[Review of the target for the deep brain stimulation of chronic cluster headache]. / Revision de la diana para la estimulacion cerebral profunda de la cefalea en racimos cronica.

Cluster headache is included in the group of trigeminal autonomic cephalalgias. Although the pathophysiology of cluster headache has not yet been sufficiently established, the theory of a central origin tells us that this headache is produced by hypothalamic dysfunction. More than 50 patients have been treated with deep brain stimulation of the posterior nucleus of the hypothalamus from 2001. The results show clinical improvement in more than 60% of the cases, opening a promising issue for the treatment of the cluster headache persistent after medical treatment. The surgical target that have been used until now is based on the origin of the cluster headache in the hypothalamic dysfunction. Nevertheless, It has still some open questions as the lack of proving the posterior nucleus of the hypothalamus is the real origin of the cluster headache, the lack of consensus about the anatomy of the surgical target and the variability of the structures stimulated with the surgery. The aim of this article is a review of the target used and propose another surgical target based on physiopathological concepts to explain the improvement with the deep brain stimulation in these patients.

Connectivity of an effective hypothalamic surgical target for cluster headache.

The purpose of this study was to look at the connectivity of the posterior inferior hypothalamus in a patient implanted with a deep brain stimulating electrode using probabilistic tractography in conjunction with postoperative MRI scans. In a patient with chronic cluster headache we implanted a deep brain stimulating electrode into the ipsilateral postero-medial hypothalamus to successfully control his pain. To explore the connectivity, we used the surgical target from the postoperative MRI scan as a seed for probabilistic tractography, which was then linked to diffusion weighted imaging data acquired in a group of healthy control subjects. We found highly consistent connections with the reticular nucleus and cerebellum. In some subjects, connections were also seen with the parietal cortices, and the inferior medial frontal gyrus. Our results illustrate important anatomical connections that may explain the functional changes associated with cluster headaches and elucidate possible mechanisms responsible for triggering attacks.

Deep brain stimulation in craniofacial pain: seven years' experience.

Cluster headache (CH) is a primary headache with excruciatingly painful attacks that are strictly unilateral. About 10% of cases experience no significant remission, and about 15% of these do not respond to medication, so surgery is considered. Neuroimaging studies show that the posterior inferior hypothalamus is activated during CH attacks and is plausibly the CH generator. We report on 16 chronic CH patients, with headaches refractory to all medication, who received long-term hypothalamic stimulation following electrode implant to the posterior inferior hypothalamus. After a mean follow-up of 23 months, a persistent pain-free to almost pain-free state was achieved in 13/16 patients (15/18 implants; 83.3%) a mean of 42 days (range 1-86 days) after monopolar stimulation initiation. Ten patients (11 implants) are completely pain-free. A common side effect was transient diplopia, which limited stimulation amplitude. In one patient, a small non-symptomatic haemorrhage into the 3rd ventricle occurred following implant, but regressed 24 h later. Persistent side effects are absent except in one patient with bilateral stimulation, in whom stimulation was stopped to resolve vertigo and worsened bradycardia, but was resumed later without further problems. Hypothalamic stimulation is an effective, safe and well tolerated treatment for chronic drug-refractory CH. It appears as a valid alternative to destructive surgical modalities, and has the additional advantage of being reversible.

Conditional CRF receptor 1 knockout mice show altered neuronal activation pattern to mild anxiogenic challenge.

RATIONALE: Regional-specific corticotropin-releasing factor receptor 1 (CRF-R1) knockout mice have been generated recently as a tool to dissociate CNS functions modulated by this receptor. In these mice, CRF-R1 function is postnatally inactivated in the anterior forebrain including limbic brain structures but not in the pituitary leading to normal activity of the hypothalamic-pituitary-adrenocortical (HPA) axis under basal conditions and reduced anxiety-related behavior in the light-dark box and the elevated plus maze (EPM) as compared to wild-type (WT) mice (Müller et al., Nat Neurosci 6:1100-1107, 2003). OBJECTIVE: To identify neurobiological correlates underlying this reduced anxiety-like behavior, the expression of c-Fos, an established marker for neuronal activation, which was examined in response to a mild anxiogenic challenge. MATERIALS AND METHODS: Mice were placed for 10 min on the open arm (OA) of the EPM, and regional c-Fos expression was investigated by immunohistochemistry. RESULTS: OA exposure enhanced c-Fos expression in both conditional CRF-R1 knockout and WT mice in a number of brain areas (39 of 55 quantified), including cortical, limbic, thalamic, hypothalamic, and hindbrain regions. The c-Fos response in conditional CRF-R1 knockout animals was reduced in a restricted subset of activated neurons (4 out of 39 regions) located in the medial amygdala, ventral lateral septum, prelimbic cortex, and dorsomedial hypothalamus. CONCLUSIONS: These results underline the importance of limbic CRF-R1 in modulating anxiety-related behavior and suggest that reduced neuronal activation in the identified limbic and hypothalamic key structures of the anxiety circuitry may mediate or contribute to the anxiolytic-like phenotype observed in mice with region-specific deletion of forebrain CRF-R1.

Localization and developmental pattern of vasoactive intestinal polypeptide binding sites in the human hypothalamus.

Using a quantitative in vitro autoradiographic approach, vasoactive intestinal polypeptide (VIP) binding site densities were compared in the post-mortem hypothalamus of human neonate/infant and adult. The densities were similar during development in most of the hypothalamic nuclei and areas examined underlying the stability of 125I-VIP binding sites in the post-mortem hypothalamus of young and adult individuals. However, the ventral part of the medial preoptic area, the medial, lateral, and supramammillary nuclei were characterized by an increase of 125I-VIP binding with age. In young and adult individuals, the highest densities of hypothalamic 125I-VIP binding sites were detected in the supraoptic and infundibular nuclei; the ependyma; the organum vasculosum of the lamina terminalis; the horizontal limb of the diagonal band of Broca; the ventral part of the medial preoptic area (in adult); the suprachiasmatic, paraventricular, and periventricular nuclei; and the medial and lateral mammillary nuclei in adult. Moderate densities were found in the vertical limb of the diagonal band of Broca, the bed nucleus of the stria terminalis, the ventral part of the medial preoptic area in neonate/infant, the medial and lateral mammillary nuclei in neonate/infant, the supramammillary nucleus in adult, the dorsal hypothalamic area, and the ventromedial nucleus. Low to moderate binding site densities were observed in the other hypothalamic regions of young or adult individuals. The nonspecific binding ranged from 15% of the total binding in the anterior hypothalamus to 20% in the mediobasal and posterior hypothalamic levels. Taken together, these results provide evidence for a large distribution of VIP binding sites in neonate/infant and adult human hypothalamus suggesting the implication of VIP in the development of this brain structure and the maintenance of its various functions.

Central dopaminergic neurons in tilapia: effects of gonadectomy and hypothalamic lesion.

The effects of gonadectomy, testosterone and estrogen on the dopamine (DA) neurons were examined by measuring the concentrations of DA and 3,4-dihydroxyphenylacetic acid (DOPAC) in the brain and pituitary of male tilapia. The tuberal area and the pituitary had significantly high levels of DA and low levels of DOPAC, indicating the existence of a rich dopaminergic innervation in these areas. Gonadectomy and sex steroid replacement had no effect on DA and DOPAC levels. Preoptic lesions (14 days survival period) significantly increased DA levels of the pituitary, indicating a possible existence of a preoptico-hypophysial neural system that inhibits pituitary DA synthesis in tilapia. The lack of effect by preoptic (4 days survival period) and posterior hypothalamic lesions on the DA content of the pituitary indicates the absence of dopaminergic innervation of the pituitary by the preoptic and the posterior hypothalamus. Instead, the overall results do suggest the anterior periventricular area as a possible source of pituitary dopaminergic innervation.

Antagonism of central pressor response to angiotensin II by alpha-human atrial natriuretic polypeptide at the preoptic area and posterior hypothalamus in rats.

Effects of alpha-human atrial natriuretic polypeptides (alpha-hANP) on pressor responses to angiotensin II (AII) were assessed at the preoptic area, posterior hypothalamus and central amygdaloid nucleus (ACE) in spontaneously hypertensive (SHR) and control normotensive Wistar-Kyoto (WKY) rats. Angiotensin II, administered intracerebroventricularly, at a dose of 100 ng produced a marked pressor response in hypertensive, as well as in normotensive rats and the response was potentiated in hypertensive rats. The response was antagonized in a dose-dependent manner by administration of alpha-hANP into the preoptic area and posterior hypothalamus but not to the amygdaloid nucleus. The antagonism was more marked in hypertensive than in normotensive rats. Angiotensin II, when injected directly to the preoptic area at a small dose of 10 ng similarly evoked a marked pressor response, which was augmented in hypertensive rats. This response was also antagonized by coadministration of alpha-hANP to the preoptic area in hypertensive but not in normotensive rats. The results suggest that the antagonistic relationship between ANP and AII exists at the preoptic area and posterior hypothalamus, probably implying that the activity of the ANP and AII systems in brain play a role in centrally controlling the cardiovascular system and is altered at these areas in genetically hypertensive rats.

The hypothalamus: anatomy and functions.

The neuroanatomy of the human hypothalamus is reviewed with special interest focused on its neuroendocrine role. The magnocellular neurons in the supraoptic and paraventricular nuclei are the site of synthesis of the nonapeptides antidiuretic hormone and oxytocin and their carriers, the neurophysins. They are in close relation with the posterior lobe of the pituitary which contains their axonal neurosecretory endings. The parvocellular neurons are scattered around the third ventricle, from the preoptic area towards the infundibulum. They control the adenohypophysis by the releasing hormones for thyrotropin (TRH), luteinizing hormone (LHGR), growth hormone (GHRH) and the inhibiting factor for growth hormone (somatostatin or SRIF) and prolactin (PIH). The mapping of the various hypothalamic structures responsible for these syntheses is still a problem although it progresses thanks to new techniques of immunocytochemistry. Recent so-called "hypothalamic" hormones like TRH and somatostatin for instance have been identified outside the hypothalamus. The posterior hypothalamus with other parts of the brain: the medial forebrain non myelinated bundle, in the lateral hypothalamus, connects the preoptic region to the midbrain. The stria terminalis connects the amygdala with the hypothalamus. Fibers of retinal origin terminate in the suprachiasmatic nuclei.

[Projections of the posterior region of the hypothalamus into its medial, anterior and lateral region]. / O proektsiiakh zadnei oblasti gipotalamusa v ego medial'nuiu, peredniuiu i lateral'nuiu oblasti.

Effect of stimulation of the lateral and medial supramammillary areas of the hypothalamus was studied in acute experiments on rabbits. The firing of neurons was recorded in the anterior, lateral, dorsal medial and ventral medial hypothalamic areas. Single pulse stimulation of the medial area of the posterior hypothalamus caused changes in discharge rate for 44% of neurons and the stimulation of the lateral area for 35% of the examined neurons. Repetitive stimulation resulted in changes of the discharge rate in 57% of neurons during stimulation of the lateral and in 74% of the medial supramammillary area. Most neurons responded by excitation. The data obtained are discussed from the view point of the role of posterior hypothalamus in the regulation of the adenohypophysis functions.