Botulinum toxin A decreases neural activity in pain-related brain regions in individuals with chronic ocular pain and photophobia

IntroductionTo examine the effect of botulinum toxin A (BoNT-A) on neural mechanisms underlying pain and photophobia using functional magnetic resonance imaging (fMRI) in individuals with chronic ocular pain.MethodsTwelve subjects with chronic ocular pain and light sensitivity were recruited from the Miami Veterans Affairs eye clinic. Inclusion criteria were: (1) chronic ocular pain; (2) presence of ocular pain over 1 week recall; and (3) presence of photophobia. All individuals underwent an ocular surface examination to capture tear parameters before and 4–6 weeks after BoNT-A injections. Using an event-related fMRI design, subjects were presented with light stimuli during two fMRI scans, once before and 4–6 weeks after BoNT-A injection. Light evoked unpleasantness ratings were reported by subjects after each scan. Whole brain blood oxygen level dependent (BOLD) responses to light stimuli were analyzed.ResultsAt baseline, all subjects reported unpleasantness with light stimulation (average: 70.8 ± 32.0). Four to six weeks after BoNT-A injection, unpleasantness scores decreased (48.1 ± 33.6), but the change was not significant. On an individual level, 50% of subjects had decreased unpleasantness ratings in response to light stimulation compared to baseline (“responders,” n = 6), while 50% had equivalent (n = 3) or increased (n = 3) unpleasantness (“non-responders”). At baseline, several differences were noted between responders and non-responders; responders had higher baseline unpleasantness ratings to light, higher symptoms of depression, and more frequent use of antidepressants and anxiolytics, compared to non-responders. Group analysis at baseline displayed light-evoked BOLD responses in bilateral primary somatosensory (S1), bilateral secondary somatosensory (S2), bilateral anterior insula, paracingulate gyrus, midcingulate cortex (MCC), bilateral frontal pole, bilateral cerebellar hemispheric lobule VI, vermis, bilateral cerebellar crus I and II, and visual cortices. BoNT-A injections significantly decreased light evoked BOLD responses in bilateral S1, S2 cortices, cerebellar hemispheric lobule VI, cerebellar crus I, and left cerebellar crus II. BoNT-A responders displayed activation of the spinal trigeminal nucleus at baseline where non-responders did not.DiscussionBoNT-A injections modulate light-evoked activation of pain-related brain systems and photophobia symptoms in some individuals with chronic ocular pain. These effects are associated with decreased activation in areas responsible for processing the sensory-discriminative, affective, dimensions, and motor responses to pain

Botulinum toxin A decreases neural activity in pain-related brain regions in individuals with chronic ocular pain and photophobia

Introduction: To examine the effect of botulinum toxin A (BoNT-A) on neural mechanisms underlying pain and photophobia using functional magnetic resonance imaging (fMRI) in individuals with chronic ocular pain. Methods: 12 subjects with chronic ocular pain and light sensitivity were recruited from the Miami Veterans Affairs eye clinic. Inclusion criteria were: 1) chronic ocular pain; 2) presence of ocular pain over 1 week recall; and 3) presence of photophobia. All individuals underwent an ocular surface examination to capture tear parameters before and 4-6 weeks after BoNT-A injections. Using an event-related fMRI design, subjects were presented with light stimuli during two fMRI scans, once before and 4-6 weeks after BoNT-A injection. Light evoked unpleasantness ratings were reported by subjects after each scan. Whole brain blood oxygen level dependent (BOLD) responses to light stimuli were analyzed. Results: At baseline, all subjects reported unpleasantness with light stimulation (average: 70.8±32.0). 4-6 weeks after BoNT-A injection, unpleasantness scores decreased (48.1±33.6), but the change was not significant. On an individual level, 50% of subjects had decreased unpleasantness ratings in response to light stimulation compared to baseline (“responders,” n=6), while 50% had equivalent (n=3) or increased (n=3) unpleasantness (“non-responders”). At baseline, several differences were noted between responders and non-responders; responders had higher baseline unpleasantness ratings to light, higher symptoms of depression, and more frequent use of antidepressants and anxiolytics, compared to non-responders. Group analysis at baseline displayed light-evoked BOLD responses in bilateral primary somatosensory (S1), bilateral secondary somatosensory (S2), bilateral anterior insula, paracingulate gyrus, midcingulate cortex (MCC), bilateral frontal pole, bilateral cerebellar hemispheric lobule VI, vermis, bilateral cerebellar crus I and II, and visual cortices. BoNT-A injections significantly decreased light evoked BOLD responses in bilateral S1, S2 cortices, cerebellar hemispheric lobule VI, cerebellar crus I, and left cerebellar crus II. BoNT-A responders displayed activation of the spinal trigeminal nucleus at baseline where non-responders did not. Discussion: BoNT-A injections modulate light-evoked activation of pain-related brain systems and photophobia symptoms in some individuals with chronic ocular pain. These effects are associated with decreased activation in areas responsible for processing the sensory-discriminative, affective, dimensions, and motor responses to pain

Local Adoptive Transfer of Plasmacytoid Dendritic Cells as a Novel Therapeutic Approach for Corneal Neovascularization

Purpose : We have recently shown that plasmacytoid dendritic cells (pDCs) exert angiostatic properties. The aim of this study is to evaluate the therapeutic efficacy of local adoptive transfer of pDCs in treating corneal neovascularization (NV). Methods : Corneas of 6-8 week-old male wildtype (WT) C57BL/6 mice underwent suture placement to induce corneal NV. Splenic GFP+ pDCs from DPE-GFP×RAG1-/- mice and WT CD11b+ myeloid cells were isolated. After trephination, 104 pDCs, CD11b+ cells, or PBS control were locally applied onto the corneas using Tisseel fibrin sealant. On day 7, corneas were stained for CD31 (vascular marker) and underwent confocal microscopy. Length of NV and the density of adoptively-transferred GFP+ pDCs were measured by ImageJ. Relative mRNA level of anti-angiogenic molecule endostatin was quantified in the corneas using qRT-PCR. ANOVA with LSD post-hoc test was used to assess statistical significance. p<0.05 was considered significant. Results : Confocal microscopy confirmed successful transfer of GFP+ pDCs to both central (452.8±39.1 cells/mm2) and peripheral corneas (435.1±52.6) on day 2 following local application of pDCs. qRT-PCR showed that local adoptive transfer of pDCs was accompanied by 4.7-fold increase in the mRNA level of anti-angiogenic molecule endostatin compared with fibrin sealant-only control (p=0.009) and 2.3-fold increase compared with adoptive transfer of CD11b+ cells (p=0.03). One-time adoptive transfer of pDCs significantly reduced NV length on day 7 following suture placement (350.1±43.4 µm), compared with transfer of CD11b+ cells (477.0±33.9 µm; p=0.004) as well as fibrin sealant-only controls (454.1±36.5 µm; p=0.01). Conclusions : Local adoptive transfer of pDCs can limit corneal NV following suture placement and may serve as a novel cell-based therapeutic approach to treat corneal NV.Fil: Arsia, Jamali. Tufts Medical Center; Estados UnidosFil: Lopez, Maria J.. Tufts Medical Center; Estados UnidosFil: Harris, Deshea L. Tufts Medical Center; Estados UnidosFil: Sendra, Victor German. Tufts Medical Center; Estados Unidos. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pondelis, Nicholas. Tufts Medical Center; Estados UnidosFil: Ortiz, Gustavo. Tufts Medical Center; Estados UnidosFil: Hamrah, Pedram. Tufts Medical Center; Estados Unidos. New England Eye Center; Estados UnidosARVO annual meeting 2019VancouverCanadáAssociation for Research in Vision and Ophthalmolog

Data_Sheet_1_Botulinum toxin A decreases neural activity in pain-related brain regions in individuals with chronic ocular pain and photophobia.docx

IntroductionTo examine the effect of botulinum toxin A (BoNT-A) on neural mechanisms underlying pain and photophobia using functional magnetic resonance imaging (fMRI) in individuals with chronic ocular pain.MethodsTwelve subjects with chronic ocular pain and light sensitivity were recruited from the Miami Veterans Affairs eye clinic. Inclusion criteria were: (1) chronic ocular pain; (2) presence of ocular pain over 1 week recall; and (3) presence of photophobia. All individuals underwent an ocular surface examination to capture tear parameters before and 4–6 weeks after BoNT-A injections. Using an event-related fMRI design, subjects were presented with light stimuli during two fMRI scans, once before and 4–6 weeks after BoNT-A injection. Light evoked unpleasantness ratings were reported by subjects after each scan. Whole brain blood oxygen level dependent (BOLD) responses to light stimuli were analyzed.ResultsAt baseline, all subjects reported unpleasantness with light stimulation (average: 70.8 ± 32.0). Four to six weeks after BoNT-A injection, unpleasantness scores decreased (48.1 ± 33.6), but the change was not significant. On an individual level, 50% of subjects had decreased unpleasantness ratings in response to light stimulation compared to baseline (“responders,” n = 6), while 50% had equivalent (n = 3) or increased (n = 3) unpleasantness (“non-responders”). At baseline, several differences were noted between responders and non-responders; responders had higher baseline unpleasantness ratings to light, higher symptoms of depression, and more frequent use of antidepressants and anxiolytics, compared to non-responders. Group analysis at baseline displayed light-evoked BOLD responses in bilateral primary somatosensory (S1), bilateral secondary somatosensory (S2), bilateral anterior insula, paracingulate gyrus, midcingulate cortex (MCC), bilateral frontal pole, bilateral cerebellar hemispheric lobule VI, vermis, bilateral cerebellar crus I and II, and visual cortices. BoNT-A injections significantly decreased light evoked BOLD responses in bilateral S1, S2 cortices, cerebellar hemispheric lobule VI, cerebellar crus I, and left cerebellar crus II. BoNT-A responders displayed activation of the spinal trigeminal nucleus at baseline where non-responders did not.DiscussionBoNT-A injections modulate light-evoked activation of pain-related brain systems and photophobia symptoms in some individuals with chronic ocular pain. These effects are associated with decreased activation in areas responsible for processing the sensory-discriminative, affective, dimensions, and motor responses to pain.</p

Data_Sheet_2_Botulinum toxin A decreases neural activity in pain-related brain regions in individuals with chronic ocular pain and photophobia.docx

IntroductionTo examine the effect of botulinum toxin A (BoNT-A) on neural mechanisms underlying pain and photophobia using functional magnetic resonance imaging (fMRI) in individuals with chronic ocular pain.MethodsTwelve subjects with chronic ocular pain and light sensitivity were recruited from the Miami Veterans Affairs eye clinic. Inclusion criteria were: (1) chronic ocular pain; (2) presence of ocular pain over 1 week recall; and (3) presence of photophobia. All individuals underwent an ocular surface examination to capture tear parameters before and 4–6 weeks after BoNT-A injections. Using an event-related fMRI design, subjects were presented with light stimuli during two fMRI scans, once before and 4–6 weeks after BoNT-A injection. Light evoked unpleasantness ratings were reported by subjects after each scan. Whole brain blood oxygen level dependent (BOLD) responses to light stimuli were analyzed.ResultsAt baseline, all subjects reported unpleasantness with light stimulation (average: 70.8 ± 32.0). Four to six weeks after BoNT-A injection, unpleasantness scores decreased (48.1 ± 33.6), but the change was not significant. On an individual level, 50% of subjects had decreased unpleasantness ratings in response to light stimulation compared to baseline (“responders,” n = 6), while 50% had equivalent (n = 3) or increased (n = 3) unpleasantness (“non-responders”). At baseline, several differences were noted between responders and non-responders; responders had higher baseline unpleasantness ratings to light, higher symptoms of depression, and more frequent use of antidepressants and anxiolytics, compared to non-responders. Group analysis at baseline displayed light-evoked BOLD responses in bilateral primary somatosensory (S1), bilateral secondary somatosensory (S2), bilateral anterior insula, paracingulate gyrus, midcingulate cortex (MCC), bilateral frontal pole, bilateral cerebellar hemispheric lobule VI, vermis, bilateral cerebellar crus I and II, and visual cortices. BoNT-A injections significantly decreased light evoked BOLD responses in bilateral S1, S2 cortices, cerebellar hemispheric lobule VI, cerebellar crus I, and left cerebellar crus II. BoNT-A responders displayed activation of the spinal trigeminal nucleus at baseline where non-responders did not.DiscussionBoNT-A injections modulate light-evoked activation of pain-related brain systems and photophobia symptoms in some individuals with chronic ocular pain. These effects are associated with decreased activation in areas responsible for processing the sensory-discriminative, affective, dimensions, and motor responses to pain.</p

FL-41 Tint Reduces Activation of Neural Pathways of Photophobia in Patients with Chronic Ocular Pain

To assess the therapeutic effect of tinted lenses (FL-41) on photophobia and light-evoked brain activity using functional magnetic resonance imaging (fMRI) in individuals with chronic ocular surface pain.Prospective case series.25 subjects from the Miami Veterans Affairs (VA) eye clinic were recruited based on the presence of chronic ocular pain, dry eye symptoms, and photophobia. Using a 3T MRI scanner, subjects underwent two fMRI scans using an event-related design based on light stimuli: one scan while wearing FL-41 lenses and one without. Unpleasantness ratings evoked by the light stimuli were collected after each scan.With FL-41 lenses, subjects reported decreased (n=19), maintained (n=2), or increased (n=4) light-evoked unpleasantness ratings. Group analysis at baseline (no lens) revealed significant light evoked responses in bilateral primary somatosensory (S1), bilateral secondary somatosensory (S2), bilateral insula, bilateral frontal pole, visual, precuneus, paracingulate, and anterior cingulate cortices (ACC) as well as cerebellar vermis, bilateral cerebellar hemispheric lobule VI, and bilateral cerebellar crus I and II. With FL-41 lenses, light-evoked responses were significantly decreased in bilateral S1, bilateral S2, bilateral insular, right temporal pole, precuneus, ACC, and paracingulate cortices as well as bilateral cerebellar hemispheric lobule VI.FL-41 lenses modulated photophobia symptoms in some individuals with chronic ocular pain. In conjunction, FL-41 lenses decreased activation in cortical areas involved in processing affective and sensory-discriminative dimensions of pain. Further research into these relationships will advance the ability to provide precision therapy for individuals with ocular pain