Article In Brief
While using investigational transcranial alternating current stimulation to help long-term memory produced encouraging results, questions remain about whether the improvements will last.
Targeted repetitive neuromodulation produces selective improvements in working memory among older adults, improvements that last up to one month or more, according to a new study published Aug. 22 in Nature Neuroscience.
But whether it produces long-lasting improvements in functional memory among people with mild cognitive impairment (MCI) and dementia is one of several unanswered questions.
Cognitive scientists have long recognized that rhythmic activity in the theta and gamma frequency ranges are thought to contribute to both working memory and long-term memory function, particularly during free recall.
A team of investigators from Boston University (BU) assessed whether augmenting these patterns using investigational transcranial alternating current stimulation (tACS), a noninvasive device that applies a low-intensity sinusoidal electrical current to the brain through electrodes on the scalp, could improve memory accuracy. Previous studies that attempted to modulate these rhythms to improve memory have produced inconsistent results.
Study Details
The BU study included 150 adults aged 65 to 88, whose mean baseline scores on the 30-point Montreal Cognitive Assessment (MoCA) test ranged from 25.45 to 27.4. (Scores of 26 or higher are considered normal, while scores from 18 to 25 suggest MCI.)
During the study, the participants were asked to encode and then recall a series of 20 words as accurately as possible, while the team applied tACS to either the dorsolateral prefrontal cortex (DLPFC) or the inferior parietal lobule (IPL) of the participants' brains.
The randomized, double-blind study consisted of two sham-controlled experiments to target memory function in older adults, along with an additional experiment to test the replicability of the principal findings.
In Experiment 1, 60 participants were randomized into three groups (sham, DLPFC gamma, and IPL theta). Each participant received eight daily stimulation episodes, according to their assigned group for 20 minutes each day on four consecutive days as they performed five runs of the 20-word free-recall test. (The repetition is a novel feature of the work; few previous studies using tACS applied it repetitively.)
In Experiment 2, the investigators switched the neuromodulation frequency between the two regions of interest, with 60 older participants randomized into three groups including sham, DLPFC theta, and IPL gamma.
Experiment 3 served as a test for replication of the primary findings from Experiment 1; a new sample of 30 participants was randomized into the two critical conditions of interest from Experiment 1 (DLPFC gamma and IPL theta) and received neuromodulation for only three consecutive days. In all three experiments, investigators examined memory performance at baseline and during each neuromodulation session.
The study found that IPL theta modulation boosted participants' ability to recall words from the end of the list, indicating working memory, while DLPFC gamma modulation improved recall from the beginning of the list, reflecting long-term memory storage.
Statistically, the effects were moderate to large, with most participants experiencing memory benefits, said lead investigator Robert Reinhart, PhD, assistant professor of psychological and brain sciences and director of the Cognitive and Clinical Neuroscience Laboratory. “Specifically, 85 percent to 90 percent experienced the memory improvements during the intervention that were then predictive of the benefits we saw at the one-month time point after the intervention.”
A key basic science takeaway from the study, Dr. Reinhart said, is that both the location and frequency of neuromodulation are important, as is the pairing of the two.
“We've known for some time that certain pieces of brain tissue are assigned to certain mental functions, but our study shows that the timing of brain activities is also important for understanding of how the brain is organized and for seeking opportunities to intervene in the brain to optimize function,” he said.
Timing is a crucial variable in the brain, Dr. Reinhart added.
“The brain communicates through neural rhythms, the coin of the realm is action potential, and those action potentials are coordinated and structured by larger-scale rhythms that are almost like a government, acting as an excitability window,” he explained.
“If that window is open, communication can flow more readily, and if it's closed, communication is less able to flow. Information is being passed in the brain at blindingly fast speeds, and if it arrives at a certain location too late or too early, the information processing modules will not be functioning optimally. When you get the timing correct, you see a beautiful entrainment process between the applied currents and the intrinsic brain rhythm, where the cells aren't spiking more per unit of time, they're spiking in a systematic way over time. You've changed when they're firing, not how much they're firing.”
“To have an intervention where it's those who start out weakest who improve the most, that's very encouraging.”—DR. ROY HAMILTON
And that timing precision creates “potentiations that are the cellular basis for memory and learning,” Dr. Reinhart said. “There is evidence that spike timing plays a role in neuroplasticity, and we presume that is why we see effects that continue past the modulation period.”
Those with lower MoCA scores appeared to receive the most benefit from neuromodulation. “Older people with poor general cognitive functioning at baseline coming into the experiment were the individuals who showed the largest improvements during both the intervention and the one-month time point,” Dr. Reinhart said. “The worse you were, the better you did. That's exciting for future applications.”
Expert Commentary
Experts not involved with the study said it contributed to the field in important ways.
“They were able to establish a double dissociation: when they stimulated at a high frequency at one site, they got an effect, but not when they used that high frequency at the other site,” said Roy Hamilton, MD, MS, FAAN, professor in the departments of neurology and physical medicine and rehabilitation at the University of Pennsylvania, where he also directs the Laboratory for Cognition and Neural Stimulation. “However, if they stimulated the first site at a low frequency, they got no effect, but they did get an effect when they stimulated the second site at a low frequency. That is almost a holy grail of cognitive neuroscience.
“And they've done it not just for the memory elements, which they link to long-term memory and working memory, but also for the specific frequencies of brain activity that are linked to the brain sites that mediate those capacities. ... [T]hey then took a totally naïve set of individuals and demonstrated they could do it all over again. There's nothing that's as convincing that something is a real phenomenon as replicability.”
Dr. Hamilton noted that people who have the poorest cognitive function don't always perform better with other interventions.
“In general, individuals who are more severely impaired across different domains of cognition don't necessarily respond as well to, for example, behavioral interventions, as those who are less impaired. To have an intervention where it's those who start out weakest who improve the most, that's very encouraging. In our laboratory, we have also shown a similar phenomenon using transcranial direct stimulation—a similar technique, but with direct rather than alternating current—in the treatment of aphasia, where those who are more impaired have also been some of our better responders.”
What's more, the degree of improvement seen early in the stimulation process appeared to be linked with the persistent improvement over the 30-day period of the study.
“Tracking the participants' progress over a set number of days was highly predictive of how they would do in the long run,” Dr. Hamilton observed. “If it proves true generally, this correlation might be very useful for prognostication of benefit.”
Remaining Questions and Next Steps
Functional neurosurgeon and deep brain stimulation expert Andres Lozano, MD, PhD, chairman of the division of neurosurgery at the University of Toronto, called the study “a window into the brain and the possibility of noninvasively modulating brain circuits to try to influence their function—in this case, to improve memory.”
“It also suggests that this type of neuromodulation only works if you're stimulating a precise area of the brain with the right settings,” Dr. Lozano said, adding, “The fact that they are homing in on the targets and the stimulation parameters is a clear step forward, addressing some of the limitations of other previous studies that were not as careful in specifying parameters and location.”
But he noted that questions remain, such as whether the memory improvements they saw will translate into real-world usefulness.
“Does the ability to recall lists of words point to any other kind of improved function?” Dr. Lozano said. “That, to me, would be the logical next question.”
Although he noted that word recall is a task routinely used in neuropsychology and neurology, with high real-world validity, Dr. Reinhart agreed with Dr. Lozano's assessment of its limitations and clear next steps.
“Word recall is only one dimension of a multi-dimensional area, and whether it transfers to other tasks is one big question mark,” Dr. Reinhart said. “How long the effects last is another question. Does this relate to real-world function and quality of life in people with cognitive impairment?”
The group plans to investigate that question next, in a larger clinical trial involving several hundred adults with MCI and early Alzheimer's disease. The grant submission for that study is now underway, and if all goes well, Dr. Reinhart said he hopes it will be funded by the summer of 2023.
“The intention is not to cure Alzheimer's in the first pass but just to provide a further proof of principle,” he said. “We want to see how long the effects last and whether we can explore parameters like intensity, duration of stimulation, and optimal spacing between sessions to maximize the benefits. There's a lot to explore.”
“When you get the timing correct, you see a beautiful entrainment process between the applied currents and the intrinsic brain rhythm, where the cells aren't spiking more per unit of time, they're spiking in a systematic way over time. You've changed when they're firing, not how much they're firing.”—DR. ROBERT REINHART
tACS has the advantage of being non-invasive, unlike deep brain stimulation and some other forms of brain stimulation. “The main advantage of this approach is that it is noninvasive and relatively inexpensive, and if benefits can be clearly demonstrated, it could probably be done at home without the need for going to a clinic,” Dr. Lozano said. “The patient would basically be wearing an electrode array implanted in some type of swim-style cap for stimulation for a certain period of time every day; it's not that complex, although it would require patient compliance.”
Dr. Reinhart agreed. “This system is probably one-fifth the cost of a transcranial magnetic stimulation [TMS] machine, and it's lightweight, small, [and] easy to use and train people on,” he said. “And unlike with repetitive TMS, which has to be applied with a physician present because of the risk of seizure, seizure has never been observed with noninvasive electrical brain stimulation. It's low-intensity and cannot make a cell fire instantaneously.”
There likely may be other applications for tACS in disorders beyond cognition, Dr. Lozano suggested.
“You could think about modulating other circuits, such as those involved in movement or mood, to treat other disorders, such as depression, pain, or movement disorders,” he said. “This technology could be useful across a number of neurologic and psychiatric disorders.”
Disclosures
Drs. Reinhart and Hamilton had no disclosures. Dr. Lozano is a consultant to Abbott, Boston Scientific, Insightec and Medtronic, and a scientific director at Functional Neuromodulation.
