ART OF BRAIN WHICH CONTROLS CONSCIOUSNESS, MEDICAL INTEREST.

Consciousness is defined as the state of awareness of self and the environment. Another way of describing it is a condition for which a person is capable of perceiving stimuli from the environment and responding appropriately.The consciousness system has two principal functions:1) Maintenance of waking state (arousal or level of consciousness)2) Content of experience (awareness or content of consciousness)

The consciousness system is a diffuse yet organized neuronal system located in the brainstem, diencephalon, and cerebral hemispheres with diffuse reciprocal connections. Although it is complex and still much to be explored, it can be divided into few groups of structures for current understanding. This includes:1) Nuclei of the brainstem reticular formation, hypothalamus, basal forebrain, and thalamus;2) The ascending projection pathways;3) Widespread areas of the cerebral cortex

Reticular FormationThis is a complex aggregate of neurons with its cell bodies form clusters in the tegmentum of brainstem, the basal forebrain, and the thalamus. It is known as reticular because of its diffuse multipolar synapses and interconnection. This reticular formation can be further subdivided functionally into 3 columns: the raphe (midline), the medial and lateral region. The function of each column is summarized in the diagram below (Fig 1). The reticular formation has tremendous afferent and efferent connection ranging from cerebral cortex, thalamus, hypothalamus, to the spinal cord. Generally, such tremendous pathway of the reticular formation can be described into 2 parts, the rostral part and the caudal part. The rostral part reticular formation, vaguely begin at the level of the upper pons and midbrain, contains neurochemically classified groups of neurons that project to the cerebral cortex either directly or by relay in the thalamus. This is the reticular ascending pathway (some named it activating reticular ascending pathway abbr. ARAS) and it is important in the consciousness system. The caudal part (vaguely the lower pons and medulla) has projection to the spinal cord and is involved in motor function, respiration and regulation of blood pressure. This is the descending pathway. Although it is divided vertically as such, you should keep in mind that the ascending pathway does arise from medulla as well. You may read in some textbooks that reticular formation can be divided into cerebellar portion and non-cerebellar portion but it is not relevant here, similarly to some of the more specifically named nuclei.

Fig 1. General organization of the brainstem reticular formation. Image obtained from [ref2]In order to further comprehend the consciousness system, the ascending pathway can be categories into different groups or nuclei by its neurochemical nature; cholinergic and monoaminergic systems. Interestingly, both these system projects extensively to the cerebral cortex via the medial forebrain bundle. This is a large tract that extends from the midbrain tegmentum through the lateral hypothalamus and into its septum and preoptic area. Some of the neural tract from medial forebrain bundle enters into cingulate gyrus.

The cholinergic systemThese cholinergic nuclear groups, which utilize acetylcholine as neurotransmitter, are situated at :

1. Basal forebrain (divided into nucleus basalis of Meynert and the medial septum)2. Mesopontine tegmentum (dorsal tegmentum of the upper pons and midbrain)

Fig 2. Cholinergic nuclear groups of the consciousness system. Shows in (A), the basal forebrain, including the nucleus basalis of Meynert and medial septum, which project to the cerebral cortex. In (B), shows the mesopontine cholinergic group, projects to the thalamus, basal forebrain, and brainstem. Image obtained from [ref2].The monoaminergic systemThis group consists of 4 different subgroup of different neurotransmitter: dopamine, norepinephrine, serotonin and histamine. Each has their specific location and pathway.1. The dopamine-synthesizing neurons are located in the substantia nigra pars compacta and ventral tegmental area of the midbrain.2. The norepinephrine synthesizing neurons are located in the locus ceruleus, which is in the lateral part of the upper pons.3. The serotonin-synthesizing neurons are located in the raphe nuclei, which occupy the midline of the brainstem as mentioned above. It is further divided into rostal and caudal parts.4. The histamine-synthesizing neurons are located in the tuberomammillary nucleus in the posterior lateral hypothalamus.

Fig 3. In (A), the dopamine-synthesizing neurons are located in the substantia nigra pars compacta. (B), the norepinephrine-synthesizing neurons located at the locus ceruleus project extensively. Image obtained from [ref2]

Fig 4. (A), The serotonin-synthesizing neurons are located in the raphe nuclei. The rostral raphe nuclei, located in the upper pons and midbrain. (B), is the histamine-synthesizing neurons of the tuberomammillary nucleus.By now, you may have notice that all these nuclei are mostly situated at the midbrain and upper pontine tegmentum. This shows how essential these parts of brainstem are in consciousness and interruption of the ascending pathway would result in coma.

Thalamus in consciousness systemThe thalamus can be divided functionally into 2 groups, the dorsal thalamus which has massive connection with the cerebral cortex and brainstem, and reticular thalamus which interconnect among the thalamic nucleus rather than externally.In the interest of consciousness, among all nucleus of thalamus, the intralaminar nuclei and the midline nuclei is significantly taking part in the consciousness role. They receive input from reticular formation, basal forebrain, basal ganglia and the limbic system and widespread output to the cerebral cortex, basal ganglia, and the hypothalamus. Another important structure in the consciousness system is the reticular nucleus of the thalamus. This nucleus although do not has efferent pathway to cerebral cortex but does receive afferent input from major portion of the brain.

Fig 5. Images show the nucleus of thalamus. Image obtained from [ref3].Cerebral cortexIt is rather obvious that there is no single cortical area that is for maintenance of consciousness. Almost all cortical interconnection has to be disrupted before someone can lose consciousness (provided the thalamus and reticular formation is intact). Hence we can conclude that all cortical area is involved in consciousness system as a whole.Medical contextWhat damage will result in loss of consciousness?From clinical and experimental evidence, we know that functional integrity of the upper pontine and midbrain reticular formation, interlaminar nucleus, midline nucleus of thalamus, reticular thalamus, and bilateral cerebral cortex is critical for the maintenance of consciousness. To summarize, there are 3 primary mechanisms that will affect the consciousness system. These are:1. Lesion of the brainstem reticular activating system or bilateral posterior hypothalamus2. Bilateral disruption of the ascending projections at the level of thalamus3. Diffuse bilateral hemispheric cortical lesion.

Although the consciousness is affected, different level of interruption results in different consequences as shown in the diagram below.

Fig 6. Image shows the effects toward consciousness resulting from different level of interruption. Image obtained from [ref2]Coma, however, can occur from the following entity:1. focal lesion of the posterior fossa that involved the brainstem2. focal supratentorial lesion, which if large enough, involved the midline diencephalic structure (e.g. intralaminar and midline nucleus of thalamus) either directly or indirectly.3. Diffuse lesion from any causes such as anoxia, toxin, metabolic factor and inflammation.

References.1. Anthony H.V. Schapira, ed. Neurology and clinical neuroscience. Elsevier, Philadelphia, PA. 20072. Eduardo E. Benarroch et al., ed. Mayo Clinic Medical Neurosciences: organized by neurological systems and levels. Fifth edition. Mayo Clinic Scientific Press. Rochester, MN. 20083. Stanley Jacobson and Elliott M. Marcus, ed. Neuroanatomy for neuroscience. Springer, Boston. MA. 2008

lateral ventricles--> foramen of Monro third ventricle --> aqueduct of Sylvius --> fourth ventricle --> foramina of Magendie and Luschka --> subarachnoid space over brain and spinal cord --> reabsorption into venous sinus blood via arachnoid granulations.

Pathological and clinical consequences of infection The macroscopic consequences of infection have been researched post mortem and, more recently, through CT and MRI (figure 2) of the brain. Neurological abnormalities occur with the development of an inflammatory exudate that affects mostly the sylvian fissures, basal cisterns, brainstem, and cerebellum.10 Three processes cause most of the common neurological deficits: the adhesive exudate can obstruct CSF causing hydrocephalus and compromise efferent cranial nerves; granulomas can coalesce to form tuberculomas (or an abscess in patients with uncharacteristic disease) which, depending on their location, cause diverse clinical consequences; and an obliterative vasculitis can cause infarction and stroke syndromes.10 T

Pathogenesis and immune response of cerebral tuberculosis: The lung is initially infected by the aereal route (1); bacilli grow in the lungs and disseminate after blood vessels invasion (2) producing systemic infection (3) affecting the brain (4). Small groups of inflammatory cells are located in the subpial or subependymal areas (Rich nodules) after early bacteremia (5), where bacilli are content and may remain dormant for long time. Later, growth and rupture of these lesions produces meningeal tuberculosis (6). Mycobacterial infection induces the production of proinflammatory cytokines that are important for bacilli killing but they can also produce immunopathology (7). Antinflammatory cytokines are also highly produced; they protect tissue damage by excessive inflammation and induce nervous tissue regeneration (7).

At the early stage of brain infection, cytokines such as TNF , IL-1, and IL-6 are released by migrated activated macrophages, αmicroglial cells, astrocytes, and endothelial cells. These cytokines can contribute to the entry of diverse compounds into the brain by breaching the BBB (16). It has been demonstrated an increase in the permeability of endothelial cells in vitro after the administration of these proinflammatory cytokines (17). Moreover, IL-1 is produced by damaged BBB and its permeability is increased by this cytokine (18). Astrocytes and microglial cells can also produce IL-1 affecting the BBB permeability (19). Thus, it seems that the function and integrity of BBB is affected by the production of proinflammatory cytokines produced by astrocytes, microglial, and endothelial cells (16), which perhaps are not specific for mycobacterial infection and other organisms may trigger this inflammatory process in the nervous system with similar consequences.

PATHOGENESIS

The large-scale inflammation that during meningitis is largely be attributed to response of immune system Immune cells of brain (astrocytes and microglia),respond by releasing large amounts of cytokines, hormone-like mediators that recruit other cells &stimulate other tissues to participate in an immuneresponse.

The blood-brain barrier becomes more permeable,leading to "vasogenic" cerebral edema (swelling ofbrain due to fluid leakage from blood vessels) Large numbers of WBC enter CSF, causinginflammation of meninges, & leading to "interstitial"edema (swelling due to fluid between cells). In addition, walls of blood vessels become inflamed(cerebral vasculitis), which leads to a decreasedblood flow and a third type of edema, "cytotoxic"edema

18. The three forms of cerebral edema all lead to an increased ICP together with low BP often encountered in acute infection, Brain cells are deprived of oxygen & undergo apoptosis (automated cell death)

Normal values (CSF):

CSF opening pressure: 50–180 mmH2OGlucose: 40–85 mg/dL.Protein (total): 15–45 mg/dL.Lactate dehyrogenase: 1/10 of serum level.Lactate: less than 35 mg/dL.Leukocytes (WBC): 0–5/µL (adults / children); up to 30/µL (newborns). Gram stain: negative.Culture: sterile.Specific gravity: 1.006–1.009.Syphilis serology: negative.Gross appearance: Normal CSF is clear and colorless.Differential: 60–70% lymphocytes; up to 30% monocytes     and macrophages; other cells 2% or less.

Tubercular Meningitis

Glucose (mg/dL): <40 mg/dL (Low)

Protein (mg/dL) (moderate to marked increase) 50 -500 mg/dL

WBCs (cells/µL) Variable (10 -1000 cells/µL) <500cells/µL.

Cell differential: Predominance of Lymphocytes

Culture: Positive for AFB

Opening Pressure Variable