Personalizing Dual-Target Cortical Stimulation with Bayesian Parameter Optimization Successfully Treats Central Post-Stroke Pain: A Case Report

Central pain disorders, such as central post-stroke pain, remain clinically challenging to treat, despite many decades of pharmacological advances and the evolution of neuromodulation. For treatment refractory cases, previous studies have highlighted some benefits of cortical stimulation. Recent advances in new targets for pain and the optimization of neuromodulation encouraged our group to develop a dual cortical target approach paired with Bayesian optimization to provide a personalized treatment. Here, we present a case report of a woman who developed left-sided facial pain after multiple thalamic strokes. All previous pharmacologic and interventional treatments failed to mitigate the pain, leaving her incapacitated due to pain and medication side effects. She subsequently underwent a single burr hole for placement of motor cortex (M1) and dorsolateral prefrontal cortex (dlPFC) paddles for stimulation with externalization. By using Bayesian optimization to find optimal stimulation parameters and stimulation sites, we were able to reduce pain from an 8.5/10 to a 0/10 during a 5-day inpatient stay, with pain staying at or below a 2/10 one-month post-procedure. We found optimal treatment to be simultaneous stimulation of M1 and dlPFC without any evidence of seizure induction. In addition, we found no worsening in cognitive performance during a working memory task with dlPFC stimulation. This personalized approach using Bayesian optimization may provide a new foundation for treating central pain and other functional disorders through systematic evaluation of stimulation parameters.

Mechanisms of Peripheral and Central Pain Sensitization: Focus on Ocular Pain

Persistent ocular pain caused by corneal inflammation and/or nerve injury is accompanied by significant alterations along the pain axis. Both primary sensory neurons in the trigeminal nerves and secondary neurons in the spinal trigeminal nucleus are subjected to profound morphological and functional changes, leading to peripheral and central pain sensitization. Several studies using animal models of inflammatory and neuropathic ocular pain have provided insight about the mechanisms involved in these maladaptive changes. Recently, the advent of new techniques such as optogenetics or genetic neuronal labelling has allowed the investigation of identified circuits involved in nociception, both at the spinal and trigeminal level. In this review, we will describe some of the mechanisms that contribute to the perception of ocular pain at the periphery and at the spinal trigeminal nucleus. Recent advances in the discovery of molecular and cellular mechanisms contributing to peripheral and central pain sensitization of the trigeminal pathways will be also presented.

Conditioned Pain Modulation Is Not Impaired in Individuals with Frozen Shoulder: A Case-Control Study

Frozen shoulder (FS) is a poorly understood condition resulting in substantial shoulder pain and mobility deficits. The mechanisms behind FS are not yet fully understood, but, similar to other persistent pain states, central pain mechanisms may contribute to ongoing symptoms in this population. The objective of this research was to investigate conditioned pain modulation (CPM) in people with FS compared with pain-free individuals. A total of 64 individuals with FS and 64 healthy volunteers participated in this cross-sectional study. CPM was assessed by using the pressure pain threshold (PPT) and an occlusion cuff (tourniquet test) as the test and conditioning stimulus, respectively. The absolute and percentage of change in PPT (CPM effect) as well as pain profiles (pro-nociceptive vs. anti-nociceptive) of individuals with FS and healthy controls were calculated. No significant differences in the absolute change in the PPT or CPM effect were found in people with FS compared to pain-free controls. Moreover, no between-group differences in the percentage of subjects with pro-nociceptive and anti-nociceptive pain profiles were observed. These results suggest that endogenous pain inhibition is normally functioning in people with FS. Altered central pain-processing mechanisms may thus not be a characteristic of this population.

The effect of one dry needling session on pain, central pain processing, muscle co-contraction and gait characteristics in patients with knee osteoarthritis: a randomized controlled trial

Objectives To assess the immediate and three days postintervention effect of one dry needling session compared to one sham needling session on pain, central pain processing, muscle co-contraction and spatiotemporal parameters during gait in knee osteoarthritis patients. Methods A double-blind randomized controlled trial was conducted. Sixty-one knee osteoarthritis patients were randomly assigned to the dry needling or sham needling group. Primary outcomes were pain and central pain processing. Secondary outcomes included muscle co-contraction and spatiotemporal parameters during gait. Patients were assessed at baseline and 15 min after the intervention, and pain also three days after the intervention. Linear mixed models were used to examine between- and within-group differences. Results No significant between-group differences for pain were found, but within-group scores showed a significant decrease 15 min after sham needling and three days after dry needling. The mean conditioned pain modulation effect measured at the m. Trapezius worsened significantly 15 min after sham needling compared to after dry needling (between-group difference). However, individual conditioned pain modulation percentage scores remained stable over time. Various significant within-group differences were found 15 min after sham needling: a decrease of conditioned pain modulation measured at m. Quadriceps and m. Trapezius and stride- and step-time scores, and an increase in step length and widespread pain pressure threshold. A significant decrease in muscle co-contraction index of the m. Vastus Medialis and Semitendinosus was found as within-group difference 15 min after dry needling. Conclusions Dry needling has no larger effect on pain, central pain processing, muscle co-contraction and gait pattern 15 min and three days postintervention compared to sham needling. Mean conditioned pain modulation scores worsened after sham needling compared to after dry needling. Further research remains necessary.

The Guts of the Opioid Crisis

Bidirectional interactions of the gut epithelium with commensal bacteria are critical for maintaining homeostasis within the gut. Chronic opioid exposure perturbs gut homeostasis through a multitude of neuro-immune-epithelial mechanisms, resulting in the development of analgesic tolerance, a major underpinning of the current opioid crisis. Differences in molecular mechanisms of opioid tolerance between the enteric and central pain pathways pose a significant challenge for managing chronic pain without untoward gastrointestinal effects.

Tetrahydrocannabinol and cannabidiol as an oromucosal spray in a 1:1 ratio: a therapeutic option for patients with central post-stroke pain syndrome?

Central pain after stroke due to brainstem infarction is very rare. Treatment is difficult and specific guidelines are lacking. This is the report of a 61-year-old female patient who, after a posterolateral left medulla oblongata insult with incomplete Wallenberg syndrome, subsequently developed a burning and tingling pain in the contralateral leg and a burning and shooting pain in the ipsilateral face in trigeminal branches 1 and 2. More than 3 years of therapy with amitriptyline, gabapentin, pregabalin and various grade II and III opioids was ineffective or showed intolerable side effects. The administration of tetrahydrocannabinol and cannabidiol as an oromucosal spray in a 1:1 ratio improved the pain situation and quality of life quickly and permanently. The encouraging results in the present case may suggest that treatment with medical cannabis should be considered in similar cases when standard therapies are insufficient.

Centromedian–Parafascicular and Somatosensory Thalamic Deep Brain Stimulation for Treatment of Chronic Neuropathic Pain: A Contemporary Series of 40 Patients

Introduction: The treatment of neuropathic and central pain still remains a major challenge. Thalamic deep brain stimulation (DBS) involving various target structures is a therapeutic option which has received increased re-interest. Beneficial results have been reported in several more recent smaller studies, however, there is a lack of prospective studies on larger series providing long term outcomes. Methods: Forty patients with refractory neuropathic and central pain syndromes underwent stereotactic bifocal implantation of DBS electrodes in the centromedian–parafascicular (CM–Pf) and the ventroposterolateral (VPL) or ventroposteromedial (VPM) nucleus contralateral to the side of pain. Electrodes were externalized for test stimulation for several days. Outcome was assessed with five specific VAS pain scores (maximum, minimum, average pain, pain at presentation, allodynia). Results: The mean age at surgery was 53.5 years, and the mean duration of pain was 8.2 years. During test stimulation significant reductions of all five pain scores was achieved with either CM–Pf or VPL/VPM stimulation. Pacemakers were implanted in 33/40 patients for chronic stimulation for whom a mean follow-up of 62.8 months (range 3–180 months) was available. Of these, 18 patients had a follow-up beyond four years. Hardware related complications requiring secondary surgeries occurred in 11/33 patients. The VAS maximum pain score was improved by ≥50% in 8/18, and by ≥30% in 11/18 on long term follow-up beyond four years, and the VAS average pain score by ≥50% in 10/18, and by ≥30% in 16/18. On a group level, changes in pain scores remained statistically significant over time, however, there was no difference when comparing the efficacy of CM–Pf versus VPL/VPM stimulation. The best results were achieved in patients with facial pain, poststroke/central pain (except thalamic pain), or brachial plexus injury, while patients with thalamic lesions had the least benefit. Conclusion: Thalamic DBS is a useful treatment option in selected patients with severe and medically refractory pain.