Machine phenotyping of cluster headache and its response to verapamil.

Cluster headache is characterized by recurrent, unilateral attacks of excruciating pain associated with ipsilateral cranial autonomic symptoms. Although a wide array of clinical, anatomical, physiological, and genetic data have informed multiple theories about the underlying pathophysiology, the lack of a comprehensive mechanistic understanding has inhibited, on the one hand, the development of new treatments and, on the other, the identification of features predictive of response to established ones. The first-line drug, verapamil, is found to be effective in only half of all patients, and after several weeks of dose escalation, rendering therapeutic selection both uncertain and slow. Here we use high-dimensional modelling of routinely acquired phenotypic and MRI data to quantify the predictability of verapamil responsiveness and to illuminate its neural dependants, across a cohort of 708 patients evaluated for cluster headache at the National Hospital for Neurology and Neurosurgery between 2007 and 2017. We derive a succinct latent representation of cluster headache from non-linear dimensionality reduction of structured clinical features, revealing novel phenotypic clusters. In a subset of patients, we show that individually predictive models based on gradient boosting machines can predict verapamil responsiveness from clinical (410 patients) and imaging (194 patients) features. Models combining clinical and imaging data establish the first benchmark for predicting verapamil responsiveness, with an area under the receiver operating characteristic curve of 0.689 on cross-validation (95% confidence interval: 0.651 to 0.710) and 0.621 on held-out data. In the imaged patients, voxel-based morphometry revealed a grey matter cluster in lobule VI of the cerebellum (-4, -66, -20) exhibiting enhanced grey matter concentrations in verapamil non-responders compared with responders (familywise error-corrected P = 0.008, 29 voxels). We propose a mechanism for the therapeutic effect of verapamil that draws on the neuroanatomy and neurochemistry of the identified region. Our results reveal previously unrecognized high-dimensional structure within the phenotypic landscape of cluster headache that enables prediction of treatment response with modest fidelity. An analogous approach applied to larger, globally representative datasets could facilitate data-driven redefinition of diagnostic criteria and stronger, more generalizable predictive models of treatment responsiveness.

Morphological Abnormalities of Thalamic Subnuclei in Migraine: A Multicenter MRI Study at 3 Tesla.

The thalamus contains third-order relay neurons of the trigeminal system, and animal models as well as preliminary imaging studies in small cohorts of migraine patients have suggested a role of the thalamus in headache pathophysiology. However, larger studies using advanced imaging techniques in substantial patient populations are lacking. In the present study, we investigated changes of thalamic volume and shape in a large multicenter cohort of patients with migraine. High-resolution T1-weighted MRI data acquired at 3 tesla in 131 patients with migraine (38 with aura; 30.8 ± 9 years old; 109 women; monthly attack frequency: 3.2 ± 2.5; disease duration: 14 ± 8.4 years) and 115 matched healthy subjects (29 ± 7 years old; 81 women) from four international tertiary headache centers were analyzed. The thalamus and thalamic subnuclei, striatum, and globus pallidus were segmented using a fully automated multiatlas approach. Deformation-based shape analysis was performed to localize surface abnormalities. Differences between patients with migraine and healthy subjects were assessed using an ANCOVA model. After correction for multiple comparisons, performed using the false discovery rate approach (p < 0.05 corrected), significant volume reductions of the following thalamic nuclei were observed in migraineurs: central nuclear complex (F(1,233) = 6.79), anterior nucleus (F(1,237) = 7.38), and lateral dorsal nucleus (F(1,238) = 6.79). Moreover, reduced striatal volume (F(1,238) = 6.9) was observed in patients. This large-scale study indicates structural thalamic abnormalities in patients with migraine. The thalamic nuclei with abnormal volumes are densely connected to the limbic system. The data hence lend support to the view that higher-order integration systems are altered in migraine. SIGNIFICANCE STATEMENT: This multicenter imaging study shows morphological thalamic abnormalities in a large cohort of patients with episodic migraine compared with healthy subjects using state-of-the-art MRI and advanced, fully automated multiatlas segmentation techniques. The results stress that migraine is a disorder of the CNS in which not only is brain function abnormal, but also brain structure is undergoing significant remodeling.

Headache.

Headache disorders are primarily managed in an outpatient setting; therefore, the authors focus on the primary headache disorders that comprise the bulk of clinical practice. Red flags for secondary headaches that may be more commonly encountered in clinic are briefly discussed.

Recent neuroimaging advances in the study of primary headaches.

Neuroimaging techniques can be used to investigate both functional and structural features of the brain in patients who have primary headache disorders such as migraine or cluster headache. Improved treatments are needed for both, and this goal will likely be facilitated by a better understanding of the underlying biology. Functional imaging studies have identified regions active during attacks, as well as abnormalities that are present during the interictal period. Volumetric, surface-based morphometric, and tractography studies have revealed structural changes, although whether these represent a cause or effect of the condition remains to be determined. The development of new techniques and modalities promises to yield additional insights in the future. This article aims to review the major findings and most recent advances in neuroimaging of migraine and cluster headache.

Generation of Human iPSC-Derived Retinal Organoids for Assessment of AAV-Mediated Gene Delivery.

Human retinal organoids derived from induced pluripotent stem cells (iPSCs) serve as a promising preclinical model for testing the safety and efficacy of viral gene therapy. Retinal organoids recapitulate the stratified multilayered epithelium structure of the developing and maturating human retina. As such, retinal organoids are unique tools to model retinal disease and to test therapeutic interventions toward their amelioration. Here, we describe a method for the generation of human iPSC-derived retinal organoids and how they can be utilized for the assessment of recombinant adeno-associated viral (rAAV)-mediated gene delivery.

Culture of Human Retinal Explants for Ex Vivo Assessment of AAV Gene Delivery.

Due to the clinically established safety and efficacy profile of recombinant adeno-associated viral (rAAV) vectors, they are considered the "go to" vector for retinal gene therapy. Design of a rAAV-mediated gene therapy focuses on cell tropism, high transduction efficiency, and high transgene expression levels to achieve the lowest therapeutic treatment dosage and avoid toxicity. Human retinal explants are a clinically relevant model system for exploring these aspects of rAAV-mediated gene delivery. In this chapter, we describe an ex vivo human retinal explant culture protocol to evaluate transgene expression in order to determine the selectivity and efficacy of rAAV vectors for human retinal gene therapy.

Interleukin-6 174G/C polymorphism and ischemic stroke: a systematic review.

BACKGROUND AND PURPOSE: Interleukin-6 (IL-6) is associated with atherosclerotic disease and is also a key mediator in the inflammatory response to cerebral ischemia. Although the IL-6 -174G/C promoter polymorphism has been associated with carotid artery atherosclerosis and coronary heart disease, its relation to ischemic stroke is unclear. This review summarizes the current literature and discusses methodological considerations for future studies. METHODS: Electronic searches were conducted in the PubMed MEDLINE, Scopus, and ISI Web of Science databases. Two investigators independently reviewed all abstracts to identify studies examining the association between the IL-6 -174G/C polymorphism and ischemic cerebrovascular events. RESULTS: Twelve relevant publications were identified. Three reported on a subset of patients from a later publication, leaving 9 independent studies. Two studies found an association between ischemic stroke and the G allele or GG genotype, whereas 4 found an association with the C allele or CC genotype. One study found the CC genotype to be significantly less frequent in retinal artery occlusion patients. Two studies found no association between the -174G/C polymorphism and stroke. CONCLUSIONS: Studies investigating stroke and the -174G/C polymorphism report conflicting results, which may reflect the complex physiology of IL-6 and true differences between stroke subtypes and populations. However, interpretation of published results is hindered by methodological limitations, and greater rigor and consistency in future studies will help unravel the relationship between the -174G/C polymorphism and stroke.

Anti-CGRP Monoclonal Antibodies: the Next Era of Migraine Prevention?

OPINION STATEMENT: Migraine is a very disabling disorder with severe impact on patients' lives and substantive costs to society in terms of healthcare costs and lost productivity. Prevention is a key component of migraine therapy, and while numerous preventive options exist, each is burdened by either troublesome side effects or insufficient efficacy. All migraine preventives currently in clinical use were licensed for other purposes and, by chance, have efficacy against migraine. As our understanding of migraine has evolved, calcitonin gene-related peptide (CGRP) has moved to the forefront as a neuropeptide central to migraine pathophysiology. Six small molecule CGRP receptor antagonists were shown to be effective for acute treatment of migraine; two were stopped for hepatotoxicity or one for formulation concern issues and one is now in phase III. Monoclonal antibodies against CGRP or the CGRP receptor have a longer duration of action and have been investigated for migraine prevention. Four are in development and three have completed phase II and one phase III trials; every reported study has been positive. Furthermore, no safety issues have arisen to date, including hepatic or cardiovascular effects, and initial tolerability appears to be excellent. Monoclonal antibodies antagonizing the CGRP pathway represent a novel approach to prevention: a mechanism-specific migraine-targeted therapy. While we must await the results of all the phase III trials, cautious excitement seems warranted as we enter a new era of better tolerated, well-understood, bespoke migraine treatment for this common and disabling neurological disorder.

Increased rate of venous thrombosis may be associated with inpatient dihydroergotamine treatment.

OBJECTIVE: To review whether the incidence of catheter-associated venous thromboses was higher in patients receiving IV dihydroergotamine compared to lidocaine. METHODS: We retrospectively reviewed all admissions at the University of California, San Francisco Headache Center from February 25, 2008, through October 31, 2014, for age, sex, diagnosis, aura, treatment dose, type of IV line used, days with line, superficial (SVT) or deep venous thrombosis (DVT), and pulmonary embolism (PE). RESULTS: A peripherally inserted central catheter (PICC) or midline catheter was placed in 315 of 589 (53%) admissions. Mean age was 38 years with a range of 6 to 79 years; 121 patients (21%) were ≤18 years old. Seventy-four percent (433 of 589) of patients were female. Of 263 dihydroergotamine admissions using a PICC or midline catheter, 19 (7.2%) had either an SVT or DVT or a PE; 2 patients were diagnosed with both DVT and PE. Of 52 lidocaine admissions using a PICC or midline catheter, none had a thrombotic event (p = 0.05, Fisher exact test). Age, sex, aura, total dihydroergotamine dose, and number of days with line were not significant predictors of venous thrombosis. CONCLUSIONS: IV dihydroergotamine treatment may be associated with an increased risk of catheter-associated venous thrombosis. A low threshold for diagnostic ultrasound investigation is appropriate because anticoagulation therapy was frequently required.

Aprepitant for the management of nausea with inpatient IV dihydroergotamine.

OBJECTIVE: To assess the efficacy and tolerability of oral aprepitant, a substance P/neurokinin A receptor antagonist, in controlling nausea associated with IV dihydroergotamine (DHE) administered for medically refractory migrainous headache in patients not responding to standard antiemetics or with a history of uncontrolled nausea with DHE. METHODS: This was a retrospective chart review of prospectively collected hourly diary data and clinical notes of patients hospitalized between 2011 and 2015 for inpatient treatment with DHE. Patients were classified using the International Classification of Headache Disorders, 3rd edition (beta version). Peak and average daily nausea scores from hourly diaries, or daily entries of notes, and concurrent antiemetic use were collected and tabulated. RESULTS: Seventy-four patients, of whom 24 had daily diaries, with chronic migraine with or without aura, with or without medication overuse, or new daily persistent headache of a migrainous type, were identified. In 36 of 57 cases in which aprepitant was administered during hospitalization, there was a 50% reduction in the average daily number of as-needed antinausea medications. Of 57 patients, 52 reported that the addition of aprepitant improved nausea. Among 21 of 24 patients with hourly diary data, nausea scores were reduced and in all 12 with vomiting there was cessation of emesis after aprepitant was added. Aprepitant was well tolerated with no treatment emergent adverse events. CONCLUSIONS: Aprepitant can be effective in the treatment of refractory DHE-induced nausea and emesis. Given the broader issue of troublesome nausea and vomiting in acute presentations of migraine, general neurologists may consider what place aprepitant has in the management of such patients. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with medically refractory migraine receiving IV DHE, oral aprepitant reduces nausea.

The anterior insula shows heightened interictal intrinsic connectivity in migraine without aura.

OBJECTIVE: We sought to explore whether patients with migraine show heightened interictal intrinsic connectivity within primary sensory networks, the salience network, and a network anchored by the dorsal pons, a region known to be active during migraine attacks. METHODS: Using task-free fMRI and a region-of-interest analysis, we compared intrinsic connectivity patterns in 15 migraineurs without aura to 15 age- and sex-matched healthy controls, focusing on networks anchored by the calcarine cortex, Heschl gyrus, right anterior insula, and dorsal pons, a region active during migraine attacks. We also examined the relationship between network connectivity, migraine frequency, and sensory sensitivity symptoms. RESULTS: Migraineurs showed increased connectivity between primary visual and auditory cortices and the right dorsal anterior insula, between the dorsal pons and the bilateral anterior insulae, and between the right and left ventral anterior insulae. Increased connectivity showed no clinical correlation with migraine frequency or sensory sensitivity. CONCLUSIONS: Patients with migraine display interictal changes in the topology of intrinsic connections, with greater connectivity between primary sensory cortices, the pons, and the anterior insula, a region involved in representing and coordinating responses to emotional salience.

InSPAL: A Novel Immersive Virtual Learning Programme.

In this paper we introduce The Interactive Sensory Program for Affective Learning (InSPAL) a pioneering virtual learning programme designed for the severely intellectually disabled (SID) students, who are having cognitive deficiencies and other sensory-motor handicaps, and thus need more help and attention in overcoming their learning difficulties. Through combining and integrating interactive media and virtual reality technology with the principles of art therapy and relevant pedagogical techniques, InSPAL aims to strengthen SID students' pre-learning abilities, promote their self-awareness, decrease behavioral interferences with learning as well as social interaction, enhance their communication and thus promote their quality of life. Results of our study show that students who went through our programme were more focused, and the ability to do things more independently increased by 15%. Moreover, 50% of the students showed a marked improvement in the ability to raise their hands in response, thus increasing their communication skills. The use of therapeutic interventions enabled a better control to the body, mind and emotions, resulting a greater performance and better participation.

New targets for migraine therapy.

OPINION STATEMENT: The shift in our understanding of migraine as a vascular disorder to a brain disorder has opened new avenues for the development of novel therapeutics with neural targets. The advent of 5-HT1B/1D receptor agonists, the triptans, in the 1990s was a crucial step in the modern evolution of treatment. The use of triptans, like their predecessors, is limited by their vasoconstrictor effects, and new development has been slowed by poor academic research funding to identify new targets. The development of agents without vascular effects, such as calcitonin gene-related peptide receptor antagonists and selective serotonin 5-HT1F receptor agonists, will bring more effective treatments to a population currently without migraine-specific options. In addition, advances in understanding migraine pathophysiology have identified new potential pharmacologic targets such as acid-sensing ion channels, glutamate and orexin receptors, nitric oxide synthase (NOS), and transient receptor potential (TRP) channels. Although previous attempts to block subtypes of glutamate receptors, NOS, and TRP channels have had mixed outcomes, new molecules for the same targets are currently under investigation. Finally, an entirely new approach to migraine treatment with noninvasive neuromodulation via transcutaneous neurostimulation or transcranial magnetic stimulation is just beginning. Hopefully in the coming years we will see a new era of migraine therapy, with multiple classes of better-tolerated, more effective agents targeting diverse yet specific migraine mechanisms.