Lateral hypothalamus

lateral hypothalamus

Lateral hypothalamus

Lateral hypothalamus also called the lateral hypothalamic area 1 is considered to be a small (6 × 6 × 3.5 mm) target within the hypothalamus located in the midbrain, lying inferior to the fornix and superoposterior to the optic nerve and chiasm 2, 3. Lateral hypothalamus is divided into three rostro-caudal zones – the anterior lateral hypothalamus, the tuberal lateral hypothalamus, and the posterior lateral hypothalamus 4. The anterior lateral hypothalamus is continuous rostrally with the lateral preoptic area, and extends caudally to the level of the rostral pole of the venteromedial nucleus (VMN). While the tuberal lateral hypothalamus is coextensive with the venteromedial nucleus (VMN), the posterior lateral hypothalamus follows the tuberal division at the level of the mamillary complex 5. The lateral hypothalamus is home to a heterogeneous population of neurons that include both gamma-aminobutyric acid (GABA)-ergic and glutamatergic neurons as well as subpopulations of neurons expressing neuropeptides that have been linked to the modulation of motivated behaviors such as orexin (hypocretin) 6, 7, melanin-concentrating hormone (MCH) 8, cocaine- and amphetamine-regulated transcript (CART)9, neurotensin (NT) 10, leptin receptor 11 and galanin 12, 13. These neurons connect to other brain structures via efferent projections from the lateral hypothalamus to multiple structures including the amygdala, hippocampal formation, thalamus, the pons, brainstem and spinal cord, as well as intra-structural projections within the lateral hypothalamus to other hypothalamic subnuclei 14, 15, 16, 17. The lateral hypothalamus also projects densely onto the ventral tegmental area (VTA) 18, 19.

The large number of inputs, outputs, neuron types and functions present within the lateral hypothalamus suggest that this structure is very complex and hosts an extremely diverse population of neurons, with many neurons co-expressing multiple neuropeptides and projecting to numerous target neural structures 20, 21, moving forward it will be important to gain a more precise understanding of these neurons, projections and functions to better disentangle the many roles of the lateral hypothalamus 20. Interestingly, neurons in the lateral hypothalamus are the largest in the hypothalamus and are topographically well organized 5. Chief among them are the orexin neurons that project widely to the neuraxis and undertake many important functions. A growing body of evidence suggests that orexin neurons play a key role in regulating wakefulness 22, sleep 23, food intake 24, autonomic and endocrine functions 25, reward-related behaviors 26 and pain-related behaviors 27. However, despite significant progress in research, a more refined understanding of the detailed functions of orexin neurons of the lateral hypothalamus in the regulation of inflammatory pain is needed 28.

The lateral hypothalamus has been implicated in numerous functions including sleep-wake transitions 29, 30, 31, feeding 32, energy balance 33, stress 34 and reward 35, 36 and plays a critical role in maintaining physiological and behavioral homeostasis. As well as being dubbed a “feeding center” or “hunger center” by Anand and Brobeck 32, the lateral hypothalamus has also been labeled as a “pleasure center” 37 after it was shown that electrode implantation into the medial forebrain bundle in the lateral hypothalamus resulted in persistent intracranial self-stimulation 38. It has been suggested that this behavior is a result of stimulation of the descending fibers in the medial forebrain bundle that feed into the ventral tegmental area (VTA), likely triggering a reward response 39.

The lateral hypothalamus was discovered to be the source of extensive projections of neurons containing 2 newly discovered neuropeptides: melanin-concentrating hormone and orexin 40, 41. Both neuronal populations have broad projections throughout the central nervous system (CNS), and direct injection of either melanin-concentrating hormone or orexin into the ventricles will cause rats to feed, and these levels increase in rats during periods of starvation 42, 40. Multiple early animal studies demonstrated that low-frequency stimulation of the lateral hypothalamus resulted in an excitatory stimulation of these fibers, with animals demonstrating food-seeking and food-hoarding behavior, increased gastrointestinal blood flow, and activation of vagal pathways 43, 44, 45. In 2007, Sani et al. 46 reported on the use of high-frequency deep brain stimulation (DBS) of the bilateral lateral hypothalamus in 16 rats that resulted in a 2.3% weight loss in stimulated rats and a 13.8% weight gain in unstimulated controls. After lateral hypothalamic damage in rats only simple automatisms (such as grooming, chewing, licking) are present, but intense stimuli can activate more complex actions (walking, orientation, swimming) 47. In the anorexic stage, tactile stimuli dominate in steering locomotion and “spontaneous” locomotion depends on activation from the empty stomach 47.

Anatomical and electrophysiological studies have shown strong neuronal connections between the olfactory system and the hypothalamus 48. Anterograde and retrograde axonal tracing studies have revealed that projections from the olfactory system are more prominent to the lateral hypothalamus than to the thalamus 48. Furthermore, four primary areas in the posterior lateral hypothalamus (anterior olfactory nucleus, olfactory tubercle, piriform cortex, and anterior cortical nucleus of amygdala) were shown to receive this input from the olfactory bulb 48.

The lateral hypothalamus became classically known as the “feeding center” or “hunger center” of the brain after multiple early animal studies demonstrated that bilateral lateral hypothalamus lesions in rats resulted in decreased food intake, weight loss, and decreased food-seeking behavior leading to anorexia, somnolence, akinesia, and sensory neglect combine to produce complete aphagia, indicating the vast importance of lateral hypothalamus circuitry in appetite and/or eating or drinking properties of feeding behavior 49, 50, 51, 52, 53, 54, 55, 56.

Targeted photostimulation of projections from the lateral hypothalamus to the paraventricular hypothalamus in mice elicited voracious feeding and repetitive self-grooming behavior 57. Compared with sham-operated controls, rats with bilateral lateral hypothalamus lesions gained significantly less weight with equal quantities of digested food, and they exhibited increased core body temperature 58, 59.

The first pilot study of bilateral lateral hypothalamus deep brain stimulation (DBS) for obesity in humans was performed in 2013 by Whiting et al. 60. Three patients who met the criteria for morbid obesity, who had had multiple unsuccessful attempts at lifestyle modification, and in whom weight loss surgery (bariatric surgery) had failed underwent stereotactic deep brain stimulation (DBS) electrode placement bilaterally in the lateral hypothalamus 60. The study was primarily focused on safety outcomes, and no serious adverse effects were observed during the mean follow-up of 35 months 60. Transient nausea, anxiety, and temperature change sensations were noted during programming changes but lasted less than 5 minutes. Throughout most of this pilot study, stimulation parameters were set at a frequency of 185 Hz and a pulse width of 90 µsec. The resting metabolic rate was tested systematically using monopolar stimulation at different voltages and electrode contacts to find the optimized stimulation parameters and contacts. Although the study was primarily focused on safety, early data on weight change showed a trend toward weight loss in 2 of the 3 patients at optimized parameters 60. Other studies are currently being completed that examine the effect of different frequencies and pulse widths on resting metabolic rate and sleep energy expenditure, and long-term studies are examining weight changes, effects on comorbidities, and the durability of resting metabolic rate changes 3.

Figure 1. Hypothalamus


Figure 2. Lateral hypothalamus

lateral hypothalamus

Footnote: Hypothalamus is composed of several spatially clustered neural populations. (Left) Location of the hypothalamus at the base of the forebrain. Dashed lines indicate a coronally-cut section of the hypothalamus shown on the right. (Right) Simplified diagram of hypothalamic nuclei involved in feeding behavior and energy metabolism.

Abbreviations: III = third ventricle; arc = arcuate nucleus; DMH = dorsomedial hypothalamus; LH = lateral hypothalamus; PVH = paraventricular hypothalamus; VMH = ventromedial hypothalamus.

[Source 57 ]

Figure 3. Lateral hypothalamus neurons and functions

Lateral hypothalamus neurons and functions

Footnotes: (A) Lateral hypothalamus neuronal subtypes. Simplistic diagram showing existing neuronal populations in the lateral hypothalamus. Neuronal populations in the lateral hypothalamus include, but are not limited to, GABA neurons, glutamate neurons, melanin-concentrating hormone (MCH)-expressing neurons, galanin-expressing neurons, leptin-receptor (LepRb)-expressing neurons, neurotensin-releasing neurons, substance P-releasing neurons and orexin neurons. The degree to which these neuronal populations overlap is not represented in this diagram. (B) Orexin neuron functions. Orexin neurons are involved in numerous physiological and behavioral processes including sleep/wakeful cycles, learning, memory, pain, nociception, food intake, metabolism, stress, energy balance and inflammation.

[Source 28 ]

Lateral hypothalamus function

The lateral hypothalamus is generally known as the hunger center or feeding center, and two of its main functions are the stimulation of feeding behavior and arousal 61, 3, 62. Electrical stimulation of the lateral hypothalamus results in ravenous eating behavior, and animals are extremely motivated to work for a food reward 56. The neurons of the lateral hypothalamus are mainly orexin expressing neurons and they respond to both melanocortins and neuropeptide Y 63, 64. Orexin neurons stimulate wakefulness, and a loss of orexin neurons causes narcolepsy 65, which in turn is associated with increased risk on the development of type 2 diabetes 66. Together, these properties of orexin promote alertness in a fasted state, which is crucial for food-seeking behavior 67. Recent animal studies indicated that the lateral hypothalamus plays a key role in eliciting violent forms of aggression 68, 69, 70, 71, 72

The lateral hypothalamus is also a site for integration of autonomic and endocrine responses, and a crucial regulator of pituitary function and homeostatic balance 73, 74. The lateral hypothalamus plays a key role in regulating autonomic functions and relays information to all major parts of the brain including the major hypothalamic nuclei 75, 56, 76, 77, 78. Converging evidence from functional, structural, and behavioral studies confirmed the importance of this region not only in regulating metabolism and feeding behavior, but also in serving as a motivation-cognition interface 56, 62.

Lateral hypothalamus neurons control feeding, blood pressure, heart rate, water intake and sodium excretion largely through the activation of adrenergic receptors 79, 80, 81. In addition, they receive inhibitory noradrenergic input from the locus coeruleus, which helps prevent excessive activity in the arousal pathway during the waking cycle 82. Also, beta (β)-adrenoceptors activation by noradrenaline in the lateral hypothalamus appears to be involved in the suppression of feeding behavior 83. On the other hand, activation of alpha 1 (α1)-adrenoceptors of the lateral hypothalamus has been linked to behavioral activation and exploration, despite the insignificant number of these receptors in the lateral hypothalamus 84.

The lateral hypothalamus also plays an important role in the brain reward system. This was demonstrated by studies using intracranial self-stimulation in rodents showing that animals will willingly perform an operant response to receive rewarding pulses of electrical stimulation within the lateral hypothalamus 85, 86. The rewarding effect of lateral hypothalamus self-simulation is largely influenced by the dopamine and opioid systems as alterations in these systems were shown to either suppress or disrupt the self-stimulation behavior 87, 86. The lateral hypothalamus, through GABAergic neurons, also plays an important role in learning to respond to cues that predict the delivery of a reward 88. In addition, GABAergic neurons of the lateral hypothalamus highly project to the ventral tegmental area (VTA) 88, a center rich in dopaminergic neurons that is known to be crucial for learning, reward processes and feeding behavior 89, 90.

Recently, many reports have implicated the lateral hypothalamus in the regulation of inflammatory pain 91, 92, 93. Studies have shown that stimulation of the lateral hypothalamus produces analgesic and anti-nociceptive effects in an animal model of inflammatory pain 92 and that this effect is largely due to the activation of α-adrenoceptors in the dorsal horn of the spinal cord 94, 92, and to the involvement of lateral hypothalamic orexin neurons 95.

Ventral tegmental area structure and reward function

The ventral tegmental area (VTA) is a semi-circular nucleus which lies along the midline in the midbrain, it is home to a heterogeneous population of neurons containing multiple neurotransmitters including neurotensin (NT) 96, cholecystokinin (CCK) 97 and dopamine 98. The ventral tegmental area (VTA) dopaminergic system has been implicated in brain-stimulation reward and food reward, psychomotor stimulation, learning and memory formation 99, 100, 101, 102, 103 and it has been shown that goal-directed behavior is promoted by dopamine release from ventral tegmental area (VTA) dopaminergic neurons 104, 105, 106. Studies have shown that both the synaptic connections and intrinsic excitability of dopaminergic neurons are highly plastic dependent on the experiences of the animals 107, 108, 109, 102, 110. This suggests the possibility for experience/outcome-based modulation of behavioral motivation to be mediated via ventral tegmental area (VTA) dopaminergic neurons and a “directing” role for dopamine in goal-oriented behaviors.

Ventral tegmental area (VTA) dopaminergic neuron involvement in reward processing has been studied extensively in an attempt to understand how these neurons code for rewards and the mechanisms through which they are able to modulate animal behaviors. However the complexity of the ventral tegmental area (VTA), as well as the lateral hypothalamus inputs into the ventral tegmental area (VTA), require equally complex methods to investigate specific neuron populations within such heterogeneous neuron populations. Eshel et al. 111 carried out a complex set of experiments using a multi-method approach combining computational modeling, extra-cellular recordings, optogenetics and viral injections to investigate the computational mechanisms by which ventral tegmental area (VTA) dopaminergic neurons calculate reward prediction error. Performing extra-cellular recordings of dopaminergic neurons while delivering expected and unexpected rewards, and using subsequent optogenetic manipulations to investigate the importance of ventral tegmental area (VTA) GABAergic neurons to normal ventral tegmental area (VTA) dopaminergic function. They found that as the size of the reward the animal receives increases, so does the dopaminergic neuron response, which was consistent with previous results 112, 113, they also found that expectation of a reward resulted in a suppression of the dopaminergic neuron response, and that this response fit to a subtractive computational model better than an alternative divisive model 111. Then, Eshel et al. 111 investigated the role of ventral tegmental area (VTA) GABAergic neurons in their subtraction model of ventral tegmental area (VTA) dopaminergic neuron suppression in expected rewards by optogenetically mimicking normal ventral tegmental area (VTA) GABAergic neuron firing patterns and observing ventral tegmental area (VTA) dopaminergic activity. They found that ventral tegmental area (VTA) GABA stimulation resulted in the suppression of dopamine responses to unexpected rewards in a similar pattern to that seen in animals receiving expected rewards. This ventral tegmental area (VTA) GABA-induced suppression of  dopaminergic responses also fit with a subtractive computational model. Additionally, they showed that inhibition of ventral tegmental area (VTA) GABAergic neurons partially reversed the expectation-dependent suppression of ventral tegmental area (VTA) dopamine reward responses. Taken together this suggests that ventral tegmental area (VTA) dopaminergic neurons calculate reward-error using a subtractive model, and that ventral tegmental area (VTA) GABAergic neurons play a role in the temporal expectation modulation of dopamine responses in a manner that is consistent with the ramping expectation function in some models of prediction error computational models 114, 115. This modulation of reward response in the ventral tegmental area (VTA) may play an important role in directing motivated behaviors to rewards that are less predictable over rewards that are more regularly available. This also suggests a mechanism by which ventral tegmental area (VTA) dopaminergic neurons can rationalize between multiple rewards within an environment by modulating the reward value of more reliable rewards to be less rewarding than unpredictable rewards to shift the animals drive to focus on less readily-available rewards. This series of experiments shows the multitude of benefits that can be gained by using a multi-method approach to investigate neural circuits, by using behavioral protocols, optogenetics, electrophysiology and computational modeling (as well as investigating the role of both dopamine and GABA activity for comparison) these researchers were able to gain a deeper understanding of ventral tegmental area (VTA) dopaminergic activity by observing it from multiple angles.

The development of new techniques and biomarkers has allowed a closer look at the roles of different populations of lateral hypothalamus neurons in ventral tegmental area (VTA) function. For example, optogenetic stimulation of lateral hypothalamus GABA inputs to the ventral tegmental area (VTA) results in conditioned place preference 116, reduces ventral tegmental area (VTA) GABA activity, and drives nucleus accumbens dopamine release 117. Nieh et al. 117 additionally showed that optogenetic stimulation of glutamatergic lateral hypothalamus inputs to the ventral tegmental area (VTA) results in conditioned place aversion. Interestingly, the behavioral response to optogenetic stimulation of ventral tegmental area (VTA)-innervating lateral hypothalamus GABAergic neurons differed depending on the stimulation frequency, with low frequency stimulation (5–10 Hz) resulting in increased feeding, and high frequency stimulation (40 Hz) appeared to trigger reward, resulting in a place preference 116. It is possible that these two functions may be being mediated by two different neuropeptides co-expressed within lateral hypothalamus GABAergic neurons, or that this stimulation triggers a general “drive” and the stimulation frequencies result in the release of different neuropeptides in the ventral tegmental area (VTA), resulting in a target for the “drive” response. This could suggest that the lateral hypothalamus and the ventral tegmental area (VTA) are the “drive” and “focus” sources for motivated behaviors, respectively, with lateral hypothalamus activation producing a general energizing of the animal to perform a behavior, and the ventral tegmental area (VTA) then directing that energy to a specific goal-oriented behavior—depending on which neurotransmitters are released, or the stimulation frequency, or some other determining factor. Additionally, the development of this gene-targeting methodology also opens up the possibility to investigate the multiple other neuron types in the lateral hypothalamus that are known to project to the ventral tegmental area (VTA) to better understand how these neuron types differentiate between multiple input signals and determine which environmental goals to pursue 20.

GABA Neurons

Lateral hypothalamus neurons are composed of many overlapping neuronal populations that play distinct functions in the central nervous system (CNS) (Figure 3) 28. Studies over the past few decades have largely focused on the functions of GABAergic neurons of the lateral hypothalamus and their projections in reward and feeding behavior 118. Evidence suggests that these neurons encode information necessary for associating specific cues with reward delivery. In experiments employing optogenetics, a highly specific technique that involves the use of light to activate or inhibit neurons, inhibition of lateral hypothalamus GABAergic neurons was shown to reduce responding to a cue predicting a food reward, indicating that these neurons encode information pertaining to reward prediction 88. On the other hand, optogenetic inhibition of lateral hypothalamus GABA neurons that project to the ventral tegmental area (VTA) increased responding to the food reward-paired cue, suggesting that these neurons may play a role in relaying reward-predictive information to other neuronal structures 88. Interestingly, a study evaluating the role of lateral hypothalamus GABA neurons projecting to the ventral tegmental area (VTA) showed that optogenetic activation of this pathway can either induce a feeding or rewarding effect depending on the frequency of the stimulation used 119. Last but not least, a recent study by Giardino et al. 120 found that the bed nucleus of the stria terminalis sends two non-overlapping GABAergic projections to the lateral hypothalamus that express several neuropeptides including corticotropin-releasing factor (CRF) and cholecystokinin (CCK).

Glutamate Neurons

Glutamate neurons of the lateral hypothalamus mediate important physiological processes in the central nervous system (CNS). Studies have shown that lateral hypothalamus glutamate neurons produce behavioral functions opposite to those of lateral hypothalamus GABAergic neurons. In mice, optogenetic activation of putative glutamate neurons of the lateral hypothalamus suppressed feeding and produced aversion-related phenotypes 121, while the opposite effect was observed following optogenetic or chemogenetic activation of lateral hypothalamus GABA neurons 122. The opposite functions of lateral hypothalamus glutamate and GABA neurons in feeding and reward-related processes are mainly explained by differences in their projection pattern. Glutamate neurons of the lateral hypothalamus send dense projections to the lateral habenula (LHb), a region involved in processing aversive stimuli 123, in contrast to lateral hypothalamus GABA neurons, whose projections mainly target the ventral tegmental area (VTA) 119. Besides its role in the regulation of feeding and aversion-related behaviors, lateral hypothalamus glutamate neurons have been implicated in compulsive 124 and hyperkinetic behaviors 125.

Melanin-Concentrating Hormone (MCH)-Expressing Neurons

Neurons expressing melanin-concentrating hormone (MCH) are also widely present in the lateral hypothalamus. Functional and anatomical studies showed that melanin-concentrating hormone (MCH) neurons co-express the vesicular glutamate transporter 2 (VGLUT2), indicating a glutamatergic identity 125 and project to several regions of the central nervous system (CNS) ranging from the cortex to the spinal cord 126. Melanin-concentrating hormone (MCH) is an appetite stimulant (orexigenic) hypothalamic peptide that exerts inhibitory effects on lateral hypothalamic neurons 127. Although the mechanism of action of melanin-concentrating hormone (MCH) is yet to be fully determined, its inhibitory effect on lateral hypothalamus neurons is largely mediated by the attenuation of excitatory glutamate transmission presynaptically 127. Melanin-concentrating hormone (MCH) was also shown to depress synaptic activity of lateral hypothalamus GABA neurons, suggesting a substantial level of complexity in its modulation of lateral hypothalamus neuron activity 128. Mounting evidence suggests that MCH neurons directly regulate feeding behavior. Both administration of melanin-concentrating hormone (MCH) 129, 130 and activation of MCH receptors 131 increases food intake and facilitates body weight gain in rodents. Conversely, genetic knockout of the MCH gene 132 or pharmacological blockade of MCH receptors 131 leads to substantial decreases in food intake in mice. In addition, through their direct projections to gonadotropin-releasing hormone (GnRH) synthesizing neurons, melanin-concentrating hormone (MCH) neurons convey critical homeostatic signals to the reproductive axis, and contribute considerably to the functional connection between the regulation of food intake and reproduction 128, 133.

Galanin and Leptin-Receptor Expressing Neurons

Another type of neuron found in the lateral hypothalamus is the galanin-containing neuron 134. These neurons represent a GABAergic subpopulation of lateral hypothalamus neurons with a distinct molecular phenotype and projection pattern. Unlike GABAergic neurons of the lateral hypothalamus, which project to the ventral tegmental area (VTA), galanin neurons of the lateral hypothalamus lack direct ventral tegmental area (VTA) innervation 134. Instead, galanin neurons of the lateral hypothalamus strongly innervate the locus coeruleus 135, a site involved in the control of arousal 136, 137 and reward processing 138, 139. Galanin is a 29 amino acid neuropeptide widely distributed in the brain 140, 141, 142 that acts as an inhibitor of synaptic transmission in the hypothalamus 143. Galanin also acts in the hypothalamus to produce behavioral hyperalgesia through activation of two descending pronociceptive pathways; one that involves the medullary dorsal reticular nucleus, and another one that involves serotonin neurons acting on the spinal cord 144. Galanin has also been reported to promote feeding behavior. Chemogenetic activation of lateral hypothalamus galanin neurons 134 or central injection of galanin 145 enhances food-seeking behavior, while targeted knockout of the galanin gene 146 or the galanin receptor 147 reduces dietary fat intake.

Another neuronal population of the lateral hypothalamus involved in the regulation of feeding behaviors is the leptin-receptor (LepRb) expressing neuron. LepRb-expressing neurons are widely expressed in the brain, but are particular enriched within the hypothalamus and the brainstem 148. In mice, leptin acts on leptin-receptor (LepRb)-expressing neurons of the lateral hypothalamus to decrease feeding and body weight 149. Leptin-receptor (LepRb)-expressing neurons of the lateral hypothalamus also innervate the ventral tegmental area (VTA), and leptin action on these neurons increases ventral tegmental area (VTA) dopaminergic neuron activity, suggesting a link between the anorexic effect of leptin and the mesolimbic dopaminergic system 149. Interestingly, leptin-receptor (LepRb)-expressing neurons in the lateral hypothalamus are thought to be GABAergic 149, and a subpopulation of these neurons in the lateral hypothalamus was shown to co-express the inhibitory acting neuropeptide galanin 150, suggesting that the anorexic effect of leptin is likely due to its interaction with other neuropeptidergic receptors in the lateral hypothalamus.

Substance P and Neurotensin-Releasing Neurons

Substance P and neurotensin-releasing neurons are also found in the lateral hypothalamus 151, 152. Substance P is a member of the tachykinin neuropeptide family and is associated with multiple physiological processes including wound healing, neurogenic inflammation and tissue homeostasis 153. In the lateral hypothalamus, substance P-containing neurons have been proposed to exert antinociceptive functions by activating spinally projecting serotonin neurons in the rostral ventromedial medulla (RVM) 91. These cells activate spinally projecting serotonin neurons either through direct contact, or indirectly through the innervation of interneurons in the rostral ventromedial medulla (RVM), thereby altering nociceptive responses in the dorsal horn of the spinal cord 91.

On the other hand, neurotensin neurons of the lateral hypothalamus are involved in the regulation of the sleep/wake cycle 154 and are implicated in feeding behavior 155 and reward processes 156. Studies exploring the role of neurotensin in reward and feeding have indicated that this neuropeptide promotes reward by enhancing glutamate transmission in the mesolimbic dopaminergic system 156 and promotes weight loss by suppressing the increased appetitive drive through activation of the G-protein-coupled neurotensin receptor-1 155. Finally, neurotensin neurons of the lateral hypothalamus have been implicated in a number of other physiological processes, including hyperthermia and energy balance, though the central mechanisms by which these processes are mediated remain to be fully elucidated 157, 158.

Orexin Neurons and Other Neuronal Populations of the lateral hypothalamus

By being an extensively researched population of cells in the past recent years, orexinergic neurons, and especially those of the lateral hypothalamus, have been shown to have different roles in inflammatory pain and in the balance of psychological functions (Figure 3B). Orexinergic neurons synthesize two neuropeptides (Orexin A and B) from the precursor prepro-orexin 159. Furthermore, inhibition of orexin neurons by local GABAergic neurons of the lateral hypothalamus is thought to disrupt the sleep cycle (Ferrari et al., 2018). On the other hand, inhibition of orexin neurons through activation of acetylcholine and dynorphin promotes wakefulness 160.

Other neuronal populations in the lateral hypothalamus not mentioned above include neurons that express cocaine- and amphetamine-regulated transcript, thyrotropin-releasing hormone, encephalin, urocortin-3 and corticotropin-releasing hormone 161, 162.

Orexin Neurons

Orexin also known as hypocretin, is a neuropeptide secreted by orexin neurons in the lateral hypothalamic area. They are two types of orexin; orexin A (hypocretin-1) and orexin B (hypocretin-2). These neuropeptides originate from the same precursor known as prepro-orexin 159. Orexin-A is a 33-amino-acid peptide while orexin-B is a 28-amino-acid peptide 159. Both orexin A and orexin B bind to the G-protein coupled receptors orexin receptor 1 (OX-1) and 2 (OX-2) (also known as hypocretin receptors type 1 and 2) 163. Orexin A binds to both OX-1 and OX-2 with the same affinity while orexin B has a higher affinity for OX-2 over OX-1 receptors 164.

In the central nervous system (CNS), orexin (hypocretin) is co-localized with other transmitters, some of which include dynorphin 165, glutamate 166, 167, galanin 168 and prolactin 169. Experiments employing in situ hybridization and immunohistochemical techniques indicate that orexin neurons in the lateral hypothalamus mostly express the vesicular glutamate transporters, VGLUT1 and VGLUT2, suggesting that they are glutamatergic 170.

Orexin neurons project their axons to most parts in the brain and spinal cord, especially to areas that are involved in the modulation of pain 171. In addition, orexin neurons in the lateral hypothalamus send projections to multiple sites related to arousal including the serotonergic dorsal raphe 172. Orexin neurons also project to the tuberomammillary nucleus (TMN) 167, a center involved in the control of arousal, learning and memory 173, 174. Pre-synaptically, orexin increases the release of glutamate and GABA in the hypothalamus, while post-synaptically, it increases Ca2+ levels, thus leading to the depolarization, hence activation, of tuberomammillary nucleus (TMN neurons by glutamatergic orexin terminals 167.

Last but not least, orexin neurons have been shown to directly interact with neuropeptide Y (NPY), a peptide that plays a role in the regulation of feeding behavior, metabolism and energy balance 175. This neuropeptide is primarily synthesized by neurons in the arcuate nucleus (ARC) and is present in different areas of the brain including the cortex, hippocampus, hindbrain and hypothalamus 175. Through its heavy projections to the arcuate nucleus (ARC) 176, orexin neurons interact with neuropeptide Y (NPY) to regulate numerous physiological processes and behaviors including food intake and calcium signaling 177, 178.

The distribution of OX-1 and OX-2 receptors has been established in different species including rats and mice. Studies employing in situ hybridization, immunohistochemistry and quantitative reverse transcription–polymerase chain reaction in rodents found that these receptors are widely distributed throughout the brain and spinal cord 179, 180. Although some overlap exist in the distribution pattern of OX-1 and OX-2 receptors, these receptors are differentially expressed in the central nervous system (CNS) 179, 181.

OX-1 receptors are primarily expressed in the ventromedial hypothalamic nucleus, prefrontal and infralimbic cortex, hippocampus, paraventricular thalamic nucleus, dorsal raphe, and locus coeruleus 179, 181, 180, and to a lesser extent in the medial preoptic area, lateroanterior and dorsomedial hypothalamic nuclei, lateral mammillary nucleus and posterior hypothalamic area 179. They are also found in the periaqueductal gray and dorsal root ganglia, which suggests a role in the regulation of pain 180, 182, and in the spinal cord, which suggests a role in the regulation of the parasympathetic and sympathetic system 180. On the other hand, OX-2 receptors are predominantly expressed in the tuberomammillary nucleus (TMN), paraventricular nucleus (PVN), cerebral cortex, nucleus accumbens (NAc), subthalamic and paraventricular thalamic nuclei, septal nuclei, raphe nuclei, and anterior pretectal nucleus, and to a lesser extent in the ventromedial/dorsomedial hypothalamic nuclei and the posterior and lateral hypothalamic areas 179, 181.

Interestingly, a study examining the expression of OX-1 and OX-2 receptors mRNA with in situ hybridization in rats and mice found some species-specific differences 183. For instance, OX-1 receptors are expressed in the caudate putamen and ventral tuberomammillary nucleus (TMN) in rats only, while they are detected in the bed nucleus of the stria terminalis, medial division, posteromedial part in mice only 183. On the other hand, OX-2 receptors show similar pattern of expression between the two species, though they are more widely expressed in the ventral tuberomammillary nucleus (TMN) of rats compared to mice 183. This differential distribution of orexin receptors is consistent with the proposed multifaceted roles of orexin in regulating homeostasis and other functions in the central nervous system (CNS).

Orexin A and B neuropeptides, as demonstrated in the literature, are also widely expressed in different regions of the brain and spinal cord. Findings from immunohistochemical and radioimmunoassay techniques indicate that orexin A fibers are found throughout the hypothalamus, septum, thalamus, locus coeruleus and spinal cord, and in the paraventricular and supraoptic nucleus 184, 185, 186, 187. In addition, orexin A fibers colocalize with substance P positive afferents of dorsal root ganglia neurons, which further strengthens its confirmed role in the regulation of pain 188. On the other hand, orexin B fibers are distributed sparsely in the hypothalamus and the spinal cord 184, 185, but are absent in the paraventricular and supraoptic nucleus 187. Interestingly, a study investigating the distribution of orexin A and orexin B in the brain of nocturnal and diurnal rodents found striking differences among species, in particular in the lateral mammillary nucleus, ventromedial hypothalamic nucleus and flocculus 187.

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BrainConditions & DiseasesInfectious DiseaseNervous System

Encephalitis in children

Encephalitis in children

Encephalitis in children

Encephalitis is a term used to describe inflammation of the brain. The inflammation causes the brain to swell, which leads to changes in the child’s neurological condition, including mental confusion and seizures. Encephalitis can be life threatening and requires urgent treatment in hospital.

It’s not always clear what causes encephalitis, but it can be caused by:

  • viral infections – several common viruses can spread to the brain and cause encephalitis in rare cases, including the herpes simplex virus (which causes cold sores and genital herpes) and the chickenpox virus
  • a problem with the immune system, the body’s defence against infection – sometimes something goes wrong with the immune system and it mistakenly attacks the brain, causing it to become inflamed
  • bacterial or fungal infections – these are much rarer causes of encephalitis than viral infections

Some types of encephalitis are spread by mosquitoes (such as Japanese encephalitis), ticks (such as tick-borne encephalitis) and mammals (such as rabies).

You cannot catch encephalitis from someone else.

Encephalitis often causes only mild flu-like signs and symptoms such as a fever or headache or no symptoms at all. Sometimes the flu-like symptoms are more severe. Encephalitis can also cause confused thinking, seizures, or problems with movement or with senses such as sight or hearing.

In some cases, encephalitis can be life-threatening. Timely diagnosis and treatment are important because it’s difficult to predict how encephalitis will affect each individual.

Encephalitis needs to be treated in a hospital. The earlier treatment is started, the more successful it’s likely to be.

Specific treatment for encephalitis will be determined by your child’s doctor based on:

  • Your child’s age, overall health, and medical history
  • The extent of the condition
  • Your child’s tolerance for specific medications, procedures, or therapies
  • Expectations for the course of the condition
  • Your opinion or preference

The key to treating encephalitis is early detection and treatment. A child with encephalitis requires immediate hospitalization and close monitoring. Sometimes, depending on what doctors think the specific cause of the encephalitis is, certain medications can be used to fight infections that may cause it.

The goal of treatment is to reduce the swelling in the head and to prevent other related complications. Medications to control the infection, seizures, fever, or other conditions may be used.

The extent of the problem is dependent on the severity of the encephalitis and the presence of other organ system problems that could affect the child. In severe cases, a breathing machine may be required to help the child breathe easier.

Treatment depends on the underlying cause, but may include:

  • antiviral medicines
  • steroid injections
  • treatments to help control the immune system
  • antibiotics or antifungal medicines
  • painkillers to reduce discomfort or a high temperature
  • medicine to control seizures or fits
  • support with breathing, such as oxygen through a face mask or a breathing machine (ventilator)

As the child recovers, physical, occupational, or speech therapy may be necessary to help the child regain muscle strength and/or speech skills.

How long someone with encephalitis needs to stay in hospital can range from a few days to several weeks or even months.

Your health care team will educate you and your family after hospitalization on how to best care for your child at home and outlines specific clinical problems that require immediate medical attention by his or her doctor. A child with encephalitis requires frequent medical evaluations following hospitalization.

When to see a doctor

Get immediate care if you are experiencing any of the more-severe symptoms associated with encephalitis. A severe headache, fever and altered consciousness require urgent care.

Infants and young children with any signs or symptoms of encephalitis should receive urgent care.

Is encephalitis contagious?

Brain inflammation itself is not contagious. But the viruses that cause encephalitis can be. Of course, getting a virus does not mean that someone will develop encephalitis.

Encephalitis in children causes

There are more than 100 different recognized causes that can lead to encephalitis in children and many of these differ with respect to the season, the area of the country, and the exposure of the child. According to a new review of medical records 1, viral, bacterial and autoimmune causes account for most cases of encephalitis in children, but more than four in 10 have no recognized cause.

Viruses are the leading cause of encephalitis. Although vaccines for many viruses, including measles, mumps, rubella, and chickenpox have greatly lowered the rate of encephalitis from these diseases, other viruses can cause encephalitis. These include herpes simplex virus (HSV), human herpesvirus 6 (HHV-6), West Nile virus (carried by mosquitoes), varicella zoster virus and rabies (carried by a number of different animals).

Encephalitis can also occur following a bacterial infection, such as Bartonella henselae (the cause of cat scratch fever), Lyme disease (carried by ticks), Streptococcus pneumoniae, Rickettsia rickettsii (the cause of Rocky Mountain spotted fever), tuberculosis and syphilis, and by parasites, such as toxoplasmosis (carried by cats).

Autoimmune and immune-mediated causes of encephalitis represented 45% of all patients with an identified etiology. The most frequently identified single cause in this group was anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis 2. Second most common was acute disseminated encephalomyelitis (ADEM) 2.

Male patients were more likely to present with infectious causes, whereas female patients were more likely to have autoimmune causes. The proportion of autoimmune cases relative to infectious cases increased with increasing age.

Compared with autoimmune encephalitis, infectious encephalitis was more likely to occur in immunocompromised patients and to be associated with abnormal brain MRI findings.

Common viral causes

The viruses that can cause encephalitis include:

  • Herpes simplex virus (HSV). Both HSV type 1 — associated with cold sores and fever blisters around your mouth — and HSV type 2 — associated with genital herpes — can cause encephalitis. Encephalitis caused by HSV type 1 is rare but can result in significant brain damage or death.
  • Other herpes viruses. These include the Epstein-Barr virus, which commonly causes infectious mononucleosis, and the varicella-zoster virus, which commonly causes chickenpox and shingles.
  • Enteroviruses. These viruses include the poliovirus and the coxsackievirus, which usually cause an illness with flu-like symptoms, eye inflammation and abdominal pain.
  • Mosquito-borne viruses. These viruses can cause infections such as West Nile, La Crosse, St. Louis, western equine and eastern equine encephalitis. Symptoms of an infection might appear within a few days to a couple of weeks after exposure to a mosquito-borne virus.
  • Tick-borne viruses. The Powassan virus is carried by ticks and causes encephalitis in the Midwestern United States. Symptoms usually appear about a week after a bite from an infected tick.
  • Rabies virus. Infection with the rabies virus, which is usually transmitted by a bite from an infected animal, causes a rapid progression to encephalitis once symptoms begin. Rabies is a rare cause of encephalitis in the United States.
  • Childhood infections. Common childhood infections — such as measles (rubeola), mumps and German measles (rubella) — used to be fairly common causes of secondary encephalitis. These causes are now rare in the United States due to the availability of vaccinations for these diseases.

Encephalitis in children prevention

It’s not always possible to prevent encephalitis, but some of the infections that cause it can be prevented with vaccinations. Keep your own and your children’s vaccinations current. Before traveling, talk to your doctor about recommended vaccinations for different destinations.

Vaccinations include the:

  • measles, mumps and rubella (MMR) vaccine – a routine vaccination offered to all children in England
  • Japanese encephalitis vaccine – recommended for travelers to at-risk areas, such as parts of Asia
  • tick-borne encephalitis vaccine – recommended for travelers to certain parts of Europe (but not the UK) and Asia
  • rabies vaccination – recommended for travelers to at-risk areas where access to medical care is likely to be limited

Speak to a doctor if you’re not sure whether your vaccinations are up to date, or you’re planning to travel abroad and do not know if you need any vaccinations.

The best way to prevent viral encephalitis is to take precautions to avoid exposure to viruses that can cause the disease.

  • Practice good hygiene. Wash hands frequently and thoroughly with soap and water, particularly after using the toilet and before and after meals.
  • Don’t share utensils. Don’t share tableware and beverages.
  • Teach your children good habits. Make sure they practice good hygiene and avoid sharing utensils at home and school.

Protection against mosquitoes and ticks

To minimize your exposure to mosquitoes and ticks:

  • Dress to protect yourself. Wear long-sleeved shirts and long pants if you’re outside between dusk and dawn when mosquitoes are most active, and when you’re in a wooded area with tall grasses and shrubs where ticks are more common.
  • Apply mosquito repellent. Chemicals such as DEET can be applied to both the skin and clothes. To apply repellent to your face, spray it on your hands and then wipe it on your face. If you’re using both sunscreen and a repellent, apply sunscreen first.
  • Use insecticide. The Environmental Protection Agency recommends the use of products containing permethrin, which repels and kills ticks and mosquitoes. These products can be sprayed on clothing, tents and other outdoor gear. Permethrin shouldn’t be applied to the skin.
  • Avoid mosquitoes. Refrain from unnecessary activity in places where mosquitoes are most common. If possible, avoid being outdoors from dusk till dawn, when mosquitoes are most active. Repair broken windows and screens.
  • Get rid of water sources outside your home. Eliminate standing water in your yard, where mosquitoes can lay their eggs. Common problems include flowerpots or other gardening containers, flat roofs, old tires and clogged gutters.
  • Look for outdoor signs of viral disease. If you notice sick or dying birds or animals, report your observations to your local health department.

Protection for young children

Insect repellents aren’t recommended for use on infants younger than 2 months of age. Instead, cover an infant carrier or stroller with mosquito netting.

For older infants and children, repellents with 10% to 30% DEET are considered safe. Products containing both DEET and sunscreen aren’t recommended for children because reapplication — which might be necessary for the sunscreen component — will expose the child to too much DEET.

Tips for using mosquito repellent with children include:

  • Always assist children with the use of mosquito repellent.
  • Spray on clothing and exposed skin.
  • Apply the repellent when outdoors to lessen the risk of inhaling the repellent.
  • Spray repellent on your hands and then apply it to your child’s face. Take care around the eyes and ears.
  • Don’t use repellent on the hands of young children who may put their hands in their mouths.
  • Wash treated skin with soap and water when you come indoors.

Encephalitis in children symptoms

Encephalitis sometimes starts off with flu-like symptoms, such as a high temperature and headache.

Encephalitis often is preceded by a viral illness, such as an upper respiratory infection, or a gastrointestinal problem, such as diarrhea, nausea, or vomiting. The following are the most common symptoms of encephalitis. However, each child may experience symptoms differently. Symptoms may include:

  • Fever
  • Headache (or bulging of the fontanelles, the soft spots on a baby’s head)
  • Sensitivity to light
  • Neck stiffness
  • Sleepiness or lethargy
  • Increased irritability
  • Seizures or fits
  • Skin rashes
  • Difficulty talking and speech changes
  • Changes in alertness, confusion, or hallucinations
  • Confusion or disorientation
  • Changes in personality and behavior
  • Weakness or loss of movement in some parts of the body
  • Loss of energy
  • Loss of appetite
  • Unsteady gait
  • Nausea and vomiting
  • Loss of consciousness

The symptoms of encephalitis may resemble other problems or medical conditions. Call for an ambulance immediately if you or someone else has these symptoms.

Symptoms of encephalitis may be mild to begin with, but can become more serious over hours or days.

Occasionally the symptoms may develop gradually over several weeks or even months.

Early symptoms

The first symptoms of encephalitis can be similar to flu, such as:

  • a high temperature
  • a headache
  • feeling and being sick
  • aching muscles and joints

Some people may also have a spotty or blistery rash on their skin.

But these early symptoms do not always appear and sometimes the first signs of encephalitis may be more serious symptoms.

Serious symptoms

More severe symptoms develop when the brain is affected, such as:

  • confusion or disorientation
  • drowsiness
  • seizures or fits
  • changes in personality and behavior, such as feeling very agitated
  • difficulty speaking
  • weakness or loss of movement in some parts of the body
  • seeing and hearing things that are not there (hallucinations)
  • loss of feeling in certain parts of the body
  • uncontrollable eye movements, such as side-to-side eye movement
  • eyesight problems
  • loss of consciousness

There may also be symptoms of meningitis, such as a severe headache, sensitivity to bright lights, a stiff neck and a spotty rash that does not fade when a glass is pressed against it.

Call your local emergency services number immediately to request an ambulance if you or someone else has serious symptoms of encephalitis.

It’s a medical emergency that needs to be seen in hospital as soon as possible.

Pediatric encephalitis common complications

Encephalitis can damage the brain and cause long-term problems including:

  • memory problems
  • personality and behavioral changes
  • speech and language problems
  • swallowing problems
  • repeated seizures or fits – known as epilepsy
  • emotional and psychological problems, such as anxiety, depression and mood swings
  • problems with attention, concentrating, planning and problem solving
  • problems with balance, co-ordination and movement
  • persistent tiredness

These problems can have a significant impact on the life of the affected person, as well as their family, friends and carers.

Inflammation can injure the brain, possibly resulting in a coma or death.

Encephalitis in children diagnosis

The diagnosis of encephalitis is made after the sudden or gradual onset of specific symptoms and after diagnostic testing. During the examination, your child’s doctor obtains a complete medical history of your child, including his or her immunization history. Your child’s doctor may also ask if your child has recently had a cold or other respiratory illness, or a gastrointestinal illness, and if the child has recently had a tick bite, has been around pets or other animals, or has traveled to certain areas of the country.

Diagnostic tests that may be performed to confirm the diagnosis of encephalitis may include the following:

  • X-ray. A diagnostic test that uses invisible electromagnetic energy beams to produce images of internal tissues, bones, and organs onto film.
  • Magnetic resonance imaging (MRI). A diagnostic procedure that uses a combination of large magnets, radiofrequencies, and a computer to produce detailed images of organs and structures within the body.
  • Computed tomography scan (also called a CT or CAT scan). A diagnostic imaging procedure that uses a combination of X-rays and computer technology to produce horizontal, or axial, images (often called slices) of the body. A CT scan shows detailed images of any part of the body, including the bones, muscles, fat, and organs. CT scans are more detailed than general X-rays.
  • Blood tests
  • Urine and stool tests
  • Sputum culture. A diagnostic test performed on the material that is coughed up from the lungs and into the mouth. A sputum culture is often performed to determine if an infection is present.
  • Electroencephalogram (EEG). A procedure that records the brain’s continuous, electrical activity by means of electrodes attached to the scalp.
  • Lumbar puncture (spinal tap). A special needle is placed into the lower back, into the spinal canal. This is the area around the spinal cord. The pressure in the spinal canal and brain can then be measured. A small amount of cerebral spinal fluid (CSF) can be removed and sent for testing to determine if there is an infection or other problems. CSF is the fluid that bathes your child’s brain and spinal cord.
  • Brain biopsy. In rare cases, a biopsy of affected brain tissue may be removed for diagnosis.

Encephalitis in children treatment

Encephalitis needs to be treated urgently. Treatment involves tackling the underlying cause, relieving symptoms and supporting bodily functions.

It’s treated in hospital – usually in an intensive care unit (ICU), which is for children who are very ill and need extra care.

How long someone with encephalitis needs to stay in hospital can range from a few days to several weeks or even months.

Treating the cause

If a cause of encephalitis is found, treatment will start straight away.

Possible treatments include:

  • antiviral medicine – used if encephalitis is caused by the herpes simplex or chickenpox viruses; it’s usually given into a vein three times a day for 2 to 3 weeks.
    • Antiviral medications commonly used to treat encephalitis include:
      • Acyclovir (Zovirax)
      • Ganciclovir (Cytovene)
      • Foscarnet (Foscavir)
    • Some viruses, such as insect-borne viruses, don’t respond to these treatments. But because the specific virus may not be identified immediately or at all, doctors often recommend immediate treatment with acyclovir. Acyclovir can be effective against HSV, which can result in significant complications when not treated promptly.
    • Antiviral medications are generally well tolerated. Rarely, side effects can include kidney damage.
  • steroid injections – used if encephalitis is caused by a problem with the immune system and sometimes in cases linked to the chickenpox virus; treatment is usually for a few days
  • immunoglobulin therapy – medicine that helps control the immune system
  • plasmapheresis – a procedure which removes the substances that are attacking the brain from the blood
  • surgery to remove abnormal growths (tumors) – if encephalitis was triggered by a tumor somewhere in the body
  • antibiotics or antifungal medicine – used if encephalitis is caused by a bacterial or fungal infection

If there’s no treatment for the underlying cause, treatment is given to support the body, relieve symptoms, and allow the best chance of recovery.

Supportive care

Encephalitis puts a lot of strain on the body and can cause a range of unpleasant symptoms.

Most children need treatment to relieve these symptoms and to support certain bodily functions until they’re feeling better.

This may involve:

  • fluids given into a vein to prevent dehydration
  • painkillers to reduce discomfort or a high temperature
  • medicine to control seizures or fits
  • medicine to help the person relax if they’re very agitated
  • oxygen given through a face mask to support the lungs – sometimes a machine called a ventilator may be used to control breathing
  • medicine to prevent a build-up of pressure inside the skull

Occasionally, surgery to remove a small piece of the skull may be needed if the pressure inside increases and medicine is not helping.

Follow-up therapy

If you experience complications of encephalitis, you might need additional therapy, such as:

  • Physical therapy to improve strength, flexibility, balance, motor coordination and mobility
  • Occupational therapy to develop everyday skills and to use adaptive products that help with everyday activities
  • Speech therapy to relearn muscle control and coordination to produce speech
  • Psychotherapy to learn coping strategies and new behavioral skills to improve mood disorders or address personality changes

Encephalitis in children prognosis

Encephalitis is a serious condition and, although some children will make a good recovery, it can cause persistent problems and can be fatal.

For example, encephalitis due to the herpes simplex virus (the most common type of encephalitis) is fatal in 1 in 5 cases even if treated, and causes persistent problems in around half the children who have it.

The chances of successful treatment are much better if encephalitis is diagnosed and treated quickly.

Some children eventually make a full recovery from encephalitis, although this can be a long and frustrating process.

Some children never make a full recovery and are left with long-term problems caused by damage to their brain.

Common complications include:

  • memory loss
  • frequent seizures or fits
  • personality and behavioral changes
  • problems with attention, concentration, planning and problem solving
  • persistent tiredness

These problems can have a significant impact on the life of the affected person, as well as their family and friends.

But help and support is available.

Support and rehabilitation

Recovering from encephalitis can be a long, slow and difficult process. Many children will never make a full recovery.

Specialized services are available to aid recovery and help the person adapt to any persistent problems – this is known as rehabilitation.

This may involve support from:

  • a neuropsychologist – a specialist in brain injuries and rehabilitation
  • an occupational therapist – who can identify problem areas in the person’s everyday life and work out practical solutions
  • a physiotherapist – who can help with movement problems
  • a speech and language therapist – who can help with communication

Before leaving hospital, the health and care needs of the affected person will be assessed and an individual care plan drawn up to meet those needs.

This should involve a discussion with the affected person and anyone likely to be involved in their care, such as close family members.

  1. Infectious and Autoimmune Causes of Encephalitis in Children. Timothy A. Erickson, Eyal Muscal, Flor M. Munoz, Timothy Lotze, Rodrigo Hasbun, Eric Brown, Kristy O. Murray. Pediatrics Jun 2020, 145 (6) e20192543; DOI: 10.1542/peds.2019-2543
  2. de Bruijn MAAM, Bruijstens AL, Bastiaansen AEM, et al. Pediatric autoimmune encephalitis: Recognition and diagnosis. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e682. Published 2020 Feb 11. doi:10.1212/NXI.0000000000000682
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BrainNervous System

Human brain

human brain

Human brain

The human brain is a component of the central nervous system. The human brain is roughly the size of two clenched fists and weighs about 1.6 kg (3.5 lb) in men and 1.45 kg in women 1. The difference between the sexes is proportional to body size, not intelligence. The organs of the central nervous system (CNS) can be divided into two groups, the brain and the spinal cord.

Anatomists conceptually divide the brain into four major parts—

  • The Cerebrum.
  • The Diencephalon (thalamus, hypothalamus, and epithalamus).
  • The Cerebellum.
  • The Brainstem.


The cerebrum is the large, outer part of the brain. The cerebrum is about 83% of the brain’s volume and consists of a pair of half globes called the cerebral hemispheres. Each hemisphere is marked by thick folds called gyri (singular, gyrus) separated by shallow grooves called sulci (singular, sulcus). A very deep median groove, the longitudinal fissure, separates the right and left hemispheres from each other. At the bottom of this fissure, the hemispheres are connected by a thick bundle of nerve fibers called the corpus callosum—a prominent landmark for anatomical description with a distinctive C shape in sagittal section.

The cerebral hemispheres control reasoning, thought, emotion, and language. It is also responsible for planned (voluntary) muscle movements (throwing a ball, walking, chewing, etc.) and for taking in and interpreting sensory information such as vision, hearing, smell, touch, and pain.

Figure 1. Human brain

human brain


The cerebellum occupies the posterior cranial fossa inferior to the cerebrum, separated from it by the transverse cerebral fissure. It is also marked by fissures, sulci, and gyri (called folia in the cerebellum). The cerebellum is the second-largest region of the brain, constituting about 10% of its volume but containing over 50% of its neurons.

The cerebellum lies under the cerebrum at the back part of the brain. It helps coordinate movement. Tumors of the cerebellum can cause problems with coordination in walking, trouble with precise movements of hands, arms, feet, and legs, problems swallowing or synchronizing eye movements, and changes in speech rhythm.

Brain stem

The brain stem is the lower part of the brain that connects to the spinal cord. It contains bundles of very long nerve fibers that carry signals controlling muscles and sensation or feeling between the cerebrum and the rest the body. Special centers in the brain stem also help control breathing and the beating of the heart. Also, most cranial nerves (see Figures 1 and 2) start in the brain stem.

The brainstem is defined all of the brain except the cerebrum and cerebellum. Its major components, from rostral (front towards the nose) to caudal (back end), are the midbrain, pons, and medulla oblongata. In a living person, the brainstem is oriented like a vertical stalk with the cerebrum perched on top like a mushroom cap. Postmortem changes give it a more oblique angle in the cadaver and consequently, in many medical illustrations. Towards the back end, the brainstem ends at the foramen magnum of the skull, and the central nervous system (CNS) continues below this as the spinal cord.

Figure 2. Medial aspect of the human brain

human brain anatomy

The brain, like the spinal cord, is composed of gray and white matter. Gray matter—the seat of the neurosomas, dendrites, and synapses—forms a surface layer called the cortex over the cerebrum and cerebellum, and deeper masses called nuclei surrounded by white matter. White matter lies deep to the cortical gray matter in most of the brain, opposite from the relationship of gray and white matter in the spinal cord. As in the spinal cord, white matter is composed of tracts, or bundles of axons, which here connect one part of the brain to another and to the spinal cord.

Parts of the brain and their functions

During fetal development the brain can be divided into five continuous parts (see Figure 3). From top to bottom they are :

  • Prosencephalon (the embryonic forebrain):
    • The telencephalon (cerebrum) becomes the large cerebral hemispheres. The surface of these hemispheres consists of elevations (gyri) and depressions (sulci) and the hemispheres are partially separated by a deep longitudinal fissure. The cerebrum fills the area of the skull above the tentorium cerebelli and is subdivided into lobes based on position.
    • The diencephalon, which is hidden from view in the adult brain by the cerebral hemispheres, consists of the thalamus, hypothalamus, and epithalamus and third ventricle.
  • Mesencephalon or the midbrain, gives rise to the midbrain and aqueduct of the midbrain (cerebral aqueduct).
  • Rhombencephalon (the hindbrain):
    • The metencephalon becomes the pons, cerebellum, and upper part of the fourth ventricle.
    • The myelencephalon forms the medulla oblongata and lower part of the fourth ventricle.

Figure 3. Parts of the brain

parts of the human brain

Note: (a) The primary vesicles at 4 weeks (fetus). (b) The secondary vesicles at 5 weeks (fetus). (c) The fully developed brain, color-coded to relate its structures to the secondary embryonic vesicles.

The Cerebrum

The cerebrum, the most upper and outer portion of the brain, is made up of two cerebral hemispheres and together these hemispheres account for 83% of total brain mass. They so dominate the brain that many people mistakenly use the word brain when referring specifically to the cerebrum. The cerebral hemispheres cover the diencephalon and the brain stem in much the same way a mushroom cap covers the top of its stalk.

The various fissures evident on and around the cerebral hemispheres separate the major portions of the brain from one another. The transverse cerebral fissure separates the cerebral hemispheres from the cerebellum inferiorly, whereas the median longitudinal fissure separates the right and left cerebral hemispheres from each other. The cerebrum is composed of a superficial cerebral cortex of gray matter, the cerebral white matter internal to it, and the deep gray matter of the cerebrum within the white matter.

Both cerebral hemispheres participate in basic functions, such as receiving and analyzing sensory impulses, controlling skeletal muscles, and storing memory. However, in most individuals, one side of the cerebrum is the dominant hemisphere, controlling the ability to use and understand language. In most people the left hemisphere is dominant for the language-related activities of speech, writing, and reading, and for complex intellectual functions requiring verbal, analytical,
and computational skills. In others, the right hemisphere is dominant for language-related abilities, or the hemispheres are equally dominant. Broca’s area in the dominant hemisphere controls the muscles that function in speaking.

In addition to carrying on basic functions, the nondominant hemisphere specializes in nonverbal functions, such as motor tasks that require orientation of the  body in space, understanding and interpreting musical patterns, and nonverbal visual experiences. The nondominant hemisphere also controls emotional and  intuitive thinking. Nerve fibers of the corpus callosum, which connect the cerebral hemispheres, allow the dominant hemisphere to control the motor cortex of  the nondominant hemisphere. These fibers also transfer sensory information reaching the nondominant hemisphere to the dominant one, where the information can be used in decision making.

Lobes of the Cerebral Cortex

There are many shallow grooves on the surface of the cerebral hemispheres called sulci (singular: sulcus, “furrow”,  “throughs”). Between the sulci are twisted ridges of brain tissue called gyri (singular: gyrus, “twister”). The more prominent gyri and sulci are similar in all people and are important anatomical landmarks. Some of the deeper sulci divide each cerebral hemisphere into five major lobes:

  1. The Frontal lobe,
  2. The Parietal lobe,
  3. The Occipital lobe,
  4. The Temporal lobe,
  5. The Insula lobe.

Most of these lobes are named for the skull bones overlying them.

Figure 4. Cerebrum of the brain

cerebral cortex of the brain

Frontal lobe of brain

The frontal lobe is located deep to the frontal bone and fills the anterior cranial fossa. It extends posteriorly to the central sulcus, which separates the frontal lobe from the parietal lobe. The precentral gyrus containing the primary motor cortex lies just anterior to the central sulcus.

The frontal lobe contains functional areas that plan, initiate, and enact motor movement including eye movement and speech production. The most anterior region of the frontal cortex performs higher-order cognitive functions, such as thinking, planning, decision making, working memory, and other executive functions.

Parietal lobe of brain

The parietal lobe, deep to the parietal bones, extends posteriorly from the central sulcus to the parieto-occipital sulcus. The lateral sulcus forms its inferior boundary. The postcentral gyrus, just posterior to the central sulcus, contains the primary somatosensory cortex. The parietal lobe processes sensory stimuli allowing (1) conscious awarness of general somatic sensation; (2) spacial awarness of objects, sounds and body parts; and (3) understanding of speech.

Occipital lobe of brain

The occipital lobe lies deep to the occipital bone and forms the most posterior portion of the cerebrum. It is separated from the parietal lobe by the parieto-occipital sulcus on the medial surface of the hemiphere. The occipital lobe contains the visual cortex.

Temporal lobe of brain

The temporal lobe, on the lateral side of the hemisphere, lies in the middle cranial fossa deep to the temporal bone. It is separated from the overlying parietal and frontal lobes by the deep lateral sulcus. The temporal lobe contains the auditory cortex and the olfactory cortex. It also functions in the recognition of objects, words, and faces; in language comprehension; and in emotional response and memory.

Insula lobe of brain

The insula (“island”) is buried deep within the lateral sulcus and forms part of its floor. The insula is covered by parts of the temporal, parietal, and frontal lobes. The visceral sensory cortex for taste and general visceral sensations are in the insula.

Cerebral White Matter

The cerebral white matter consists primarily of myelinated axons in three types of tracts:

  1. Association tracts contain axons that conduct nerve impulses between gyri in the same hemisphere.
  2. Commissural tracts contain axons that conduct nerve impulses from gyri in one cerebral hemisphere to corresponding gyri in the other cerebral hemisphere. Three important groups of commissural tracts are the corpus callosum (the largest fiber bundle in the brain, containing about 300 million fibers), anterior commissure, and posterior commissure.
  3. Projection tracts contain axons that conduct nerve impulses from the cerebrum to lower parts of the central nervous system (thalamus, brainstem or spinal cord) or from lower parts of the central nervous system to the cerebrum. An example is the internal capsule, a thick band of white matter that contains both ascending and descending axons.

Cerebral Gray Matter (Functional Areas of the Cerebral Cortex)

The cerebral cortex is composed of gray matter because it contains neuron cell bodies, dendrites, and very short unmyelinated axons but no fiber tracts. Even though the cerebral cortex is only 2–4 mm thick, its many gyri and sulci triple its surface area to approxmately 2500 cm2, about the size of a large desk calendar, and it accounts for about 40% of the total mass of the brain.

The cerebral cortex contains 14 to 16 billions of neurons and about 90% of the human cerebral cortex is a six-layered tissue called neocortex because of its relatively recent evolutionary origin. The six layers of neocortex, vary from one part of the cerebrum to another in relative thickness, cellular composition, synaptic connections, size of the neurons, and destination of their axons. Layer IV is thickest in sensory regions and layer V in motor regions, for example. All axons that leave the cortex and enter the white matter arise from layers III, V, and VI.

Figure 5. Gray matter of the neocortex

neocortex cell layers

The cerebral cortex possesses two principal types of neurons called stellate cells and pyramidal cells. Stellate cells have spheroidal somas with short axons and dendrites projecting in all directions. They are concerned largely with receiving sensory input and processing information on a local level. Pyramidal cells are tall and conical. Their apex points toward the brain surface and has a thick dendrite with many branches and small, knobby dendritic spines. The base gives rise to horizontally oriented dendrites and an axon that passes into the white matter. Pyramidal cells include the output neurons of the cerebrum—the only cerebral neurons whose fibers leave the cortex and connect with other parts of the CNS. Pyramidal cell axons have collaterals that synapse with other neurons in the cortex or in deeper regions of the brain.

In 1909, a German neurologist, Korbinian Brodmann, mapped the cerebral cortex into 47 structural areas based on subtle variations in the thickness of the six layers. In the 21st century with the advent of functional neuroimaging techniques—PET (positron emission tomography) and fMRI (functional magnetic resonance imaging)—these techniques reveal areas of maximal metabolic activity and blood flow to the brain, which are presumed to be areas participating in the mental task being performed. A fMRI obtained during a variety of tasks indicates areas of increased blood flow, as shown by the red-yellow color, in the regions of the cerebral cortex associated with each task.

Three general kinds of functional areas are recognized in the cerebral cortex:

  1. Sensory areas, which allow conscious awareness of sensation;
  2. Association areas, which integrate diverse information to enable purposeful action; and
  3. Motor areas, which control voluntary motor functions.

Figure 6. Functional areas of the cerebral cortex

functional areas of the cerebral cortex

There is a sensory area for each of the major senses. Each region is called a primary sensory cortex. Each primary sensory cortex has association areas linked to it that process the sensory information. These areas are sensory association areas. Other association areas receive and integrate input from multiple regions of the cerebral cortex. These regions are called multimodal association areas. Finally, the regions of the cortex that plan and initiate voluntary motor functions are called the motor areas. Information is processed through these regions of the cerebral cortex in the following hierarchical manner.

  1. Sensory information is received by the primary sensory cortex, and the arrival of this information results in awareness of the sensation.
  2. The information is relayed to the sensory association area that gives meaning to the sensory input.
  3. The multimodal association areas receive input in parallel from multiple sensory association areas, integrating all of the sensory input to create a complete understanding of the sensory information. These regions also integrate sensory input with past experience and develop a motor response.
  4. The motor plan is enacted by the motor cortex.

Figure 7. Primary motor cortex and somatosensory cortex of the cerebrum

somatosensory and motor cortex of the cerebrum

Basal Nuclei

Deep within each cerebral hemisphere are three nuclei (masses of gray matter) that are collectively termed the basal nuclei. Historically, these nuclei have been called the basal ganglia. Two of the basal nuclei lie side by side, just lateral to the thalamus. They are the globus pallidus, which is closer to the thalamus, and the putamen, which is closer to the cerebral cortex. Together, the globus pallidus and putamen are referred to as the lentiform nucleus. The third of the basal nuclei
is the caudate nucleus, which has a large “head” connected to a smaller “tail” by a long, comma-shaped “body.”

Together, the lentiform and caudate nuclei are known as the corpus striatum. The term corpus striatum refers to the striated (striped) appearance of the internal capsule as it passes among the basal nuclei. Nearby structures that are functionally linked to the basal nuclei are the substantia nigra of the midbrain and the subthalamic nuclei of the diencephalon. Axons from the substantia nigra terminate in the caudate nucleus and putamen. The subthalamic nuclei interconnect
with the globus pallidus.

Figure 8. Basal nuclei of human brain

basal nuclei of brain
The claustrum is a thin sheet of gray matter situated lateral to the putamen. It is considered by some to be a subdivision of the basal nuclei. The function of the claustrum in humans has not been clearly defined, but it may be involved in visual attention.

The basal nuclei receive input from the cerebral cortex and provide output to motor parts of the cortex via the medial and ventral group nuclei of the thalamus. In addition, the basal nuclei have extensive connections with one another. A major function of the basal nuclei is to help regulate initiation and termination of movements. Activity of neurons in the putamen precedes or anticipates body movements; activity of neurons in the caudate nucleus occurs prior to eye movements.

The globus pallidus helps regulate the muscle tone required for specific body movements. The basal nuclei also control subconscious contractions of skeletal muscles. Examples include automatic arm swings while walking and true laughter in response to a joke. In addition to influencing motor functions, the basal nuclei have other roles. They help initiate and terminate some cognitive processes, attention, memory, and planning, and may act with the limbic system to
regulate emotional behaviors. Disorders such as Parkinson’s disease, obsessive–compulsive disorder, schizophrenia, and chronic anxiety are thought to involve dysfunction of circuits between the basal nuclei and the limbic system.

The Diencephalon

Deep in the core area of the brain, just above the top of the brainstem, is the diencephalon that consists largely of three paired structures—the thalamus, the hypothalamus and the epithalamus. The diencephalon are structures that have a great deal to do with perception, movement, and the body’s vital functions.

Figure 9. Diencephalon of the human brain

dienchephalon of the brain

The Thalamus

The egg-shaped thalamus is a paired structure that makes up 80% of the diencephalon and forms the superolateral walls of the third ventricle. Usually the right and left parts of the thalamus are joined by a small midline connection, the interthalamic adhesion (intermediate mass).

The thalamus consists of two oval masses that contain about a dozen major nuclei, each of which sends axons to a particular portion of the cerebral cortex (Figure 5). The thalamic masses contain nerve cell bodies that sort information from four of the senses—sight, hearing, taste, and touch—and relay it to the cerebral cortex. (Only the sense of smell sends signals directly to the cortex, bypassing the thalamus.) Sensations of pain, temperature, and pressure are also relayed through the thalamus, as are the nerve impulses from the cerebral hemispheres that initiate voluntary movement.

For example,

  • The ventral posterolateral nuclei act as relay stations for the sensory information ascending to the primary sensory areas of the cerebral cortex.
  • The medial geniculate body receives auditory input and links to the auditory cortex.
  • The lateral geniculate body receives visual input and transmits to the visual cortex.

Sensory inputs are not the only type of information relayed through the thalamus. Every part of the brain that communicates with the cerebral cortex must relay its signals through a nucleus of the thalamus. The thalamus can therefore be thought of as the “gateway” to the cerebral cortex.

The thalamus not only relays information to the cerebral cortex but also processes the information as it passes through.

The thalamic nuclei organize and then either amplify or “tone down” the signals headed for the cerebral cortex. This is why, for example, you can focus on a conversation with a single person in large, noisy cafeteria.

Figure 10. Thalamus and Hypothalamus of the brain

hypothalamus and thalamus of the brain

The Hypothalamus

The hypothalamus (“below the thalamus”) is the inferior portion of the diencephalon. Projecting inferiorly from the hypothalamus is the pituitary gland (Figure 1) and the hypothalamus occupies approximately 2 per cent of the brain volume. The hypothalamus is situated in a strategic position at the crossroad of four systems, neurovegetative, neuroendocrine, limbic, and optic 2.

The hypothalamus forms the inferolateral walls of the third ventricle. On the underside of the brain, the hypothalamus lies between the optic chiasma (point of crossover of cranial nerves II, the optic nerves) and the posterior border of the mammillary bodies, rounded bumps that bulge from the hypothalamic floor (mammillary = “little breast”).

The hypothalamus, like the thalamus, contains about a dozen brain nuclei of gray matter. Despite its relatively small size (roughly that of a thumbnail or an almond), functionally, the hypothalamus is the main visceral control center of the body, regulating many activities of the visceral organs.

The hypothalamus is the main point of interaction for the body’s two physical control systems: the nervous system, which transmits information in the form of minute electrical impulses, and the endocrine system, which brings about changes of state through the release of chemical factors. It is the hypothalamus that first detects crucial changes in the body and responds by stimulating various glands and organs to release hormones.

Its functions include the following:

  • Control of the autonomic nervous system. At the autonomic level, the hypothalamus stimulates smooth muscle (which lines the blood vessels, stomach, and intestines) and receives sensory impulses from these areas. Thus it controls the heart rate and blood pressure, the passage of food through the alimentary canal, the secretion from sweat glands and salivary glands and contraction of the bladder and many other visceral activities. The hypothalamus
    exerts its control over visceral functions by relaying its instructions through the periaqueductal gray matter of the midbrain and the reticular formation of the brain stem, which then carry out those instructions.
  • Regulation of body temperature. The body’s thermostat is in the hypothalamus. In the hypothalamus are neurons that monitor body temperature at the surface through nerve endings in the skin and other neurons that monitor the blood flowing through this part of the brain itself, as an indicator of core body temperature. The front part of the hypothalamus contains neurons that act to lower body temperature by relaxing smooth muscle in the blood vessels, which causes them to dilate and increases the rate of heat loss from the skin. Through its neurons associated with the sweat glands of the skin, the hypothalamus can also promote heat loss by increasing the rate of perspiration. In opposite conditions, when the body’s temperature falls below the (rather narrow) ideal range, a portion of the hypothalamus directs the contraction of blood vessels, slows the rate of heat loss, and causes the onset of shivering (which produces a small amount of heat). Hypothalamic centers also induce fever.
  • Regulation of hunger and thirst sensations. The hypothalamus is the control center for the stimuli that underlie eating and drinking. By sensing the concentrations of nutrients and salts in the blood, certain hypothalamic neurons mediate feelings of hunger and thirst and thus aid in maintaining the proper concentrations of these substances. The sensations that you interpret as hunger arise partly from a degree of emptiness in the stomach and partly from a drop in the level of two substances: glucose circulating in the blood and a hormone that the intestine produces shortly after the intake of food. Receptors for this hormone gauge how far digestion has proceeded since the last meal. This system is not a simple “on” switch for hunger, however: another portion of the hypothalamus, when stimulated, actively inhibits eating by promoting a feeling of satiety. In experimental animals, damage to this portion of the brain is associated with continued excessive eating, eventually leading to obesity.
  • Regulation of sleep-wake cycles. Acting with other brain regions, the hypothalamus helps regulate the complex phenomenon of sleep. The suprachiasmatic nucleus is the body’s biological clock. It generates the daily circadian rhythms and synchronizes these cycles in response to dark-light information sensed via the optic nerve. In response to such signals, the preoptic nucleus induces sleep. Electrical stimulation of a portion of the hypothalamus has been shown to induce sleep in experimental animals, although the mechanism by which this works is not yet known. Other hypothalamic nuclei near the mammillary body mediate arousal from sleep. Furthermore, the hypothalamus forms part of the reticular activating system, the physical basis for that hard-to-define state known as consciousness.
  • Control of the endocrine system. The hypothalamus controls the secretion of hormones by the pituitary gland, which in turn influences the activity of many other endocrine organs.
  • Control of emotional responses. The hypothalamus lies at the center of the emotional part of the brain, the limbic system. Regions involved in pleasure, rage, and fear are located in the hypothalamus. The hypothalamus is the brain’s intermediary for translating emotion into physical response. When strong feelings (rage, fear, pleasure, excitement) are generated in the mind, whether by external stimuli or by the action of thoughts, the cerebral cortex transmits impulses to the hypothalamus; the hypothalamus may then send signals for physiological changes through the autonomic nervous system and through the release of hormones from the pituitary. Physical signs of fear or excitement, such as a racing heartbeat, shallow breathing, and perhaps a clenched “gut feeling,” all originate here.
  • Control of motivational behavior. The hypothalamus controls behavior that is rewarding. For example, the hypothalamus influences your motivation for feeding, thereby determining how much you eat, and also influences sex drive and sexual behavior.
  • Formation of memory. The brain nucleus in the mammillary body receives many inputs from the major memory processing structure of the cerebrum, the hippocampal formation.

Lesions of the hypothalamus cause disorders in visceral functions and in emotions. Thus, injuries to the hypothalamus can result in severe weight loss or obesity, sleep disturbances, dehydration, and a broad range of emotional disorders.

In all, the hypothalamus is a richly complex cubic centimeter of vital connections, which will continue to reward close study for some time to come. Because of its unique position as a midpost between thought and feeling and between conscious act and autonomic function, a thorough understanding of its workings should tell us much about the earliest history and development of the human animal.

The Epithalamus

The epithalamus, the third and most dorsal (back end) part of the diencephalon, forms part of the roof of the third ventricle. It consists of one tiny group of brain nuclei and a small, unpaired knob called the pineal gland. This gland, which derives from ependymal glial cells, is a hormone-secreting organ. Under the influence of the hypothalamus, the pineal gland secretes the hormone melatonin, which signals the body to prepare for the nighttime stage of the sleep-wake cycle.

The Limbic System

The limbic system is sometimes called the “emotional brain” because it plays a primary role in a range of emotions, including pain, pleasure, docility, affection, and anger. It also is involved in olfaction (smell), learning and memory.

Together with parts of the cerebrum, the limbic system also functions in memory; damage to the limbic system causes memory impairment. One portion of the limbic system, the hippocampus, is seemingly unique among structures of the central nervous system—it has cells reported to be capable of mitosis. Thus, the  portion of the brain that is responsible for some aspects of memory may develop new neurons, even in the elderly.

The limbic system is a ring of cortex on the medial side of each hemisphere, encircling the corpus callosum and thalamus. The main components of the limbic system are as follows:

  • The so-called limbic lobe is a rim of cerebral cortex on the medial surface of each hemisphere. It includes the cingulate gyrus, which lies above the corpus callosum, and the parahippocampal gyrus, which is in the temporal lobe below. The hippocampus is a portion of the parahippocampal gyrus that extends into the floor of the lateral ventricle.
  • The dentate gyrus lies between the hippocampus and parahippocampal gyrus.
  • The amygdala is composed of several groups of neurons located close to the tail of the caudate nucleus.
  • The septal nuclei are located within the septal area formed by the regions under the corpus callosum and the paraterminal gyrus (a cerebral gyrus).
  • The mammillary bodies of the hypothalamus are two round masses close to the midline near the cerebral peduncles.
  • Two nuclei of the thalamus, the anterior nucleus and the medial nucleus, participate in limbic circuits.
  • The olfactory bulbs are flattened bodies of the olfactory pathway that rest on the cribriform plate.
  • The fornix, stria terminalis, stria medullaris, medial forebrain bundle, and mammillothalamic tract are linked by bundles of interconnecting myelinated axons.

Its most anatomically prominent components are the cingulate gyrus, which arches over the top of the corpus callosum in the frontal and parietal lobes; the hippocampus in the medial temporal lobe; and the amygdala immediately rostral to the hippocampus, also in the temporal lobe. There are still differences of opinion on what structures to consider as parts of the limbic system, but these three are agreed upon.

Other components include the mammillary bodies and other hypothalamic nuclei, some thalamic nuclei, parts of the basal nuclei, and parts of the frontal lobe called prefrontal and orbitofrontal cortex. Limbic system components are interconnected through a complex loop of fiber tracts allowing for somewhat circular patterns of feedback among its nuclei and cortical neurons. All of these structures are bilaterally paired; there is a limbic system in each cerebral hemisphere.

The limbic system was long thought to be associated with smell because of its close association with olfactory pathways, but beginning in the early 1900s and continuing even now, experiments have abundantly demonstrated more significant roles in emotion and memory. Most limbic system structures have centers for both gratification and aversion. Stimulation of a gratification center produces a sense of pleasure or reward; stimulation of an aversion center produces unpleasant sensations such as fear or sorrow. Gratification centers dominate some limbic structures, such as the nucleus accumbens (not illustrated), while aversion centers dominate others such as the amygdala. The roles of the amygdala in emotion and the hippocampus in memory.

Figure 11. Limbic system

limbic system

The Cerebellum

The cerebellum is the largest part of the hindbrain and second largest part of the brain as a whole. It consists of right and left cerebellar hemispheres connected by a narrow worm like bridge called the vermis. Each hemisphere exhibits slender, transverse, parallel folds called folia separated by shallow sulci. The cerebellum has a surface cortex of gray matter and a deeper layer of white matter. In a sagittal section, the white matter exhibits a branching, fernlike pattern called the arbor vitae. Each hemisphere has four masses of gray matter called deep nuclei embedded in the white matter. All input to the cerebellum goes to the cortex and all of its output comes from the deep nuclei.

Although the cerebellum is only about 10% of the mass of the brain, it has about 60% as much surface area as the cerebral cortex and it contains more than half of all brain neurons—about 100 billion of them. Its tiny, densely spaced granule cells are the most abundant type of neuron in the entire brain. Its most distinctive neurons, however, are the unusually large, globose Purkinje cells. These have a tremendous profusion of dendrites compressed into a single plane like a flat tree. Their axons travel to the deep nuclei, where they synapse on output neurons that issue fibers to the brainstem.

The cerebellum is connected to the brainstem by three pairs of stalks called cerebellar peduncles: a pair of inferior peduncles connected to the medulla oblongata, a pair of middle peduncles to the pons, and a pair of superior peduncles to the midbrain. These consist of thick bundles of nerve fibers that carry signals to and from the cerebellum. Connections between the cerebellum and brainstem are very complex.

Most spinal input enters the cerebellum by way of the inferior peduncles; most input from the rest of the brain enters by way of the middle peduncles; and cerebellar output travels mainly by way of the superior peduncles.

The cerebellum had come to be regarded as a center for monitoring muscle contractions and aiding in motor coordination. People with cerebellar lesions exhibit serious deficits in coordination and locomotor ability. However with fMRI and PET scan, the cerebellum’s general role in the evaluation of certain kinds of sensory input, and monitoring muscle movement is only part of its broader function. The cerebellum is highly active when a person explores objects with the fingertips, for example to compare the textures of two objects without looking at them.

Some spatial perception also resides here. The cerebellum is much more active when a person is required to solve a pegboard puzzle than when moving pegs randomly around the same puzzle board. People with cerebellar lesions also have difficulty identifying different views of a three-dimensional object as belonging to the same object. The cerebellum is also a timekeeper. An important aspect of cerebellar timekeeping is the ability to predict where a moving object will be in the next second or so.

The cerebellum also helps to predict how much the eyes must move in order to compensate for head movements and remain fixed on an object. Even hearing has some newly discovered and surprising cerebellar components. Cerebellar lesions impair a person’s ability to judge differences in pitch between two tones and to distinguish between similar-sounding words such as rabbit and rapid. Language output also involves the cerebellum. If a person is given a noun such as apple and told to think of a related verb such as eat, the cerebellum shows higher PET scan activity than if the person is told merely to repeat the word apple.

People with cerebellar lesions also have difficulty planning and scheduling tasks. They tend to overreact emotionally and have difficulty with impulse control.

Figure 12. Cerebellum of brain

cerebellum of brain

The Brainstem

The brainstem is continuous with the spinal cord and consists of the medulla oblongata, pons, and midbrain.

Figure 13. The Brainstem

the brainstem

The Midbrain

The midbrain contains the cerebral aqueduct, continuations of the medial lemniscus and reticular formation, and the motor nuclei of two cranial nerves that control eye movements: cranial nerves III (oculomotor) and IV (trochlear).

The part of the midbrain posterior to the cerebral aqueduct is a rooflike tectum. It exhibits four bulges, the corpora quadrigemina. The upper pair, called the superior colliculi, functions in visual attention; visually tracking moving objects; such reflexes as blinking, focusing, pupillary dilation and constriction; and turning the eyes and head in response to a visual stimulus (for example, to look at something that you catch sight of in your peripheral vision). The lower pair, called the inferior colliculi, receives signals from the inner ear and relays them to other parts of the brain, especially the thalamus. Among other functions, they mediate the reflexive turning of the head in response to a sound, and one’s tendency to jump when startled by a sudden noise.

Anterior to the cerebral aqueduct, the midbrain consists mainly of the cerebral peduncles—two stalks that anchor the cerebrum to the brainstem. Each peduncle has three main components: tegmentum, substantia nigra, and cerebral crus. The tegmentum is dominated by the red nucleus, named for a pink color imparted by its high density of blood vessels. Fibers from the red nucleus its connections go mainly to and from the cerebellum, with which it collaborates in fine motor control. The substantia nigra is a dark gray to black nucleus pigmented with melanin. It is a motor center that relays inhibitory signals to the thalamus and basal nuclei (both of which are discussed later), preventing unwanted body movement. Degeneration of the neurons in the substantia nigra leads to the muscle tremors of Parkinson disease. The cerebral crus is a bundle of nerve fibers that connect the cerebrum to the pons and carry the corticospinal nerve tracts.

The cerebral aqueduct is encircled by the central (periaqueductal) gray matter. This is involved with the reticulospinal tracts in controlling awareness of pain.

Figure 14. Midbrain


The Reticular Formation

The reticular formation is a loose web of gray matter that runs vertically through all levels of the brainstem, appearing at all three levels of figure. It occupies  much of the space between the white fiber tracts and the more anatomically distinct brainstem nuclei, and has connections with many areas of the cerebrum. It consists of more than 100 small neural networks defined less by anatomical boundaries than by their use of different neurotransmitters. The functions of these networks include the following:

  • Somatic motor control. Some motor neurons of the cerebral cortex send their axons to reticular formation nuclei, which then give rise to the reticulospinal tracts of the spinal cord. These tracts adjust muscle tension to maintain tone, balance, and posture, especially during body movements. The reticular formation also relays signals from the eyes and ears to the cerebellum so the cerebellum can integrate visual, auditory, and vestibular (balance and motion) stimuli into its role in motor coordination. Other motor nuclei include gaze centers, which enable the eyes to track and fixate objects, and central pattern generators—neural pools that produce rhythmic signals to the muscles of breathing and swallowing.
  • Cardiovascular control. The reticular formation includes the previously mentioned cardiac and vasomotor centers of the medulla oblongata.
  • Pain modulation. The reticular formation is one route by which pain signals from the lower body reach the cerebral cortex. It is also the origin of the  descending analgesic pathways. Under certain circumstances, the nerve fibers in these pathways act in the spinal cord to deaden one’s awareness of pain.
  • Sleep and consciousness. The reticular formation has projections to the thalamus and cerebral cortex that allow it some control over what sensory signals reach the cerebrum and come to your conscious attention. It plays a central role in states of consciousness such as alertness and sleep. Injury to the reticular formation can result in irreversible coma.
  • Habituation. This is a process in which the brain learns to ignore repetitive, inconsequential stimuli while remaining sensitive to others. In a noisy city,  for example, a person can sleep through traffic sounds but wake promptly to the sound of an alarm clock or a crying baby. Reticular formation nuclei that modulate activity of the cerebral cortex are called the reticular activating system or extrathalamic cortical modulatory system.

The Pons

The pons measures about 2.5 cm long. Most of it appears as a broad anterior bulge rostral to the medulla. Posteriorly, it consists mainly of two pairs of thick  stalks called cerebellar peduncles. They connect the cerebellum to the pons and midbrain. In cross section, the pons exhibits continuations of the previously mentioned reticular formation, medial lemniscus, tectospinal tract, and other spinal tracts. The anterior half of the pons is dominated by tracts of white matter, including transverse fascicles that cross between left and right and connect the two hemispheres of the cerebellum, and longitudinal fascicles that carry sensory and motor signals up and down the brainstem.

Cranial nerves V to VIII begin or end in the pons. The other three emerge from the groove between the pons and medulla. The functions of these four nerves, include sensory roles in hearing, equilibrium, and taste; facial sensations such as touch and pain; and motor roles in eye movement, facial expressions, chewing, swallowing, urination, and the secretion of saliva and tears. The reticular formation in the pons contains additional nuclei concerned with sleep, respiration, and

The Medulla Oblongata

The medulla oblongata extends from the pons to the foramen magnum of the skull. Its posterior surface flattens to form the floor of the fourth ventricle. Its  anterior surface is marked by two longitudinal enlargements called the pyramids, which contain the corticospinal tracts. Most of the fibers of the corticospinal tracts cross over at this level. All of the ascending and descending nerve fibers connecting the brain and spinal cord must pass through the medulla oblongata because of its location. In the spinal cord the white matter surrounds a central mass of gray matter. Here in the medulla oblongata, however, nerve fibers separate the gray matter into nuclei, some of which relay ascending impulses to the other side of the brainstem and then on to higher brain centers. Other nuclei in the medulla oblongata control vital visceral activities.

These centers include:

  • The cardiac center. Impulses originating in the cardiac center are conducted to the heart on peripheral nerves, altering heart rate.
  • The vasomotor center. Certain neurons of the vasomotor center initiate impulses that travel to smooth muscle in the walls of certain blood vessels and stimulate the smooth muscle to contract. This constricts the blood vessels (vasoconstriction), raising blood pressure. Other neurons of the vasomotor center produce the opposite effect—dilating blood vessels (vasodilation) and consequently dropping blood pressure.
  • The respiratory center. Groups of neurons in the respiratory center maintain breathing rhythm and adjust the rate and depth of breathing. Still other nuclei in the medulla oblongata are centers for the reflexes associated with coughing, sneezing, swallowing, and vomiting.

Protective Coverings of the Brain

The brain is enveloped in three membranes called the meninges, which lie between the nervous tissue and bone. They protect the brain and provide a structural framework for its arteries and veins. As in the spinal cord, these are the dura mater, arachnoid mater, and pia mater. However, the cranial dura mater consists of two layers—an outer periosteal layer equivalent to the periosteum of the cranial bones, and an inner meningeal layer. Only the meningeal layer continues into the vertebral canal, where it forms the dural sheath around the spinal cord. The cranial dura mater is pressed closely against the cranial bone, with no intervening epidural space like the one around the spinal cord. It is not attached to the bone, however, except in limited places: around the foramen magnum, the sella turcica, the crista galli, and the sutures of the skull.

Meningitis is inflammation of the meninges that surrounds the brain and spinal cord. There are several types of meningitis. The most common is viral meningitis. You get it when a virus enters the body through the nose or mouth and travels to the brain. Bacterial meningitis is rare, but can be deadly. It usually starts with bacteria that cause a cold-like infection. It can cause stroke, hearing loss, and brain damage. It can also harm other organs. Pneumococcal infections and meningococcal infections are the most common causes of bacterial meningitis. Anyone can get meningitis, but it is more common in people with weak immune systems. Meningitis can get serious very quickly.

Figure 15. Meninges of the brain

meninges of the brain

In some places, the two layers of dura are separated by dural sinuses, spaces that collect blood that has circulated through the brain. Two major, superficial ones are the superior sagittal sinus, found just under the cranium along the median line, and the transverse sinus, which runs horizontally from the rear of the head toward each ear. These sinuses meet like an inverted T at the back of the brain and ultimately empty into the internal jugular veins of the neck.

In certain places, the meningeal layer of the dura folds inward to separate major parts of the brain from each other and limit brain movements within the cranium, as when one receives a blow to the head. There are three of these: (1) the falx cerebri, which extends into the longitudinal fissure as a tough, crescent-shaped wall between the right and left cerebral hemispheres; (2) the tentorium cerebelli, which stretches like a roof over the posterior cranial fossa and separates the cerebellum from the overlying cerebrum; and (3) the falx cerebelli, a vertical partition between the right and left halves of the cerebellum on the inferior side.

The arachnoid mater and pia mater are similar to those of the spinal cord. The arachnoid mater is a transparent membrane over the brain surface, deep to the dura. A subarachnoid space separates it from the pia below, and in some places, a subdural space separates it from the dura above. The subarachnoid space contains the largest blood vessels of the cerebral surface. The pia mater is a very thin, delicate membrane, not usually visible without a microscope. Whereas the arachnoid meninx only overlies the sulci of the cerebral surface, the pia mater dips down into them and closely follows all the contours of the brain.

Ventricles and Cerebrospinal Fluid

The brain has four internal chambers called ventricles. The largest and most frontal ones are the two lateral ventricles, which form an arc in each cerebral hemisphere. Through a tiny pore called the interventricular foramen, each lateral ventricle is connected to the third ventricle, a narrow median space inferior to the corpus callosum. From here, a canal called the cerebral aqueduct passes down the core of the midbrain and leads to the fourth ventricle, a small triangular chamber between the pons and cerebellum. Caudally, this space narrows and forms a central canal that extends through the medulla oblongata into the spinal cord.

Figure 16. Ventricles of the brain

ventricles of the brain

On the floor or wall of each ventricle is a spongy mass of blood capillaries called a choroid plexus, named for its histological resemblance to a fetal membrane called the chorion. Ependyma, a type of neuroglia that resembles a cuboidal epithelium, lines the ventricles and canals and covers the choroid plexuses. It produces cerebrospinal fluid (CSF).

Cerebrospinal fluid is a clear, colorless liquid that fills the ventricles and canals of the CNS and bathes its external surface. The brain produces about 500 mL of cerebrospinal fluid per day, but the fluid is constantly reabsorbed at the same rate and only 100 to 160 mL is normally present at one time. About 40% of it is formed in the subarachnoid space external to the brain, 30% by the general ependymal lining of the brain ventricles, and 30% by the choroid plexuses. Cerebrospinal fluid production begins with the filtration of blood plasma through the capillaries of the brain. Ependymal cells modify the filtrate as it passes through them, so the cerebrospinal fluid has more sodium chloride than blood plasma, but less potassium, calcium, and glucose and very little protein.

Cerebrospinal fluid serves three functions for the brain:

  1. Buoyancy. Because the brain and cerebrospinal fluid are similar in density, the brain neither sinks nor floats in the cerebrospinal fluid. It hangs from delicate specialized fibroblasts of the arachnoid meninx. A human brain removed from the body weighs about 1.5 kg, but when suspended in cerebrospinal fluid its effective weight is only about 50 g. This buoyancy allows the brain to attain considerable size without being impaired by its own weight. If the brain rested heavily on the floor of the cranium, the pressure would kill the nervous tissue.
  2. Protection. Cerebrospinal fluid also protects the brain from striking the cranium when the head is jolted. If the jolt is severe, however, the brain still may strike the inside of the cranium or suffer shearing injury from contact with the angular surfaces of the cranial floor. This is one of the common findings in head injuries (concussions) from contact sports like NFL, rugby and boxing.
  3. Chemical stability. Cerebrospinal fluid rinses metabolic wastes from the nervous tissue and regulates its chemical environment. Slight changes in cerebrospinal fluid composition can cause malfunctions of the nervous system. For example, a high glycine concentration disrupts the control of body temperature and blood pressure, and a high pH causes dizziness and fainting.

Cerebrospinal fluid continually flows through and around the brain and spinal cord, driven partly by its own pressure, partly by the beating of ependymal cilia, and partly by rhythmic pulsations of the brain produced by each heartbeat. The cerebrospinal fluid of the lateral ventricles flows through the interventricular foramina into the third ventricle, then down the cerebral aqueduct to the fourth ventricle. The third and fourth ventricles and their choroid plexuses add more cerebrospinal fluid along the way. A small amount of cerebrospinal fluid fills the central canal of the spinal cord, but ultimately, all of it escapes through three pores in the fourth ventricle—a median aperture and two lateral apertures. These lead into the subarachnoid space on the brain and spinal cord surface. From here, cerebrospinal fluid is reabsorbed by arachnoid granulations, extensions of the arachnoid meninx shaped like little sprigs of cauliflower, protruding through the dura mater into the superior sagittal sinus. Cerebrospinal fluid penetrates the walls of the granulations and mixes with blood in the sinus.

Figure 17. Cerebrospinal fluid formation, absorption and circulation around and within the brain

Cerebrospinal fluid formation and circulation in the brain

Blood Supply to the Brain and the Brain Barrier System

Although the brain is only 2% of the adult body weight, it receives 15% of the blood (about 750 mL/min.) and consumes 20% of its oxygen and glucose. Because neurons have such a high demand for ATP (adenosine triphosphate is a high-energy molecule found in every cell, its job is to store and supply the cell with needed energy) and therefore glucose and oxygen, the constancy of blood supply is especially critical to the nervous system. A mere 10-second interruption in blood flow can cause loss of consciousness; an interruption of 1 to 2 minutes can significantly impair neural function; and 4 minutes without blood usually causes
irreversible brain damage.

The brain receives its arterial supply from two pairs of vessels, the vertebral and internal carotid arteries, which are interconnected in the cranial cavity to produce a cerebral arterial circle (of Willis). The two vertebral arteries enter the cranial cavity through the foramen magnum and just inferior to the pons fuse to form the basilar artery. The two internal carotid arteries enter the cranial cavity through the carotid canals on either side.

Figure 18. Brain blood supply

brain blood supply

Despite blood’s critical importance to the brain, blood is also a source of antibodies, macrophages, bacterial toxins, and other potentially harmful agents. Damaged brain tissue is essentially irreplaceable, and the brain therefore must be well protected. Consequently, there is a brain barrier system that strictly regulates what can get from the bloodstream into the tissue fluid of the brain.

There are two potential points of entry that must be guarded:

  1. Blood capillaries throughout the brain tissue and
  2. Capillaries of the choroid plexuses.

At the blood capillaries that are present throughout the brain tissue, the brain is well protected by the blood–brain barrier, which consists of tight junctions between the endothelial cells that form the capillary walls. In the developing brain, astrocytes reach out and contact the capillaries with their perivascular feet, stimulating the endothelial cells to form tight junctions that completely seal off the gaps between them. This ensures that anything leaving the blood must pass through the cells and not between them. The endothelial cells are more selective than gaps between them would be, and can exclude harmful substances from the brain tissue while allowing necessary ones to pass through.

At the choroid plexuses, the brain is protected by a similar blood–cerebrospinal fluid barrier formed by tight junctions between the ependymal cells. Tight junctions are absent from ependymal cells elsewhere, because it is important to allow exchanges between the brain tissue and cerebrospinal fluid. That is, there is no brain–cerebrospinal fluid barrier.

The blood–brain barrier is highly permeable to water, glucose, and lipid soluble substances such as oxygen, carbon dioxide, alcohol, caffeine, nicotine, and anesthetics. It is slightly permeable to sodium, potassium, chloride, and the waste products urea and creatinine. While the blood–brain barrier is an important protective device, it is an obstacle to the delivery of medications such as antibiotics and cancer drugs, and thus complicates the treatment of brain diseases.

Trauma and inflammation sometimes damage the blood–brain barrier and allow pathogens to enter the brain tissue. Furthermore, there are places called circumventricular organs in the third and fourth ventricles where the barrier is absent and the blood has direct access to brain neurons. These enable the brain to monitor and respond to fluctuations in blood glucose, pH, osmolarity, and other variables. Unfortunately, circumventricular organs also afford a route of invasion by pathogens.

  1. National Center for Biotechnology Information, U.S. National Library of Medicine. Hypothalamus.
  2. Lemaire J-J, Nezzar H, Sakka L, et al. Maps of the adult human hypothalamus. Surgical Neurology International. 2013;4(Suppl 3):S156-S163. doi:10.4103/2152-7806.110667.
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