Overcompensation—It Could Work for the Brain

Some people seem to cope better than others with having amyloid plaques in their brains. According to a study in the September 14 Nature Neuroscience, they maintain cognitive prowess by kicking neural networks into overdrive. Such hyperactivity had been observed before, but researchers were unsure if it was beneficial. The new study, led by William Jagust at the University of California, Berkeley, suggests that it is. In cognitively normal people harboring amyloid, those with greater activation remembered in greater detail.

“This is incredibly intriguing,” said John Cirrito of Washington University, who was not involved in the study. “One of the most remarkable things about the brain is that it adapts and compensates in response to injury.”

Compensation Through Activation.

As a memory is made, the brain tones down activity in some regions (blue), while ramping it up in others (orange). People who have amyloid in their brain seem to compensate for it by activating those brain regions even more. [Image courtesy of Elman et al., Nature Neuroscience 2014.]

Cognitively normal people whose brains are riddled with amyloid plaques have baffled AD researchers, especially those who subscribe to the hypothesis that amyloid causes the disease. Some neural networks are hyperactive when otherwise healthy people with brain Aβ perform learning and memory tasks, while other networks fail to switch off when they should (see Aug 2009 news story; Mormino et al., 2011; Dickerson et al., 2004; and Apr 2014 news story). Researchers have wondered whether these abnormal neural activation patterns reflect a dedicated compensatory mechanism, a harbinger of dementia, or both.

To address the first possibility, co-first authors Jeremy Elman and Hwamee Oh tested whether rises in neural activity in people harboring amyloid plaques correlated with better memory. They studied 22 healthy young participants and 49 cognitively normal people over age 65. The researchers split the older participants into two groups—amyloid positive and amyloid negative—based on PiB retention. All were presented with a series of complex images of everyday scenes, while their neural activity was recorded via fMRI. Fifteen minutes later, the researchers showed the participants a simple true-or-false question about each of the images to assess the extent of their “gist memory.” If a person remembered the gist of the image, for example, whether it showed a boy on a skateboard, then the researchers asked six more detailed questions about the image to measure the richness of the memory, e.g., was he wearing a blue shirt?  On average, the three groups performed equally well on the memory tests. The researchers then averaged the participants’ memory scores and correlated them with the patterns of neural activity observed while the memories were encoded.

Overall, the investigators found that when people were viewing a picture they later remembered, the regions of the brain involved in memory—called the task-positive network, or TPN—lit up, whereas the default mode network (DMN), which normally fires while the brain is at rest, was shut down (see image above). Compared with older people without amyloid, people with amyloid displayed higher levels of neural activity in the TPN and lower levels of DMN deactivation when looking at images that they later recalled.

The researchers took advantage of the memory detail data to determine whether heightened neural activity in people with amyloid deposition gave them an edge. They correlated the number of details each participant recalled with their neural activity when the memory was made. For older people devoid of amyloid, neural activity in the TPN switched on, but did not ramp up linearly with more details being recalled. Rather, the DMN progressively deactivated as the details improved in this group. In contrast, in both young people and older people with amyloid, TPN activation, but not deactivation of the DMN, correlated with greater details remembered.

“People with amyloid recalled more details as their brain activity went up, so that seems to tell us that this ramping up of activity serves a function,” Jagust told Alzforum. “It’s not some kind of random noise, and in fact it seems to be helping people,” he said. Older people without amyloid may rely more on the deactivation of the DMN to focus, as opposed to the increases of TPN activity seen in people with amyloid, he speculated.

Gael Chetelat of the French Institute of Health and Medical Research in Paris agreed that this was one possible explanation. “While in normal aging, difficulties may arise from an inability to focus attention resources on the task, elderly with amyloid deposits specifically increase their activity in task-related regions to maintain their performance,” she wrote in an email to Alzforum.

Interestingly, in people with the highest levels of amyloid, the researchers noticed that the tight coupling between neural activity and detailed recall started to unravel. “This might be a sign that this compensation wears out,” Jagust suggested, although the researchers will not know this until follow-up studies are done.

Previous studies have reported that neuronal activity triggers the release of amyloid and tau (see May 2011 news story and Feb 2014 news story). This suggests that this compensatory mechanism, though beneficial in the short run, could one day lead to a further spread of pathology, said Willem Huijbers of Harvard University. “Something might be beneficial for memory performance, but in the long run it could be detrimental to the brain,” he said, “That’s the question you’re left with.”

—Jessica Shugart

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References

News Citations

  1. BOLD New Look—Aβ Linked to Default Network Dysfunction
  2. Do Earliest Cognitive Deficits in Alzheimer's Appear in the Entorhinal Cortex?
  3. Do Overactive Brain Networks Broadcast Alzheimer’s Pathology?
  4. Neurons Release Tau in Response to Excitation

Paper Citations

  1. Mormino EC, Brandel MG, Madison CM, Marks S, Baker SL, Jagust WJ. A{beta} Deposition in Aging Is Associated with Increases in Brain Activation during Successful Memory Encoding. Cereb Cortex. 2011 Sep 23; PubMed.
  2. Dickerson BC, Salat DH, Bates JF, Atiya M, Killiany RJ, Greve DN, Dale AM, Stern CE, Blacker D, Albert MS, Sperling RA. Medial temporal lobe function and structure in mild cognitive impairment. Ann Neurol. 2004 Jul;56(1):27-35. PubMed.

Further Reading

Primary Papers

  1. Elman JA, Oh H, Madison CM, Baker SL, Vogel JW, Marks SM, Crowley S, O'Neil JP, Jagust WJ. Neural compensation in older people with brain amyloid-β deposition. Nat Neurosci. 2014 Sep 14; PubMed.

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