Abstract: The aim of this research was to study paradoxical lucidity—the unexpected return of cognition and communication in patients with diagnosed dementia—systematically in a contemporary sample. We conducted a survey of caregivers who had witnessed at least one case of paradoxical lucidity in the year prior to survey completion. We assessed diagnosis and degree of preexisting cognitive impairment, cognitive state during the lucid episode, and temporal proximity of the lucid episode to death. Detailed case reports of 124 dementia patients who experienced an episode of paradoxical lucidity were received. In more than 80% of these cases, complete remission with return of memory, orientation, and responsive verbal ability was reported by observers of the lucid episode. The majority of patients died within hours to days after the episode. Further prospective study is warranted, as paradoxical lucidity suggests that there may exist a reversible and functional aspect of pathophysiology in severe dementia.
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Check also Check also Paradoxical lucidity: A potential paradigm shift for the neurobiology and treatment of severe dementias. George A. Mashoura et al. Check also Alzheimer's & Dementia, Volume 15, Issue 8, August 2019, Pages 1107-1114. https://doi.org/10.1016/j.jalz.2019.04.002
Abstract: Unexpected cognitive lucidity and communication in patients with severe dementias, especially around the time of death, have been observed and reported anecdotally. Here, we review what is known about this phenomenon, related phenomena that provide insight into potential mechanisms, ethical implications, and methodologic considerations for systematic investigation. We conclude that paradoxical lucidity, if systematically confirmed, challenges current assumptions and highlights the possibility of network-level return of cognitive function in cases of severe dementias, which can provide insight into both underlying neurobiology and future therapeutic possibilities.
4. Possible mechanisms of PL
Several forms of dementia, including Alzheimer's dementia, are largely associated with irreversible degeneration of the cerebral cortex and the hippocampus, resulting in confusion, disorientation, and memory loss, among other symptoms [35], [36]. Because the episodes of PL occur rather suddenly, it is unlikely that regeneration of neurons can account for them. Such fluctuations may reflect complex adjustments in signaling cascades, synaptic modifications, neuronal network interactions, and, perhaps, temporary reversal of, or compensation for, chronic functional inhibition due to neurotoxic proteins [37]. We acknowledge that there are different modes of cognitive fluctuation in varying types of dementia [38], [39], such as dementia with Lewy bodies. As noted in the Introduction, our focus is on the dramatic behavioral recovery at the time when the functional consequences of the neurodegeneration are thought to be irreversible, although a more comprehensive understanding of mechanisms of cognitive fluctuation across the full disease course for a range of dementias is lacking.
There have been no neuroscientific studies of PL, and thus, any mechanistic framework must be considered speculative. However, the related phenomena described previously speak to the biological possibility of PL and provide some insight into a potential mechanism. Because episodes of PL often occur just before death, the emerging neurobiological data related to NDEs are of relevance. As noted, surges of neurophysiological activity have been observed in humans just before death in the critical or operative care setting [21], [22], [23] and in experimental rodent models after cardiac or respiratory arrest [24]. It is thus conceivable that some patients with severe dementia might also experience a surge of neurophysiological activity before death, which is manifested as a lucid episode. Furthermore, extrapolating from studies of rats assessing neurochemistry after two minutes of asphyxia [25], it is possible that as oxygen and glucose levels fall or fluctuate, there is a surge of neurotransmitter levels that results in transient or metastable activation of the brain. However, such surges of electrical activity or neurotransmitter release do not explain how there can be enhanced synchronization or communication across the brain, which has been observed in dying rats and which could possibly account for a spontaneous recovery of cogent behavior in a patient with severe dementia. A network-level explanation is likely required.
The dynamics of complex networks are of relevance to neural function and have long been studied in the field of physics. There are precedents for the spontaneous recovery of nonbiological networks after periods of inactivity or damage [40]. In fact, network concepts related to “amplitude death” and “oscillation death” might be applicable to the observed surge in neurophysiological coherence just before functional network breakdown in the brain around the time of death. Using a Stuart-Landau model, one investigation described the dynamics of how such oscillations can spontaneously “revive,” [41] while another study described how the revival of such oscillations can be accompanied by rhythmicity and dynamic activity across the network [42]. These concepts have also been instantiated in neuronal models, with the conclusion that at a certain point of neuronal inhibition in a sparsely connected network, there is a counterintuitive “rebirth” of neuronal activity [43] that is manifested across the network. Furthermore, conditions for rapid and nonlinear synchronization (sometimes referred to as “explosive synchronization”) occur in association with arousal when brain network hubs are suppressed [44], as in dementia [45].
Thus, although the mechanism of PL is unknown, there is evidence that the dying or hypoxic brain can generate neurochemical and neuroelectrical surges that might be associated with the network dynamics of complex systems and that might generate spontaneous network integration manifesting as lucid behavior. We emphasize that this is speculative, but computational modeling studies of large-scale brain networks, which have been applied to Alzheimer's disease, could be investigated to establish foundational credibility for such network phenomena in those with severe dementia. It must also be noted that there may not be a unique mechanism for PL that is restricted to the days before death but rather a mechanism that is common to cognitive fluctuations in less severe stages of the disease [12], [13]. Furthermore, changes in systemic factors, rather than intrinsic neural dynamics, might drive the causal mechanisms responsible for lucid episodes. For example, one case report of a patient with Parkinson's disease dementia was able to correlate cognitive fluctuations with paroxysmal episodes of hypotension [46]. Thus, systemic physiologic factors must also be considered in the mechanism of PL.
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