Central effects of erenumab in migraine patients

ObjectiveTo determine whether erenumab, a new monoclonal antibody to the calcitonin gene-related peptide (CGRP) receptor, exerts functional central effects in migraineurs by performing functional imaging scans on patients treated with erenumab.MethodsWe conducted an fMRI study on 27 patients with migraine using a well-established trigeminal nociceptive paradigm, examining patients before and 2 weeks after administration of the CGRP receptor antibody erenumab 70 mg.ResultsComparing both visit days in all patients (n = 27) revealed that erenumab leads to a decrease in activation in the right thalamus (i.e., contralateral to the stimulated side), right middle temporal gyrus, right lingual gyrus, left operculum, and several clusters on both sides of the cerebellum. Furthermore, when responders (n = 9) and nonresponders (n = 8) of the respective same headache state were compared, we found a significant reduction of hypothalamic activation after the administration of erenumab in responders only (t = 4.78; contrast estimate 29.79 [90% confidence interval 19.53–40.05]). This finding of reduced hypothalamic activation was confirmed when absolute headache days was used as a regressor.InterpretationThese findings suggest that erenumab may not be an exclusively peripheral migraine treatment but has additional central effects. Whether this is due to secondary changes after peripheral modulation of sensory input or indeed represents a direct central mode of action is discussed.

Hypothalamic Responses to Cocaine and Food Cues in Individuals with Cocaine Dependence

Background Individuals with cocaine addiction are characterized by under-responsiveness to natural reinforcers. As part of the dopaminergic pathways, the hypothalamus supports motivated behaviors. Rodent studies suggested inter-related roles of the hypothalamus in regulating drug and food intake. However, few studies have investigated hypothalamic responses to drugs and food or related cues in humans. Methods We examined regional responses in 20 cocaine-dependent and 24 healthy control participants exposed to cocaine/food (cocaine dependent) and food (healthy control) vs neutral cues during functional magnetic resonance imaging. We examined the relationship between imaging findings and clinical variables and performed mediation analyses to examine the inter-relationships between cue-related activations, tonic cocaine craving, and recent cocaine use. Results At a corrected threshold, cocaine-dependent participants demonstrated higher activation to cocaine than to food cues in the hypothalamus, inferior parietal cortex, and visual cortex. Cocaine-dependent participants as compared with healthy control participants also demonstrated higher hypothalamic activation to food cues. Further, the extent of these cue-induced hypothalamic activations was correlated with tonic craving, as assessed by the Cocaine Craving Questionnaire, and days of cocaine use in the prior month. In mediation analyses, hypothalamic activation to cocaine and food cues both completely mediated the relationship between the Cocaine Craving Questionnaire score and days of cocaine use in the past month. Conclusions The results were consistent with the proposition that the mechanisms of feeding and drug addiction are inter-linked in the hypothalamus and altered in cocaine addiction. The findings provide new evidence in support of hypothalamic dysfunction in cocaine addiction.

Hypothalamic activation discriminates painful and non-painful initiation of the trigeminal autonomic reflex – an fMRI study

Background The role of the trigeminal autonomic reflex in headache syndromes, such as cluster headache, is undisputed but sparsely investigated. The aim of the present study was therefore, to identify neural correlates that play a role in the initiation of the trigeminal autonomic reflex. We further aimed to discriminate between components of the reflex that are involved in nociceptive compared to non-nociceptive processing. Methods Kinetic Oscillation Stimulation (KOS) in the left nostril was applied in order to provoke autonomic symptoms (e.g. lacrimation) via the trigeminal autonomic reflex in 26 healthy participants using functional magnetic resonance imaging. Unpleasantness and painfulness were assessed on a visual analog scale (VAS), in order to assess the quality of the stimulus (e.g. pain or no pain). Results During non-painful activation, specific regions involved in the trigeminal autonomic reflex became activated, including several brainstem nuclei but also cerebellar and bilateral insular regions. However, when the input leading to activation of the trigeminal autonomic reflex was perceived as painful, activation of the anterior hypothalamus, the locus coeruleus (LC), the ventral posteriomedial nucleus of the thalamus (VPM), as well as an activation of ipsilateral insular regions, was observed. Conclusion Our results suggest the anterior hypothalamus, besides the thalamus and specific brain stem regions, play a significant role in networks that mediate autonomic output (e.g. lacrimation) following trigeminal input, but only if the trigeminal system is activated by a stimulus comprising a painful component.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Regulates the Hypothalamo-Pituitary-Thyroid (HPT) Axis via Type 2 Deiodinase in Male Mice

The hypothalamic activation of thyroid hormones by type 2 deiodinase (D2), catalyzing the conversion of thyroxine to T3, is critical for the proper function of the hypothalamo-pituitary-thyroid (HPT) axis. Regulation of D2 expression in tanycytes alters the activity of the HPT axis. However, signals that regulate D2 expression in tanycytes are poorly understood. The pituitary adenylate cyclase-activating polypeptide (PACAP) increases intracellular cAMP level, a second messenger known to stimulate the DIO2 gene; however, its importance in tanycytes is not completely characterized. Therefore, we tested whether this ubiquitously expressed neuropeptide regulates the HPT axis through stimulation of D2 in tanycytes. PACAP increased the activity of human DIO2 promoter in luciferase reporter assay that was abolished by mutation of cAMP-response element. Furthermore, PAC1R receptor immunoreactivity was identified in hypothalamic tanycytes, suggesting that these D2-expressing cells could be regulated by PACAP. Intracerebroventricular PACAP administration resulted in increased D2 activity in the mediobasal hypothalamus, suppressed Trh expression in the hypothalamic paraventricular nucleus, and decreased Tshb expression in the pituitary demonstrating that PACAP affects the D2-mediated control of the HPT axis. To understand the role of endogenous PACAP in the regulation of HPT axis, the effect of decreased PACAP expression was studied in heterozygous Adcyap1 (PACAP) knockout mice. These animals were hypothyroid that may be the consequence of altered hypothalamic T3 degradation during set-point formation of the HPT axis. In conclusion, PACAP is an endogenous regulator of the HPT axis by affecting T3-mediated negative feedback via cAMP-induced D2 expression of tanycytes.

Cyclic nocturnal awakening: A warning sign of a cluster bout

Introduction Cluster headache is an excruciating unilateral headache with autonomic symptoms whose periodic nocturnal activity, which interrupts sleep, has been attributed to a hypothalamic generator. Case report We describe a patient with a longstanding episodic cluster headache who experienced, on two occasions, a period of nocturnal awakenings without pain or autonomic symptoms, lasting one week before the onset of a cluster bout. Awakenings occurred twice/night at the same hours of impending cluster attacks and had no apparent trigger, being unusual for this patient who had no previous sleep disturbances. Neurological examination and brain imaging were normal. Discussion This case documents two new aspects of cluster headache. It suggests that repeated nocturnal awakenings can be a warning sign of an impending cluster period, a finding that may have therapeutic implications, and also that hypothalamic activation may begin several days before trigemino-autonomic symptoms, thus behaving as a true bout generator.