Posterior Hypothalamic Region Research Articles

Harnessing axonal transport to map reward circuitry: Differing brain-wide projections from medial prefrontal cortical domains.

Neurons project long axons that contact other distant neurons. Neurons in the medial prefrontal cortex project into the limbic system to regulate responses to reward or threat. Diminished neural activity in prefrontal cortex is associated with loss of executive function leading to drug use, yet the specific circuitry that mediate these effects is unknown. Different regions within the medial prefrontal cortex may project to differing limbic system nuclei. Here, we exploited the cell biology of intracellular membrane trafficking, fast axonal transport, to map projections from two adjacent medial prefrontal cortical regions. We used Mn(II), a calcium analog, to trace medial prefrontal cortical projections in the living animal by magnetic resonance imaging (MRI). Mn(II), a contrast agent for MRI, enters neurons through voltage-activated calcium channels and relies on kinesin-1 and amyloid-precursor protein to transport out axons to distal destinations. Aqueous MnCl2 together with fluorescent dextran (3--5nL) was stereotactically injected precisely into two adjacent regions of the medial prefrontal cortex: anterior cingulate area (ACA) or infralimbic/prelimbic (IL/PL) region. Projections were traced, first live by manganese-enhanced MRI (MEMRI) at four time points in 3D, and then after fixation by microscopy. Data-driven unbiased voxel-wise statistical maps of aligned normalized MR images after either ACA or IL/PL injections revealed statistically significant progression of Mn(II) over time into deeper brain regions: dorsal striatum, globus pallidus, amygdala, hypothalamus, substantia nigra, dorsal raphe and locus coeruleus. Quantitative comparisons of these distal accumulations at 24h revealed dramatic differences between ACA and IL/PL injection groups throughout the limbic system, and most particularly in subdomains of the hypothalamus. ACA projections targeted dorsomedial nucleus of the hypothalamus, posterior part of the periventricular region and mammillary body nuclei as well as periaqueductal gray, while IL/PL projections accumulated in anterior hypothalamic areas and lateral hypothalamic nuclei as well as amygdala. As hypothalamic subsegments relay CNS activity to the body, our results suggest new concepts about mind-body relationships and specific roles of distinct yet adjacent medial prefrontal cortical segments. Our MR imaging strategy, when applied to follow other cell biological processes in the living organism, will undoubtedly lead to an expanded perspective on how minute details of cellular processes influence whole body health and wellbeing.

Changes in pituitary gonadotropin subunits and hypothalamic Kiss-1 gene expression by administration of sex steroids in ovary-intact female rats.

We examined how the sex steroids influence the synthesis of gonadotropins. The effects of sex steroids estradiol (E2), progesterone (P4), and dihydrotestosterone (DHT) in pituitary gonadotroph cell model (LβT2 cells) in vitro and ovary-intact rats in vivo were examined. The effects of sex steroids on Kiss1 gene expression in the hypothalamus were also examined in ovary-intact rats. In LβT2 cells, E2 increased common glycoprotein alpha (Cga) and luteinizing hormone beta (Lhb) subunit promoter activity as well as their mRNA expression. Although gonadotropin subunit promoter activity was not modulated by P4, Cga and Lhb mRNA expression was increased by P4. DHT inhibited Cga and Lhb mRNA expression with a concomitant decrease in their promoter activity. During the 2-week administration of exogenous E2 to ovary-intact rats, the estrous cycle determined by vaginal smears was disrupted. P4 or DHT administration completely eliminated the estrous cycle. Protein expression of all three gonadotropin subunits within the pituitary gland was inhibited by E2 or P4 treatment in vivo; however, DHT reduced Cga expression but did not modulate Lhb or follicle-stimulating hormone beta subunit expression. E2 administration significantly repressed Kiss1 mRNA expression in a posterior hypothalamic region that included the arcuate nucleus. P4 and DHT did not modulate Kiss1 mRNA expression in this region. In contrast, P4 administration significantly inhibited Kiss1 mRNA expression in the anterior region of the hypothalamus that included the anteroventral periventricular nucleus. The expression of gonadotropin-releasing hormone (Gnrh) mRNA in the anterior hypothalamic region, where the preoptic area is located, appeared to be decreased by treatment with E2 and P4. Our findings suggest that sex steroids have different effects in the hypothalamus and pituitary gland.

Determination of steady-state transcriptome modifications associated with repeated homotypic stress in the rat rostral posterior hypothalamic region.

Chronic stress is epidemiologically correlated with physical and psychiatric disorders. Whereas many animal models of chronic stress induce symptoms of psychopathology, repeated homotypic stressors to moderate intensity stimuli typically reduce stress-related responses with fewer, if any, pathological symptoms. Recent results indicate that the rostral posterior hypothalamic (rPH) region is a significant component of the brain circuitry underlying response reductions (habituation) associated with repeated homotypic stress. To test whether posterior hypothalamic transcriptional regulation associates with the neuroendocrine modifications induced by repeated homotypic stress, RNA-seq was performed in the rPH dissected from adult male rats that experienced either no stress, 1, 3, or 7 stressful loud noise exposures. Plasma samples displayed reliable increases of corticosterone in all stressed groups, with the smallest increase in the group exposed to 7 loud noises, indicating significant habituation compared to the other stressed groups. While few or no differentially expressed genes were detected 24-h after one or three loud noise exposures, relatively large numbers of transcripts were differentially expressed between the group exposed to 7 loud noises when compared to the control or 3-stress groups, respectively, which correlated with the corticosterone response habituation observed. Gene ontology analyses indicated multiple significant functional terms related to neuron differentiation, neural membrane potential, pre- and post-synaptic elements, chemical synaptic transmission, vesicles, axon guidance and projection, glutamatergic and GABAergic neurotransmission. Some of the differentially expressed genes (Myt1l, Zmat4, Dlx6, Csrnp3) encode transcription factors that were independently predicted by transcription factor enrichment analysis to target other differentially regulated genes in this study. A similar experiment employing in situ hybridization histochemical analysis in additional animals validated the direction of change of the 5 transcripts investigated (Camk4, Gabrb2, Gad1, Grin2a and Slc32a) with a high level of temporal and regional specificity for the rPH. In aggregate, the results suggest that distinct patterns of gene regulation are obtained in response to a repeated homotypic stress regimen; they also point to a significant reorganization of the rPH region that may critically contribute to the phenotypic modifications associated with repeated homotypic stress habituation.

Oxytocin signaling in the posterior hypothalamus prevents hyperphagic obesity in mice.

Decades of studies have revealed molecular and neural circuit bases for body weight homeostasis. Neural hormone oxytocin (Oxt) has received attention in this context because it is produced by neurons in the paraventricular hypothalamic nucleus (PVH), a known output center of hypothalamic regulation of appetite. Oxt has an anorexigenic effect, as shown in human studies, and can mediate satiety signals in rodents. However, the function of Oxt signaling in the physiological regulation of appetite has remained in question, because whole-body knockout (KO) of Oxt or Oxt receptor (Oxtr) has little effect on food intake. We herein show that acute conditional KO (cKO) of Oxt selectively in the adult PVH, but not in the supraoptic nucleus, markedly increases body weight and food intake, with an elevated level of plasma triglyceride and leptin. Intraperitoneal administration of Oxt rescues the hyperphagic phenotype of the PVH Oxt cKO model. Furthermore, we show that cKO of Oxtr selectively in the posterior hypothalamic regions, especially the arcuate hypothalamic nucleus, a primary center for appetite regulations, phenocopies hyperphagic obesity. Collectively, these data reveal that Oxt signaling in the arcuate nucleus suppresses excessive food intake.

Seeking motivation and reward: Roles of dopamine, hippocampus, and supramammillo-septal pathway.

Reinforcement learning and goal-seeking behavior are thought to be mediated by midbrain dopamine neurons. However, little is known about neural substrates of curiosity and exploratory behavior, which occur in the absence of clear goal or reward. This is despite behavioral scientists having long suggested that curiosity and exploratory behaviors are regulated by an innate drive. We refer to such behavior as information-seeking behavior and propose 1) key neural substrates and 2) the concept of environment prediction error as a framework to understand information-seeking processes. The cognitive aspect of information-seeking behavior, including the perception of salience and uncertainty, involves, in part, the pathways from the posterior hypothalamic supramammillary region to the hippocampal formation. The vigor of such behavior is modulated by the following: supramammillary glutamatergic neurons; their projections to medial septal glutamatergic neurons; and the projections of medial septal glutamatergic neurons to ventral tegmental dopaminergic neurons. Phasic responses of dopaminergic neurons are characterized as signaling potentially important stimuli rather than rewards. This paper describes how novel stimuli and uncertainty trigger seeking motivation and how these neural substrates modulate information-seeking behavior.

Understanding the Significance of the Hypothalamic Nature of the Subthalamic Nucleus.

The subthalamic nucleus (STN) is an essential component of the basal ganglia and has long been considered to be a part of the ventral thalamus. However, recent neurodevelopmental data indicated that this nucleus is of hypothalamic origin which is now commonly acknowledged. In this work, we aimed to verify whether the inclusion of the STN in the hypothalamus could influence the way we understand and conduct research on the organization of the whole ventral and posterior diencephalon. Developmental and neurochemical data indicate that the STN is part of a larger glutamatergic posterior hypothalamic region that includes the premammillary and mammillary nuclei. The main anatomic characteristic common to this region involves the convergent cortical and pallidal projections that it receives, which is based on the model of the hyperdirect and indirect pathways to the STN. This whole posterior hypothalamic region is then integrated into distinct functional networks that interact with the ventral mesencephalon to adjust behavior depending on external and internal contexts.

Chapter 7 - Posterior hypothalamus as a target in the treatment of aggression: From lesioning to deep brain stimulation

Intermittent explosive disorder can be described as a severe "affective aggression" condition, for which drugs and other supportive therapies are not fully effective. In the first half of the 19th century, experimental studies progressively increased knowledge of aggressive disorders. A neurobiologic approach revealed the posterior hypothalamic region as a key structure for the modulation of aggression. In the 1960s, patients with severe aggressive disorder, frequently associated with intellectual disability, were treated by bilateral stereotactic lesioning of the posterior hypothalamic area, with efficacy. This therapy was later abandoned because of issues related to the misuse of psychosurgery. In the last 2 decades, however, the same diencephalic target has been selected for the reversible treatment by deep brain stimulation, with success. This chapter presents a comprehensive approach to posterior hypothalamic surgery for the treatment of severely aggressive patients and discusses the experimental steps that allowed this surgical target to be selected. Surgical experiences are reported, together with considerations on target features and related encephalic circuits.

Electrophysiology and Structural Connectivity of the Posterior Hypothalamic Region: Much to Learn From a Rare Indication of Deep Brain Stimulation.

Cluster headache (CH) is among the most common and debilitating autonomic cephalalgias. We characterize clinical outcomes of deep brain stimulation (DBS) to the posterior hypothalamic region through a novel analysis of the electrophysiological topography and tractography-based structural connectivity. The left posterior hypothalamus was targeted ipsilateral to the refractory CH symptoms. Intraoperatively, field potentials were captured in 1 mm depth increments. Whole-brain probabilistic tractography was conducted to assess the structural connectivity of the estimated volume of activated tissue (VAT) associated with therapeutic response. Stimulation of the posterior hypothalamic region led to the resolution of CH symptoms, and this benefit has persisted for 1.5-years post-surgically. Active contacts were within the posterior hypothalamus and dorsoposterior border of the ventral anterior thalamus (VAp). Delta- (3 Hz) and alpha-band (8 Hz) powers increased and peaked with proximity to the posterior hypothalamus. In the posterior hypothalamus, the delta-band phase was coupled to beta-band amplitude, the latter of which has been shown to increase during CH attacks. Finally, we identified that the VAT encompassing these regions had a high proportion of streamlines of pain processing regions, including the insula, anterior cingulate gyrus, inferior parietal lobe, precentral gyrus, and the brainstem. Our unique case study of posterior hypothalamic region DBS supports durable efficacy and provides a platform using electrophysiological topography and structural connectivity, to improve mechanistic understanding of CH and this promising therapy.

Deep brain stimulation of chronic cluster headaches: Posterior hypothalamus, ventral tegmentum and beyond.

We present long-term follow-up results and analysis of stimulation sites of a prospective cohort study of six patients with chronic cluster headaches undergoing deep brain stimulation of the ipsilateral posterior hypothalamic region. The primary endpoint was the postoperative change in the composite headache severity score "headache load" after 12 months of chronic stimulation. Secondary endpoints were the changes in headache attack frequency, headache attack duration and headache intensity, quality of life measures at 12, 24, and 48 months following surgery. Stimulating contact positions were analysed and projected onto the steroetactic atlas of Schaltenbrand and Wahren. There was a significant reduction of headache load of over 93% on average at 12 months postoperatively that persisted over the follow-up period of 48 months (p = 0.0041) and that was accompanied by a significant increase of reported quality of life measures (p = 0.03). Anatomical analysis revealed that individual stimulating electrodes were located in the red nucleus, posterior hypothalamic region, mesencephalic pretectal area and centromedian nucleus of the thalamus. Our findings confirming long-term effectiveness of deep brain stimulation for chronic cluster headaches suggest that the neuroanatomical substrate of deep brain stimulation-induced headache relief is probably not restricted to the posterior hypothalamic area but encompasses a more widespread area.

Short-lasting unilateral neuralgiform headache attacks: where is the headache generator?

This scientific commentary refers to ‘Ventral tegmental area deep brain stimulation in refractory short-lasting unilateral neuralgiform headache attacks’, by Miller et al. (doi:10.1093/brain/aww204) . Short-lasting unilateral neuralgiform headache attacks last seconds to minutes, occur up to hundreds of times a day and are usually associated with prominent lacrimation and redness of the ipsilateral eye. The condition is classified in the headache group known as the trigeminal autonomic cephalalgias, together with cluster headache, paroxysmal hemicrania and hemicrania continua, all of them characterized by strictly unilateral headaches associated with prominent craniofacial autonomic phenomena, usually involving the eye and the nostril (Headache Classification Committee of the International Headache Society, 2013). Activation of the posterior hypothalamic region during the pain has been shown in short-lasting unilateral neuralgiform headache attacks (May et al. , 1999) as well in other trigeminal autonomic cephalalgias (for review see May, 2009), leading to the suggestion that this is the location of the headache generator. Hypothalamic involvement was first proposed in cluster headache, based on the assumption that involvement of the biological clock in the hypothalamus could explain the clockwork regularity of single headache attacks and the typical seasonal recurrence of bouts, thereafter reinforced by altered hypothalamo-pituitary axis responses and abnormal circadian production of certain hormones. The hypothalamic hypothesis led to the successful use of deep brain stimulation (DBS) of the posterior hypothalamus to treat otherwise intractable chronic cluster headache (Leone et al. , 2001). Hypothalamic DBS was subsequently also used successfully to treat intractable short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) (Leone et al. , 2005). In this issue of Brain , Miller et al. present the results from the largest group of patients suffering from intractable short-lasting unilateral neuralgiform headache attacks to be successfully treated with DBS (Miller et al. , …

Ventral tegmental area deep brain stimulation in refractory short-lasting unilateral neuralgiform headache attacks.

SEE LEONE AND PROIETTI CECCHINI DOI101093/AWW233 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Short-lasting unilateral neuralgiform headache attacks are primary headache disorders characterized by short-lasting attacks of unilateral pain accompanied by autonomic features. A small minority are refractory to medical treatment. Neuroimaging studies have suggested a role of the posterior hypothalamic region in their pathogenesis. Previous case reports on deep brain stimulation of this region, now understood to be the ventral tegmental area, for this disorder are limited to a total of three patients. We present a case series of 11 new patients treated with ventral tegmental area deep brain stimulation in an uncontrolled, open-label prospective observational study. Eleven patients with refractory short-lasting unilateral neuralgiform headache attacks underwent ipsilateral ventral tegmental area deep brain stimulation in a specialist unit. All patients had failed, or been denied access to, occipital nerve stimulation within the UK's National Health Service. Primary endpoint was change in mean daily attack frequency at final follow-up. Secondary outcomes included attack severity, attack duration, headache load (a composite score of attack frequency, severity and duration), quality of life measures, disability and affective scores. Information was also collected on adverse events. Eleven patients (six male) with a median age of 50 years (range 26-67) were implanted between 2009 and 2014. Median follow-up was 29 months (range 7-63). At final follow-up the median improvement in daily attack frequency was 78% (interquartile range 33%). Response rate (defined as at least a 50% improvement in daily attack frequency) was 82% and four patients were rendered pain-free for prolonged periods of time. Headache load improved by 99% (interquartile range 52%). Improvements were observed in a number of quality of life, disability and affect measures. Adverse events included mild incision site pain, subcutaneous displacement of the implantable pulse generator, transient oscillopsia and minor wound infection. One patient required removal of the system due to wound infection. Ventral tegmental area deep brain stimulation may be an effective treatment option for refractory short-lasting unilateral neuralgiform headache attack patients who have failed other therapies.

Deep-brain photoreceptors (DBPs) involved in the photoperiodic gonadal response in an avian species, Gallus gallus

Three primitive photoreceptors [melanopsin (Opn4), neuropsin/opsin5 (Opn5) and vertebrate ancient opsin (VAOpn)] were reported as possible avian deep-brain photoreceptors (DBPs) involved in the perception of photoperiodic information affecting the onset and development of reproduction. The objective of this study was to determine the effect of long-day photostimulation and/or sulfamethazine treatment (SMZ, a compound known to advance light-induced testes development) on gene expression of DBPs and key hypothalamic and pituitary genes involved in avian reproductive function. Two-week old chicks were randomly selected into four experimental groups: short-day control (SC, LD8:16), short-day+SMZ (SS, LD8:16, 0.2% diet SMZ), long-day control (LC, LD16:8), and long-day+SMZ (LS, LD16:8, 0.2% diet SMZ). Birds were sampled on days 3, 7, and 28 after initiation of a long-day photoperiod and/or SMZ dietary treatments. Three brain regions [septal–preoptic, anterior hypothalamic (SepPre/Ant-Hypo) region, mid-hypothalamic (Mid-Hypo) region, posterior-hypothalamic (Post-Hypo) region], and anterior pituitary gland were dissected. Using quantitative real-time RT-PCR, we determined changes of expression levels of genes in distinct brain regions; Opn4 and Opn5 in SepPre/Ant-Hypo and Post-Hypo regions and, VAOpn in the Mid-Hypo region. Long-day treatment resulted in a significantly elevated testes weight on days 7 and 28 compared to controls, and SMZ augmented testes weight in both short- and long-day treatment after day 7 (P<0.05). Long-day photoperiodic treatment on the third day unexpectedly induced a large 8.4-fold increase of VAOpn expression in the Mid-Hypo region, a 15.4-fold increase of Opn4 and a 97.8-fold increase of Opn5 gene expression in the Post-Hypo region compared to SC birds (P<0.01). In contrast, on days 7 and 28, gene expression of the three DBPs was barely detectable. LC group showed a significant increase in GnRH-1 and TRH mRNA in the Mid-Hypo compared to SC on day 3. Pituitary LHβ and FSHβ mRNA were significantly elevated in LC and LS groups compared to SC on days 3 and 7 (P<0.05). On days 3 and 7, TSHβ mRNA level was significantly elevated by long-day treatment compared to the SC groups (P<0.05). Results suggest that long-day photoperiodic activation of DBPs is robust, transient, and temporally related with neuroendocrine genes involved in reproductive function. Additionally, results indicate that two subsets of GnRH-1 neurons exist based upon significantly different gene expression from long-day photostimulation and long-day plus SMZ administration. Taken together, the data indicate that within 3days of a long-day photoperiod, an eminent activation of all three types of DBPs might be involved in priming the neuroendocrine system to activate reproductive function in birds.

EHMTI-0282. Deep brain stimulation in chronic cluster headache: lead location, clinical response and neuronal signatures

Background Chronic Cluster Headache (CCH) is refractory to medical therapy in a small minority of patients. Neuroimaging implicateS the ipsilateral posterior hypothalamic region (PH) in its pathogenesis. PH deep brain stimulation (PH-DBS) has shown promise in the management of refractory CCH. Here we investigate the value of local field potentials (LFPs) in relation to the site of active DBS contact used for chronic stimulation.

Different Critical Perinatal Periods and Hypothalamic Sites of Oestradiol Action in the Defeminisation of Luteinising Hormone Surge and Lordosis Capacity in the Rat

Female rats show a gonadotrophin-releasing hormone (GnRH)/luteinising hormone (LH) surge in the presence of a preovulatory level of oestrogen, whereas males do not because of brain defeminisation during the developmental period by perinatal oestrogen converted from androgen. The present study aimed to identify the site(s) of oestrogen action and the critical period for defeminising the mechanism regulating the GnRH/LH surge. Animals given perinatal treatments, such as steroidal manipulations, brain local implantation of oestradiol (E(2) ) or administration of an NMDA antagonist, were examined for their ability to show an E(2) -induced LH surge at adulthood. Lordosis behaviour was examined to compare the mechanisms defeminising the GnRH/LH surge and sexual behaviour. A single s.c. oestradiol-benzoate administration on either the day before birth (E21), the day of birth (D0) or day 5 (D5) postpartum completely abolished the E(2) -induced LH surge at adulthood in female rats, although the same treatment did not inhibit lordosis. Perinatal castration on E21 or D0 partially rescued the E2-induced LH surge in genetically male rats, whereas castration from E21 to D5 totally rescued lordosis. Neonatal E(2) implantation in the anterior hypothalamus including the anteroventral periventricular nucleus (AVPV)/preoptic area (POA) abolished the E(2) -induced LH surge in female rats, whereas E(2) implantation in the mid and posterior hypothalamic regions had no inhibitory effect on the LH surge. Lordosis was not affected by neonatal E(2) implantation in any hypothalamic regions. In male rats, neonatal NMDA antagonist treatment rescued lordosis but not the LH surge. Taken together, these results suggest that an anterior hypothalamic region such as the AVPV/POA region is a perinatal site of oestrogen action where the GnRH/LH regulating system is defeminised to abolish the oestrogen-induced surge. The mechanism for defeminisation of the GnRH/LH surge system might be different from that of sexual behaviour, in terms of the site(s) of oestrogen action and critical period, as well as the neurotransmitter system involved.

Paroxysmal sneezing after hypothalamic deep brain stimulation for cluster headache

Cluster headache (CH) is the most common of the trigeminal autonomic cephalalgias (TAC), presenting with excruciatingly severe, short-lasting, unilateral headache accompanied by cranial autonomic symptoms. Chronic CH occurs in 10-15% of patients. Deep brain stimulation in the posterior hypothalamic region (hDBS) is successful in treating about 60% of patients otherwise refractory to medical treatment. A 28-year-old man had hDBS for medically refractory left-sided chronic CH, with a resultant reduction in frequency and severity of his attacks. He developed recurrent paroxysms of sneezing soon after the stimulation was started that have reduced after increasing the pulse width from 60 to 90 µs. Stimulation of the brain in the region of the posterior hypothalamus could produce sneezing from activation of facial nerve parasympathetic or trigeminal afferent pathway activation through the trigeminohypothalamic tract, or through other central mechanisms. DBS in general offers the opportunity to illuminate our understanding of brain function and for CH offers particular opportunities to understand a devastating primary headache syndrome.

Circadian Preference Modulates the Neural Substrate of Conflict Processing across the Day

Human morning and evening chronotypes differ in their preferred timing for sleep and wakefulness, as well as in optimal daytime periods to cope with cognitive challenges. Recent evidence suggests that these preferences are not a simple by-product of socio-professional timing constraints, but can be driven by inter-individual differences in the expression of circadian and homeostatic sleep-wake promoting signals. Chronotypes thus constitute a unique tool to access the interplay between those processes under normally entrained day-night conditions, and to investigate how they impinge onto higher cognitive control processes. Using functional magnetic resonance imaging (fMRI), we assessed the influence of chronotype and time-of-day on conflict processing-related cerebral activity throughout a normal waking day. Sixteen morning and 15 evening types were recorded at two individually adapted time points (1.5 versus 10.5 hours spent awake) while performing the Stroop paradigm. Results show that interference-related hemodynamic responses are maintained or even increased in evening types from the subjective morning to the subjective evening in a set of brain areas playing a pivotal role in successful inhibitory functioning, whereas they decreased in morning types under the same conditions. Furthermore, during the evening hours, activity in a posterior hypothalamic region putatively involved in sleep-wake regulation correlated in a chronotype-specific manner with slow wave activity at the beginning of the night, an index of accumulated homeostatic sleep pressure. These results shed light into the cerebral mechanisms underlying inter-individual differences of higher-order cognitive state maintenance under normally entrained day-night conditions.

Functional anatomy of headache: hypothalamus

There is now compelling evidence that the hypothalamus exerts a major role in the mechanism of headache triggering. Pain and concomitant changes in the hormonal secretory pattern occur during an attack of headache when hypothalamic structures are involved. During spontaneous migraine or cluster headache attacks activation of the hypothalamus is shown by positron emission tomography. Over the past 10 years a number of patients with refractory chronic cluster headache have received neurostimulation of the posteroinferior hypothalamus as a form of treatment. The clinical use of deep brain stimulation (DBS) is based on the theory of posterior hypothalamic nucleus dysfunction as the cause of cluster headache attacks. In this article the authors review the functional anatomy of the hypothalamic region and its neighborhood, using silicone-injected cadaveric head and MRI. In conclusion, a better understanding of the functional anatomy of the hypothalamus and its neighborhood is imperative for understanding the pathophysiology of several of the primary headaches, particularly migraine and the trigemino-autonomic headaches. Direct stimulation of the posterior hypothalamic region using DBS devices is now the "state of the art" form of treatment indicated for refractory chronic cluster headache. The exact mechanism and the actual region where the DBS may act are still unknown, and studies on the functional anatomy of the hypothalamus are crucial to the progress in this marvelous field of functional neurosurgery.

Deep brain stimulation of the posterior hypothalamic area in intractable short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT)

SUNCT (short-lasting unilateral neuralgiform headache with conjunctival injection and tearing) is a rare syndrome characterized by the sudden onset of excruciating unilateral periorbital pain that is accompanied by conjunctival injection and lacrimation or further autonomic signs. Similar to patients with chronic cluster headache, Leone and Lyons showed a beneficial effect of deep brain stimulation of the posterior hypothalamic region in two patients with a chronic SUNCT. Here, we present the case of a man with a chronic SUNCT responding to deep brain stimulation of the posterior hypothalamic area. This case supports the idea of a central origin of SUNCT and shows that deep brain stimulation of the hypothalamic region can be effective in the treatment of the chronic form of this rare disorder.

Modulatory Effects of Melatonin on Cadmium-Induced Changes in Biogenic Amines in Rat Hypothalamus

This study was undertaken to examine whether cadmium oral exposure modifies biogenic amine concentration at hypothalamic level in adult male rats, and to investigate the possible modulatory effects of melatonin against cadmium-induced changes on these neurotransmitters. For this purpose, rats were exposed to cadmium (25mg/l of CdCl(2) in the drinking water) with or without melatonin (30μg/rat/day intraperitoneally) for 30days. Norepinephrine (NE), dopamine (DA), serotonin (5-HT), 3,4-dihydroxyphenyl acetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) were quantified by high performance liquid chromatography (HPLC). Oral cadmium administration led to decrease of NE, DA, and 5-HT content and DA turnover within the three hypothalamic regions examined, and therefore an inhibition of 5-HT turnover at posterior hypothalamus. Sensitivity to melatonin was specific to the hypothalamic region evaluated. Thus, the anterior hypothalamus was not nearly sensitive to exogenously administered melatonin, whereas the neurohormone decreased the content of these amines in the mediobasal hypothalamus, and melatonin increased it in the posterior hypothalamic region. Melatonin effectively prevented some cadmium-induced alterations on hypothalamic amine concentration. This is the case of DA in the anterior and posterior hypothalamus, and 5-HT metabolism in the posterior hypothalamic region. In conclusion, the obtained results indicate that melatonin treatment may be effective modulating some neurotoxic effects induced by cadmium exposure, and, more to the point, a possible role of this indolamine as a preventive agent for environmental or occupational cadmium contamination.

Optimal spectral tracking—Adapting to dynamic regime change

Real world data do not always obey the statistical restraints imposed upon them by sophisticated analysis techniques. In spectral analysis for instance, an ergodic process – the interchangeability of temporal for spatial averaging – is assumed for a repeat-trial design. Many evolutionary scenarios, such as learning and motor consolidation, do not conform to such linear behaviour and should be approached from a more flexible perspective. To this end we previously introduced the method of optimal spectral tracking (OST) in the study of trial-varying parameters. In this extension to our work we modify the OST routines to provide an adaptive implementation capable of reacting to dynamic transitions in the underlying system state. In so doing, we generalise our approach to characterise both slow-varying and rapid fluctuations in time-series, simultaneously providing a metric of system stability. The approach is first applied to a surrogate dataset and compared to both our original non-adaptive solution and spectrogram approaches. The adaptive OST is seen to display fast convergence and desirable statistical properties. All three approaches are then applied to a neurophysiological recording obtained during a study on anaesthetic monitoring. Local field potentials acquired from the posterior hypothalamic region of a deep brain stimulation patient undergoing anaesthesia were analysed. The characterisation of features such as response delay, time-to-peak and modulation brevity are considered.