Paraventricular area: Critical focus of a longitudinal neurocircuitry mediating food intake

Hyperphagia, obesity, and excessive linear growth, but not hyperdipsia, were produced by the asymmetrical combination of a parasagittal hypothalamic knife cut and a contralateral coronal knife cut. When the location of the coronal cut was varied systematically, it was found that cuts rostral to the coronal level of the paraventricular nucleus (PVN) neither produced nor prevented overeating, while cuts caudal to the PVN produced a robust hyperphagic response. Thus, the coronal level of the paraventricular nucleus was revealed as the rostral focus of a longitudinal satiety neurocircuitry.     

Hyperphagia and obesity following ventromedial hypothalamic lesions in rats with subdiaphragmatic vagotomy

Bilateral subdiaphragmatic vagotomy chronically reduced body weight to 85–90% of sham vagotomy weight levels in female rats maintained on a standard pellet diet (observed for 114 days). Ventromedial hypothalamic lesions 70 days after vagotomy resulted in marked hyperphagia and obesity, although the increases were not as great as those following lesions in nonvagotomized animals. When the order of surgery was reversed, vagotomy reduced the body weight of obese VMH-lesioned rats to vagotomized control levels, with no evidence of recovery after 90 days. These results suggest that while enhanced vagal activity and/or vagally mediated hyperinsulinemia contribute to VMH lesion-induced overeating and weight gains, they are not necessary for the manifestation of either the hyperphagia or obesity. The importance of adaptation to the effects of vagal transections for the appearance of hypothalamic hyperphagia and obesity is discussed.     

Deposit free electrolytic brain lesions: Methodologic and histologic observations

The morphologic features of deposit free electrolytic brain lesions made by passing cathodal current through stainless steel electrodes or anodal current through platinum-iridium electrodes were studied. Both procedures produced lesions which resemble those made with radio frequency current in that they are composed of a central cavity surrounded by a narrow annulus of pathologic tissue and are equally effective in grey and white matter. It was found that problems of current blockage due to gas formation and of irregular lesion configuration can be minimized by increasing the electrode tip exposure and decreasing the intensity of the current. Lesions made with a platinum anode were more uniformly of smooth, spherical shape than were cathodal lesions. Reliable relationships between coulombs of current and lesion volumes were demonstrated for both cathodal and anodal deposit-free procedures.     

Meal size as a determinant of food intake in normal and hypothalamic obese rats

Size of meals taken by normal rats was greatly increased by following each spontaneously initiated meal with gastric infusion of additional diet. In a second experiment, rats in the dynamic phase of hypothalamic obesity were limited to meals much smaller than the unusually large ones they usually take. In both experiments rats made precise adjustments in meal frequency which maintained daily food intakes at or close to pre-experimental levels.     

Ventromedial hypothalamic lesions in rats: Gradual elevation of body weight set-point

Bilateral electrolytic (DC) or radiofrequency (RF) lesions of the ventromedial hypothalamic (VMH) area produced two abnormal stages of fattening in adult female rats. Following a negatively-accelerated, curvilinear phase of weight gain which lasted 10 weeks, a linear phase of fattening continued for an additional 30 weeks at a rate approximately double that of operated control rats of the same age. During this second phase of fattening, lesioned rats were food-restricted between the 20th and 26th weeks postlesion. Compared to the rate of weight gain in the linear phase prior to food restriction, the rate over the same weight range following release from food restriction was significantly greater for both DC and RF-lesioned rats. Furthermore, by the 40th postlesion week, the lesioned rats had approached the weight they would have been if not food restricted. These observations suggest that VMH area lesions induce a gradual climbing of the set-point for body weight which occurs independently of actual food intake or body weight, and which either follows or is superimposed on the immediate elevation of the set-point responsible for the initial, curvilinear phase of weight gain. As a model for human idiopathic obesity, the long-term effect of VMH area lesions may be more important than the immediate effect.     

Ibotenic acid lesions of the lateral hypothalamus: comparison with the electrolytic lesion syndrome

Rats received either ibotenic acid, electrolytic or sham lesions of the lateral hypothalamic area. Compared to sham operated rats, both lesion groups showed aphagia and adipsia following the lesion; this was less severe in the ibotenic acid lesioned rats. Once recovered, the ibotenic acid lesioned rats showed residual regulatory impairments in their compensatory responses to glucoprivation and to extracellular and intracellular dehydration. However, unlike the electrolytic lesioned rats, those with ibotenic acid lesions did not show akinesia and exhibited normal responses to both d-amphetamine and apomorphine. Ibotenic acid lesions resulted in extensive loss of cell bodies within the lateral hypothalamic area while sparing ascending dopamine neurones. The results are interpreted as suggesting that the lateral hypothalamic area and ascending dopamine neurones are components of a single system involved in the regulation of food and water intake.     

Overeating and obesity produced by interruption of the caudal connections of the hypothalamus: evidence of hormonal and metabolic disruption.

Surgical transection of the posterior connections of the medial basal hypothalamus is much more effective in producing hyperphagia and obesity in female than in male rats. The hyperphagia of female rats can be attenuated by daily injections of estradiol. When starved to the weight of control animals, previously obese female rats with cuts through the posterior hypothalamus showed only mild hyperphagia but quickly returned to their elevated body weights. The results indicated that hormonal and metabolic disturbance are important factors in determining food intake and body weight following damage to the ventromedial hypothalamus.     

The consequences of hyperphagia in people with Prader-Willi Syndrome: A systematic review of studies of morbidity and mortality

Prader-Willi Syndrome (PWS) is a multi-system genetically determined neurodevelopmental disorder and the commonest cause of syndromal obesity. The development of hyperphagia in early childhood is part of the phenotype arising as a result of an impaired neural response to food intake and the inability to regulate food intake in line with energy needs. Severe obesity develops if access to food is not controlled.In this review we evaluate the evidence for increased morbidity and mortality in PWS in order to establish the extent to which it is directly related to the obesity; a consequence of the eating behaviour itself independent of obesity; or associated with other characteristics of the syndrome.Medline, Cochrane, PsychINFO, CINAHL, Web of Science and Scopus databases were used to systematically identify published material on PWS and hyperphagia and syndrome–related morbidity and mortality. One hundred and ten key papers were selected. Data on 500 people with PWS indicated that the average age of death was 21 years and obesity was, as expected, a significant factor. However, the behaviour of hyperphagia itself, independent of obesity, was also important, associated with choking, gastric rupture, and/or respiratory illness. Other syndrome-related factors increased the risk for, and seriousness of, co-morbid illness or accidents. We conclude that improving life-expectancy largely depends on managing the immediate non-obesity and obesity-related consequences of the hyperphagia, through improved support. The development of new treatments that significantly reduce the drive to eat are likely to decrease morbidity and mortality improving quality of life and life expectancy.     

The influence of reactivity of the electrode–brain interface on the crossing electric current in therapeutic deep brain stimulation

The use of deep brain stimulation (DBS) as an effective clinical therapy for a number of neurological disorders has been greatly hindered by the lack of understanding of the mechanisms which underlie the observed clinical improvement in patients. This problem is confounded by the difficulty of investigating the neuronal effects of DBS in situ, and the impossibility of measuring the induced current in vivo. In our recent computational work using a quasi-static finite element (FEM) model we have quantitatively shown that the properties of the depth electrode–brain interface (EBI) have a significant effect on the electric field induced in the brain volume surrounding the DBS electrode. In the present work, we explore the influence of the reactivity of the EBI on the crossing electric current using the Fourier-FEM approach to allow the investigation of waveform attenuation in the time domain. Results showed that the EBI affected the waveform shaping differently at different post-implantation stages, and that this in turn had implications on induced current distribution across the EBI. Furthermore, we investigated whether hypothetical waveforms, which were shown to have potential usefulness for neural stimulation but are not yet applied clinically, would have any advantage over the currently used square pulse. In conclusion, the influence of reactivity of the EBI on the crossing stimulation current in therapeutic DBS is significant, and affects the predictive estimation of current distribution around the implanted DBS electrode in the human brain.     

Secondary brain changes following lesions: a new paradigm for lesion experimentation.

The surgically-induced lesion has traditionally been used to study the localization of functions in the brain. The basic tenets for its use are that (1) functions are represented in discrete brain structures such as nuclei and fiber tracts and that (2) lesions disrupt function by removal of functional tissue in circumscribed sites in the brain. Contrary to this traditional view, there is growing evidence that the secondary changes in the brain which are induced by a lesion, both directly (necrosis, anterograde and retrograde degeneration) and indirectly (transneuronal degeneration, regeneration and sprouting, denervation supersensitivity, alteration of neurochemical pools, vascular disruption, diaschisis), may comprise the more significant neurological changes which can account for alteration of behavior in a lesion experiment. This evidence is reviewed and a new strategy of research utilizing lesions is proposed, suggesting that greater emphasis be placed on the a posteriori assessment of secondary changes in the brain as they are correlated with changes in behavior. The implications of such considerations for establishing brain-behavior relationships are discussed.     

Nerve stimulation with an electrode of finite size: differences between constant current and constant voltage stimulation

Differences between constant current and constant voltage nerve stimulation are controversial. To elucidate this controversy, exact solutions are found for the electrical potential and current of a conducting electrode of finite size placed near a boundary of altered conductivity. Substantial differences in the effects of a finite and a point stimulator are predicted. This was strongly dependent on the stimulator-boundary distance, the conductivity of the media, and the curvature of the boundary. The difference between constant voltage and constant current stimulation was smaller than the effects of changes in medium conductivity and electrode distance. A poorly conducting boundary layer surrounding the stimulator minimized these differences.     

Carcinoma and atypical hyperplasia in radial scars and complex sclerosing lesions: importance of lesion size and patient age

One hundred and twenty-six radial scars and complex sclerosing lesions from 91 women were examined to determine the incidence of and the clinical and pathological factors associated with the development of carcinoma and atypical hyperplasia within them. There was a clear relationship between the presence of carcinoma and atypical hyperplasia and the size of the lesion. This was not, however, a progressive relationship, there being a cut-off point about 6-7 mm. below which carcinoma was very uncommon and above which it was relatively frequent. A similar relationship was seen with patient age. Carcinoma was not seen in lesions removed from women under 40, was rare in the decade 41-50 and was relatively common above this age but with no further increase in the over 60s. A significantly higher incidence of carcinoma and atypical hyperplasia was encountered in scars detected by mammographic screening and could be explained by lesion size and the ages of the patients from which they were removed. No relationship was found between the presence of carcinoma within radial scars and complex sclerosing lesions and the existence of carcinoma in the residual breast tissue when direct extension was excluded. The carcinomas identified in the scars were of variable type and included small and large cell ductal carcinoma in situ, lobular carcinoma in situ and invasive carcinoma of tubular and ductal types. In situ carcinoma and atypical hyperplasia involved a very variable percentage of the epithelium of the lesions with mean values for ductal carcinoma in situ of 32%, lobular carcinoma in situ 25% and atypical hyperplasia 25%. It is concluded that all screen-detected radial scars and complex sclerosing lesions should be excised and subjected to thorough histological examination. Further studies on larger numbers of screened women are indicated to determine more precisely the incidence of carcinoma in these lesions and the risk of developing cancer in women in whom uncomplicated scars are detected.     

The effects of hypothalamic and mesencephalic lesions on food and water intakes,adiposity and some endocrine criteria,in the red-winged blackbird (Agelaius phoeniceus)

Bilateral electrolytic lesions were placed either in the basomedial hypothalamus (BMH) or in the mesencephalic interpeduncular nucleus of male red-winged blackbirds. The BMH lesions induced hyperphagia, obesity and functional castration. The mesencephalic lesions induced primary hyperdipsia and hypersensitivity to angiotensin II. Some of the mesencephalic lesioned birds were hyperphagic and obese. These birds had involuted testes but still had normal levels of serum testosterone. A discussion of these results pertaining to the literature concerning avian and mammalian species is presented.     

Involvement of protein tyrosine phosphatases and inflammation in hypothalamic insulin resistance associated with ageing: effect of caloric restriction

Aged Wistar rats present central insulin resistance associated with ageing. Several steps of the insulin signaling pathway have been described to be impaired in aged rats at hypothalamic level. In the present article we have explored possible alterations in protein tyrosine phosphatases (PTPs) involved in insulin receptor dephosphorylation, as well as pro-inflammatory pathways and serine kinases such as inhibitory kappa β kinase-nuclear factor kappa-B (IKKβ-NFκB), p38 mitogen-activated protein kinase (p38) and protein kinase C θ (PKCθ) that may also be involved in the decreased insulin signaling during ageing. We detected that ageing brings about a specific increase in insulin receptor tyrosine phosphatase activity and PTP1B serine phosphorylation. Increased association of PTP1B and leukocyte common antigen-related tyrosine protein phosphatase (LAR) with insulin receptor was also observed in hypothalamus from aged rats. Besides these mechanisms, increased activation of the IKKβ-NFκB pathway, p38 and PKCθ serine/threonine kinases were also detected. These data contribute to explain the hypothalamic insulin resistance associated with ageing. Caloric restriction ameliorates most of the effects of ageing on the above mentioned increases in PTPs and serine/threonine kinases activities and points to age-associated adiposity and inflammation as key factors in the development of age-associated insulin resistance.     

Evolutionary perspectives on human nutrition: The influence of brain and body size on diet and metabolism

Human dietary patterns and metabolic requirements are compared to those of nonhuman primate species in order to gain insights into the evolution of our nutritional needs. In general, primate diet quality (i.e., caloric and nutrient density) is inversely related to body size and total resting metabolic requirements (RMR). Humans, however, consume a diet of much higher quality than is expected for our size and metabolic needs. This energy-rich diet appears to reflect an adaptation to the high metabolic cost of our large brain. Among primates, the relative proportion of resting metabolic energy used for brain metabolism is positively correlated with relative diet quality. Humans represent the positive extreme, having both a very high quality diet and a large brain that accounts for 20–25% of resting metabolism. Evidence from the hominid fossil record implies that major changes in diet and relative brain metabolism occurred with the emergence of the genus Homo. © 1994 Wiley-Liss, Inc.     

An expanded view of energy homeostasis: Neural integration of metabolic, cognitive, and emotional drives to eat

The traditional view of neural regulation of body energy homeostasis focuses on internal feedback signals integrated in the hypothalamus and brainstem and in turn leading to balanced activation of behavioral, autonomic, and endocrine effector pathways leading to changes in food intake and energy expenditure. Recent observations have demonstrated that many of these internal signals encoding energy status have much wider effects on the brain, particularly sensory and cortico-limbic systems that process information from the outside world by detecting and interpreting food cues, forming, storing, and recalling representations of experience with food, and assigning hedonic and motivational value to conditioned and unconditioned food stimuli. Thus, part of the metabolic feedback from the internal milieu regulates food intake and energy balance by acting on extrahypothalamic structures, leading to an expanded view of neural control of energy homeostasis taking into account the need to adapt to changing conditions in the environment. The realization that metabolic signals act directly on these non-traditional targets of body energy homeostasis brings opportunities for novel drug targets for the fight against obesity and eating disorders.     

Relationships between plasma leptin concentrations and human brain structure: a voxel-based morphometric study

We have previously demonstrated that obese people have reduced grey matter (GM) in several brain areas, including regions implicated in the regulation of taste (i.e., inferior frontal operculum and postcentral gyrus), reward (i.e., putamen), and behavioural processing (i.e., middle frontal gyrus), compared with their lean counterparts. It is well established that the brain may serve as a direct target for adiposity signals, one of the most important being leptin. We investigated the relationships between fasting plasma leptin concentrations and brain tissue composition in a group of 32 young adult Caucasians (12M/20F, age 32+/-1 years, body fat 29+/-1%, mean+/-S.E.) with normal glucose tolerance by using voxel-based morphometry of magnetic resonance imaging scans. Fasting plasma leptin concentrations were positively correlated with GM volumes of the left cerebellum and left inferior temporal gyrus and negatively associated with GM volumes of the left inferior frontal operculum, left postcentral gyrus, and right putamen (P<0.001, uncorrected for multiple comparisons) after adjustment for sex, percent body fat, age, fasting plasma insulin concentrations (i.e., the major determinants of plasma leptin), and global GM volume (thus allowing for an assessment of regional effects only). This study showed an independent, negative correlation between fasting plasma leptin concentrations, which are increased in obesity, and the volumes of GM in brain areas where obese people have reduced GM compared to their lean counterparts. These relationships may explain some of the abnormalities in brain morphology recently found to be associated with excess body fatness.     

Body weight regulation in ground squirrels and hypothalamically lesioned rats: slow and sudden set point changes

Golden-mantled ground squirrels. Citellus lateralis, have a near annual cycle in body weight. In the present experiments their weights were temporarily forced off the usual levels either by food deprivation during a phase of weight gain or by offering extra palatable food during a phase of weight loss. When these treatments ceased the weights returned to levels appropriate for that time of year rather than to pretreatment values. Therefore the cycle of body weight in uniform and ad lib conditions reflects an underlying cycle in slowly climbing or sliding set points for body weight. In contrast to fattening ground squirrels, lesioned rats in the dynamic phase of hypothalamic hyperphagia did not compensate well for weight losses incurred during food deprivation. Weight gain during the dynamic phase appears to be roughly proportional to the discrepancy between actual and set weights, the latter being suddenly much elevated by the lesion.     

Spatial potential and current distributions along transvenous defibrillation electrodes: Variation of electrode characteristics

The therapeutic efficacy of an endocardial defibrillation lead system can be improved by controlling the profile of current delivery through a suitable choice of electrode characteristics, which include the length, radius, number of conductor elements, electrode resistance, and point of connection to the voltage source. Such control will minimize tissue and lead damage during long-term use. In this study, a semianalytical model was developed to study cylindrical electrodes of different constructions in an idealized electrolytic medium. Simulations were performed to investigate the effects of varying the electrode characteristics on the spatial voltage and current distributions and interelectrode resistance for cylindrical electrodes of different constructions. The results show that, for transvenous electrodes of realistic dimensions, the current distributions are determined largely by edge effects. The edge effects increase as the aspect ratio of the electrode (length/radius) decrease. The multiple edges resulting from wrapping conductor elements over a non-conducting base are found to increase the nonuniformity and the current density over the conductor-covered surface. The model is used to demonstratetwo techniques of controlling the current distribution. The first method involve modifying the electrode resistivity profile and point of connection. In the second approach, the electrode surface is covered with a thin film having a model-computed resistance profile. By using either methods to produced isocurrent electrodes, the interelectrode resistance is found to increase.     

Expanding the horizons of melatonin use: An immunohistochemical neuroanatomic distribution of MT1 and MT2 receptors in human brain and retina

Introduction

There is increasing evidence implicating the active role of melatonin beyond regulation of the human biological clock and reproduction. Its therapeutic use has been extended to neurodegenerative disorders, psychiatric disturbances, memory as well as a host of other neurological manifestations. This study was thus designed to identify regions of brain and retina for the expression of different types of melatonin receptors.