10 Jun 2004

People with Alzheimer's disease clearly have deficits in explicit memory—the type that can be deliberately accessed. But there is good evidence that some implicit memory processes—those "subconscious" memories that are only revealed in certain behaviors—may be preserved, at least in the early stages of the disease.

In today’s issue of Neuron, Cindy Lustig and Randy Buckner of Washington University in St. Louis, Missouri, report that some of the cortical areas underlying priming, a form of implicit memory, are still up to the task in older adults. The results suggest that Alzheimer's patients will be better able to comply with regular routines if the surrounding context and instructions are kept stable and consistent, at least in the early stages of their disease.

"Priming" describes a class of implicit memory wherein repeated exposure to a bit of information allows a person to use or manipulate that bit of information more quickly or more accurately. In the example the authors give, a person classifying the word "cloud" as a living or nonliving thing will assign the word to the appropriate category more quickly the second time she encounters it in a word list.

Previous research has found that baseline performance on verbal tasks declines with age, but older adults, even those with Alzheimer's disease, retain a capacity for priming comparable to that of younger adults (Gabrieli et al., 1999). Lustig and Buckner sought to determine the fMRI neural correlates of this effect, comparing young adults in their early twenties with older adults in their seventies and eighties, with or without Alzheimer's. They focused their analysis on verbal processing areas of the left prefrontal cortex (Brodmann's areas 45/47 and 44/6), which are known to show reduced activity in young adults as a result of priming.

The researchers found that this prefrontal activity decreased about as much in older people, both with or without Alzheimer's, as it did in the younger adults in the study. The activity reductions correlated with priming effects. Interestingly, similar reductions in neural activity with priming were found on fMRI of corresponding areas in the right hemisphere, though not in visual or motor cortical areas.

Lars Nyberg, of Umea University in Sweden, finds it noteworthy that the older adults were capable of priming acquisition of similar magnitude, considering that overall left prefrontal cortical activity differed significantly between old and young adults. "This might reflect a relatively greater difficulty in initially recruiting frontal regions by the old—but once recruited, the repetition-related effects seem to parallel those in younger adults," writes Nyberg in an accompanying editorial.

The researchers suggest that their data might have implications for improving the performance of older adults in daily activities. "For the groups observed here, the neuroimaging findings help to localize the benefits of repetition to a reduced need for frontally mediated, controlled processing, rather than a nonspecific facilitation of early perceptual or motor processes. In combination with previous behavioral and neuropsychological findings, this suggests that manipulations that reduce the need for such controlled processing by recapitulating task structure, rather than only items, may have the best chance of improving the performance of older adults both with and without dementia," the authors conclude. For more on what this could mean in practice, see author Q&A below.—Hakon Heimer

Q&A with Cindy Lustig

Q: You mention that the left prefrontal cortical areas Brodmann's 45/47 and 44/6 play a role in "controlled" verbal processing. What is controlled vs. uncontrolled verbal processing?

A: Controlled verbal tasks are those that require us to generate a response slowly and with effort, such as when you need to answer a novel question. Uncontrolled (or what we sometimes call automated) processes are those that, through practice, become like habits and can be completed rapidly, in a stereotyped manner.

Q: How broad are your results? For example, are they generalizable to nonverbal forms of implicit memory?

A: We haven't extended the fMRI study to nonverbal forms of memory in patients. However, based on other studies, we would expect to get similar results. On the fMRI front, our lab and others have shown that young adults show similar changes in brain activity in response to practice for pictures and other nonverbal stimuli (e.g., Buckner et al., 1998).

On a behavioral level, other investigators have found that older adults and Alzheimer patients show similar benefits for practiced pictures, patterns, and other nonverbal stimuli as they do for words (Fleischman and Gabrieli, 1998; Postle et al., 1996). We haven't yet looked to see if the changes in brain activity would also be the same, but it's reasonable to think they would be.

Q: How can a caregiver put your findings into practice?

A: First off, let me be clear that we're not proposing a "cure" for the memory problems that come with Alzheimer's disease. What our study does do is highlight some of the memory abilities and brain areas that may be preserved at least in the early stages of the disease, so that people can make the most of those.

One optimistic note from our work and that of other researchers in this area is that even though patients may not be able to consciously recognize that they've been in the same situation before, they still can show some more automatic benefits related to practice, especially if we can keep the situation as similar as possible from one time to the next.

Let's say the caregiver needs the patient to help out with some aspect of their care, for example to roll their sleeve up and put their arm into a certain position for medication. If we can keep this procedure the same from one time to the next--always the same room, the same chair, the same person assisting them--they may begin to automatically roll up their sleeve and get into position when they enter the room. They may show this kind of benefit even when they can't consciously remember the last time they came in.

Q: What can you conclude about the role of these left prefrontal areas in memory? Is your work consistent with previous understanding?

A: The changes we see in these brain areas seem to be related to a practice-like, "automatic" memory that is different from the deliberate, conscious memory supported by the medial temporal lobe structures that are first attacked by Alzheimer's disease. The idea that this more automatic kind of memory relies on different brain systems than does deliberate memory is by now pretty well-accepted.

Where our study differs from some others is that it offers a more optimistic view of brain and memory changes in aging and Alzheimer's disease. We know that the brain areas we looked at are among those showing the greatest atrophy and change even in normal aging. When faced with new items that they hadn't practiced, older adults and patients actually showed more activity here than the young adults did--rather like a person with less muscle needing to work harder to get something done.

Practiced activities are a different story, however. We found that the older adults and patients showed changes in brain activity in response to practice that were very similar to the changes in young adults. That suggests that these brain areas still have some flexibility and ability to change—a conclusion rather different from the proverb of "You can't teach old dogs (or brains) new tricks." To borrow another adage, our work suggests that for some forms of memory “Practice makes perfect” is relevant to older people, even those with early AD.

Another interesting aspect of the study is that we found a direct relationship (correlation) between the changes in brain activity and the changes in performance. Although the relationship isn't perfect, those people who showed the most change in brain activity tended to be the ones who showed the biggest benefits to their performance. There are some new papers to come out from our lab and others that also find this brain-behavior relationship in young adults. In this study, we found that the strength of this relationship is preserved or perhaps even stronger in old age and early Alzheimer's.

Q: Do older people achieve priming in the same way as young adults? You mentioned compensatory recruitment in older adults and in patients with frontal lobe damage. What areas might the brain call upon?

A: We see the compensatory recruitment as being more related to how older adults are dealing with new items, rather than a difference in their priming. As I mentioned, older adults and patients showed more activity than young adults in those left frontal brain regions in response to new, unpracticed items. We also found evidence that for these new items, older adults and patients had more activity than the young adults in a similar region on the right side of the brain. This increase in "two-sided" or "bilateral" recruitment is something that many researchers are noticing in older adults. However, both the left and right sides showed similar changes in response to practice in the young and old subjects. Again, our take on this is that older adults and patients may have to work harder (in this case, use both sides of the brain more) to do that initial controlled processing to answer the question, but they benefit from practice about as well as young adults.

Q: What’s next?

A: An important practical question will be how best to translate these data into training and rehabilitation programs for older adults and Alzheimer patients. On a related note, there is still a lot of work to be done to understand more specifically what memory abilities and brain functions can still be preserved in aging and Alzheimer's. Older adults and patients do as well as young adults on some but not all of the tests that tap this automatic, or "implicit" memory. Getting a better understanding of when older adults and Alzheimer patients will show similar brain activations and performance as compared to young adults, and when they will be different, is going to be useful not only from a research standpoint but also for helping older adults and patients make the most of the abilities that are preserved.

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References

Paper Citations

1. Gabrieli JD, Vaidya CJ, Stone M, Francis WS, Thompson-Schill SL, Fleischman DA, Tinklenberg JR, Yesavage JA, Wilson RS. Convergent behavioral and neuropsychological evidence for a distinction between identification and production forms of repetition priming. J Exp Psychol Gen. 1999 Dec;128(4):479-98. PubMed.
2. Buckner RL, Goodman J, Burock M, Rotte M, Koutstaal W, Schacter D, Rosen B, Dale AM. Functional-anatomic correlates of object priming in humans revealed by rapid presentation event-related fMRI. Neuron. 1998 Feb;20(2):285-96. PubMed.
3. Fleischman DA, Gabrieli JD. Repetition priming in normal aging and Alzheimer's disease: a review of findings and theories. Psychol Aging. 1998 Mar;13(1):88-119. PubMed.
4. Postle BR, Corkin S, Growdon JH. Intact implicit memory for novel patterns in Alzheimer's disease. Learn Mem. 1996 Nov-Dec;3(4):305-12. PubMed.

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