Aging Clin Exp Res DOI 10.1007/s40520-015-0379-3
SHORT COMMUNICATION
Functional interrelationship of brain aging and delirium Piero Rapazzini1
Received: 8 April 2015 / Accepted: 12 May 2015 Ó Springer International Publishing Switzerland 2015
Abstract Theories on the development of delirium are complementary rather than competing and they may relate to each other. Here, we highlight that similar alterations in functional brain connectivity underlie both the observed age-related deficits and episodes of delirium. The default mode network (DMN) is a group of brain regions showing a greater level of activity at rest than during attention-based tasks. These regions include the posteromedial–anteromedial cortices and temporoparietal junctions. Evidence suggests that awareness is subserved through higher order neurons associated with the DMN. By using functional MRI disruption of DMN, connectivity and weaker taskinduced deactivations of these regions are observed both in age-related cognitive impairment and during episodes of delirium. We can assume that an acute up-regulation of inhibitory tone within the brain acts to further disrupt network connectivity in vulnerable patients, who are predisposed by a reduced baseline connectivity, and triggers the delirium. Keywords
Brain aging Delirium Network connectivity
Introduction Advanced aging is accompanied by cognitive decline even in the absence of disease [1]. Several theories suggest that cognitive deficits in normal aging arise from alterations in functional properties of coordinated brain systems or from & Piero Rapazzini [email protected] 1
Geriatrics Division, Ospedale di Circolo e Fondazione Macchi, 21100 Varese, Italy
a subtle anatomical disconnection between brain regions, which ordinarily function together. Potentially the latter is due to white matter loss or demyelination [2, 3]. The ‘‘disconnection’’ hypothesis has been described [4] as follows: the decline in normal aging emerges from changes in functional integration between systems of brain areas in addition to dysfunction of specific gray matter areas. Delirium is characterized by an alteration in the level of attention and awareness secondary to systemic disturbances, which develops over a relatively short period of time, and represents a change from subject’s baseline [5]. It is a serious and often-fatal disorder that affects as much as 50 % of elderly people in hospital, and those who survive are more likely to experience long-term cognitive impairment [6]. To date, no single unitary pathophysiologic mechanism has been identified and the majority of the existing theories are complementary rather than discordant [7]. Sanders suggested that delirium results from an acute breakdown in network connectivity within the brain [8]. Many of the non-modifiable risk factors for delirium affect baseline network connectivity such as age, pre-existing cognitive impairment, dementia and depression. The modifiable risk factors for delirium including inflammation, metabolic abnormalities, sleep deprivation and medication further disrupt network connectivity by increasing GABAergic inhibitory tone. In this paper, we highlight that new neuroimaging studies show similar alterations in functional brain connectivity, both in observed age-related deficits and in episodes of delirium. It is interesting to notice that the same large network, the default mode network (DMN), is indeed affected. This further confirms the hypothesis that, should there be already a reduced baseline network connectivity, a smaller increase in inhibitory tone is then required to breakdown the network and to trigger delirium [9].
123
Aging Clin Exp Res
The default mode network When not involved in an attention-demanding task, the human brain switches to a ‘‘resting mode’’ that is thought to predominantly support a state of inner awareness. Resting state functional MRI (f-MRI) is an ideal technique in order to examine spontaneous neuronal activity and connectivity [10]. Amongst these patterns of spontaneous neuronal function that can be identified with f-MRI, there is a network that displays strong activity along the frontoparietal midline of the brain. This network has been named the DMN, as its presence is thought to reflect a default state of brain activity vital for the brain functioning and possibly consciousness [11]. The DMN encompasses the following cortex areas: the medial prefrontal cortex; the posterior cingulated cortex; the precuneus and anterior cingulated cortex; and parietal cortex. Further theories suggest self-awareness is neuroanatomically distinct from cognitive engagement and action [12]. What is observed at a neurophysiological and shared at an experiential level is a consciousness–cognitive dissonance. When the precision of cognition is evaluated, the personal resonance implicit in consciousness is bypassed. Similarly when consciousness is measured, the personal experiential nature of the response avoids the exactitude of orientation and memory. Evidence suggests that awareness is a discrete entity subserved through higher order neurons associated with the DMN and active when an individual is relaxed and at wakeful rest [13]. Presumably it is in this state of awareness that one can access higher level cognitive functions such as judgment or reflection. Once a goal-directed behavior (such as accessing memory or performing calculations) intervenes, then the DMN is switched off and the task-positive network is activated.
The default mode network in brain aging Andrews-Hanna et al. [14] reported that anterior to posterior components within the DMN were most severely disrupted with age. Moreover, older adults exhibited weaker task-induced deactivations in these regions, and those individuals exhibiting the lowest functional correlations also performed the poorest cognitive test scores. Correlation reductions were severe in older adults free from Alzheimer’s disease (AD) pathology as determined by amyloid imaging, suggesting that functional disruptions were not the result of AD. Instead reduced correlations were associated with disruptions in white matter integrity. These results indicate that cognitive decline in normal aging
123
arises from functional disruption in the coordination of large-scale brain systems, especially between anterior and posterior components of the DMN. Another study addressed this topic by monitoring regional grey matter volume, using an average measure of grey matter volume of the DMN in each individual [15]. After correction for atrophy, the f-MRI observed the decrease in functional connectivity remained significant, indicating that the aging-related changes in connectivity are not solely associated with reductions in grey matter volume. Also Damoiseaux et al. [16] observed that intrinsic activity within the DMN is decreased in the elderly, showing a negative association between age and DMN connectivity. The decreased activity occurred mainly in the anterior DMN and was indeed associated with cognitive decline, which is exhibited by reduced attention, concentration, processing speed and/or executive function. Although some evidences suggest a widespread neuronal loss as a cause of the cognitive frailty, current works indicate a more subtle and restricted reorganization of neuronal circuits [17]. Functionally dendritic spines are plastic and dynamic structures influenced by their electrophysiological activity and, more importantly, they are the contact point between neurons for the formation of neural circuitry. During normal conditions fast turnover of spines occurs as part of long-term learning and memory maintenance; however, a massive loss of functional dendritic spines is detrimental as it is highly associated with brain aging and pathologies. In general in the prefrontal cortex of old humans there is a decrease between 25 and 34 % in spine density.
The default mode network during delirium Choi et al. [18] investigated resting-state brain networks during and after an episode of delirium using f-MRI. The cortical DMN connectivity was disrupted during delirium and normalized after the resolution. In addition connectivity was inversely correlated with duration of delirium, suggesting that partial maintenance may have helped to facilitate the resolution. In the same study, the posterior cingulate cortex (a hub node of the DMN) and the dorsolateral prefrontal cortex (a part of the executive network or task-positive component) were inversely correlated in comparison subjects, but strongly correlated in patients during an episode of delirium, as indicated by increased functional connectivity between the two regions. A disruptive alteration in the reciprocity between the posterior cingulate cortex and the dorsolateral prefrontal cortex may explain impaired
Aging Clin Exp Res
attention and consciousness, which is considered a cardinal symptom of delirium. It is also important to mention that this anticorrelation was not revived shortly after the recovery of delirium. This means that delirium-related DMN changes can be maintained for a certain period even after clinical improvement and may underlie some residual delirium symptoms such as mild inattention. Whilst we cannot meaningfully engage in both experience and thought at the same time, we do have the capacity according to DMN to switch between them freely. It is tantalizing to conjecture that loss of DMN dexterity has important implications for the conceptualisation and management of delirium [19]. A hypothesis has been proposed that delirium results from an acute breakdown in network connectivity within the brain [8]. The hypothesis predicts that the extent to which the network connectivity breaks down depends on two factors: the baseline connectivity within the brain and the level of inhibitory tone. An acute up-regulation of inhibitory tone, especially by GABAergic neurotransmissions, acts to further disrupt network connectivity and precipitates delirium. In summary, the network disconnectivity theory on the pathogenesis of delirium intersects with the neuronal aging and the neurotransmitter theory [20]. It also intersects with the neuroinflammatory theory, as systemic inflammation affects neuronal and synaptic function with consequent disconnection between different cortical structures [21].
Conclusion Aging is accompanied by disruptive alterations in the coordination of large-scale brain systems that support highlevel cognition. Although neuronal loss is minimal in most cortical regions of the normal aging brain, changes in the synaptic physiology may contribute to altered connectivity [9]. Disruption of functional connectivity of the DMN and weaker task-induced deactivations of these regions occur both in normal aging related to cognitive impairment and during an episode of delirium. As delirium has many causing factors, it is unlikely to be a single mechanism that accounts for its many manifestations. The observed changes in neurotransmitters are not uniform. The most commonly described changes are deficiencies in acetylcholine availability; excess in dopamine, norepinephrine or glutamate release; and variable alterations in GABA [22, 23]. Instead of being seen as a specific neurotransmitter deficit, delirium might be better conceived as the failure of a high order function in a complex system, which is in a state of increased vulnerability to poor resolution of homeostasis after a stressor event [24].
Our understanding of delirium remains significantly limited. The motor subtypes of delirium include hyperactive (pure agitation), hypoactive (pure lethargy), and mixed (fluctuation between lethargy and agitation) [25]. A critical step will be to study each subtype more closely, because these forms probably represent separate dysfunctions of neural networks. Until they are further dissected, the development of therapies for delirium will be impaired [9]. Conflict of interest interest.
The author declares that he has no conflict of
Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors.
References 1. Park OC, Reuter-Lorenz P (2009) The adaptive brain: aging and neurocognitive scaffolding. Annu Rev Psychol 60:169–173 2. Yankner BA, Lu T, Loerch P (2008) The aging brain. Ann Rev Path 3:41–66 3. Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464(7228):529–535 4. O’ Sullivan M, Jones DK, Summers PE et al (2001) Evidence of cortical disconnection as a mechanism of age related cognitive decline. Neurology 57:632–638 5. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Association, Washington, DC 6. Inouye SK, Westendorp RJ, Saczynski JS (2014) Delirium in elderly people. Lancet 383:911–922 7. Maldonado JR (2013) Neuropathogenesis of delirium: review of current etiologic theories and common pathways. Am J Ger Psychiatry 21:1190–1222 8. Sanders RD (2011) Hypothesis for the pathophysiology of delirium: role of baseline brain network connectivity and changes in inhibitory tone. Med Hypotheses 77:140–143 9. Sanders RD (2013) Delirium, neurotransmission, and network connectivity. Anaesthesiology 118:494–496 10. Fox MD, Rachile ME (2007) Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci 8:700–711 11. Guldenmund P, Vanhaudenhuyse A, Boly M et al (2012) A default mode of brain function in altered states of consciousness. Arch Ital Biol 150:107–121 12. Andrews-Hanna JR, Reidler JS, Sepulcre J et al (2010) Functional-anatomic fractionation of the brain’s default network. Neuron 65:550–562 13. Buckner RL, Andrews-Hanna JR, Schacter DL (2008) The brain’s default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci 1124:1–38 14. Andrews-Hanna JR, Snyder AZ, Vincent JL et al (2007) Disruption of large-scale brain systems and advanced age. Neuron 56(5):924–935 15. Hafkemeijer A, van der Grond J, Rombouts S (2012) Imaging the default mode network in aging and dementia. Bioch Biophys Acta 1822:431–441 16. Damaoiseaux JS, Beckmann CF, Sanz Arigita EJ et al (2008) Reduced resting-state brain activity in the default network in normal aging. Cerebral Cortex 18:1856–1864
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Aging Clin Exp Res 17. Bano D, Agosti M, Melino G, Nicotera P (2011) Ageing, connectivity and brain disorders: an unsolved ripple effect. Mol Neurobiol 43:124–130 18. Choi HS, Lee H, Chung TS et al (2012) Neural network functional connectivity during and after an episode of delirium. Am J Psychiatry 169:498–507 19. Eeles EM, Pandy S, Ray JL (2013) Delirium: a disorder of consciousness? Med Hypotheses 80:399–404 20. Maldonado JR (2008) Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin 24:789–856 21. Serantes R, Arnalich F, Figueroa M (2006) Interleukin-1 beta enhances GABA receptor cell-surface expression. J Biol Chem 281:14632–14643
123
22. Cererejra J, Nogueira V, Luis P (2012) The cholinergic system and inflammation: common pathways in delirium pathophysiology. J Am Geriatr Soc 60:669–675 23. Teslyar P, Stock WM, Wilk CM (2013) Prophylaxis with antipsychotic medications reduces the risk of post-operative delirium in elderly patients. Psychosomatics 54:124–131 24. Bhat R, Rockwood K (2007) Delirium as a disorder of consciousness. J Neurol Neurosurg Psychiatry 78:1167–1170 25. Robinson TN, Reaburn CD, Tran ZV et al (2011) The motor subtypes of post-operative delirium in the elderly. Arch Surg 146(3):295–300
SHORT COMMUNICATION
Functional interrelationship of brain aging and delirium Piero Rapazzini1
Received: 8 April 2015 / Accepted: 12 May 2015 Ó Springer International Publishing Switzerland 2015
Abstract Theories on the development of delirium are complementary rather than competing and they may relate to each other. Here, we highlight that similar alterations in functional brain connectivity underlie both the observed age-related deficits and episodes of delirium. The default mode network (DMN) is a group of brain regions showing a greater level of activity at rest than during attention-based tasks. These regions include the posteromedial–anteromedial cortices and temporoparietal junctions. Evidence suggests that awareness is subserved through higher order neurons associated with the DMN. By using functional MRI disruption of DMN, connectivity and weaker taskinduced deactivations of these regions are observed both in age-related cognitive impairment and during episodes of delirium. We can assume that an acute up-regulation of inhibitory tone within the brain acts to further disrupt network connectivity in vulnerable patients, who are predisposed by a reduced baseline connectivity, and triggers the delirium. Keywords
Brain aging Delirium Network connectivity
Introduction Advanced aging is accompanied by cognitive decline even in the absence of disease [1]. Several theories suggest that cognitive deficits in normal aging arise from alterations in functional properties of coordinated brain systems or from & Piero Rapazzini [email protected] 1
Geriatrics Division, Ospedale di Circolo e Fondazione Macchi, 21100 Varese, Italy
a subtle anatomical disconnection between brain regions, which ordinarily function together. Potentially the latter is due to white matter loss or demyelination [2, 3]. The ‘‘disconnection’’ hypothesis has been described [4] as follows: the decline in normal aging emerges from changes in functional integration between systems of brain areas in addition to dysfunction of specific gray matter areas. Delirium is characterized by an alteration in the level of attention and awareness secondary to systemic disturbances, which develops over a relatively short period of time, and represents a change from subject’s baseline [5]. It is a serious and often-fatal disorder that affects as much as 50 % of elderly people in hospital, and those who survive are more likely to experience long-term cognitive impairment [6]. To date, no single unitary pathophysiologic mechanism has been identified and the majority of the existing theories are complementary rather than discordant [7]. Sanders suggested that delirium results from an acute breakdown in network connectivity within the brain [8]. Many of the non-modifiable risk factors for delirium affect baseline network connectivity such as age, pre-existing cognitive impairment, dementia and depression. The modifiable risk factors for delirium including inflammation, metabolic abnormalities, sleep deprivation and medication further disrupt network connectivity by increasing GABAergic inhibitory tone. In this paper, we highlight that new neuroimaging studies show similar alterations in functional brain connectivity, both in observed age-related deficits and in episodes of delirium. It is interesting to notice that the same large network, the default mode network (DMN), is indeed affected. This further confirms the hypothesis that, should there be already a reduced baseline network connectivity, a smaller increase in inhibitory tone is then required to breakdown the network and to trigger delirium [9].
123
Aging Clin Exp Res
The default mode network When not involved in an attention-demanding task, the human brain switches to a ‘‘resting mode’’ that is thought to predominantly support a state of inner awareness. Resting state functional MRI (f-MRI) is an ideal technique in order to examine spontaneous neuronal activity and connectivity [10]. Amongst these patterns of spontaneous neuronal function that can be identified with f-MRI, there is a network that displays strong activity along the frontoparietal midline of the brain. This network has been named the DMN, as its presence is thought to reflect a default state of brain activity vital for the brain functioning and possibly consciousness [11]. The DMN encompasses the following cortex areas: the medial prefrontal cortex; the posterior cingulated cortex; the precuneus and anterior cingulated cortex; and parietal cortex. Further theories suggest self-awareness is neuroanatomically distinct from cognitive engagement and action [12]. What is observed at a neurophysiological and shared at an experiential level is a consciousness–cognitive dissonance. When the precision of cognition is evaluated, the personal resonance implicit in consciousness is bypassed. Similarly when consciousness is measured, the personal experiential nature of the response avoids the exactitude of orientation and memory. Evidence suggests that awareness is a discrete entity subserved through higher order neurons associated with the DMN and active when an individual is relaxed and at wakeful rest [13]. Presumably it is in this state of awareness that one can access higher level cognitive functions such as judgment or reflection. Once a goal-directed behavior (such as accessing memory or performing calculations) intervenes, then the DMN is switched off and the task-positive network is activated.
The default mode network in brain aging Andrews-Hanna et al. [14] reported that anterior to posterior components within the DMN were most severely disrupted with age. Moreover, older adults exhibited weaker task-induced deactivations in these regions, and those individuals exhibiting the lowest functional correlations also performed the poorest cognitive test scores. Correlation reductions were severe in older adults free from Alzheimer’s disease (AD) pathology as determined by amyloid imaging, suggesting that functional disruptions were not the result of AD. Instead reduced correlations were associated with disruptions in white matter integrity. These results indicate that cognitive decline in normal aging
123
arises from functional disruption in the coordination of large-scale brain systems, especially between anterior and posterior components of the DMN. Another study addressed this topic by monitoring regional grey matter volume, using an average measure of grey matter volume of the DMN in each individual [15]. After correction for atrophy, the f-MRI observed the decrease in functional connectivity remained significant, indicating that the aging-related changes in connectivity are not solely associated with reductions in grey matter volume. Also Damoiseaux et al. [16] observed that intrinsic activity within the DMN is decreased in the elderly, showing a negative association between age and DMN connectivity. The decreased activity occurred mainly in the anterior DMN and was indeed associated with cognitive decline, which is exhibited by reduced attention, concentration, processing speed and/or executive function. Although some evidences suggest a widespread neuronal loss as a cause of the cognitive frailty, current works indicate a more subtle and restricted reorganization of neuronal circuits [17]. Functionally dendritic spines are plastic and dynamic structures influenced by their electrophysiological activity and, more importantly, they are the contact point between neurons for the formation of neural circuitry. During normal conditions fast turnover of spines occurs as part of long-term learning and memory maintenance; however, a massive loss of functional dendritic spines is detrimental as it is highly associated with brain aging and pathologies. In general in the prefrontal cortex of old humans there is a decrease between 25 and 34 % in spine density.
The default mode network during delirium Choi et al. [18] investigated resting-state brain networks during and after an episode of delirium using f-MRI. The cortical DMN connectivity was disrupted during delirium and normalized after the resolution. In addition connectivity was inversely correlated with duration of delirium, suggesting that partial maintenance may have helped to facilitate the resolution. In the same study, the posterior cingulate cortex (a hub node of the DMN) and the dorsolateral prefrontal cortex (a part of the executive network or task-positive component) were inversely correlated in comparison subjects, but strongly correlated in patients during an episode of delirium, as indicated by increased functional connectivity between the two regions. A disruptive alteration in the reciprocity between the posterior cingulate cortex and the dorsolateral prefrontal cortex may explain impaired
Aging Clin Exp Res
attention and consciousness, which is considered a cardinal symptom of delirium. It is also important to mention that this anticorrelation was not revived shortly after the recovery of delirium. This means that delirium-related DMN changes can be maintained for a certain period even after clinical improvement and may underlie some residual delirium symptoms such as mild inattention. Whilst we cannot meaningfully engage in both experience and thought at the same time, we do have the capacity according to DMN to switch between them freely. It is tantalizing to conjecture that loss of DMN dexterity has important implications for the conceptualisation and management of delirium [19]. A hypothesis has been proposed that delirium results from an acute breakdown in network connectivity within the brain [8]. The hypothesis predicts that the extent to which the network connectivity breaks down depends on two factors: the baseline connectivity within the brain and the level of inhibitory tone. An acute up-regulation of inhibitory tone, especially by GABAergic neurotransmissions, acts to further disrupt network connectivity and precipitates delirium. In summary, the network disconnectivity theory on the pathogenesis of delirium intersects with the neuronal aging and the neurotransmitter theory [20]. It also intersects with the neuroinflammatory theory, as systemic inflammation affects neuronal and synaptic function with consequent disconnection between different cortical structures [21].
Conclusion Aging is accompanied by disruptive alterations in the coordination of large-scale brain systems that support highlevel cognition. Although neuronal loss is minimal in most cortical regions of the normal aging brain, changes in the synaptic physiology may contribute to altered connectivity [9]. Disruption of functional connectivity of the DMN and weaker task-induced deactivations of these regions occur both in normal aging related to cognitive impairment and during an episode of delirium. As delirium has many causing factors, it is unlikely to be a single mechanism that accounts for its many manifestations. The observed changes in neurotransmitters are not uniform. The most commonly described changes are deficiencies in acetylcholine availability; excess in dopamine, norepinephrine or glutamate release; and variable alterations in GABA [22, 23]. Instead of being seen as a specific neurotransmitter deficit, delirium might be better conceived as the failure of a high order function in a complex system, which is in a state of increased vulnerability to poor resolution of homeostasis after a stressor event [24].
Our understanding of delirium remains significantly limited. The motor subtypes of delirium include hyperactive (pure agitation), hypoactive (pure lethargy), and mixed (fluctuation between lethargy and agitation) [25]. A critical step will be to study each subtype more closely, because these forms probably represent separate dysfunctions of neural networks. Until they are further dissected, the development of therapies for delirium will be impaired [9]. Conflict of interest interest.
The author declares that he has no conflict of
Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors.
References 1. Park OC, Reuter-Lorenz P (2009) The adaptive brain: aging and neurocognitive scaffolding. Annu Rev Psychol 60:169–173 2. Yankner BA, Lu T, Loerch P (2008) The aging brain. Ann Rev Path 3:41–66 3. Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464(7228):529–535 4. O’ Sullivan M, Jones DK, Summers PE et al (2001) Evidence of cortical disconnection as a mechanism of age related cognitive decline. Neurology 57:632–638 5. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Association, Washington, DC 6. Inouye SK, Westendorp RJ, Saczynski JS (2014) Delirium in elderly people. Lancet 383:911–922 7. Maldonado JR (2013) Neuropathogenesis of delirium: review of current etiologic theories and common pathways. Am J Ger Psychiatry 21:1190–1222 8. Sanders RD (2011) Hypothesis for the pathophysiology of delirium: role of baseline brain network connectivity and changes in inhibitory tone. Med Hypotheses 77:140–143 9. Sanders RD (2013) Delirium, neurotransmission, and network connectivity. Anaesthesiology 118:494–496 10. Fox MD, Rachile ME (2007) Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci 8:700–711 11. Guldenmund P, Vanhaudenhuyse A, Boly M et al (2012) A default mode of brain function in altered states of consciousness. Arch Ital Biol 150:107–121 12. Andrews-Hanna JR, Reidler JS, Sepulcre J et al (2010) Functional-anatomic fractionation of the brain’s default network. Neuron 65:550–562 13. Buckner RL, Andrews-Hanna JR, Schacter DL (2008) The brain’s default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci 1124:1–38 14. Andrews-Hanna JR, Snyder AZ, Vincent JL et al (2007) Disruption of large-scale brain systems and advanced age. Neuron 56(5):924–935 15. Hafkemeijer A, van der Grond J, Rombouts S (2012) Imaging the default mode network in aging and dementia. Bioch Biophys Acta 1822:431–441 16. Damaoiseaux JS, Beckmann CF, Sanz Arigita EJ et al (2008) Reduced resting-state brain activity in the default network in normal aging. Cerebral Cortex 18:1856–1864
123
Aging Clin Exp Res 17. Bano D, Agosti M, Melino G, Nicotera P (2011) Ageing, connectivity and brain disorders: an unsolved ripple effect. Mol Neurobiol 43:124–130 18. Choi HS, Lee H, Chung TS et al (2012) Neural network functional connectivity during and after an episode of delirium. Am J Psychiatry 169:498–507 19. Eeles EM, Pandy S, Ray JL (2013) Delirium: a disorder of consciousness? Med Hypotheses 80:399–404 20. Maldonado JR (2008) Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin 24:789–856 21. Serantes R, Arnalich F, Figueroa M (2006) Interleukin-1 beta enhances GABA receptor cell-surface expression. J Biol Chem 281:14632–14643
123
22. Cererejra J, Nogueira V, Luis P (2012) The cholinergic system and inflammation: common pathways in delirium pathophysiology. J Am Geriatr Soc 60:669–675 23. Teslyar P, Stock WM, Wilk CM (2013) Prophylaxis with antipsychotic medications reduces the risk of post-operative delirium in elderly patients. Psychosomatics 54:124–131 24. Bhat R, Rockwood K (2007) Delirium as a disorder of consciousness. J Neurol Neurosurg Psychiatry 78:1167–1170 25. Robinson TN, Reaburn CD, Tran ZV et al (2011) The motor subtypes of post-operative delirium in the elderly. Arch Surg 146(3):295–300
