Atypical spatiotemporal activation of cerebellar lobules during emotional face processing in adolescents with autism.

Autism spectrum disorder (ASD) is characterized by social deficits and atypical facial processing of emotional expressions. The underlying neuropathology of these abnormalities is still unclear. Recent studies implicate cerebellum in emotional processing; other studies show cerebellar abnormalities in ASD. Here, we elucidate the spatiotemporal activation of cerebellar lobules in ASD during emotional processing of happy and angry faces in adolescents with ASD and typically developing (TD) controls. Using magnetoencephalography, we calculated dynamic statistical parametric maps across a period of 500 ms after emotional stimuli onset and determined differences between group activity to happy and angry emotions. Following happy face presentation, adolescents with ASD exhibited only left-hemispheric cerebellar activation in a cluster extending from lobule VI to lobule V (compared to TD controls). Following angry face presentation, adolescents with ASD exhibited only midline cerebellar activation (posterior IX vermis). Our findings indicate an early (125-175 ms) overactivation in cerebellar activity only for happy faces and a later overactivation for both happy (250-450 ms) and angry (250-350 ms) faces in adolescents with ASD. The prioritized hemispheric activity (happy faces) could reflect the promotion of a more flexible and adaptive social behavior, while the latter midline activity (angry faces) may guide conforming behavior.

Acute Diffusivity Biomarkers for Prediction of Motor and Language Outcome in Mild-to-Severe Stroke Patients.

Background and Purpose- Early severity of stroke symptoms-especially in mild-to-severe stroke patients-are imperfect predictors of long-term motor and aphasia outcome. Motor function and language processing heavily rely on the preservation of important white matter fasciculi in the brain. Axial diffusivity (AD) from the diffusion tensor imaging model has repeatedly shown to accurately reflect acute axonal damage and is thus optimal to probe the integrity of important white matter bundles and their relationship with long-term outcome. Our aim was to investigate the independent prognostic value of the AD of white matter tracts in the motor and language network evaluated at 24 hours poststroke for motor and aphasia outcome at 3 months poststroke. Methods- Seventeen (motor cohort) and 28 (aphasia cohort) thrombolyzed patients with initial mild-to-severe stroke underwent a diffusion tensor imaging sequence at 24 hours poststroke. Motor and language outcome were evaluated at 3 months poststroke with a composite motor score and the aphasia handicap scale. We first used stepwise regression to determine which classic (age, initial motor or aphasia severity, and lesion volume) and imaging (ratio of affected/unaffected AD of motor and language fasciculi) factors were related to outcome. Second, to determine the specificity of our a priori choices of fasciculi, we performed voxel-based analyses to determine if the same, additional, or altogether new regions were associated with long-term outcome. Results- The ratio of AD in the corticospinal tract was the sole predictor of long-term motor outcome, and the ratio of AD in the arcuate fasciculus-along with age and initial aphasia severity-was an independent predictor of 3-month aphasia outcome. White matter regions overlapping with these fasciculi naturally emerged in the corresponding voxel-based analyses. Conclusions- AD of the corticospinal tract and arcuate fasciculus are effective biomarkers of long-term motor and aphasia outcome, respectively.

Elucidating the Structural and Functional Correlates of Upper-Limb Poststroke Motor Impairment.

Background and Purpose- Many studies have attempted to bring to light the neural correlates of poststroke motor impairment, but few have used multimodal approach to explain it. The aim of this study was to elucidate neural structural and functional correlates of upper limb motor impairment by combining electrophysiological, anatomic, and functional neuroimaging data. Methods- Forty ischemic stroke patients (median [min-max] age: 63 [33-82] years, time poststroke: 3.5 [1.1-58] months) with unilateral upper limb weakness were included. The upper limb motor impairment was defined by a motor composite score. Simple linear analysis followed by multiple linear regression analysis were performed to identify which variables (corticospinal excitability, laterality indices within the primary motor cortex or corticospinal [CST], and corpus callosum tracts integrity) were the best explaining factors of upper limb motor impairment. Results- There was a significant correlation between the resting motor threshold ratio and CST damage (r= -0.50 [95% CI, -0.70 to -0.22]; P<0.001) as well as the motor-evoked potentials amplitude (r= -0.73 [95% CI, -0.85 to -0.54]; P<0.001). Only the resting motor threshold ratio was retained by the multiple regression model and explained half of the variance (49%; P<0.001) of the upper limb motor impairment after stroke. Conclusions- The implementation of quantitative neurophysiological measurements such as the resting motor threshold as a surrogate marker of impairment could be considered in neurorehabilitation trials.

Comparison of spatial normalization strategies of diffusion MRI data for studying motor outcome in subacute-chronic and acute stroke.

A common means of studying motor recovery in stroke patients is to extract Diffusion Tensor Imaging (DTI) parameters from the corticospinal tract (CST) and correlate them with clinical outcome scores. To that purpose, conducting group-level analyses through spatial normalization has become a popular approach. However, the reliability of such analyses depends on the accuracy of the particular registration strategy employed. To date, most studies have employed scalar-based registration using either high-resolution T1 images or Fractional Anisotropy (FA) maps to warp diffusion data to a common space. However, more powerful registration algorithms exist for aligning major white matter structures, such as Fiber Orientation Distribution (FOD)-based registration. Regardless of the strategy chosen, automatic normalization algorithms are prone to distortions caused by stroke lesions. While lesion masking is a common means to lessen such distortions, the extent of its effect on tract-related DTI parameters and their correlation with motor outcome has yet to be determined. Here, we aimed to address these concerns by first investigating the effect of common T1 and FA-based registration as well as novel FOD-based registration algorithms with and without lesion masking on lesion load and DTI parameter extraction of the CST in datasets typically acquired for subacute-chronic and acute stroke patients. Second, we studied how differences in these procedures influenced correlation strength between CST damage (through DTI parameters) and motor outcome. Our results showed that, for high-quality subacute-chronic stroke data, FOD-based registration captured significantly higher lesion loads and significantly larger FA asymmetries in the CST. This was also associated with significantly stronger correlations in motor outcome with respect to T1 or FA-based registration methods. For acute data acquired in a clinical setting, there were few observed differences, suggesting that commonly employed FA-based registration is appropriate for group-level analyses.

Red-Tinted Contact Lenses May Improve Quality of Life in Retinal Diseases.

Supplemental digital content is available in the text. ABSTRACT: To determine the benefits provided by centrally red-tinted contact lenses on visual acuity, contrast sensitivity (CS), photophobia, and quality of life in patients with degenerative retinal diseases.We evaluated the impact of centrally red-tinted hydrogel contact lenses on nine patients (aged 15 to 22 years) with severe photophobia and poor visual acuity. Each patient underwent a full eye examination with and without contact lenses, including visual acuity at distance and near, CS, eye movement recording for nystagmus, refraction, and a fundus examination. All patients completed a low vision-adapted VFQ 25-Version 2000 quality-of-life questionnaire.Seven of nine patients demonstrated improvement in binocular visual acuity as well as improvement in CS with the tinted contact lenses. Subjectively, all patients described a major improvement in their photophobia both outdoors and indoors, as well as a marked improvement in quality of life.Red-tinted contact lenses may dramatically improve visual functions, outdoor performance, and quality of life of patients suffering from retinal diseases. These lenses should be a part of the regular assessment in specialty clinics treating patients with low vision, glare, and photophobia.

Consensus paper: the role of the cerebellum in perceptual processes.

Various lines of evidence accumulated over the past 30 years indicate that the cerebellum, long recognized as essential for motor control, also has considerable influence on perceptual processes. In this paper, we bring together experts from psychology and neuroscience, with the aim of providing a succinct but comprehensive overview of key findings related to the involvement of the cerebellum in sensory perception. The contributions cover such topics as anatomical and functional connectivity, evolutionary and comparative perspectives, visual and auditory processing, biological motion perception, nociception, self-motion, timing, predictive processing, and perceptual sequencing. While no single explanation has yet emerged concerning the role of the cerebellum in perceptual processes, this consensus paper summarizes the impressive empirical evidence on this problem and highlights diversities as well as commonalities between existing hypotheses. In addition to work with healthy individuals and patients with cerebellar disorders, it is also apparent that several neurological conditions in which perceptual disturbances occur, including autism and schizophrenia, are associated with cerebellar pathology. A better understanding of the involvement of the cerebellum in perceptual processes will thus likely be important for identifying and treating perceptual deficits that may at present go unnoticed and untreated. This paper provides a useful framework for further debate and empirical investigations into the influence of the cerebellum on sensory perception.

The human amygdala and pain: evidence from neuroimaging.

The amygdala, a small deep brain structure involved in behavioral processing through interactions with other brain regions, has garnered increased attention in recent years in relation to pain processing. As pain is a multidimensional experience that encompasses physical sensation, affect, and cognition, the amygdala is well suited to play a part in this process. Multiple neuroimaging studies of pain in humans have reported activation in the amygdala. Here, we summarize these studies by performing a coordinate-based meta-analysis within experimentally induced and clinical pain studies using an activation likelihood estimate analysis. The results are presented in relation to locations of peak activation within and outside of amygdala subregions. The majority of studies identified coordinates consistent with human amygdala cytoarchitecture indicating reproducibility in neuroanatomical labeling across labs, analysis methods, and imaging modalities. Differences were noted between healthy and clinical pain studies: in clinical pain studies, peak activation was located in the laterobasal region, suggestive of the cognitive-affective overlay present among individuals suffering from chronic pain; while the less understood superficial region of the amygdala was prominent among experimental pain studies. Taken together, these findings suggest several important directions for further research exploring the amygdala's role in pain processing.

The cerebellum and addiction: insights gained from neuroimaging research.

Although cerebellar alterations have been consistently noted in the addiction literature, the pathophysiology of this link remains unclear. The cerebellum is commonly classified as a motor structure, but human functional neuroimaging along with clinical observations in cerebellar stroke patients and anatomical tract tracing in non-human primates suggests its involvement in cognitive and affective processing. A comprehensive literature search on the role of the cerebellum in addiction was performed. This review article (1) considers the potential role of the cerebellum in addiction; (2) summarizes the cerebellar structural alterations linked to addiction; (3) presents the functional neuroimaging evidence linking the cerebellum with addiction; and (4) proposes a model for addiction that underscores the role of the cerebellum. The data implicate the cerebellum as an intermediary between motor and reward, motivation and cognitive control systems, as all are relevant etiologic factors in addiction. Furthermore, consideration of these findings could contribute to deeper and more sophisticated insights into normal reward and motivational function. The goal of this review is to spread awareness of cerebellar involvement in addictive processes, and to suggest a preliminary model for its potential role.

Allergic rhinitis and keratoconus: a systematic review and meta-analysis.

BACKGROUND: The relationship between keratoconus and various allergic diseases has been a subject of controversy. OBJECTIVE: In the present study, a systematic review and meta-analysis was conducted to investigate the association between allergic rhinitis (AR) and keratoconus. METHODS: Relevant and eligible studies from PubMed, Web of Science, and Cochrane Library were systematically reviewed to evaluate the association between AR and keratoconus. Observational studies containing the number of patients with and without keratoconus and the number of patients with keratoconus diagnosed with or without AR were included. Two reviewers independently screened for eligible studies and extracted data from the included studies. A bivariate meta-analysis was conducted to compare the odds of keratoconus occurrence in patients with and without AR. The main outcome was the odds ratio of keratoconus occurrence in patients with AR. A sensitivity test was performed using the adjusted odds ratio reported in the included studies to validate the findings. RESULTS: Seven studies involving 775,574 participants were included in this meta-analysis. Among them, 29,082 patients had keratoconus. The pooled odds ratio of keratoconus occurrence in patients with AR was 1.71 (95% confidence interval [CI]: 1.36-2.15; P < 0.001; I2 = 96%), and the pooled adjusted odds ratio was 1.72 (95% CI: 1.23-2.40; P = 0.001; I2 = 97%). CONCLUSION: Patients with AR showed significantly higher odds of keratoconus occurrence than those without AR. Future studies are warranted to investigate the causal relationship and evaluate the cost-effectiveness of early screening using methods such as corneal topography and referral for keratoconus in patients with AR.

Refractive errors in patients with Bardet Biedl syndrome.

PURPOSE: Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive ciliopathy. Within corneal development, primary cilia serve a critical role. We sought to investigate the association of BBS with corneal astigmatism among a cohort of patients with BBS. METHODS: This was a cross-sectional, retrospective study performed at a pediatric ophthalmology department of a tertiary hospital. The study enrolled 45 patients with genetically confirmed Bardet-Biedl syndrome, encompassing a total of 90 eyes observed from February 2011 to August 2021. Spherical and cylindrical refractive errors and keratometry outcome measures, including diopter (D) values at the flattest and steepest axes, were recorded. Corneal astigmatism of greater than 3D is considered extreme corneal astigmatism based on previously published data. RESULTS: Among 45 patients (M:26; F:19), the mean age was 16.4 ± 8.2 years, and the mean best-corrected visual acuity was 20/60. The most common molecular diagnosis was BBS1, seen in 24 of 45 (53.3%). Among all the patients, the mean spherical refractive error was -2.9 ± 3.8D. The mean cylindrical refractive error was 2.6 ± 1.5D. The mean keratometry values at the flattest axis was 43.5 ± 5.3D (39.4-75.0) and at the steepest axis was 47.2 ± 7.3D(41.5-84.0). Among all the patients with BBS, the mean corneal astigmatism was 3.7 ± 1.0D(0.5-7.1), which is considered extreme. CONCLUSION: A cohort of individuals with BBS demonstrated high corneal astigmatism. These results suggest an association between corneal astigmatism and primary ciliary dysfunction and may assist in clinical management and future therapeutic targets among BBS and other corneal disorders.

The long-term impact of cerebellar tumor resection on executive functioning, anxiety, and fear of pain: A mixed methodology pilot study.

This pilot study investigated the long-term impact of a surgery-only treatment (no exposure to other treatments, such as chemotherapy and radiation) for pediatric cerebellar low-grade gliomas on executive function, anxiety, and fear of pain (FOP) beliefs. Twelve patients who underwent surgical glioma resection during childhood (surgery age was 4-16 years, study visit age was 10-28 years), and 12 pain-free controls matched for age, sex, race, and handedness were tested. The spatial extent of resection was precisely mapped using magnetic resonance imaging (MRI). Executive function, anxiety, and FOP were assessed using validated self-report age-appropriate questionnaires for children and adults. Structured clinical interviews at a post-surgery follow-up visit were completed (average: 89 months, range: 20-99). No significant differences in FOP (FOPQ-C t[14 = 1.81, p = 0.09; FOPQ-III t[4] = 0.29, p = 0.79), executive function scores (BRIEF t[20] = 0.30, p = 0.28), or anxiety scores (MASC t[16] = 0.19, p = 0.85; MAQ t[4] = 1.80, p = 0.15) were found in pediatric or adult patients compared to pain-free controls. Clinical interviews mainly categorized pediatric patients as not anxious. One participant reported mild/subclinical anxiety, and one had moderate clinical anxiety. Neither psychologists nor patients endorsed impairments to executive functioning, anxiety, or FOP. Our pilot results suggest that pediatric cerebellar tumor survivors treated with surgery-only have favorable long-term functioning related to these themes. While these results are promising, they will need to be replicated in a larger patient sample.

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

PURPOSE: 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. DESIGN: Prospective case series. METHODS: 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 2 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. RESULTS: 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. CONCLUSION: 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.

BOLD responses in somatosensory cortices better reflect heat sensation than pain.

The discovery of cortical networks that participate in pain processing has led to the common generalization that blood oxygen level-dependent (BOLD) responses in these areas indicate the processing of pain. Physical stimuli have fundamental properties that elicit sensations distinguishable from pain, such as heat. We hypothesized that pain intensity coding may reflect the intensity coding of heat sensation during the presentation of thermal stimuli during fMRI. Six 3T fMRI heat scans were collected for 16 healthy subjects, corresponding to perceptual levels of "low innocuous heat," "moderate innocuous heat," "high innocuous heat," "low painful heat," "moderate painful heat," and "high painful heat" delivered by a contact thermode to the face. Subjects rated pain and heat intensity separately after each scan. A general linear model analysis detected different patterns of brain activation for the different phases of the biphasic response to heat. During high painful heat, the early phase was associated with significant anterior insula and anterior cingulate cortex activation. Persistent responses were detected in the right dorsolateral prefrontal cortex and inferior parietal lobule. Only the late phase showed significant correlations with perceptual ratings. Significant heat intensity correlated activation was identified in contralateral primary and secondary somatosensory cortices, motor cortex, and superior temporal lobe. These areas were significantly more related to heat ratings than pain. These results indicate that heat intensity is encoded by the somatosensory cortices, and that pain evaluation may either arise from multimodal evaluative processes, or is a distributed process.

Clinical Neuroimaging of Photophobia in Individuals With Chronic Ocular Surface Pain.

PURPOSE: To examine neural mechanisms underlying photophobia in individuals with chronic ocular surface pain by using functional magnetic resonance imaging (fMRI). DESIGN: Cross-sectional case/control analysis. METHODS: A total of 16 individuals from the Miami Veterans Affairs eye clinic underwent comprehensive ocular surface evaluations and were surveyed for ocular surface symptoms. Case patients included patients who reported chronic ocular surface pain symptoms and light sensitivity at least most of the time over 1 week. Controls included persons without chronic ocular surface pain who reported no or minimal light sensitivity. All patients viewed light stimuli during 2 fMRI scans, one before and one after topical anesthetic instillation, and rated their level of pain intensity to the stimulus at the end of each scan. Areas of brain activation in response to light stimuli presentation were correlated with pain responses and examined post- vs pre-anesthesia. RESULTS: Case patients (n = 8) reported higher pain intensity ratings than controls (n = 8) in response to light stimuli during fMRI. Case patient ratings correlated more with light-evoked activation in pain-related areas within the trigeminal brainstem, primary somatosensory cortex (S1), anterior mid-cingulate cortex (aMCC), and insula than in controls. Topical anesthesia led to varying responses in pain ratings among case patients as well as decreased light-evoked activation in S1 and aMCC. CONCLUSIONS: The trigeminal nociceptive system may contribute to photophobia in individuals with chronic ocular surface pain. We demonstrate modulation of cortical structures in this pathway with topically applied anesthetic to the eyes. Further understanding of modulatory interactions that govern ocular surface pain and photophobia is critical for developing effective, precision-based therapies.

The Past, Present, and Future Role of Artificial Intelligence in Ventilation/Perfusion Scintigraphy: A Systematic Review.

Ventilation-perfusion (V/Q) lung scans constitute one of the oldest nuclear medicine procedures, remain one of the few studies performed in the acute setting, and are amongst the few performed in the emergency setting. V/Q studies have witnessed a long fluctuation in adoption rates in parallel to continuous advances in image processing and computer vision techniques. This review provides an overview on the status of artificial intelligence (AI) in V/Q scintigraphy. To clearly assess the past, current, and future role of AI in V/Q scans, we conducted a systematic Ovid MEDLINE(R) literature search from 1946 to August 5, 2022 in addition to a manual search. The literature was reviewed and summarized in terms of methodologies and results for the various applications of AI to V/Q scans. The PRISMA guidelines were followed. Thirty-one publications fulfilled our search criteria and were grouped into two distinct categories: (1) disease diagnosis/detection (N = 22, 71.0%) and (2) cross-modality image translation into V/Q images (N = 9, 29.0%). Studies on disease diagnosis and detection relied heavily on shallow artificial neural networks for acute pulmonary embolism (PE) diagnosis and were primarily published between the mid-1990s and early 2000s. Recent applications almost exclusively regard image translation tasks from CT to ventilation or perfusion images with modern algorithms, such as convolutional neural networks, and were published between 2019 and 2022. AI research in V/Q scintigraphy for acute PE diagnosis in the mid-90s to early 2000s yielded promising results but has since been largely neglected and thus have yet to benefit from today's state-of-the art machine-learning techniques, such as deep neural networks. Recently, the main application of AI for V/Q has shifted towards generating synthetic ventilation and perfusion images from CT. There is therefore considerable potential to expand and modernize the use of real V/Q studies with state-of-the-art deep learning approaches, especially for workflow optimization and PE detection at both acute and chronic stages. We discuss future challenges and potential directions to compensate for the lag in this domain and enhance the value of this traditional nuclear medicine scan.

Association between superior longitudinal fasciculus, motor recovery, and motor outcome after stroke: a cohort study.

Introduction: Parieto-frontal interactions are mediated by the superior longitudinal fasciculus (SLF) and are crucial to integrate visuomotor information and mediate fine motor control. In this study, we aimed to characterize the relation of white matter integrity of both parts of the SLF (SLF I and SLF II) to both motor outcome and recovery and its evolution over time in stroke patients with upper limb motor deficits. Materials and methods: Fractional anisotropy (FA) values over the SLF I, SLF II, and corticospinal tract (CST) and upper limb motor performance evaluated by both the upper limb Fugl-Meyer Assessment score and maximum grip strength were measured for 16 patients at 3 weeks, 6 weeks, and 12 weeks poststroke. FA changes were assessed over time using repeated-measures Friedman ANOVA, and correlations between motor recovery, motor outcome at 12 weeks, and FA values in the CST, SLF I, and SLF II at 3 weeks were performed using Spearman's rank-order correlation. Results: FA values in the affected hemisphere's SLF I and SLF II at 3 weeks correlated with motor recovery at 12 weeks when assessed by the Fugl-Meyer Assessment for upper limb extremity (rho: 0.502, p: 0.04 and rho: 0.510, p: 0.04, respectively) but not when assessed by grip strength. FA values in the SLF I and SLF II were not correlated with motor outcomes. FA values in the SLF II in the affected hemisphere changed significantly over time (p: 0.016). Conclusion: Both SLF I and SLF II appeared to participate in poststroke motor recovery of complex movements but not in the motor outcome. These results argue that visually/spatially oriented motor tasks as well as more complex motor tasks using parietal associative areas should be used for poststroke rehabilitation strategies.

Interpretable deep learning for the prognosis of long-term functional outcome post-stroke using acute diffusion weighted imaging.

Advances in deep learning can be applied to acute stroke imaging to build powerful and explainable prediction models that could supersede traditionally used biomarkers. We aimed to evaluate the performance and interpretability of a deep learning model based on convolutional neural networks (CNN) in predicting long-term functional outcome with diffusion-weighted imaging (DWI) acquired at day 1 post-stroke. Ischemic stroke patients (n = 322) were included from the ASTER and INSULINFARCT trials as well as the Pitié-Salpêtrière registry. We trained a CNN to predict long-term functional outcome assessed at 3 months with the modified Rankin Scale (dichotomized as good [mRS ≤ 2] vs. poor [mRS ≥ 3]) and compared its performance to two logistic regression models using lesion volume and ASPECTS. The CNN contained an attention mechanism, which allowed to visualize the areas of the brain that drove prediction. The deep learning model yielded a significantly higher area under the curve (0.83 95%CI [0.78-0.87]) than lesion volume (0.78 [0.73-0.83]) and ASPECTS (0.77 [0.71-0.83]) (p < 0.05). Setting all classifiers to the specificity as the deep learning model (i.e., 0.87 [0.82-0.92]), the CNN yielded a significantly higher sensitivity (0.67 [0.59-0.73]) than lesion volume (0.48 [0.40-0.56]) and ASPECTS (0.50 [0.41-0.58]) (p = 0.002). The attention mechanism revealed that the network learned to naturally attend to the lesion to predict outcome.

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: Twelve 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). 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. 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.

Placebos in pediatrics: A cross-sectional survey investigating physicians' perspectives.

OBJECTIVE: Placebo responses are significantly higher in children than in adults, suggesting a potential underused treatment option in pediatric care. To facilitate the clinical translation of these beneficial effects, we explored physicians' current practice, opinions, knowledge, and likelihood of recommending placebos in the future. METHODS: A cross-sectional web-based survey administered by REDCap was conducted at Boston Children's Hospital between October 2021 and March 2022. Physicians (n = 1157) were invited to participate through an email containing a link to a 23-item survey designed to assess physicians' attitudes and perceptions towards the clinical use of placebo in pediatrics. RESULTS: From 207 (18%) returned surveys, 109 (9%) were fully completed. Most respondents (79%) believed that enhancing the therapeutic components that contribute to the placebo response may be a way of improving pediatric care. However, whereas most (62%) found placebo treatments permissible, only one-third reported recommending them. In pediatrics, placebos are typically introduced as a medicine that "might help" (43%). The most common treatments recommended to enhance placebo effects are physical therapy, vitamins, and over-the-counter analgesics. Physicians most frequently recommend placebos for occasional pain, headaches, and anxiety disorders. Finally, the great majority of physicians (87%) stated they would be more likely to recommend placebo treatments if there were safety and ethical guidelines for open-label placebos. CONCLUSIONS: Placebo treatments seem permissible to physicians in pediatric care, but the development of safety and ethical guidelines may be necessary before physicians systematically incorporate the benefits of the placebo effect in pediatrics.

Disentangling the neurological basis of chronic ocular pain using clinical, self-report, and brain imaging data: use of K-means clustering to explore patient phenotypes.

Introduction: The factors that mediate the expression of ocular pain and the mechanisms that promote chronic ocular pain symptoms are poorly understood. Central nervous system involvement has been postulated based on observations of pain out of proportion to nociceptive stimuli in some individuals. This investigation focused on understanding functional connectivity between brain regions implicated in chronic pain in persons reporting ocular pain symptoms. Methods: We recruited a total of 53 persons divided into two cohorts: persons who reported no ocular pain, and persons who reported chronic ocular pain, irrespective of ocular surface findings. We performed a resting state fMRI investigation that was focused on subcortical brain structures including the trigeminal nucleus and performed a brief battery of ophthalmological examinations. Results: Persons in the pain cohort reported higher levels of pain symptoms relating to neuropathic pain and ocular surface disease, as well as more abnormal tear metrics (stability and tear production). Functional connectivity analysis between groups evinced multiple connections exemplifying both increases and decreases in connectivity including regions such as the trigeminal nucleus, amygdala, and sub-regions of the thalamus. Exploratory analysis of the pain cohort integrating clinical and brain function metrics highlighted subpopulations that showed unique phenotypes providing insight into pain mechanisms. Discussion: Study findings support centralized involvement in those reporting ocular-based pain and allude to mechanisms through which pain treatment services may be directed in future research.