MANIPULATING RIPPLES TO ENHANCE MEMORY

Hippocampus Neuron, computer illustration Credit: Kateryna Kon Getty Images

from Scientific American.

Specific patterns of brain activity are thought to underlie specific processes or computations important for various mental faculties, such as memory. One such “brain signal” that has received a lot of attention recently is known as a “sharp wave ripple”—a short, wave-shaped burst of high-frequency oscillations.

Researchers originally identified ripples in the hippocampus, a region crucially involved in memory and navigation, as central to diverting recollections to long-term memory during sleep. Then a 2012 study by neuroscientists at the University of California, San Francisco, led by Loren Frank and Shantanu Jadhav, the latter now at Brandeis University, showed that the ripples also play a role in memory while awake. The researchers used electrical pulses to disrupt ripples in rodents’ brains and showed that, by doing so,  performance in a memory task was reduced. However, nobody had manipulated ripples to enhance memory—until now, that is.

Researchers at NYU School of Medicine led by neuroscientist György Buzsáki have now done exactly that. In a June 14 study in Science, the team showed that prolonging sharp wave ripples in the hippocampus of rats significantly improved their performance in a maze task that taxes working memory—the brain’s “scratch pad” for combining and manipulating information on the fly. “This is a very novel and impactful study,” says Jadhav, who was not involved in the research. “It’s very hard to do ‘gain-of-function’ studies with physiological processes in such a precise way.” As well as revealing new details about how ripples contribute to specific memory processes, the work could ultimately have implications for efforts to develop interventions for disorders of memory and learning.

The researchers first examined the properties of ripples recorded in rats performing tasks from a database acquired over years of experiments. They found more long-duration ripples occurred when rats had to make their way through mazes than when they were simply exploring or running along tracks. Negotiating mazes required rats to exercise their memories.

In one task, the M-maze, rats were trained to first navigate through the right-hand arm of a maze shaped as an “M” to receive a sugary reward, then through the left-hand arm on the next trial. The researchers saw significantly longer ripples in trials the rats performed correctly, compared to those they got wrong. “You can record a very simple electrical pattern in the brain and tell whether the animal's performance will be good or not, or whether the animal is learning or not,” Buzsáki says. These findings suggest that the hippocampus generates longer ripples during memory-intensive activities and that these longer-duration signals improve performance.

To verify that longer ripples contribute to better performance, the team artificially prolonged ripples in rats performing the M-maze task. The researchers used optogenetics, involving the use of light piped through a fiber-optic cable to activate genetically engineered light-sensitive neurons in the rats’ hippocampi. They recorded collective neural activity in the hippocampus during the task, to enable them to detect spontaneously occurring ripples. Upon detection of a ripple, light pulses were triggered to activate engineered neurons. This “closed-loop” stimulation roughly doubled the duration of ripples and significantly improved the rats’ performance, compared to control conditions with either no light stimulation or stimulation applied after short, random delays.

The rats also learned faster, reaching 80 percent correct performance in remembering which route would lead to a reward earlier than rats in the control conditions. The researchers also switched off any beneficial effects by aborting ripples using high-intensity light pulses, confirming that performance was impaired. “It's really nice to see another group do something slightly different and get the same result,” Frank says. “It makes you feel confident we're all on to something.”

To investigate how longer ripples might be enhancing performance, the team inspected the properties of the neurons involved. A ripple is not simply the repeated activity of the same neurons oscillating over time; instead, its activity spreads to more neurons as the signal continues.

The team observed that particular neurons tend to “fire” either in the early or in the later portion of the signal, and they found intriguing differences between these two groups. “Early” neurons were “chatterboxes” with high baseline activity, whereas “late” neurons were more sluggish, with lower average activity. “Neurons that fire fast are like talkative people, they are active in many situations,” Buzsáki explains.  “The majority typically don't fire, but once they do, they say something important.”

The hippocampus contains neurons specialized for navigation, called “place” cells, which fire when an animal is in a specific location. The researchers found that neurons firing in the late part of long ripples (either spontaneously occurring, or artificially prolonged), were more highly tuned to location, and the spots tended to be on the arms of the maze. Previous research suggests one function of ripples may be to “replay” memories. The new findings support that idea and suggest that prolonging ripples recruits extra neurons to generate the signal, whose activity is relevant to the task at hand. “When they extend the length of ripples, they’re recruiting cells that are reactivating paths the animals take,” Jadhav explains. “This might be a mechanism for doing a cognitive search of all the available paths, that other brain areas can read out and act on.”

The researchers hope this work eventually may help develop ways to treat the type of memory problems that occur in age-related cognitive decline or Alzheimer’s disease. Learning difficulties might also be addressed. The techniques in the experiments would be tricky to apply to humans because they are invasive and involve genetic manipulation, but Buzsáki says they are working on noninvasive methods. A recent study, published in April and led by neuroscientist Robert Reinhart of Boston University used weak electrical currents applied to the scalps of elderly participants to obtain an increase in working memory performance, accompanied by greater synchrony between oscillations of certain (theta) frequencies in different cortical regions. “There are intriguing points of connection between the elegant work by [Buzsáki’s team] and research conducted in my laboratory,” Reinhart says. “Research in systems and cognitive neuroscience is laying critical basic science groundwork, which may open up an entirely new avenue of circuit-based therapeutics for the prevention and treatment of brain disorders.”

The problem with existing non-invasive methods, such as transcranial magnetic stimulation (TMS), or the transcranial electrical stimulation (TES) technique, used in Reinhart’s study, is their inability to  penetrate into the brain, so manipulating signals in the deeply seated hippocampus is difficult. Recording from deep in the brain non-invasively is even more tricky. One possible solution would be to infer when ripples occur in the hippocampus from activity recorded from the brain’s surface. “There might be a very specific pattern of, say, prefrontal activity that precedes these events” and produces ripples in the hippocampus. Frank says. "But we don’t understand what that looks like yet.” 

Also, modifying cortical activity using these techniques may, as a consequence, affect activity in the hippocampus. “We know that these sharp wave ripples can be biased by [specific] neocortical patterns,” Buzsáki says. “In fact, many companies are trying to affect memory, by changing neocortical patterns.” Finally, invasive methods, similar to implants used to detect and interfere with seizures in epilepsy, could be employed, either for detecting, or manipulating ripples, or both. Invasive and non-invasive methods could even be combined. “As long as you can measure these events and come up with some way to manipulate them, you have the possibility of making the system work better,” Frank says. “There's a world of possibilities there.”

Note: György Buzsáki's affiliation was corrected from "New York University" to "NYU School of Medicine." 

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