Hypothesis for the pathophysiology of delirium: Role of baseline brain network connectivity and changes in inhibitory tone

Normal brain function is facilitated by a highly organized and interconnected structure allowing complex integration of sensory information and motor responses. The acute confusional state of delirium is characterized by a fluctuating disturbance in consciousness, arousal level and cognition-memory; as such, delirium represents a failure in the integration and appropriate processing of information. The pathogenesis of this cognitive disintegration is unclear; herein a hypothesis is proposed that delirium results from an acute breakdown in network connectivity within the brain. The hypothesis predicts that the extent to which the network connectivity breaks down is dependent on two factors: (i) the baseline connectivity within the brain and (ii) the level of inhibitory tone. Baseline connectivity is the connectivity of neural networks within the brain before the precipitating insult provoking delirium. Many non-modifiable risk factors for delirium influence baseline connectivity such as age, cognitive impairment, dementia and depression. Precipitant events that provoke delirium (modifiable risk factors) are hypothesized to further, and acutely, breakdown network connectivity by increasing inhibitory tone within the brain. Modifiable risk factors include inflammation, metabolic abnormalities, sleep deprivation and medication such as benzodiazepines. An important role for GABAergic neurotransmission is implicated in increasing the inhibitory tone to produce delirium. This theory accounts for the various forms of delirium, hypoactive, hyperactive and mixed. The form of delirium that ensues will depend upon how and which networks breakdown (dependent on both the individual’s baseline network connectivity and the degree change in inhibitory tone produced).