Autonomic-Hypothalamic-Limbic systems

The hypothalamus and brainstem structures are involved in regulating the sleep-wake cycle . Ablative lesions of the preoptic area result in insomnia. Some preoptic neurons appear to be maximally activated during sleep and may inhibit neurons in the posterior hypothalamus (such as tuberomammillary neurons) that contribute to wakefulness. The LHA also contains neurons involved in wakefulness through the secretion of an activating neuropeptide, hypocretin. Neurons of the LHA activate the tuberomammillary neurons as well as the locus coeruleus in the pons, a noradrenergic cell group with widespread projections to all regions of the central nervous system (CNS) and a major role in arousal and wakefulness. Early epidemics of encephalitis lethargica (sleeping sickness) demonstrated damage to the midbrain and posterior regions of the hypothalamus. This scheme is consistent with a role for the posterior hypothalamus in sympathetic activation and arousal and with a role for the anterior and preoptic hypothalamus in parasympathetic activation and quiet, reparative, homeostatic functions. Narcolepsy is a condition of episodic periods of overwhelming daytime drowsiness and then an abrupt episode of sleep, even in the middle of an activity. The person then awakens and feels alert. Nighttime sleep may be disturbed, but this is not the cause of daytime sleep episodes; patients with narcolepsy go into rapid eye movement sleep in a matter of minutes rather than hours. Many stimuli (e.g., intense emotion, excitation, laughter) may precipitate an episode of cataplexy in which the knees give out, the person falls, and an abrupt sleep episode follows. Sleep apnea is a major sleep disorder, often associated with obesity, in which patients have prolonged periods of apnea, followed by gasping and including disturbed sleep and loud snoring. It is a major risk factor for heart disease.

The suprachiasmatic nucleus (SCN) sits just above the optic chiasm and contains the major neurons of the CNS that act as a “pacemaker” system for the control of diurnal, or circadian, rhythms . The intrinsic pacemaker has a cycle that is a bit longer than 24 hours (studied in humans who lived in caves with no external light cues); however, input from the retina to the suprachiasmatic nucleus entrains the diurnal rhythms to a 24-hour period. These diurnal rhythms drive many hormone and metabolic levels (e.g., cortisol is low in the late evening and high in the morning before rising; melatonin is highest in late evening) and physiological functions (blood pressure and core body temperature are lowest in early morning and highest in late afternoon). Superimposed on these diurnal rhythms are broader factors, such as effects of the sleep-wake cycle, life stress, levels of activity, and other environmental factors. Sleep has a particularly important influence on cortisol rhythms. Disrupted or poor sleep habits can ablate the diurnal cortisol rhythm, leading to a propensity for fat to be deposited in a central abdominal location because of the effects of high cortisol levels. This can contribute to the likelihood of metabolic syndrome , with its elevated inflammatory mediators (C-reactive protein and interleukin [IL]-6) and increased risk for cardiovascular disease, stroke, type II diabetes, and many cancers. The SCN is influenced by a host of limbic and other forebrain influences superimposed on diurnal rhythms. The SCN, in turn, has axonal projections to other regions of the hypothalamus, the locus coeruleus, and limbic sites through which the diurnal regulatory control of these hormones and physiological functions is achieved.

The secretion of hormones by the anterior pituitary gland is regulated by releasing factors (hormones) and inhibitory factors (hormones) that are produced by neurons of the hypothalamus and adjacent sites and are secreted by their axons into the hypophyseal portal vasculature for delivery in extraordinarily high concentrations to cells of the anterior pituitary. A well-known releasing factor is corticotropin–releasing hormone or factor (CRH or CRF), produced by parvocellular neurons of the paraventricular nucleus, which regulates subsequent secretion of adrenocorticotropic hormone (ACTH) and cortisol. Another important releasing hormone, growth hormone-releasing hormone, is produced by neurons in the arcuate nucleus and delivered by their axons to the hypophyseal portal system. Somatostatin is a growth hormone-inhibitory hormone and is produced by other neurons in the arcuate nucleus as well as elsewhere. These hormones are regulated by neural connections, hormonal influences, and metabolic factors.

Growth hormone (GH) is released in pulsatile bursts during stage 3 and stage 4 sleep, accounting for 70% of GH release. GH release also is stimulated by exercise, acute stressors, hypoglycemia, and intake of protein, and is suppressed by intake of glucose and many fatty acids. Children who experience emotional deprivation secrete low levels of GH and may fail to grow. Recent studies have shown that mirthful laughter associated with viewing humorous videos markedly stimulates GH secretion and diminishes cortisol and epinephrine secretion. Even more remarkable, when subjects anticipate viewing something humorous, the anticipation itself provokes GH secretion that is as great as or greater than the GH secretion seen in stage 3 and stage 4 sleep.

Sex steroid hormones influence brain development. In a male fetus, the developing testes provide androgens (converted in the brain to estradiol) that influence CNS development in a male pattern during critical developmental periods. All developing fetuses are exposed to maternal estrogen as well as some placental hormones, but the estrogen is bound by alpha-fetoprotein, which protects the female fetus from masculinization by the CNS. One important consequence of fetal exposure to sex steroids is the subsequent hypothalamic control of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland. In females, these hormones are released in a cyclic fashion. In males, FSH and LH are released in steady amounts, a phenomenon dependent upon CNS exposure to estradiol via androgens during fetal development. In the CNS, FSH and LH secretion is controlled by gonadotropin-releasing hormone (GnRH), formerly called luteinizing hormone-releasing hormone. GnRH neurons in the preoptic area project to the contact zone of the median eminence, ending on the hypophyseal-portal vessels. The GnRH neurons are responsive to estrogen in the female brain but not in the male brain, perhaps accounting for the cyclic secretion of FSH and LH in females. The ventromedial (VM) nucleus of the hypothalamus appears to control some aspects of sexual behavior; VM neurons respond to progesterone via receptors in the female brain but not in the male brain. The male brain responds behaviorally to circulating androgens but not to estrogen. Anatomically, preoptic and VM neurons show male-female differences in morphological and synaptic features. A specialized portion of the preoptic area, the sexually dimorphic nucleus, is considerably larger in the male brain than in the female brain, apparently triggered by developmental hormonal exposure.

In the 1930s, James Papez proposed a brain circuit that was viewed as a substrate for control of emotional behavior and later as a substrate for memory, especially for consolidation of immediate and short-term memory into long-term memory. This Papez circuit includes hippocampal formation (especially the subiculum) via the fornix to the mammillary nuclei (especially medial nuclei); via the mammillothalamic tract to the anterior thalamic nuclei; via the internal capsule to the anterior cingulate cortex; and via polysynaptic connections in the cingulum to the entorhinal cortex, subiculum, and hippocampus. This circuit is proposed as a site of major damage in Wernicke-Korsakoff syndrome , a disorder that is commonly seen in chronic alcoholic patients with a vitamin B ₁ (thiamine) deficiency. This syndrome includes Wernicke’s encephalopathy and the memory dysfunction of Korsakoff’s syndrome. Wernicke’s encephalopathy involves a confused and psychotic state involving confabulation (made-up stories derived from a host of confused past memories or experiences), cerebellar ataxia, extraocular and gaze palsies, and nystagmus. Korsakoff amnestic syndrome involves the inability to consolidate immediate and short-term memory into long-term traces (anterograde amnesia) as well as long-term memory loss concerning events that have occurred since the onset of the disease. Degeneration has been described in the mammillary bodies, fornix, hippocampal formation, and anterior and medial dorsal thalamus. However, the extent to which the mammillary nuclei themselves play a role in consolidation of memory traces remains to be shown. Thiamine administration may help to reverse some of the symptoms, but the amnesias may persist. Administration of glucose (carbohydrate loading) without thiamine may cause death as the result of nutritional cardiomyopathy.

The placebo effect is a positive change in a patient’s symptoms or subjective experience, or in a patient’s physiological state, including pain modulation, altered cardiovascular function, and immune reactivity (both innate and acquired), based on the patient’s expectations, interactions with health care personnel and treatments, or administration of medication (e.g., a pill) that normally has little direct pharmacological effects. Negative effects from such expectations or interactions are called a nocebo effect. The placebo effect has been described as “not real, ” “not a medicine,” “based on belief,” and having “no effect on disease processes or illnesses.” However, in pharmaceutical testing of highly reactive medications, it is often observed that the placebo is almost as effective as the pharmacological medication for altering clinical outcomes. Placebo effects, often involving conditioned responses, do indeed alter physiological processes, sometimes profoundly, with effects on disease outcome, as happens with conditioned immune responses in which a “placebo” alters lethal outcomes in experimental models of immune-related diseases (see the work of Robert Ader and Nicholas Cohen).

Placebo effects occur through known pathways and circuitry of the brain, including prefrontal cortex, anterior insular cortex, rostral anterior cingulate cortex, some amygdaloid nuclei, and in the brainstem, the periaqueductal gray. These structures act through influences on autonomic and neuroendocrine outflow, as well as by initiating appropriate behavioral responses. Disruption of these forebrain circuits can prevent the physiological effects of the placebo. Neurotransmitter systems such as endorphins, cannabinoids, dopamine and other catecholamines, and cortisol are involved in mediating placebo effects, and their pharmacological alterations (e.g., naloxone blockade of opioid receptors in placebo administration for pain) can prevent the physiological and behavioral alterations seen in the placebo effect.

Use of placebo effects and acknowledgment of conditioned responses have an important role in clinical medicine and disease treatment. It is likely that many complementary medicine approaches utilize, in part, placebo effects with their appropriate forebrain circuitry and neurotransmitter systems. This is consistent with the “relaxation response” described and documented by Herb Benson and colleagues, and the use of guided imagery, meditation, qi gong, and other parasympathetic-inducing practices.

See references for thoughtful discussions of placebo effect:

Colloca L, Barsky AJ: Placebo and nocebo effects. N Engl J Med 382:555–562, 2020.

Finnias DG, Kaptchuk TJ, Miller FG, Bennetti F: Biological, clinical, and ethical advances of placebo effect. Lancet 375:686-695, 2010.

Kaptchuk TJ, Miller FG: Placebo effects in medicine. N Engl J Med 373:8-9, 2015.

The hypothalamus receives inputs from the hippocampal formation and subiculum, amygdaloid nuclei, habenula, retina, some cortical areas, and many brainstem regions; a good number of these inputs are limbic forebrain and brainstem connections. The role of the hypothalamus is to regulate the visceral milieu and neuroendocrine secretion, particularly via the anterior and posterior pituitary. The efferents of the hypothalamus reflect this role and are directed to the posterior pituitary and contact zone of the median eminence (for control of anterior pituitary hormonal secretion), some limbic forebrain structures, and widespread areas of the brainstem and spinal cord that are involved in autonomic and visceral regulation. These connections help to coordinate appropriate behavioral responses to external and internal inputs and perceived challenges in the environment. The posterior and lateral hypothalamic regions are particularly involved in sympathetic drive and activational responses, such as the acquisition of food and water, the increase of core body temperature, sympathetic arousal, activities involved in aggressive interactions with the environment, and wakefulness states. Many of these activities are coordinated through connections in the median forebrain bundle. In contrast, the anterior and medial hypothalamic regions are particularly involved in parasympathetic functions, such as satiation, decreased core body temperature, quiet and reparative homeostatis-related activities, and sleep. Many of these activities are coordinated through connections in the dorsal longitudinal fasciculus and other descending pathways.

The PVN of the hypothalamus is a small region along the upper borders of the third ventricle in the dorsal hypothalamus. It contains a remarkable array of chemically specific neural populations. The magnocellular neurons produce oxytocin and vasopressin along with neurophysins and project to the median eminence. Some parvocellular neurons synthesize corticotropin-releasing hormone and send axons to the contact zone of the median eminence, where corticotropin- releasing hormone is released into the hypophyseal portal vessels. Parvocellular neurons also send descending projections to the brainstem (particularly the nucleus solitarius) and the intermediolateral cell column of the thoracolumbar spinal cord, where activation of the SNS can occur. The PVN therefore can coordinate the activation of both the neuroendocrine components (hypothalamic-pituitary-adrenal axis and cortisol secretion) and the autonomic components (sympathetic activation, diminished parasympathetic activity) of a stress response or activational response. The PVN receives inputs from many limbic regions and from brainstem sites (parabrachial nuclei, brainstem noradrenergic nuclei, nucleus tractus solitarius) that provide visceral information to the PVN. In addition, the PVN receives a variety of inputs that help it to monitor inflammatory mediators (IL-1β, IL-6, tumor necrosis factor [TNF]-α, prostaglandin E2 [PGE ₂ ]), and other small molecules (nitric oxide) that reflect the outside chemical milieu. This information is received through the hypothalamus and circumventricular organs, and some of it through the vagus nerve afferents and nucleus tractus solitarius. Thus, PVN is a key regulatory site for behavioral responses that require autonomic reactivity.

There is a widespread influence of cytokines , especially inflammatory cytokines (IL-1β, IL-6, TNF-α), as well as prostaglandin E ₂ (PGE ₂ ), on the nervous system. A key target of these influences is the PVN of the hypothalamus. Inflammatory cytokines can provoke a robust activation of cortisol secretion (through the hypothalamo-pituitary-adrenal axis) and SNS activation (via descending projections of the PVN). The consequences of prolonged stress activation include increased risk for many chronic diseases, such as cardiovascular disease and stroke, metabolic syndrome, type II diabetes, and many cancers. The cytokines can influence the PVN and other central neurons through several mechanisms, including some direct transport into the forebrain, actions on neurons of the OVLT that release PGE ₂ and signal the PVN, release of nitric oxide and PGE ₂ from vascular endothelial cells, and activation of vagal afferents and other afferents that send neural signals to the PVN. Inflammatory cytokines also can stimulate the release of some hormones from pituitary cells, can alter neurotransmitter release in both the CNS and the autonomic nervous system (especially sympathetic norepinephrine), and can interact with neurotransmitter effects on target cells of autonomic innervation. Other cytokines such as IL-2 also appear to have central effects; the infusion of IL-2 in immunotherapy for some cancers was curtailed because of adverse effects of IL-2 on the brain, including depression and suicidal behavior.

The CNS is protected from damage caused by many potentially harmful substances in the periphery by the blood-brain barrier. The CNS capillary endothelial cells contain tight junctions as well as specific transport mechanisms for the uptake of certain important substances (such as amino acids needed for neurotransmitter synthesis, glucose). Brain capillaries also can actively pump some substances out of the brain. Some regions of the brain contain fenestrated capillaries, and this permits the sampling of circulating substances. These are the circumventricular organs. The area postrema contains neurons that project to the nucleus tractus solitarius and activate the vomiting reflex. The subfornical organ contains neurons that respond to salt content in the blood and elicit protective neuroendocrine responses. The OVLT contains neurons that help to regulate blood pressure through an angiotensin II mechanism; these neurons also regulate PGE ₂ availability to the PVN and other central areas to influence activation of the hypothalamo-pituitary-adrenal axis and the SNS. The OVLT and subfornical organ also respond to pyrogens and help to regulate hypothalamic responses for control of body temperature. At the median eminence, circulating hormones and other substances can interact with the projecting axonal terminals that secrete releasing hormones and inhibitory hormones at the contact zone for regulation of anterior pituitary hormonal secretion. The posterior pituitary and the pineal gland also have fenestrated capillaries, enabling their secretion of hormones directly into the systemic circulation.