Delirium is a neurobehavioral syndrome caused by dysregulation of neuronal activity secondary to systemic disturbances. Over time, a number of theories have been proposed in an attempt to explain the processes leading to the development of delirium. Each proposed theory has focused on a specific mechanism or pathologic process (e.g., dopamine excess or acetylcholine deficiency theories), observational and experiential evidence (e.g., sleep deprivation, aging), or empirical data (e.g., specific pharmacologic agents' association with postoperative delirium, intraoperative hypoxia). This article represents a review of published literature and summarizes the top seven proposed theories and their interrelation. This review includes the "neuroinflammatory," "neuronal aging," "oxidative stress," "neurotransmitter deficiency," "neuroendocrine," "diurnal dysregulation," and "network disconnectivity" hypotheses. Most of these theories are complementary, rather than competing, with many areas of intersection and reciprocal influence. The literature suggests that many factors or mechanisms included in these theories lead to a final common outcome associated with an alteration in neurotransmitter synthesis, function, and/or availability that mediates the complex behavioral and cognitive changes observed in delirium. In general, the most commonly described neurotransmitter changes associated with delirium include deficiencies in acetylcholine and/or melatonin availability; excess in dopamine, norepinephrine, and/or glutamate release; and variable alterations (e.g., either a decreased or increased activity, depending on delirium presentation and cause) in serotonin, histamine, and/or γ-aminobutyric acid. In the end, it is unlikely that any one of these theories is fully capable of explaining the etiology or phenomenologic manifestations of delirium but rather that two or more of these, if not all, act together to lead to the biochemical derangement and, ultimately, to the complex cognitive and behavioral changes characteristic of delirium.

Neuropathogenesis of delirium: review of current etiologic theories and common pathways.

http://www.wakeems.com/ICE/Hypothermia/mech%20brain%20inj%20after%20hypoxia.pdf

Mechanisms of Brain Injury after Global Cerebral Ischemia

https://www.criticalcare.theclinics.com/article/S0749-0704(08)00055-9/pdf

Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment.

l-DOPA is converted to dopamine in serotonergic fibers of the striatum of the rat: a double-labeling immunofluorescence study

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system, which starts in the majority of patients with a relapsing/remitting MS (RRMS) course , which after several years of disease duration converts into a progressive disease. Since anti-inflammatory therapies and immune modulation exert a beneficial effect at the relapsing/remitting stage of the disease, but not in the progressive stage, the question was raised whether inflammation drives tissue damage in progressive MS at all. We show here that also in progressive MS, inflammation is the driving force for brain injury and that the discrepancy between inflammation-driven tissue injury and response to immunomodulatory therapies can be explained by different pathomechanisms acting in RRMS and progressive MS.

http://cbr.meduniwien.ac.at/fileadmin/db_files/pub_art_246.pdf

Progressive multiple sclerosis.

The cerebral dialysis technique was employed to monitor extracellular concentrations of dopamine (DA), norepinephrine (NE), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in the dorsal hippocampus of gerbils before and after cerebral ischemia induced by carotid artery occlusion. Extracellular concentrations of DA and NE in the dorsal hippocampus increased from baseline levels of <35 fmol/collection interval to 180 and 200 fmol/collection, respectively, within 36 minutes following carotid artery ligation (n=8 animals). Extracellular concentrations of the DA metabolites, DOPAC and HVA, did not change significantly following carotid artery ligation. These data demonstrate that ischemia in the dorsal hippocampus is associated with a mared release of DA and NE. This release may contribute to the selective vulnerability of the dorsal hippocampus to neuronal damage during ischemia.

Ischemia in the dorsal hippocampus is associated with acute extracellular release of dopamine and norepinephrine

We have used cerebral dialysis to monitor striatal metabolism of exogenously administered L-dopa (L-dihydroxyphenylalanine) in rats with unilateral lesions of the substantia nigra. The concentration of extracellular dopamine (DA) increased in both striata following L-dopa administration but the increase was markedly attenuated in the lesioned striatum. The formation of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the major DA metabolites, was also reduced in the lesioned striata following L-dopa administration; however, the reduction was not as great as was that of DA formation. A significant metabolism of exogenous L-dopa to 3-O-methyldopa occurred in both striata. L-dopa administration transiently increased extracellular levels of 5-hydroxyindoleacetic acid (5 HIAA) in both the lesioned and intract striata.

Striatal L-dopa metabolism studied in vivo in rats with nigrostriatal lesions.

We examined whether pentobarbital (PB) inhibited the acute extracellular release of dopamine that occurs in the striatum following the onset of ischemic injury in the gerbil model of stroke. The cerebral dialysis technique was employed to monitor striatal extracellular dopamine concentrations before and after carotid artery occlusion while perfusing either a control solution of artificial cerebrospinal fluid (CSF) or a 1 mM solution of pentobarbital in CSF (PB/CSF). During perfusion with CSF, extracellular dopamine increased from a baseline concentration of 0.40±0.09 (SEM) pmoles/10 minute collection interval to 30.0± 9.0 pmoles/10 minutes after carotid artery occlusion. In contrast, during perfusion with PB/CSF, dopamine levels increased from a baseline of 1.37±0.3 pmoles/10 minutes to 8.30±2.6 pmoles/10 minutes; this increase was significantly less than the increase in controls. In animals with established ischemia, repeatedly alternating the perfusion fluid between CSF and PB/CSF demonstrated that dopamine concentrations were significantly increased with CSF alone and decreased with PB/CSF. These findings demonstrate that pentobarbital perfusion either before or following the onset of ischemia inhibits extracellualr release of dopamine in the striatum. Inhibition of neurotransmitter release may, in part, be responsible for the protective effect of pentobarbital in ischemic brain injury.

Pentobarbital inhibits extracellular release of dopamine in the ischemic striatum

Extracellular norepinephrine levels in the striatum of normal rats increased significantly following the administration of l-threodops. When peripheral decarboxylase activity was inhibited with carbidopa, administration of the same dose of l-threodops induced a 2.5-fold greater increase in norepinephrine levels.

Anish Bhardwaj

Papers

Ischemia in the dorsal hippocampus is associated with acute extracellular release of dopamine and norepinephrine

Striatal L-dopa metabolism studied in vivo in rats with nigrostriatal lesions.

Pentobarbital inhibits extracellular release of dopamine in the ischemic striatum

L-threodops increases extracellular norepinephrine levels in the brain: an in vivo study.