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晚期老年痴呆症患者的“清醒”暗示了脑储备的未开发性

"Awakenings" in Advanced Dementia Patients Hint at Untapped Brain Reserves
晚期老年痴呆症患者的“清醒”暗示了脑储备的未开发性
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2019-08-11 11:40
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晚期老年痴呆症患者的“清醒”暗示了脑储备的未开发性

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.

一位处在阿尔兹海默症晚期的老年女性已经好几年没有与家庭成员沟通交流了。有一天,她突然与孙女聊天并询问其他家庭成员最近的消息,甚至给了孙女一些建议。孙女向弗吉尼亚大学的研究员表示了自己的震惊,“就像在跟里普.万.温克尔聊天一样。”但遗憾的是这种在觉醒状态并没有持续时间,这位老年女性在下周便去世了。

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.

这一事件被研究作者写作为终期清醒的案例,这适用于那些被认定为无法与外界沟通的人们在临死前发生的令人惊讶的、具有连贯部分的有意义的交谈。但是这并不是单一的情况。物理学家罗勒.爱尔达尔是国家老龄研究所老年医学部的领头人,他听说了这个案例并将它归档为很有趣的事件。但是在2018年,在对抗阿尔兹海默症的促使下,爱尔达尔认为是时候组织那些感兴趣的科学家建立一个工作室来进行更多研究。毕竟,如果那位老年女性可以利用未知的神经储备,那些类似的案例可以帮助科学家来探索认知是如何被储存的,即使对于那些处于极晚期对的神经退行性疾病的患者只是短暂的帮助。

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.”

这个夏天,爱尔达尔与他组织的科学家们开始进行研究的第一步,系统的、粗略的研究他们称矛盾清醒的现象,(矛盾清醒)这是一个旨在调查这一现象戏剧性、未预性和令人吃惊性质的更广泛的名称。工作室参与者在八月期刊的《阿尔兹海默症与老年痴呆》发表了两页纸,并且NIA声明将在明年为相关研究提供资金。早期目标较为适度—制定实用性定义并测量这一现象的发生率。然而潜在的长期影响是非常诱人的。“如果大脑可以进入正常状态,即使是暂时性的,那就意味着在某种特殊的环境下,有一定程度的机制能够工作。”麻醉师和神经科学家乔治.摩守是密歇根大学意识科学系的主任,也是相关文献的第一作者,说道,“这促使我们重新考虑这是否处于疾病晚期,即使有已知的退变,但有一部分功能配置可以让大脑用剩下的部分来完成,甚至这是一次让我们重新考虑这些机制的机会,这是很有说服力的。”

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.

没有人可以对矛盾清醒下准确的定义。基于很少的病例报道和先例,这像是自发的有意义的活动,比大多数痴呆患者偶尔发生的“好日子(比较清醒的时刻)”要好得多。清醒时刻是短暂的,持续几分钟、几小时,或者可能是一天。这似乎是发生在在死亡前的几小时 、几天活几周。即使它到现在还没有一个名称,很多人都能认出这些迹象。“当我描述它时你会看到很多人在点头,”爱尔达尔说“人们都说‘是的,我见过。’因为它发生的比较频繁,所以我们推断里面有什么机制。我们的任务就是来研究这到底是什么。”不管这究竟什么,爱尔达尔怀疑道,“它发生的次数比我们想象中的更多。”

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.”

矛盾清醒现象还发生于脑卒中、颅脑外伤以及其他情况的病人。但是现在研究这一现象的动力是由于对阿尔茨海默氏症和相关痴呆疾病的紧迫感不断上升,这是经过多年的努力而未能成功地发展出任何有意义的治疗方法,微弱的希望之光提供了一种可能性,即痴呆症可能不会,实际上,是完全不可逆转的。Eldadah说:“这似乎是一个进行创新和拓展的好时机。很高兴能进入科学领域的基层"

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.

与其他一些病人在麻醉状态下清醒的情况有相似之处,如濒死经历和术中清醒。对于矛盾清醒,许多人都以奇闻轶事来议论,直到少部分科学家决定认真的研究这一现象。这个研究有利于验证术中清醒患者的经历,这会改变麻醉的实施,并且在必要时提供心理支持。

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.”

关于濒死经历的研究也可能包含了矛盾清醒的解释。在2013年,Mashour和同事在大鼠体内引导了血管呼吸的停止,他们在动物大脑内发现了电记录在平静之前的激增现象。当计算机模型模拟神经活动的动态,网络接近崩溃时,也会发生类似的情况。这意味着当大脑处于生理危机状态时,Mashour说,“可能有某种短暂的时刻,你会在得到网络的激活。”

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.

这个发现暗示了系统神经科学方法的潜在功能,这考虑的不仅仅是单个神经而是神经组群对网络的反应。把一个信号分子--类似GABA的抑制性神经递质--应用到单个神经元上,例如,抑制神经功能,但在神经元群之间GABA可能会抑制其他抑制剂(实际上是神经双负),并产生激发的净结果。这样的广阔的预想,可以帮助解释出乎意料的现象,并为那些像矛盾清醒的不寻常现象提供一些神经生物学的可能性。

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.

在科学难题之外,研究还带来了方法学的改变。这里还有一些伦理方面的顾虑,因为晚期痴呆症患者是法务表达自己是否许可的。对于家庭成员来说,私人顾虑是一个问题。事实上如果他们能与失联很多年的爱人有一次意想不到的交流,他们会希望这被科学家打扰或者中断吗?第一次研究以观察为主,结合看护者的描述和自动记录装置来捕捉短暂的清醒时刻。Lori Frank是NIA的职员来在RAND公司研究与健康相关的生活质量,说家庭成员也是很重要的。她还指出,研究应该“以重视临床和非临床观察者关注和了解的方式进行。”Frank说,这项研究不会干预生命的终结,但“对矛盾的清醒的关注可能会改变人们在生命终结时的交流方式。”例如,预期的认知清晰时刻可能会导致提前指令措辞的改变。

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.”

Eldadah说,目前,关于矛盾清醒一切都是推测性的,但即使希望渺茫,发现有利信息的可能性也是令人兴奋的。"现在可能还没有结果,但它是一块我们必须转向的石头。"

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Lydia Denworth

Lydia Denworth

Lydia Denworth is a Brooklyn-based science writer and author of I Can Hear You Whisper: An Intimate Journey through the Science of Sound and Language (Dutton, 2014). She is working on a book about the science of friendship.

Lydia Denworth是一位布鲁克林的科学作家,著有《我能听到你的低语:声音和语言科学的亲密之旅》(达顿,2014年)。她正在写一本关于友谊科学的书。

Credit: Nick Higgins

Nick Higgins

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