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“Awakenings” in Advanced Dementia Patients Hint at Untapped Brain Reserves

By Lydia Denworth | August 1, 2019 | Scientific American | Topics: Brain, Science and Health

Numerous reports documenting lucid moments at the end of life spur Alzheimer’s researchers to explore the phenomenon

An elderly woman suffering from late-stage Alzheimer’s disease had neither talked to nor reacted to any of her family members for years. Then, one day, she suddenly started chatting with her granddaughter, asking for news of other family members and even giving her granddaughter advice. “It was like talking to Rip van Winkle,” the granddaughter told University of Virginia researchers of her astonishment. Unfortunately, the reawakening did not last—the grandmother died the next week.

That event got written up as what the case study authors called terminal lucidity—a surprising, coherent episode of meaningful communication just before death in someone presumed incapable of social interaction. Yet it was by no means unique. Physician Basil Eldadah, who heads the geriatric branch at the National Institute on Aging (NIA), had heard such stories and filed them away as intriguing accounts. But in 2018, spurred by the need to make progress combatting Alzheimer’s, Eldadah began to think it was time to do more and organized a workshop for interested scientists. After all, if the grandmother was able to tap into mysterious neural reserves, cases such as hers might help scientists explore how cognition could possibly be restored—even briefly—in patients with the most advanced neurodegenerative disease.

This summer Eldadah and the scientists he assembled have taken the first steps toward systematic and rigorous study of what they are now calling paradoxical lucidity, a broader label intended to capture the dramatic, unexpected and puzzling nature of the phenomenon. The workshop participants published two papers on it in the August issue of Alzheimer’s and Dementia, and the NIA announced plans to fund relevant research next year. The early goals are modest—the formulation of an operational definition and a gauging of the phenomenon’s prevalence. The possible long-term implications, however, are tantalizing. “If the brain were able to access that normal state, even if it’s transient, it would suggest that there’s some requisite level of machinery that can work under some kind of unique circumstance,” anesthesiologist and neuroscientist George Mashour, director of the Center for Consciousness Science at the University of Michigan and lead author of one of the papers, says. “That prompts a reconsideration of whether or not at this late stage in the disease, even with known degeneration, there is some kind of functional configuration that the brain can achieve with what remains. Even a chance at rethinking the foundations is compelling.”

No one can say yet precisely what paradoxical lucidity is. Based on the limited case reports and anecdotes, it seems to be a spontaneous, meaningful event that goes well beyond the occasional “good days” most dementia patients experience. The period of clarity is brief, lasting minutes, hours or possibly a day. It seems to come in the hours, days or weeks before death. Even though it hasn’t had a label until now, many people recognize the signs. “I start describing it and you start to see heads nodding,” Eldadah says. “People say, ‘oh yes, I’ve seen that.’ It’s happened so many times that we’re reassured that there is something there. Our job is to figure out what that it is.” Whatever it is, Eldadah suspects, “it happens more often than we think.” Caregivers might not be reporting what they see, he says, and medications could mask its presence.

Episodes of paradoxical lucidity have also been seen in patients with stroke, brain tumors and other conditions. But the impetus for studying the phenomenon now is because of the rising sense of urgency about Alzheimer’s disease and related dementias after years of unsuccessful efforts to develop any meaningful treatment as well as the faint glimmer of hope that paradoxical lucidity offers the possibility that dementia may not, in fact, be entirely irreversible. “It seemed like this would be an opportune time to do something innovative and to push the envelope,” Eldadah says. “It’s gratifying to get in on the ground floor of an area of science.”

There are parallels to some other conditions such as near-death experiences and intraoperative awareness, in which patients can recall events that happened while they were under anesthesia. As with paradoxical lucidity, both were largely discussed anecdotally until a few scientists decided to study them more seriously. That research helped validate patient experiences and, in the case of intraoperative awareness, led to clinical changes in anesthesia practices and the provision of psychological support where necessary.

Work on near-death experiences might also contain hints of an explanation for paradoxical lucidity. In 2013 Mashour and his colleagues induced cardiac or respiratory arrest in rats. They observed a surge of electrical activity in the animals’ brains before the recording flatlined. Something similar happens when the dynamics of neural activity are simulated in a computer model and the network nears collapse. This means that when the brain is in a state of physiologic crisis, Mashour says, “there might be some sort of transient phase where you’re getting an activation of networks.”

Such findings suggest the potential usefulness of a systems neuroscience approach, which considers not just neurons in isolation but how groups of neurons interact in a network. Applying a signaling molecule—an inhibitory neurotransmitter like GABA—to a single neuron, for instance, depresses neural function, but across groups of neurons GABA might inhibit other inhibitors—a neural double negative, in effect—and produce a net result of excitation. Such a big picture perspective, then, can help explain unexpected results and might provide some neurobiological plausibility to a phenomenon as unusual as paradoxical lucidity.

Beyond the scientific puzzle it presents, studying it brings some methodological challenges. There are ethical concerns because late-stage dementia patients are not capable of informed consent. For family members, privacy concerns might be an issue. If, in fact, they can have an unexpected connection, and perhaps closure, with a loved one who has been lost for years, will they want those moments disrupted by scientists? The first studies will likely be observational, either via reports from caregivers or with automated recording devices to catch fleeting bursts of lucidity. Either way, family involvement will be important, says Lori Frank, who studies health-related quality of life at RAND Corporation and was a fellow at the NIA. She also notes studies should be conducted “in a way that values what clinical and nonclinical observers notice and know.” The research need not interfere with the end of life experience, Frank says, but “attention to paradoxical lucidity might change the way people interact at the end of life.” Anticipating moments of cognitive clarity could lead to changes in the wording of advance directives, for example.

For now, everything about paradoxical lucidity is speculative, but even with long odds, the possibility of useful findings is exciting, Eldadah says. “This may end up going nowhere, but it’s a stone that we have to turn.”

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