At the extreme end of the psychoneuroimmunological spectrum: delirium as a maladaptive sickness behaviour response

Abstract

Delirium is a common and severe neuropsychiatric syndrome characterised by acute deterioration and fluctuations in mental status. It is precipitated mainly by acute illness, trauma, surgery, or drugs. Delirium affects around one in eight hospital inpatients and is associated with multiple adverse consequences, including new institutionalisation, worsening of existing dementia, and death. Patients with delirium show attentional and other cognitive deficits, altered alertness (mostly reduced, but some patients develop agitation and hyperactivity), altered sleep-wake cycle and psychoses. The pathways from the various aetiologies to the heterogeneous clinical presentations are hardly studied and are poorly understood. One of the key questions, which research is only now beginning to address, is how the factors determining susceptibility interact with the stimuli that trigger delirium. Inflammatory signals arising during systemic infection evoke sickness behaviour, a coordinated set of adaptive changes initiated by the host to respond to, and to counteract, infection. It is now clear that the same systemic inflammatory signals can have severe deleterious effects on brain function when occuring in old age or in the presence of neurodegenerative disease. Multiple animal studies now show that even mild acute systemic inflammation can induce exaggerated sickness behaviour responses and cognitive dysfunction in aged animals or those with prior degenerative pathology when compared to young and/or healthy controls. These findings appear highly promising in understanding aspects of delirium. In this review our aim is to describe and assess the parallels between exaggerated sickness behaviour in vulnerable animals and delirium in older humans. We discuss inflammatory and stress-related triggers of delirium in the context of new animal models that allow us to dissect some aspects of the mechanisms underpinning these episodes. We discuss some differences between the sickness behaviour syndrome model and delirium in the context of the complexity in the latter due to other factors such as prior pathology, psychological stress and drug effects. We conclude that, with appropriate caveats, the study of sickness behaviour in the vulnerable brain offers a promising route to uncover the mechanisms of this common and serious unmet medical need.

Figure 1

Adaptive Sickness Behaviour Response: This scheme simplifies and summarises current knowledge of the sickness behaviour response as elucidated in rodents. Systemic inflammation is signalled to the brain via activation of the brain endothelium, the vagus nerve or circumventricular organs, such as the area postrema. The endothelial cells and perivascular macrophages express COX2 and COX1 to synthesize PGE2 and other prostanoids. PGE2 is known to acitvate hypothalamic centres (MPO: blue, PVN: red) via EP3 and EP1 receptors to drive fever and stress responses. Anxiety responses are mediated by the amygdala (yellow), which is activated directly by both IL-1β and brainstem noradrenaline release (indirect neuronal activation by the parabrachial nucleus detailed in main text). The hippocampus (green) can be activated by both IL-1β and PGE2 contributing to disengagement from the environment and cognitive changes. Abbreviations: PGE2: prostaglandin E2, IL-1β: interleukin-1β; COX: cyclooxygenase; HPA: hypothalamic pituitary adrenal; PVN: paraventricular nucleus; MPO: medial preoptic nucleus.

Figure 2

Maladaptive Sickness Behaviour response: This scheme superimposes observations from the rodent and clinical literature onto the broadly accepted model of sickness behaviour to propose ‘maladaptive sickness behaviour’. The pathways are largely as described in figure 1 with the following exceptions: increased blood brain barrier permeability may facilitate increased access of serum factors to the brain parenchyma, primed microglia (shown in grey) may cause amplified CNS responses to systemic inflammation, dysregulated HPA function may allow excessive stress responses. Putatively, altered HPA and amygdala responses, in addition to elevated inflammatory mediators may also have robust effects on the prefrontal cortex or other areas likely to be important in delirium in humans. Coupled with these changes, prior pathology in brain areas such as the cholinergic basal forebrain, the noradrenergic brainstem or the dopaminergic midbrain may have significant impacts on the presentation of inflammation-induced sickness behaviour. While the idea that delirium is compatible with an elevated and maladaptive sickness behavioural response remains speculative, evidence exists for marked hypoactivity and apathy (humans and rodents), dysregulated HPA function (humans and rodents), afebrile infections (humans) and exaggerated hypothermia (rodents), delirium (humans) and robustly impaired working memory/mental flexibility (rodents). Abbreviations: PGE2: prostaglandin E2, IL-1β: interleukin-1β; COX: cyclooxygenase; HPA: hypothalamic pituitary adrenal; PVN: paraventricular nucleus; MPO: medial preoptic nucleus.

Figure 3

Prior pathology and superimposed systemic inflammation interact to produce acute and transient working memory deficits: towards reconciling cholinergic and inflammatory hypotheses of delirium. This scheme shows the basal forebrain cholinergic nuclei (BFCN), illustrating the septohippocampal pathway, the ventral diagonal band projections to the amygdala and piriform and insular cortices and the nucleus basalis projection to the frontal, parietal and temporal cortices (after Wolff 1991). Intracerebroventricular injection (left panel) of the ribosomal toxin saporin, linked to an antibody against the p75 neurotrophin receptor, which is enriched on BFCN cells, induces selective neuronal death in these regions. This approach facilitates targeted, selective and limitable lesioning of this area and consequently decreased cholinergic tone (shown in grey, right panel) in these projection fields. In lesioned animals, LPS induces acute and transient working memory deficits, resembling delirium. Neither lesion nor LPS alone were sufficient to induce such deficits. LPS-induced CNS inflammatory responses were equivalent in lesioned and non-lesioned animals and the acetylcholinesterase inhibitor donepezil could block these deficits (Field et al., 2012). This model serves as a useful exemplar of how systemic inflammation in ‘vulnerable’ animals may be used to interrogate aspects of delirium pathophysiology.