Involvement of the ipsilateral-to-the-pain anterior-superior hypothalamic subunit in chronic cluster headache.

BACKGROUND: Despite hypothalamus has long being considered to be involved in the pathophysiology of cluster headache, the inconsistencies of previous neuroimaging studies and a limited understanding of the hypothalamic areas involved, impede a comprehensive interpretation of its involvement in this condition. METHODS: We used an automated algorithm to extract hypothalamic subunit volumes from 105 cluster headache patients (57 chronic and 48 episodic) and 59 healthy individuals; after correcting the measures for the respective intracranial volumes, we performed the relevant comparisons employing logist regression models. Only for subunits that emerged as abnormal, we calculated their correlation with the years of illness and the number of headache attacks per day, and the effects of lithium treatment. As a post-hoc approach, using the 7 T resting-state fMRI dataset from the Human Connectome Project, we investigated whether the observed abnormal subunit, comprising the paraventricular nucleus and preoptic area, shows robust functional connectivity with the mesocorticolimbic system, which is known to be modulated by oxytocin neurons in the paraventricular nucleus and that is is abnormal in chronic cluster headache patients. RESULTS: Patients with chronic (but not episodic) cluster headache, compared to control participants, present an increased volume of the anterior-superior hypothalamic subunit ipsilateral to the pain, which, remarkably, also correlates significantly with the number of daily attacks. The post-hoc approach showed that this hypothalamic area presents robust functional connectivity with the mesocorticolimbic system under physiological conditions. No evidence of the effects of lithium treatment on this abnormal subunit was found. CONCLUSIONS: We identified the ipsilateral-to-the-pain antero-superior subunit, where the paraventricular nucleus and preoptic area are located, as the key hypothalamic region of the pathophysiology of chronic cluster headache. The significant correlation between the volume of this area and the number of daily attacks crucially reinforces this interpretation. The well-known roles of the paraventricular nucleus in coordinating autonomic and neuroendocrine flow in stress adaptation and modulation of trigeminovascular mechanisms offer important insights into the understanding of the pathophysiology of cluster headache.

Burden of headache in a HIV-positive population of sub-Saharan Africa.

BACKGROUND: About 26 million people are living with HIV in sub-Saharan Africa. The DREAM programme in sub-Saharan Africa provides free healthcare for HIV/AIDS and a range of chronic non-communicable diseases. HIV is a risk factor for neurological non-communicable diseases including stroke and epilepsy, which themselves are associated with headache, and HIV may be a direct risk factor for headache. We investigated the prevalence and burden of headache in a HIV+ population in sub-Saharan Africa. METHODS: At the DREAM Centre in Blantyre, Malawi, a low-income country with a population of 19 million and 9.2% HIV prevalence, a structured questionnaire was administered by a trained lay interviewer to consecutively attending HIV+ patients aged 6-65 years. All were monitored with regular viral load detection. RESULTS: Of 513 eligible patients invited, 498 were included (mean age 34.1 ± 12.8 years; 72% females; 15 declined). All were on antiretroviral treatment, with viral load undetectable in 83.9%. The 1-year prevalence of headache was 80.3% (females 83.6%, males 71.9%); 3.8% had ≥15 headache days/month, 1.4% had probable medication-overuse headache. Mean overall headache frequency was 4.4 ± 5.4 days/month. Those reporting headache lost means of 2.3% of paid workdays and 3.3% of household workdays because of headache. Only one third had sought advice for their headache. CONCLUSIONS: Headache is very prevalent among HIV+ patients in Malawi, imposing additional burden and costs on individuals and the community. Management of headache disorders should be implemented in HIV centres, as it is for other chronic non-communicable diseases.

Mesocorticolimbic system abnormalities in chronic cluster headache patients: A neural signature?

BACKGROUND: Converging evidence suggests that anatomical and functional mesocorticolimbic abnormalities support the chronicization of pain disorders. METHODS: We mapped structural and functional alterations of the mesocorticolimbic system in a sample of chronic cluster headache patients (n = 28) in comparison to age and sex-matched healthy individuals (n = 28) employing structural MRI and resting-state functional MRI. RESULTS: Univariate logistic regression models showed that several of the examined structures/areas (i.e., the bilateral nucleus accumbens, ventral diencephalon, hippocampus, and frontal pole, and the right amygdala) differentiated chronic cluster headache patients from healthy individuals (p < 0.05, uncorrected). Specifically, all the significant structures/areas had increased volumes in chronic cluster headache patients compared to healthy individuals. The examination of the groups suffering from left and right-sided cranial attacks showed a lateralization effect: ipsilateral to the pain ventral diencephalic regions and contralateral to the pain nucleus accumbens discriminated chronic cluster headache patients from healthy individuals. The resting-state functional MRI data analyses showed that chronic cluster headache patients compared to CTRL individuals present robust reduced functional connectivity in the right frontal pole-right amygdala pathway (p < 0.05, FDR-corrected). CONCLUSION: Our results showed that chronic cluster headache patients present anatomical and functional maladaptation of the mesocorticolimbic system, with functional data indicating a possible prefrontal areas' failure to modulate the mesolimbic structures. These results were opposite to what we hypothesized based on the previous literature on chronic pain conditions.Future studies should assess whether the observed mesocorticolimbic abnormalities are due to the neuroprotective effects of the assumed medications, or to the frequent comorbidity of CH with neuropsychiatric disorders or if they are a genuine neural signature of CH and/or chronic cluster headache condition.

Chronic cluster headache: A study of the telencephalic and cerebellar cortical thickness.

PURPOSE: Previous studies on brain morphological alterations in chronic cluster headache revealed inconsistent findings. METHOD: The present cross-sectional explorative study determined telencephalic and cerebellar cortex thickness alterations in a relatively wide sample of chronic cluster headache patients (n = 28) comparing them to matched healthy individuals. RESULTS: The combination of two highly robust state-of-the-art approaches for thickness estimation (Freesurfer, CERES), strengthened by functional characterization of the identified abnormal regions, revealed four main results: chronic cluster headache patients show 1) cortical thinning in the right middle cingulate cortex, left posterior insula, and anterior cerebellar lobe, regions involved in nociception's sensory and sensory-motor aspects and possibly in autonomic functions; 2) cortical thinning in the left anterior superior temporal sulcus and the left collateral/lingual sulcus, suggesting neuroplastic maladaptation in areas possibly involved in social cognition, which may promote psychiatric comorbidity; 3) abnormal functional connectivity among some of these identified telencephalic areas; 4) the identified telencephalic areas of cortical thinning present robust interaction, as indicated by the functional connectivity results, with the left posterior insula possibly playing a pivotal role. CONCLUSION: The reported results constitute a coherent and robust picture of the chronic cluster headache brain. Our study paves the way for hypothesis-driven studies that might impact our understanding of the pathophysiology of this condition.

Cluster headache not responsive to sumatriptan: A retrospective study.

INTRODUCTION: Subcutaneous sumatriptan, a 5HT1B/1D agonist, is the most effective drug in cluster headache acute treatment. About 25% of the patients do not respond to subcutaneous sumatriptan; the reasons for this are unknown. In this study, we compare clinical characteristics of cluster headache patients responding and non-responding to subcutaneous sumatriptan. METHODS: We retrospectively investigated the clinical records of 277 cluster headache patients. Patients reporting repeated satisfactory response to subcutaneous sumatriptan within 15 minutes were considered responders. RESULTS: Of 206 cluster headache patients who had used subcutaneous sumatriptan (mean age 45.6, 16% females, 48% chronic), 91% were responders, and 9% non-responders. Compared to responders, non-responders had longer and more frequent attacks: 60 (median; IQR 38-90) vs. 100 (60-120) minutes (p = 0.028), 4 (2.5-5) vs. 3 (2-4) attacks/day (p = 0.024). No other difference was found. CONCLUSIONS: In cluster headache attacks with long duration and high frequency, pain mechanisms not involving 5HT1B/1D receptors may play a more relevant role.

Cluster headache and TACs: state of the art.

Cluster headache (CH), paroxysmal hemicrania (PH), short-lasting unilateral neuralgiform headache attacks (including SUNCT and SUNA), and hemicrania continua (HC) compose the group of trigeminal autonomic cephalalgias (TACs). Here, we review the recent advances in the field and summarize the current knowledge about the origin of these headaches. Similar to the other primary headaches, the pathogenesis is still much obscure. However, advances are being made in both animal models and humans studies. Three structures clearly appear to be crucial in the pathophysiology of TACs: the trigeminal nerve, the facial parasympathetic system, and the hypothalamus. The physiologic and pathologic functioning of each of these elements and their interactions is being progressively clarified, but critical questions are still open.

Anti-CGRP in cluster headache therapy.

Cluster headache is a primary headache characterized by recurring excruciating pain and autonomic signs, leading to significant suffering and derangement of patients' life. Efficacious new preventive treatments are needed. The pathophysiology of cluster headache comprises mechanisms both in the peripheral and central nervous system, involving the trigeminovascular system, the trigemino-parasympathetic reflex, and central modulating systems. Calcitonin gene-related peptide (CGRP) has an active role throughout these systems. It is increased during spontaneous and provoked attacks, and itself can induce attacks. Recently, drugs against this neuropeptide have been developed for the treatment of different headache disorders. In particular, monoclonal antibodies vs CGRP as galcanezumab and fremanezumab have been tested in cluster headache, with promising results for the episodic form. Considering the relevance of central mechanisms in CH, drugs interfering with the CGRP pathway in the central nervous system can enlarge the therapeutic armamentarium against this highly disabling condition.

Cluster headache: insights from resting-state functional magnetic resonance imaging.

The comprehension of cluster headache (CH) has greatly benefited from the tremendous progress of the neuroimaging techniques over the last 20 years. Since the pioneering study of May et al. (1998), the neuroimaging results have indeed revolutionized the conception of this disease, now considered as a dysfunction of the central nervous system. Clinical, neuroendocrinological, and neuroimaging studies strongly suggested the involvement of the hypothalamus as the generator of cluster headache attacks. However, the latency of the improvement and the inefficacy of the hypothalamic deep brain stimulation (DBS) in the acute phase suggested that the hypothalamus might play a modulating role, pointing to the presence of some dysfunctional brain networks, normalized or modulated by the DBS. Despite the great importance of possible dysfunctional hypothalamic networks in cluster headache pathophysiology, only quite recently the scientific community has begun to explore the functional connectivity of these circuits using resting-state functional magnetic resonance imaging. This is a neuroimaging technique extensively employed to investigate the functional connectivity among separated regions of the brain at rest in the low-frequency domain (< 0.1 Hz). Here, we present a review of the few resting-state functional magnetic resonance imaging studies investigating the hypothalamic network contributing to a deeper comprehension of this neurological disorder. These studies seem to demonstrate that both the hypothalamus and the diencephalic-mesencephalic junction regions might play an important role in the pathophysiology of CH. However, future studies are needed to confirm the results and to clarify if the observed dysfunctional networks are a specific neural fingerprint of the CH pathophysiology or an effect of the severe acute pain. It will be also crucial to clarify the neural pathways of the chronicization of this disorder.

CGRP and migraine from a cardiovascular point of view: what do we expect from blocking CGRP?

Calcitonin gene-related peptide (CGRP) is a neuropeptide with a pivotal role in the pathophysiology of migraine. Blockade of CGRP is a new therapeutic target for patients with migraine. CGRP and its receptors are distributed not only in the central and peripheral nervous system but also in the cardiovascular system, both in blood vessels and in the heart. We reviewed the current evidence on the role of CGRP in the cardiovascular system in order to understand the possible short- and long-term effect of CGRP blockade with monoclonal antibodies in migraineurs.In physiological conditions, CGRP has important vasodilating effects and is thought to protect organs from ischemia. Despite the aforementioned cardiovascular implication, preventive treatment with CGRP antibodies has shown no relevant cardiovascular side effects. Results from long-term trials and from real life are now needed.

Validation of a self-reported instrument to assess work-related difficulties in patients with migraine: the HEADWORK questionnaire.

BACKGROUND: The degree to which work-related difficulties are recognized in headache research is poor and often carried out with inadequate information such as "reduced ability to work as usual", which do not capture at all the variety of difficulties and the factors that impact over them. The aim of this paper is to present the validation of the HEADWORK questionnaire, which addresses the amount and severity of difficulties in work-related tasks and the factors that impact over them. METHODS: We developed a set of items based on a previous literature review and patients' focus groups and tested it on a wide set of patients with episodic and chronic migraine attending eight different Italian headache centers. HEADWORK factor structure was assessed with exploratory and confirmatory factor analysis; internal consistency and construct validity were addressed as well. RESULTS: The validation sample (N = 373) was mostly composed of patients with episodic migraine without aura (64.3%) and of females (81%). Factor analysis retrieved two different scales: "Work-related difficulties", composed of eleven items which explain 67.1% of the total variance, and "Factors contributing to work difficulties", composed of six items which explain 52.1% of the total variance. Both HEADWORK subscales have good measurement properties, with higher scores being associated to higher disability, lower quality of life, lower productivity, higher headache frequency and pain intensity. CONCLUSIONS: HEADWORK is a 17-item, two-scale questionnaire addressing the impact of migraine on work-related difficulties in terms of difficulties in general or specific skills, and the factors contributing to these difficulties, defined as negative impact on work tasks. It can be used to address disability weights for the purpose of calculating the burden of migraine, and to assess the balance between therapeutic and side effects of medication on productivity.

Action mechanisms of Onabotulinum toxin-A: hints for selection of eligible patients.

In the past few decades, the so-feared botulinum toxin has conversely acquired the role of a ever more versatile therapeutic substance, used in an increasing number of pathological situations, including chronic headache and more precisely in the prophylaxis of chronic migraine. The medical use of botulinum toxin allowed to better understand its multiple mechanisms of action. Investigations about the pathophysiology of primary and secondary headaches has shown a series of common biological elements that frequently are also targets of the action of botulinum toxin. These increasing evidences allowed to identify some biochemical, neurophysiological and radiological markers that may be useful in the individuation of patients which probably will respond to the treatment with Onabotulinum toxin-A among chronic migraineurs. These predictors include CGRP plasmatic levels, specific laser-evoked potential responses, peculiar brain MRI and fMRI and characteristic clinical manifestations. Unfortunately, at now, these predictors are still not available for the clinical practice. Furthermore, the better knowledge about biology of headaches and regarding botulinum toxin activities may also help in directing investigations on the possible use of Onabotulinum toxin-A in other headaches different from migraine. This review tries to show in detail these biological mechanisms and their implication in selecting patients eligible for the treatment with Onabotulinum toxin-A.

Does Body Memory Exist? A Review of Models, Approaches and Recent Findings Useful for Neurorehabilitation.

Over the past twenty years, scientific research on body representations has grown significantly, with Body Memory (BM) emerging as a prominent area of interest in neurorehabilitation. Compared to other body representations, BM stands out as one of the most obscure due to the multifaceted nature of the concept of "memory" itself, which includes various aspects (such as implicit vs. explicit, conscious vs. unconscious). The concept of body memory originates from the field of phenomenology and has been developed by research groups studying embodied cognition. In this narrative review, we aim to present compelling evidence from recent studies that explore various definitions and explanatory models of BM. Additionally, we will provide a comprehensive overview of the empirical settings used to examine BM. The results can be categorized into two main areas: (i) how the body influences our memories, and (ii) how memories, in their broadest sense, could generate and/or influence metarepresentations-the ability to reflect on or make inferences about one's own cognitive representations or those of others. We present studies that emphasize the significance of BM in experimental settings involving patients with neurological and psychiatric disorders, ultimately analyzing these findings from an ontogenic perspective.

An Overview of the Bodily Awareness Representation and Interoception: Insights and Progress in the Field of Neurorehabilitation Research.

In the last two decades, the scientific literature on so-called body representations has been increasing, and the notion of body awareness (BA) is particularly interesting for neurorehabilitation. In this article, we present results derived from recent studies on this representation, considering the different definitions and explicative models proposed as well as the empirical settings used to test it, providing an extensive overview of these issues. This article discusses the challenge of understanding how we integrate the sensory experiences of proprioception (knowing where our body is in space) and interoception (sensing internal bodily sensations, like hunger of thirst) with our perception of self. This is a difficult problem to analyze because our awareness of our body is inherently linked to our perspective, since the body is the means through which we interact with the world. Presenting the different viewpoints offered by recent theories on this concern, we highlighted that the neurorehabilitation and psychiatric settings offer two important fields useful for the study of BA because in them it is possible to analyze bodily representations by inducing/observing a controlled discrepancy between dysfunctional content and sensory inputs.