned, the idea of an over-activation of these deep structures has been supported by functional brain imaging studies in normal humans in acute pain as well as in patients with neuropathic pain (34). Similarly, functional connectivity studies (35) have also reported a central role of these structures in neuropathic pain.

Low-intensity pulsed focused ultrasound (LIFUP) is a novel medical technology platform capable of neuromodulating regions of interest in the brain with high precision. Recent studies have shown LIFUP to be a safe and effective means of neuromodulation in pathologies such as trauma and epilepsy (36-37). Furthermore, focused ultrasound has been shown to induce reversible physiological effects on the nervous system, ranging from increased excitation in regions of interest to suppression of visual evoked potentials (38-39). Importantly, previous studies have observed both excitation and inhibition of neuronal circuits without characteristic physiological changes within the area of focus, such as cavitation or heat damage (40-44). Extrapolating from previous studies, LIFUP may have a modulatory effect on neuronal circuitry involved in pain, specifically when applied to the anterior thalamic nuclei, which is an important part of the pain circuitry (45). Precise laboratory studies will reveal the circumstances under which LIFUP produces analgesia. The first step in evaluating LIFUP as a therapy for pain management is to determine whether LIFUP produces analgesia through suppression of the anterior thalamus. Neurosurgical lesioning of the anterior thalamus has been used for many years as an invasive and risky treatment for this pain.

The primary objective is to evaluate the short-term analgesic effects of thalamic analgesia caused by LIFUP through:

1. Quantitative sensory testing (QST) and conditioned pain modulation testing (CPM) that allow the assessment of perceptual responses to quantifiable sensory stimuli, evaluated to characterize somatosensory function or dysfunction.
2. Short-form McGill Pain Questionnaire;
3. Brief Inventory Form, which includes pain severity index (average of questions 3-6) and pain interference with daily activities (average of questions 9A-9G, ranging from 0 to 70, where 70 indicates maximum possible pain interference);
4. Douleur Neuropathique-4 to assess neuropathic pain, being positive for scores ≥4;
5. Neuropathic Pain Symptom Inventory (NPSI), which provides characterization of neuropathic pain symptoms in 5 domains (superficial and deep) spontaneous pain, paroxysmal pain, evoked pain and paresthesia.

In association, analysis of its responses with others qualitative scales will be made described above:

1. Hamilton D + A
2. Medication use (Brief Pain Inventory)
3. Interference with daily activities (Brief Pain Inventory, quantified by Medication Quantification Scale)
4. Cognition - Montreal Cognitive Assessment (Mo CA)5 Adverse events
5. Blinding assessment
6. Variation in Global Impression of Change (CGI).