Effect of Model Complexity on Fiber Activation Estimates in a Wearable Neuromodulator for Migraine

Migraine is a prevalent and highly disabling disorder. The pharmaceutical and invasive treatment methods have trouble-some side effects and associated risks, hence undesirable. Transcutaneous supraorbital neuromodulation has been shown to potentially suppress episodic migraine attacks yet results have low efficacy. This inconclusive response may be associated with neuroanatomical variations of patients which may be investigated using computational models. Model complexity is a limiting factor in implementing such techniques. This paper investigates the effect of model complexity on fiber activation estimates in transcutaneous frontal nerve stimulation. It is shown that the model can be simplified while minimally affecting the outcome

Impact of neuroanatomical variations and electrode orientation on stimulus current in a device for migraine: a computational study

Objective. Conventional treatment methods for migraine often have side effects. One treatment involves a wearable neuromodulator targeting frontal nerves. Studies based on this technique have shown limited efficacy and the existing setting can cause pain. These may be associated with neuroanatomical variations which lead to high levels of required stimulus current. The aim of this paper is to study the effect of such variations on the activation currents of the Cefaly neuromodulator. Also, using a different electrode orientation, the possibility of reducing activation current levels to avoid painful side-effects and improve efficacy, is explored. Approach. This paper investigates the effect of neuroanatomical variations and electrode orientation on the stimulus current thresholds using a computational hybrid model involving a volume conductor and an advanced nerve model. Ten human head models are developed considering statistical variations of key neuroanatomical features, to model a representative population. Main results. By simulating the required stimulus current level in the head models, it is shown that neuroanatomical variations have a significant impact on the outcome, which is not solely a function of one specific neuroanatomical feature. The stimulus current thresholds based on the conventional Cefaly system vary from 4.4 mA to 25.1 mA across all head models. By altering the electrode orientation to align with the nerve branches, the stimulus current thresholds are substantially reduced to between 0.28 mA and 15 mA, reducing current density near pain-sensitive structures which may lead to a higher level of patient acceptance, further improving the efficacy. Significance. Computational modeling based on statistically valid neuroanatomical parameters, covering a representative adult population, offers a powerful tool for quantitative comparison of the effect of the position of stimulating electrodes which is otherwise not possible in clinical studies

Computational Study on Transcutaneous Frontal Nerve Stimulation: Simplification of Human Head Model

Migraine is a highly disabling disorder of the brain which may affect patients both socially and economically. The pharmaceutical and invasive treatment methods may have undesirable side effects and associated risks. It has recently been shown that transcutaneous supraorbital neuromodulation may suppress episodic migraine attacks. However, results have indicated low efficacy. This inconclusive response may be associated with neuro-anatomical variations in patients which may be investigated using computational models. Model complexity is a limiting factor in implementing such techniques. This paper investigates the effect of model complexity on fiber activation estimates in transcutaneous frontal nerve stimulation. It is shown that the model can be simplified while minimally affecting the outcome

Optimisation of a Wearable Neuromodulator for Migraine Using Computational Methods

Migraine is the third most common neurological disorder and the sixth cause of disability. It may be characterized by a headache, nausea, vomiting, photo- phobia and phonophobia. Available pharmaceutical treatments of migraine are not completely effective and have troublesome side-effects. Thus, there is a need for alternative treatments such as neuromodulation. Neuromodulation may be delivered invasively; however, this exposes the patients to the associated risks. Transcutaneous electrical nerve stimulation is a non-invasive technique that is widely used to relieve pain. A significant number of migraine sufferers complaint the symptoms of pain originating in the frontal region of the head. Thus, mi- graine may be associated with the supraorbital nerve and supratrochlear nerve which passes below the frontal bone exits from the orbital rim and penetrates the corrugator and frontalis muscles. Transcutaneous frontal nerve stimulation has been applied on a large group of patients who have episodic migraine us- ing a device called Cefaly. This study produced mixed results (50% response rate). A post–marketing survey led to 53% satisfaction while the most limiting factor is reported to be paraesthesia and painful sensation. The possible causes of these inconclusive results may be associated with neuroanatomical variations, patient compliance and neurophysiological effects. The most plausible cause may be related to the neuroanatomical variations across different subjects. The neu- roanatomical variations may lead to excessively high current levels being required. Since this solution is patient–operated, these relatively high required levels are not applied. In addition, as the electrodes are positioned near pain–sensitive structures, pain may be induced even at low current levels, further limiting the efficacy of the solution. There has been no robust investigation identifying the underlying causes of ineffi- cacy. This is partly due to the physical limitations of studying the neuroanatomy of each subject and different settings of electrode arrangements. Computational models may enable researchers to estimate current stimulation thresholds in neu- romodulation therapy and investigate the effects of various parameters. Such computational models are composed of a volume conductor model and an ad- vanced Hodgkin–Huxley–type model of neural tissue referred to as a hybrid model. Once the human head anatomy, the human nervous system and available solu- tions for migraine are detailed, the computational model of the human head is generated. A highly detailed human head model based on magnetic resonance imaging (MRI) studies, microscopic structure of the skin(including sweat ducts, keratinocytes and lipid) and those of a simplified head model (which built from geometric shapes) are compared based on neural excitation to assess the usabil- ity of geometrically realistic(simplified) human head models in the subsequent studies to save computations cost. The induced electric field due to an electrode setting is simulated in the volume conductor model and the resulting electric potential values along the nerve are passed on to the neural model to simulate nerve’s response. It is shown that a simplified model may be used with a marginal error (≈2%) in the subsequent work when assessing the effect of neuroanatomical variations on the efficacy of the target solution and possible ensuing optimiza- tions. The first step is to identify if neuroanatomical variations had any effect on the required stimulus current levels using state of the art computational bio–models. Ten realistic human head models are developed by varying thirteen neuroanatom- ical features including human head size, thicknesses of the tissue layers and vari- ations in the courses of the nerve by considering their respective statistical distributions as reported in the literature. A novel algorithm is developed to account for the variations of the nerve in different individuals and mimic statistically relevant large population. In each case, the required stimulus current levels are simulated. The findings show that the combined neuroanatomical variations have a significant effect on the neural response for the electrode setting used in Cefaly device. Therefore, a potential improvement is to align the axis of electrodes with the target nerve, so that the electrical potential along the trajectory of the nerve changes polarity. This may lead to lower required stimulus current levels. Align- ing electrodes with the nerve, the required current may be reduced by at least 60%. This new orientation reduces current density near pain– sensitive struc- tures by diverting the current away from them, which may lead to a higher level of patient compliance, further improving the efficacy of the solution. Using an electrodes array arrangement, the required current levels is further reduced due to incorporating multiple electrodes array elements to maximise the variations of the electrical field in the simulation of the fibres in one phase. The findings of this thesis indicate that the highly detailed human head model can be simplified while minimally affecting the outcome. Additionally, it is shown that neuroanatomical variations have a significant impact on the stimulus current thresholds but it is not possible to conclude if these thresholds solely depend on a specific neuroanatomical variation. The relatively high required levels of the stimulus currents are beyond the current capabilities of existing device and pos- sible pain thresholds. Furthermore, the proposed new electrode arrangement has multiple benefits including the reduction of the stimulus current levels and diver- sion of current spread from possible pain–sensitive structures. This improvement, based on modelling, can potentially improve the clinical outcome of the neuro- modulator substantially if confirmed in the subsequent clinical studies

Characterisation of the neurobiological phenotype of pain in psoriatic arthritis

Psoriatic arthritis (PsA) is a prevalent immune-mediated inflammatory arthritis marked by chronic inflammation in both articular and periarticular regions. Advances in understanding the immunopathogenesis have paved the way for the development of advanced immunotherapies, effectively controlling inflammation and the associated tissue damage linked with PsA. Nevertheless, the chronic pain remains a significant issue for individuals with PsA. Chronic pain, frequently linked with musculoskeletal conditions, represents a substantial burden on those affected, leading to diminished quality of life and increased mortality. The classical pain mechanisms involve damage to peripheral tissues (nociceptive) or peripheral nerves (neuropathic), causing pain. In PsA, nociceptive pain mechanisms are classically considered to prevail, primarily due to peripheral inflammation. Recently, however, a novel pain mechanism, described as nociplastic pain, characterised by dysfunctional nociception processes within the central nervous system (CNS) has been identified. This type of pain lacks evidence of peripheral damage. Fibromyalgia serves as a prototype for nociplastic pain. Specific neurobiological features are identified in fibromyalgia through functional neuroimaging and quantitative sensory testing (QST). Clinically, fibromyalgia (nociplastic pain) appears to co-exist in PsA, however there is no objective evidence to support this observation yet. This thesis's primary hypothesis is that chronic pain in PsA manifests as a mixed pain state in individuals with a substantial pain burden, potentially explaining the high rates of chronic pain in PsA. To test this hypothesis, this study examines nociplastic pain features and their neurobiological correlations within a wellcharacterised cohort of 50 individuals with PsA with active disease and employing QST and functional MRI to objectively assess nociplastic pain. The study's evidenced a heightened pressure pain sensitivity at articular and entheseal sites among participants experiencing pronounced nociplastic pain, indicating peripheral sensitisation where inflammation prevails. Observations also unveil altered functional connectivity in subjects with PsA with substantial nociplastic pain, particularly within the insula and DMN regions. Intriguingly, distinct features in the parahippocampal and visual areas predominate within this subgroup, reflecting the complexities of pain perception. This individual and condition-specific diversity defines a distinctive “pain signature”. These findings present an opportunity to pinpoint specific neurobiological markers in PsA. Despite available evidence suggesting the role of inflammation, the mechanisms sustaining the interaction between the nervous and immune systems remain elusive. Chronic inflammation in rheumatoid arthritis relates to altered connectivity in the inferior parietal lobule (IPL), a similar phenomenon is identified within this study participants with PsA. However, peripheral circulating pro-inflammatory cytokines did not exhibit significant associations with the nociplastic pain neurobiological features investigated in this study. To date, this study represents the first exploration into the neurobiological features of nociplastic pain in PsA, employing advanced neuroimaging techniques alongside an extensive QST protocol. The findings suggest a distinct pain signature of PsA, sharing characteristics with fibromyalgia and rheumatoid arthritis. To confirm these findings and gain further insights into the role of inflammation in nervous system sensitisation, additional studies are needed. Ultimately, a better understanding of pain mechanisms in PsA will translate into improved patient management and a better quality of life for those affected by this challenging disease

Activation of the pro-resolving receptor Fpr2 attenuates inflammatory microglial activation

Poster number: P-T099 Theme: Neurodegenerative disorders & ageing Activation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activation Authors: Edward S Wickstead - Life Science & Technology University of Westminster/Queen Mary University of London Inflammation is a major contributor to many neurodegenerative disease (Heneka et al. 2015). Microglia, as the resident immune cells of the brain and spinal cord, provide the first line of immunological defence, but can become deleterious when chronically activated, triggering extensive neuronal damage (Cunningham, 2013). Dampening or even reversing this activation may provide neuronal protection against chronic inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced inflammation could be abrogated through activation of the receptor Fpr2, known to play an important role in peripheral inflammatory resolution. Immortalised murine microglia (BV2 cell line) were stimulated with LPS (50ng/ml) for 1 hour prior to the treatment with one of two Fpr2 ligands, either Cpd43 or Quin-C1 (both 100nM), and production of nitric oxide (NO), tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) were monitored after 24h and 48h. Treatment with either Fpr2 ligand significantly suppressed LPS-induced production of NO or TNFα after both 24h and 48h exposure, moreover Fpr2 ligand treatment significantly enhanced production of IL-10 48h post-LPS treatment. As we have previously shown Fpr2 to be coupled to a number of intracellular signaling pathways (Cooray et al. 2013), we investigated potential signaling responses. Western blot analysis revealed no activation of ERK1/2, but identified a rapid and potent activation of p38 MAP kinase in BV2 microglia following stimulation with Fpr2 ligands. Together, these data indicate the possibility of exploiting immunomodulatory strategies for the treatment of neurological diseases, and highlight in particular the important potential of resolution mechanisms as novel therapeutic targets in neuroinflammation. References Cooray SN et al. (2013). Proc Natl Acad Sci U S A 110: 18232-7. Cunningham C (2013). Glia 61: 71-90. Heneka MT et al. (2015). Lancet Neurol 14: 388-40

Analytical validation of innovative magneto-inertial outcomes: a controlled environment study.

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