Memory Disorder Findings Suggest New Therapies

by James Cavuoto, editor

September 2015 issue

The potential market for neurotech therapies to treat age-related memory and cognitive disorders took a hit recently with the report of less than encouraging results from Functional Neuromodulation’s ADvance study of DBS of the fornix for Alzheimer’s disease [NBR Jul15 p1]. But two new studies that shed light on possible neurological mechanisms for memory and cognitive decline offer hope for new therapeutic approaches.

One of the studies suggests a role for a new target area in the hippocampus, while the other points to a faulty neural signal that could potentially be addressed with novel neuromodulation paradigms. Together, these and other mechanism-related studies hold promise for elucidating new DBS targets and waveforms for treating cognitive and memory disorders.

Recently, researchers at Northwestern Medicine examined activity in a little-studied area of the hippocampus and found for the first time the reason that neurons there become more active in old age. Previous research has extensively investigated cells within CA1, but comparatively little attention has been paid to CA3.

The new study, published in the Journal of Neuroscience, found surprising patterns of activity in detailed recordings of CA3 pyramidal cells from aging rats. Up until now, scientists have assumed that the cells in CA3 acted similarly to those in CA1. But when senior author John Disterhoft and colleagues at Northwestern University compared the activity of CA3 cells in hippocampal slices from young rats and older rats, they found the neurons were hyperactive in older animals—in CA3, cells became more excitable and fired more often in old age.

“We were actually quite surprised at the pattern of changes we saw in the recordings,” Disterhoft said. “Before this, there had been some evidence that CA3 was more excitable during aging and cognitive impairment in humans, but we didn’t understand the mechanism. These findings are pointing us to more effective therapeutics.”

The increased excitability in CA3 was exactly the opposite of the decreased activity previously seen in nearby CA1, which has long been associated with memory impairment and cognitive decline.

Next, the scientists altered the behavior of CA3 neurons’ ion channels to explain the exact mechanism behind that increase in activity. They discovered that a subset of voltage-gated potassium channels, called A-type Kv4.2 and Kv4.3 potassium channels, were specifically associated with the increase in CA3 activity seen in older brains. When the potassium channels were blocked, the cells’ activity became similar to that in a young brain.

Meanwhile, another research team in California has published research in the Journal of Neuroscience that suggests that brain circuits that grow noisier over time may be responsible for ways in which we slow mentally as we grow old. The new intracranial and EEG research supports the neural noise hypothesis, which proposes that the signal-to-noise ratio in nerve circuits diminishes with aging and leads to worse performance. The studies were designed and conducted by Brad Voytek, when he was a postdoctoral research fellow working in the lab of Adam Gazzaley at UC San Francisco.

In two new experiments, Voytek, now at UC San Diego, found that background noise in key cortical regions responsible for higher functions was associated with poorer memorization of visual information, and that this noise also was associated with age. He concluded that neural noise might be the mechanism behind aging-associated loss of cognitive ability, slowing of behavioral responses, uncertain memories and wavering concentration.

The noise measured in the studies was random signaling that did not fit the pattern of the brain’s natural oscillations. In recent years brain oscillations have become an intense focus of research by Voytek and others seeking to discover any functional roles they might play. Emerging evidence suggests that oscillations might prime nerve circuits to respond more efficiently to stimuli.

On average, older subjects performed worse than younger subjects. The scientists determined that this poorer performance was due to additional noise in circuits in the visual cortex; neurons did not appear to coordinate as well in generating lower-frequency oscillations. When the researchers accounted for the noise, age was no longer an independent, significant factor in performance in this experiment.