Showing papers in "Handbook of Clinical Neurology in 2021"

Histamine receptors, agonists, and antagonists in health and disease.

Abstract: Histamine in the brain is produced by a group of tuberomamillary neurons in the posterior hypothalamus and a limited number of mast cells in different parts of the brain. Four G-protein-coupled receptors mediate the effects of histamine. Two of these receptors, H3 and H4 receptors, are high-affinity receptors in the brain and immune system, respectively. The two classic histamine receptors, H1 receptor and H2 receptor, are well known as drug targets for allergy and gastric ulcer, respectively. These receptors have lower affinity for histamine than the more recently discovered H3 and H4 receptors. The H1 and H2 receptors are important postsynaptic receptors in the brain, and they mediate many of the central effects of histamine on, e.g., alertness and wakefulness. H3 receptor is a pre- and postsynaptic receptor, which regulates release of histamine and several other neurotransmitters, including serotonin, GABA, and glutamate. H4 receptor is found in cerebral blood vessels and microglia, but its expression in neurons is not yet well established. Pitolisant, a H3 receptor antagonist, is used to treat narcolepsy and hypersomnia. H1 receptor antagonists have been used to treat insomnia, but its use requires precautions due to potential side effects. H2 receptor antagonists have shown efficacy in treatment of schizophrenia, but they are not in widespread clinical use. H4 receptor ligands may in the future be tested for neuroimmunological disorders and potentially neurodegenerative disorders in which inflammation plays a role, but clinical tests have not yet been initiated.

The neuroscience of emotional disorders

Abstract: Emotions can be defined as states elicited by rewards or punishments, and indeed the neurology of emotional disorders can be understood in terms of this foundation. The orbitofrontal cortex in humans and other primates is a critical area in emotion processing, determining the value of stimuli and whether they are rewarding or nonrewarding. The cortical processing that occurs before the orbitofrontal cortex primarily involves defining the identity of stimuli, i.e., "what" is present and not reward value. There is evidence that this holds true for taste, visual, somatosensory, and olfactory stimuli. The human medial orbitofrontal cortex is important in processing many different types of reward, and the lateral orbitofrontal cortex in processing nonreward and punishment. Humans with damage to the orbitofrontal cortex have an impaired ability to identify facial and voice expressions of emotions, and impaired subjective experience of emotion. They can have an altered personality and be impulsive because they are impaired at processing failures to receive expected rewards and at processing punishments. In humans, the role of the amygdala in the processing of emotions is reduced because of the great evolutionary development of the orbitofrontal cortex: amygdala damage has much less effect on emotion than does orbitofrontal cortex damage. The orbitofrontal cortex projects reward value information to the anterior cingulate cortex, which is involved in learning those actions required to obtain rewards and avoid punishments. The cingulate cortex thus provides an output route for emotional behavior. In depression, the medial orbitofrontal cortex has decreased connectivity and sensitivity to reward, and the lateral orbitofrontal cortex has increased connectivity and sensitivity to nonreward. The orbitofrontal cortex has major projections to the anterior cingulate cortex, including its subcommissural region, and the anterior cingulate cortex is also implicated in depression.

Brain arteriovenous malformations.

Abstract: Brain arteriovenous malformations are an important cause of intracerebral hemorrhage in the young. Ruptured AVM's are often treated, as the risk of rebleeding is high. The treatment of incidentally discovered, unruptured AVMs is controversial as the morbidity and mortality of treatment may exceed that of the AVM's natural history. Management is multimodal and includes observation with follow up, as well as microsurgical resection, endovascular embolization, and stereotactic radiosurgery. Multidisciplinary teams are important in evaluating patients for treatment. The goal of treatment is complete AVM obliteration while preserving neurologic function.

The circadian system: From clocks to physiology.

Abstract: The circadian system, composed of the central autonomous clock, the suprachiasmatic nucleus (SCN), and systems of the body that follow the signals of the SCN, continuously change the homeostatic set points of the body over the day-night cycle. Changes in the body's physiological state that do not agree with the time of the day feedback to the hypothalamus, and provide input to the SCN to adjust the condition, thus reaching another set point required by the changed conditions. This allows the adjustment of the set points to another level when environmental conditions change, which is thought to promote adaptation and survival. In fasting, the body temperature drops to a lower level only at the beginning of the sleep phase. Stressful conditions raise blood pressure relatively more during the active period than during the rest phase. Extensive, mostly reciprocal SCN interactions, with hypothalamic networks, induce these physiological adjustments by hormonal and autonomic control of the body's organs. More importantly, in addition to SCN's hormonal and autonomic influences, SCN induced behavior, such as rhythmic food intake, induces the oscillation of many genes in all tissues, including the so-called clock genes, which have an essential role as a transcriptional driving force for numerous cellular processes. Consequently, the light-dark cycle, the rhythm of the SCN, and the resulting rhythm in behavior need to be perfectly synchronized, especially where it involves synchronizing food intake with the activity phase. If these rhythms are not synchronous for extended periods of times, such as during shift work, light exposure at night, or frequent night eating, disease may develop. As such, our circadian system is a perfect illustration of how hypothalamic-driven processes depend on and interact with each other and need to be in seamless synchrony with the body's physiology.

Melatonin and the circadian system: Keys for health with a focus on sleep.

Abstract: Melatonin (MLT), secreted during the night by the pineal gland, is an efferent hormonal signal of the master circadian clock located in the suprachiasmatic nucleus (SCN). Consequently, it is a reliable phase marker of the SCN clock. If one defines as "chronobiotic," a drug able to influence the phase and/or the period of the circadian clock, MLT is a very potent one. The most convincing data obtained so far come from studies on totally blind individuals. Exogenous MLT administered daily entrains the sleep-wake cycle of these individuals to a 24-h cycle. MLT, however, is not essential to sleep. In nocturnally, active mammals, MLT is released during the night concomitantly with the daily period of wakefulness. Therefore, MLT cannot be simply considered as a sleep hormone, but rather as a signal of darkness. Its role in the circadian system is to reinforce nighttime physiology, including timing of the sleep-wake cycle and other circadian rhythms. MLT exerts its effects on the sleep cycle especially by a direct action on the master circadian clock. The sleep-wake cycle is depending not only on the circadian clock but also on an orchestrated network of different centers in the brain. Thus, the control of sleep-wake rhythm might be explained by a parallel and concomitant action of MLT on the master clock (chronobiotic effect) and on sleep-related structures within the brain. MLT acts through two high-affinity membrane receptors (MT1 and MT2) with striking differences in their distribution pattern. MLT is a powerful synchronizer of human circadian rhythms, thus justifying the use of MLT and MLT agonists in clinical medicine as pharmacological tools to manipulate the sleep-wake cycle, and to treat sleep disorders and other circadian disorders. Available MLT analogs/drugs are all nonspecific MT1/MT2 agonists. The development of new ligands which are highly selectivity for each subtype is clearly a new challenge for the field and will be at the root of new therapeutic agents for curing specific pathologies, including sleep disorders.

Emotional disorders and the cerebellum: Neurobiological substrates, neuropsychiatry, and therapeutic implications.

Abstract: The notion that the cerebellum is devoted exclusively to motor control has been replaced by a more sophisticated understanding of its role in neurological function, one that includes cognition and emotion. Early clinical reports, as well as physiological and behavioral studies in animal models, raised the possibility of a nonmotor role for the cerebellum. Anatomical studies demonstrate cerebellar connectivity with the distributed neural circuits linked with autonomic, sensorimotor, vestibular, associative, and limbic/paralimbic brain areas. Identification of the cerebellar cognitive affective syndrome in adults and children underscored the clinical relevance of the role of the cerebellum in cognition and emotion. It opened new avenues of investigation into higher-order deficits that accompany the ataxias and other cerebellar diseases, as well as the contribution of cerebellar dysfunction to neuropsychiatric and neurocognitive disorders. Brain imaging studies have demonstrated the complexity of cerebellar functional topography, revealing a double representation of the sensorimotor cerebellum in the anterior lobe and lobule VIII and a triple cognitive representation in the cerebellar posterior lobe, as well as representation in the cerebellum of the intrinsic connectivity networks identified in the cerebral hemispheres. This paradigm shift in thinking about the cerebellum has been advanced by the theories of dysmetria of thought and the universal cerebellar transform, harmonizing the dual anatomic realities of homogeneously repeating cerebellar cortical microcircuitry set against the heterogeneous and topographically arranged cerebellar connections with extracerebellar structures. This new appreciation of cerebellar incorporation into circuits that subserve cognition and emotion mandates a deeper understanding of the cerebellum by practitioners in behavioral neurology and neuropsychiatry because it impacts the understanding and diagnosis of disorders of emotion and intellect and has potential for novel cerebellar-based approaches to therapy.

Central and peripheral release of oxytocin: Relevance of neuroendocrine and neurotransmitter actions for physiology and behavior.

Abstract: The hypothalamic neuropeptide oxytocin (OT) is critically involved in the modulation of socio-emotional behavior, sexual competence, and pain perception and anticipation. While intracellular signaling of OT and its receptor (OTR), as well as the functional connectivity of hypothalamic and extra-hypothalamic OT projections, have been recently explored, it remains elusive how one single molecule has pleotropic effects from cell proliferation all the way to modulation of complex cognitive processes. Moreover, there are astonishing species-dependent differences in the way OT regulates various sensory modalities such as touch, olfaction, and vision, which can be explained by differences in OTR expression in brain regions processing sensory information. Recent research highlights a small subpopulation of OT-synthesizing cells, namely, parvocellular cells, which merely constitute 1% of the total number of OT cells but act as "master cells' that regulate the activity of the entire OT system. In this chapter, we summarize the latest advances in the field of OT research with a particular focus on differences between rodents, monkeys and humans and highlight the main differences between OT and its "sister" peptide arginine-vasopressin, which often exerts opposite effects on physiology and behavior.

Aphantasia: The science of visual imagery extremes.

Abstract: Visual imagery allows us to revisit the appearance of things in their absence and to test out virtual combinations of sensory experience. Visual imagery has been linked to many cognitive processes, such as autobiographical and visual working memory. Imagery also plays symptomatic and mechanistic roles in neurologic and mental disorders and is utilized in treatment. A large network of brain activity spanning frontal, parietal, temporal, and visual cortex is involved in generating and maintain images in mind. The ability to visualize has extreme variations, ranging from completely absent (aphantasia) to photo-like (hyperphantasia). The anatomy and functionality of visual cortex, including primary visual cortex, have been associated with individual differences in visual imagery ability, pointing to a potential correlate for both aphantasia and hyperphantasia. Preliminary evidence suggests that lifelong aphantasia is associated with prosopagnosia and reduction in autobiographical memory; hyperphantasia is associated with synesthesia. Aphantasic individuals can also be highly imaginative and are able to complete many tasks that were previously thought to rely on visual imagery, demonstrating that visualization is only one of many ways of representing things in their absence. The study of extreme imagination reminds us how easily invisible differences can escape detection.

Craniopharyngiomas primarily affecting the hypothalamus.

Abstract: The concept of craniopharyngiomas (CPs) primarily affecting the hypothalamus, or "hypothalamic CPs" (Hy-CPs), refers, in a restrictive sense, to the subgroup of CPs originally developing within the neural tissue of the infundibulum and tuber cinereum, the components of the third ventricle floor. This subgroup, also known as infundibulo-tuberal CPs, largely occupies the third ventricle and comprises up to 40% of this pathological entity. The small subgroup of strictly intraventricular CPs (5%), lesions wholly developed within the third ventricle above an anatomically intact third ventricle floor, can also be included within the Hy-CP category. The remaining types of sellar and/or suprasellar CPs may compress or invade the hypothalamic region during their growth but will not be considered in this review. Hy-CPs predominantly affect adults, causing a wide range of symptoms derived from hypothalamic dysfunction, such as adiposogenital dystrophy (Babinski-Frohlich's syndrome), diabetes insipidus (DI), abnormal diurnal somnolence, and a complex set of cognitive (dementia-like, Korsakoff-like), emotional (rage, apathy, depression), and behavioral (autism-like, psychotic-like) disturbances. Accordingly, Hy-CPs represent a neurobiological model of psychiatric disorders caused by a lesion restricted to the hypothalamus. The vast majority (90%) of squamous-papillary CPs belong to the Hy-CP category. Pathologically, most Hy-CPs present extensive and strong adhesions to the surrounding hypothalamus, usually formed of a thick band of gliotic tissue encircling the central portion of the tumor ("ring-like" attachment) or its entire boundary ("circumferential" attachment). CPs with these severe adhesion types associate high surgical risk, with morbidity and mortality rates three times higher than those for sellar/suprasellar CPs. Consequently, radical surgical removal of Hy-CPs cannot be generally recommended. Rather, Hy-CPs should be accurately classified according to an individualized surgery-risk stratification scheme considering patient age, CP topography, presence of hypothalamic symptoms, tumor size, and, most importantly, the CP-hypothalamus adhesion pattern.

Melatonin receptors, brain functions, and therapies

Abstract: In mammals, including humans, the neurohormone melatonin is mainly secreted from the pineal gland at night and acts on two high-affinity G protein-coupled receptors, the melatonin MT1 and MT2 receptors. Major functions of melatonin receptors in the brain are the regulation of circadian rhythms and sleep. Correspondingly, the main indications of the currently available drugs for these receptors indicate this as targets. Yet these drugs may not only improve circadian rhythm- and sleep-related disorders but may also be beneficial for complex diseases like major depression, Alzheimer's disease, autism, and attention-deficit/hyperactivity disorders. Here, we will focus on the hypothalamic functions of melatonin receptors by updating our knowledge on their hypothalamic expression pattern at normal, aged, and disease states, by discussing their capacity to regulate circadian rhythms and sleep and by presenting the clinical applications of the melatonin receptor-targeting drugs ramelteon, tasimelteon, and agomelatine or of prolonged-release melatonin formulations. Finally, we speculate about future trends in the field of melatonin receptor drugs.

Arcuate nucleus, median eminence, and hypophysial pars tuberalis.

Abstract: The arcuate nucleus (ARC) is located in the mediobasal hypothalamus and forms a morphological and functional entity with the median eminence (ME), the ARC-ME. The ARC comprises several distinct types of neurons controlling prolactin release, food intake, and metabolism as well as reproduction and onset of puberty. The ME lacks a blood-brain barrier and provides an entry for peripheral signals (nutrients, leptin, ghrelin). ARC neurons are adjacent to the wall of the third ventricle. This facilitates the exchange of signals from and to the cerebrospinal fluid. The ventricular wall is composed of tanycytes that serve different functions. Axons of ARC neurons contribute to the tuberoinfundibular tract terminating in the ME on the hypophysial portal vessels (HPV) and establish one of the neurohumoral links between the hypothalamus and the pituitary. ARC neurons are reciprocally connected with several other hypothalamic nuclei, the brainstem, and reward pathways. The hypophysial pars tuberalis (PT) is attached to the ME and the HPV. The PT, an important interface of the neuroendocrine system, is mandatory for the control of seasonal functions. This contribution provides an update of our knowledge about the ARC-ME complex and the PT which, inter alia, is needed to understand the pathophysiology of metabolic diseases and reproduction.

Neurobiology of puberty and its disorders.

Abstract: Puberty, which in humans is considered to include both gonadarche and adrenarche, is the period of becoming capable of reproducing sexually and is recognized by maturation of the gonads and development of secondary sex characteristics. Gonadarche referring to growth and maturation of the gonads is fundamental to puberty since it encompasses increased gonadal steroid secretion and initiation of gametogenesis resulting from enhanced pituitary gonadotropin secretion, triggered in turn by robust pulsatile GnRH release from the hypothalamus. This chapter reviews the development of GnRH pulsatility from before birth until the onset of puberty. In humans, GnRH pulse generation is restrained during childhood and juvenile development. This prepubertal hiatus in hypothalamic activity is considered to result from a neurobiological brake imposed upon the GnRH pulse generator resident in the infundibular nucleus. Reactivation of the GnRH pulse generator initiates pubertal development. Current understanding of the genetics and physiology of the brake will be discussed, as will hypotheses proposed to account for timing the resurgence in pulsatile GnRH and initiation of puberty. The chapter ends with a discussion of disorders associated with precocious or delayed puberty with a focus on those with etiologies attributed to aberrant GnRH neuron anatomy or function. A pediatric approach to patients with pubertal disorders is provided and contemporary treatments for both precocious and delayed puberty outlined.

Tanycytes in the infundibular nucleus and median eminence and their role in the blood–brain barrier

Abstract: The blood-brain barrier is generally attributed to endothelial cells. However, in circumventricular organs, such as the median eminence, tanycytes take over the barrier function. These ependymoglial cells form the wall of the third ventricle and send long extensions into the parenchyma to contact blood vessels and hypothalamic neurons. The shape and location of tanycytes put them in an ideal position to connect the periphery with central nervous compartments. In line with this, tanycytes control the transport of hormones and key metabolites in and out of the hypothalamus. They function as sensors of peripheral homeostasis for central regulatory networks. This chapter discusses current evidence that tanycytes play a key role in regulating glucose balance, food intake, endocrine axes, seasonal changes, reproductive function, and aging. The understanding of how tanycytes perform these diverse tasks is only just beginning to emerge and will probably lead to a more differentiated view of how the brain and the periphery interact.

Neurogenesis in the adult hypothalamus: A distinct form of structural plasticity involved in metabolic and circadian regulation, with potential relevance for human pathophysiology

Abstract: The adult brain harbors specific niches where stem cells undergo substantial plasticity and, in some regions, generate new neurons throughout life. This phenomenon is well known in the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampus and has recently also been described in the hypothalamus of several rodent and primate species. After a brief overview of preclinical studies illustrating the pathophysiologic significance of hypothalamic neurogenesis in the control of energy metabolism, reproduction, thermoregulation, sleep, and aging, we review current literature on the neurogenic niche of the human hypothalamus. A comparison of the organization of the niche between humans and rodents highlights some common features, but also substantial differences, e.g., in the distribution and extent of the hypothalamic neural stem cells. Exploring the full dynamics of hypothalamic neurogenesis in humans raises a formidable challenge however, given among others, inherent technical limitations. We close with discussing possible functional role(s) of the human hypothalamic niche, and how gaining more insights into this form of plasticity could be relevant for a better understanding of pathologies associated with disturbed hypothalamic function.

The contribution of mamillary body damage to Wernicke's encephalopathy and Korsakoff's syndrome.

Abstract: Histopathological alterations of the mamillary bodies are the most conspicuous and the most consistent neuropathological features of several disorders that occur after severe thiamine deficiency, such as Wernicke's encephalopathy and Korsakoff's syndrome. Moreover, they are among the few abnormalities that are visible to the naked eye in these disorders. With a lifetime prevalence of approximately 1.3%, Wernicke's encephalopathy is by far the most frequent cause of damage to the mamillary bodies in humans. Still, there is a persisting uncertainty with regard to the development and the clinical consequences of this damage, because it is virtually impossible to study in isolation. As a rule, it always occurs alongside neuropathology in other subcortical gray matter structures, notably the medial thalamus. Converging evidence from other pathologies and animal experiments is needed to assess the clinical impact of mamillary body damage and to determine which functions can be attributed to these structures in healthy subjects. In this chapter, we describe the history and the current state of knowledge with regard to thiamine deficiency disorders and the contribution of mamillary body damage to their clinical presentations.

Neurovascular disease, diagnosis, and therapy: Subarachnoid hemorrhage and cerebral vasospasm

Abstract: The worldwide incidence of spontaneous subarachnoid hemorrhage is about 6.1 per 100,000 cases per year (Etminan et al., 2019). Eighty-five percent of cases are due to intracranial aneurysms. The mean age of those affected is 55 years, and two-thirds of the patients are female. The prognosis is related mainly to the neurologic condition after the subarachnoid hemorrhage and the age of the patient. Overall, 15% of patients die before reaching the hospital, another 20% die within 30 days, and overall 75% are dead or remain disabled. Case fatality has declined by 17% over the last 3 decades. Despite the improvement in outcome probably due to improved diagnosis, early aneurysm repair, administration of nimodipine, and advanced intensive care support, the outcome is not very good. Even among survivors, 75% have permanent cognitive deficits, mood disorders, fatigue, inability to return to work, and executive dysfunction and are often unable to return to their premorbid level of functioning. The key diagnostic test is computed tomography, and the treatments that are most strongly supported by scientific evidence are to undertake aneurysm repair in a timely fashion by endovascular coiling rather than neurosurgical clipping when feasible and to administer enteral nimodipine. The most common complications are aneurysm rebleeding, hydrocephalus, delayed cerebral ischemia, and medical complications (fever, anemia, and hyperglycemia). Management also probably is optimized by neurologic intensive care units and multidisciplinary teams.

Chemoarchitecture of the bed nucleus of the stria terminalis: Neurophenotypic diversity and function

Abstract: The bed nucleus of the stria terminalis (BNST) is a compact but neurophenotypically complex structure in the ventral forebrain that is structurally and functionally linked to other limbic structures, including the amygdala nuclear complex, hypothalamic nuclei, hippocampus, and related midbrain structures, to participate in a wide range of functions, especially emotion, emotional learning, stress-related responses, and sexual behaviors. From a variety of sensory inputs, the BNST acts as a node for signal integration and coordination for information relay to downstream central neuroendocrine and autonomic centers for appropriate homeostatic physiological and behavioral responses. In contrast to the role of the amygdala in fear, the BNST has gained wide interest from work suggesting that it has main roles in mediating sustained responses to diffuse, unpredictable and/or long-duration threats that are typically associated with anxiety-related responses. Further, some BNST subregions are highly sexually dimorphic which appear contributory to the differential stress and social interactive behaviors, including reproductive responses, between males and females. Notably, maladaptive BNST neuroplasticity and function have been implicated in chronic pain, depression, anxiety-related abnormalities, and other psychopathologies including posttraumatic stress disorders. The BNST circuits are predominantly GABAergic-the glutaminergic neurons represent a minor population-but the complexity of the system results from an overlay of diverse neuropeptide coexpression in these neurons. More than a dozen neuropeptides may be differentially coexpressed in BNST neurons, and from variable G protein-coupled receptor signaling, may inhibit or activate downstream circuit activities. The mechanisms and roles of these peptides in modulating intrinsic BNST neurocircuit signaling and BNST long-distance target cell projections are still not well understood. Nevertheless, an understanding of some of the principal players may allow assembly of the circuit interactions.

Spatial topography of the basal forebrain cholinergic projections: Organization and vulnerability to degeneration.

Abstract: The basal forebrain (BF) cholinergic system constitutes a heterogeneous cluster of large projection neurons that innervate the entire cortical mantle and amygdala. Cholinergic neuromodulation plays a critical role in regulating cognition and behavior, as well as maintenance of cellular homeostasis. Decades of postmortem histology research have demonstrated that the BF cholinergic neurons are selectively vulnerable to aging and age-related neuropathology in degenerative diseases such as Alzheimer's and Parkinson's diseases. Emerging evidence from in vivo neuroimaging research, which permits longitudinal tracking of at-risk individuals, indicates that cholinergic neurodegeneration might play an earlier and more pivotal role in these diseases than was previously appreciated. Despite these advances, our understanding of the organization and functions of the BF cholinergic system mostly derives from nonhuman animal research. In this chapter, we begin with a review of the topographical organization of the BF cholinergic system in rodent and nonhuman primate models. We then discuss basic and clinical neuroscience research in humans, which has started to translate and extend the nonhuman animal research using novel noninvasive neuroimaging techniques. We focus on converging evidence indicating that the selective vulnerability of cholinergic neurons in Alzheimer's and Parkinson's diseases is expressed along a rostral-caudal topography in the BF. We close with a discussion of why this topography of vulnerability in the BF may occur and why it is relevant to the clinician.

Olfaction as an early marker of Parkinson's disease and Alzheimer's disease

Abstract: Olfactory impairment is a common and early sign of Parkinson's disease (PD) and Alzheimer's disease (AD), the two most prevalent neurodegenerative conditions in the elderly. This phenomenon corresponds to pathologic processes emerging in the olfactory system prior to the onset of typical clinical manifestations. Clinically available tests can establish hyposmia through odor identification assessment, discrimination, and odor detection threshold. There are significant efforts to develop preventative or disease-modifying therapies that slow down or halt the progression of PD and AD. Due to the convenience and low cost of its assessment, olfactory impairment could be used in these studies as a screening instrument. In the clinical setting, loss of smell may also help to differentiate PD and AD from alternative causes of Parkinsonism and cognitive impairment, respectively. Here, we discuss the pathophysiology of olfactory dysfunction in PD and AD and how it can be assessed in the clinical setting to aid in the early and differential diagnosis of these disorders.

Perinatal stress and epigenetics.

Abstract: Animal and humans exposed to stress early in life are more likely to suffer from long-term behavioral, mental health, metabolic, immune, and cardiovascular health consequences. The hypothalamus plays a nodal role in programming, controlling, and regulating stress responses throughout the life course. Epigenetic reprogramming in the hippocampus and the hypothalamus play an important role in adapting genome function to experiences and exposures during the perinatal and early life periods and setting up stable phenotypic outcomes. Epigenetic programming during development enables one genome to express multiple cell type identities. The most proximal epigenetic mark to DNA is a covalent modification of the DNA itself by enzymatic addition of methyl moieties. Cell-type-specific DNA methylation profiles are generated during gestational development and define cell and tissue specific phenotypes. Programming of neuronal phenotypes and sex differences in the hypothalamus is achieved by developmentally timed rearrangement of DNA methylation profiles. Similarly, other stations in the life trajectory such as puberty and aging involve predictable and scheduled reorganization of DNA methylation profiles. DNA methylation and other epigenetic marks are critical for maintaining cell-type identity in the brain, across the body, and throughout life. Data that have emerged in the last 15 years suggest that like its role in defining cell-specific phenotype during development, DNA methylation might be involved in defining experiential identities, programming similar genes to perform differently in response to diverse experiential histories. Early life stress impact on lifelong phenotypes is proposed to be mediated by DNA methylation and other epigenetic marks. Epigenetic marks, as opposed to genetic mutations, are reversible by either pharmacological or behavioral strategies and therefore offer the potential for reversing or preventing disease including behavioral and mental health disorders. This chapter discusses data testing the hypothesis that DNA methylation modulations of the HPA axis mediate the impact of early life stress on lifelong behavioral and physical phenotypes.

Prader-Willi syndrome: Hormone therapies.

Abstract: Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder linked to the lack of expression of specific maternally imprinted genes located in the chromosomal region 15q11-q13. Impaired hypothalamic development and function explain most of the phenotype that is characterized by a specific trajectory from anorexia at birth to excessive weight gain at later ages, which is accompanied by hyperphagia and early severe obesity, as well as by other hormonal deficiencies, behavioral deficits, and dysautonomia. In almost all patients, their endocrine dysfunction involves growth hormone deficiency and hypogonadism, which originate from a combination of both peripheral and hypothalamic origin, central hypothyroidism in 40%, precocious adrenarche in 30% of the cases, and in rare cases, also adrenocorticotropin deficiency and precocious puberty. In addition, the oxytocin (OXT) and ghrelin systems are impaired in most patients and involved in a poor suckling response at birth, and hyperphagia with food addiction, poor social skills, and emotional dysregulation. Current hormonal replacement treatments are the same as used in classical hormonal deficiencies, and recombinant human GH treatment is registered since 2000 and has dramatically changed the phenotype of these children. OXT and OXT analogue treatments are currently investigated as well as new molecules targeting the ghrelin system. The severe condition of PWS can be seen as a model to improve the fine description and treatments of hypothalamic dysfunction.

Narcolepsy Type I as an autoimmune disorder.

Abstract: Narcolepsy Type 1 (NT1) is hypothesized to be an autoimmune disease targeting the hypocretin/orexin neurons in the lateral hypothalamus. Ample genetic and epidemiologic evidence point in the direction of a pathogenesis involving the immune system. Many autoantibodies have been detected in blood samples from NT1 patients, but none in a consistent manner. Importantly, T cells directed toward hypocretin/orexin neurons have been detected in samples from NT1 patients. However, it remains to be seen if these potentially autoreactive T cells are also present in the hypothalamus and if they are pathogenic. For this reason, NT1 does still not fully meet the criteria for being classified as a genuine autoimmune disease, even though more and more results are pointing in that direction as will be described in this chapter. The autoimmune hypothesis has led to many attempts at slowing or stopping disease progression with immunomodulatory treatment, but so far the overall results have not been very encouraging. It is clear that more research into the pathogenesis of NT1 is needed to establish the precise role of the immune system in disease development.

Functional anatomy of the bed nucleus of the stria terminalis-hypothalamus neural circuitry: Implications for valence surveillance, addiction, feeding, and social behaviors

Abstract: The bed nucleus of the stria terminalis (BNST) is a medial basal forebrain structure that modulates the hypothalamo-pituitary-adrenal (HPA) axis. The heterogeneous subnuclei of the BNST integrate inputs from mood and reward-related areas and send direct inhibitory projections to the hypothalamus. The connections between the BNST and hypothalamus are conserved across species, promote activation of the HPA axis, and can increase avoidance of aversive environments, which is historically associated with anxiety behaviors. However, BNST-hypothalamus circuitry is also implicated in motivated behaviors, drug seeking, feeding, and sexual behavior. These complex and diverse roles, as well its sexual dimorphism, indicate that the BNST-hypothalamus circuitry is an essential component of the neural circuitry that may underlie various psychiatric diseases, ranging from anorexia to anxiety to addiction. The following review is a cross-species exploration of BNST-hypothalamus circuitry. First, we describe the BNST subnuclei, microcircuitry and complex reciprocal connections with the hypothalamus. We will then discuss the behavioral functions of BNST-hypothalamus circuitry, including valence surveillance, addiction, feeding, and social behavior. Finally, we will address sex differences in morphology and function of the BNST and hypothalamus.

Nucleus basalis of Meynert degeneration predicts cognitive impairment in Parkinson's disease.

Abstract: Cognitive impairment affects approximately 20%-50% of patients with Parkinson's disease (PD), with a higher prevalence as the disease advances. The nucleus basalis of Meynert (NBM) provides the majority of cholinergic innervations to the cerebral cortex. Dysfunction of the cholinergic system and degeneration of the NBM have been implicated in the pathophysiology of cognitive impairment in neurodegenerative disorders including PD. Several studies have aimed to identify risk factors associated with cognitive decline in order to construct models to predict future cognitive impairment in PD. Given the link between cholinergic dysfunction and the pathogenesis of cognitive decline in PD, a number of studies have focused on the role of the NBM underlying cognitive performance. Recently, microstructural alterations within the NBM, detected using diffusion tensor imaging, have been identified as a strong predictor for the development of cognitive impairment in patients with PD. These microstructural changes in NBM have been shown to precede structural gray matter volumetric loss and may present with an early marker to predict cognitive decline in patients with PD. Longitudinal studies are warranted to provide insights into the potential utility of cholinergic positron emission tomography imaging to predict the development of cognitive impairment in PD and other neurodegenerative disorders. Provided the urgent need for disease modifying therapies aiming to slow and ultimately halt the progression of cognitive impairment, neuromodulation of NBM, and treatments targeting the cholinergic system may hold a promising potential. In this review, we discuss the link between NBM pathology and clinical symptomatology of cognitive impairment in PD with a focus on the use of in vivo imaging techniques and potential therapeutic interventions.

Endocrine dysfunction in adrenoleukodystrophy.

Abstract: X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene and characterized by impaired very long-chain fatty acid beta-oxidation. Clinically, male patients develop adrenal failure and a progressive myelopathy in adulthood, although age of onset and rate of progression are highly variable. Additionally, 40% of male patients develop a leukodystrophy (cerebral ALD) before the age of 18 years. Women with ALD also develop a myelopathy but generally at a later age than men and with slower progression. Adrenal failure and leukodystrophy are exceedingly rare in women. Allogeneic hematopoietic cell transplantation (HCT), or more recently autologous HCT with ex vivo lentivirally transfected bone marrow, halts the leukodystrophy. Unfortunately, there is no curative treatment for the myelopathy. In the following chapter, the biochemistry, pathology, and clinical spectrum of ALD are discussed in detail.

Sexual differentiation of the human hypothalamus: Relationship to gender identity and sexual orientation.

Abstract: Gender identity (an individual's perception of being male or female) and sexual orientation (heterosexuality, homosexuality, or bisexuality) are programmed into our brain during early development. During the intrauterine period in the second half of pregnancy, a testosterone surge masculinizes the fetal male brain. If such a testosterone surge does not occur, this will result in a feminine brain. As sexual differentiation of the brain takes place at a much later stage in development than sexual differentiation of the genitals, these two processes can be influenced independently of each other and can result in gender dysphoria. Nature produces a great variability for all aspects of sexual differentiation of the brain. Mechanisms involved in sexual differentiation of the brain include hormones, genetics, epigenetics, endocrine disruptors, immune response, and self-organization. Furthermore, structural and functional differences in the hypothalamus relating to gender dysphoria and sexual orientation are described in this review. All the genetic, postmortem, and in vivo scanning observations support the neurobiological theory about the origin of gender dysphoria, i.e., it is the sizes of brain structures, the neuron numbers, the molecular composition, functions, and connectivity of brain structures that determine our gender identity or sexual orientation. There is no evidence that one's postnatal social environment plays a crucial role in the development of gender identity or sexual orientation.

The heart is lost without the hypothalamus.

Abstract: Neuroanatomic and functional studies show the paraventricular (PVN) of the hypothalamus to have a central role in the autonomic control that supports cardiovascular regulation. Direct and indirect projections from the PVN preautonomic neurons to the sympathetic preganglionic neurons in the spinal cord modulate sympathetic activity. The preautonomic neurons of the PVN adjust their level of activation in response to afferent signals arising from peripheral viscerosensory receptors relayed through the nucleus tractus solitarius. The prevailing sympathetic tone is a balance between excitatory and inhibitory influences that arises from the preautonomic PVN neurons. Under physiologic conditions, tonic sympathetic inhibition driven by a nitric oxide-γ-aminobutyric acid-mediated mechanism is dominant, but in pathologic situation such as heart failure there is a switch from inhibition to sympathoexcitation driven by glutamate and angiotensin II. Angiotensin II, reactive oxygen species, and hypoxia as a result of myocardial infarction/ischemia alter the tightly regulated posttranslational protein-protein interaction of CAPON (carboxy-terminal postsynaptic density protein ligand of neuronal nitric oxide synthase (NOS1)) and PIN (protein inhibitor of NOS1) signaling mechanism. Within the preautonomic neurons of the PVN, the disruption of CAPON and PIN signaling leads to a downregulation of NOS1 expression and reduced NO bioavailability. These data support the notion that CAPON-PIN dysregulation of NO bioavailability is a major contributor to the pathogenesis of sympathoexcitation in heart failure.

Illusions, hallucinations, and visual snow.

Abstract: Illusions and hallucinations are commonly encountered in both daily life and clinical practice. In this chapter, we review definitions and possible underlying mechanisms of these phenomena and then review what is known about specific conditions that are associated with them, including ophthalmic causes, migraine, epilepsy, Parkinson's disease, and schizophrenia. We then discuss specific syndromes including the Charles Bonnet syndrome, visual snow syndrome, Alice in Wonderland syndrome, and peduncular hallucinosis. The scientific study of illusions and hallucinations has contributed significantly to our understanding of how eye and brain process vision and contribute to perception. Important concepts are the distinction between topologic and hodologic mechanisms underlying hallucinations and the involvement of attentional networks. This chapter examines the various ways in which pathological illusions and hallucinations might arise in relation to the phenomenology and known pathology of the various conditions associated with them.

Hypothalamic symptoms of frontotemporal dementia disorders.

Abstract: Frontotemporal dementia (FTD) has traditionally been regarded as a disease of cognition and behavior, but emerging evidence suggests that the disease also affects body functions including changes in eating behavior and metabolism, autonomic function, sleep behavior, and sexual function. Central to these changes are potentially complex neural networks involving the hypothalamus, with hypothalamic atrophy shown in behavioral variant FTD. The physiological changes found in FTD are reviewed and the key neural networks and neuroendocrine changes mediating these changes in function discussed, including the ability to use these changes as biomarkers to aid in disease diagnosis, monitoring disease progression, and as potential treatment targets.

Organization of the neuroendocrine and autonomic hypothalamic paraventricular nucleus

Abstract: A major function of the nervous system is to maintain a relatively constant internal environment. The distinction between our external environment (i.e., the environment that we live in and that is subject to major changes, such as temperature, humidity, and food availability) and our internal environment (i.e., the environment formed by the fluids surrounding our bodily tissues and that has a very stable composition) was pointed out in 1878 by Claude Bernard (1814-1878). Later on, it was indicated by Walter Cannon (1871-1945) that the internal environment is not really constant, but rather shows limited variability. Cannon named the mechanism maintaining this limited variability homeostasis. Claude Bernard envisioned that, for optimal health, all physiologic processes in the body needed to maintain homeostasis and should be in perfect harmony with each other. This is illustrated by the fact that, for instance, during the sleep-wake cycle important elements of our physiology such as body temperature, circulating glucose, and cortisol levels show important variations but are in perfect synchrony with each other. These variations are driven by the biologic clock in interaction with hypothalamic target areas, among which is the paraventricular nucleus of the hypothalamus (PVN), a core brain structure that controls the neuroendocrine and autonomic nervous systems and thus is key for integrating central and peripheral information and implementing homeostasis. This chapter focuses on the anatomic connections between the biologic clock and the PVN to modulate homeostasis according to the daily sleep-wake rhythm. Experimental studies have revealed a highly specialized organization of the connections between the clock neurons and neuroendocrine system as well as preautonomic neurons in the PVN. These complex connections ensure a logical coordination between behavioral, endocrine, and metabolic functions that helps the organism maintain homeostasis throughout the day.