Repetitive Neuromodulation Leads to Memory Improvements in Older Adults

Selective improvements in working memory and long-term memory in older adults have been reported via the use of dissociable spatiospectral entrainment of brain rhythm with repetitive neuromodulation. Improvements sustained for
1 month or more following the intervention. These are the findings of an analysis published in Nature Neuroscience.

Recognizing that the development of technologies to protect or enhance memory among older individuals is an enduring goal of translational medicine, researchers sought to describe repetitive (ie, 4-day) transcranial alternating current stimulation (tACS) protocols for the selective, sustainable enhancement of auditory-verbal working memory and long-term memory in older adults aged between 65 and 88 years.

The researchers conducted a randomized double-blind study that comprised 2 sham-controlled experiments to target memory function in older adults, along with an additional experiment to test the replicability of the main findings.

In experiment 1, a total of 60 participants were randomized into 3 groups: (1) sham; (2) dorsolateral prefrontal cortex (DLPFC) gamma; and (3) inferior parietal lobule (IPL) theta. A repetitive neuromodulation protocol was used in which all of the participants received 8 x 1 tACS, according to their assigned group, for 20 minutes each day on 4 consecutive days. Gamma frequency of 8 x 1 tACS was administered at 60 Hz and theta frequency of 8 x 1 tACS was administered at 4 Hz.

On each day of the test, the participants performed 5 runs of the free recall task. In each of the runs, they encoded a list of 20 words and were asked to immediately recall the words at the conclusion of the presentation of the list. Neuromodulation was carried out throughout the duration of encoding and recall of all 5 lists, in order to enhance functional specificity, with this procedure lasting about 20 minutes. Memory performance was examined across the 5 runs as a function of the serial position of the presented words, thus allowing for the isolation of changes in long-term memory and working memory separately.

At baseline, general cognitive function was established with the use of the Montreal Cognitive Assessment and depression symptoms were determined via the use of the Geriatric Depression Scale.

Experiment 2 served as the control, in which the frequency specificity of the effects in experiment 1 was evaluated. In Experiment 2, the neuromodulation frequency was switched between the 2 regions of interest. Overall, 60 older participants were randomized into 1 of 3 groups in Experiment 2 — (1) sham; (2) DLPFC theta; and (3) IPL gamma — which proceeded similarly to Experiment 1.

Experiment 3 served as a test for replicating the primary findings from Experiment 1. In Experiment 3, a new sample of 30 participants was randomized into the 2 critical conditions of interest from Experiment 1 — that is, DLPFC gamma and IPL theta — and they received neuromodulation for 3 consecutive days only.

In Experiment 1, free recall performance across the 5-word lists administered during neuromodulation was averaged and entered into a mixed analysis of variance (ANOVA), with day (ie, baseline, day 1, day 2, day 3, day 4, and 1 month following the intervention) and serial position (ie, primacy, middle 1, middle 2, middle 3, and recency) used as within-subjects factors, and group (ie, sham, DLPFC gamma, and IPL theta) used as between-subjects factors. A significant day x serial position x group interaction was observed (P <.001). Further, a follow-up mixed ANOVA that examined performance between the sham and DLPFC gamma groups demonstrated a similar day x serial position x group interaction effect (P <.001).

Additional follow-up analyses that examined the effect of day on the serial position x group interaction demonstrated that the differences in the sham and DLPFC gamma groups existed on day 2 (P <.001), day 3 (P <.001), day 4 (P <.001), and 1 month after the intervention (P =.024). When the effect of serial position on the day x group interaction was examined, significant improvements were observed in memory performance for the primacy cluster in the DLPFC gamma group with respect to sham (P <.001), with no statistically significant differences in any other serial position cluster.

Examination of the day x serial position x group interaction effect between the sham and IPL theta groups in Experiment 1 with a mixed ANOVA showed the interaction effect to be significant (P =.001). Significant improvements in memory performance were seen on day 3 (P <.001), day 4 (P <.001), and 1 month following the intervention (P =.013). Per additional ANOVAs, the day x group interaction was significant only for the recency serial position cluster (P =.004), but not for any other position clusters.

These findings showed that modulation of synchronous low-frequency, but not high-frequency, activity in the parietal cortex preferentially improved working memory on day 3, day 4, and 1 month after the intervention, whereas modulation of synchronous high-frequency, but not low-frequency, activity in the prefrontal cortex preferentially improved long-term memory on day 2, day 3, day 4, and 1 month following the intervention. In fact, the rate of memory improvements observed over 4 days was predictive of the size of the memory benefits seen 1 month later. Participants with lower baseline cognitive function were shown to experience larger, more enduring improvements in their memory.

“Our findings demonstrate that the plasticity of the aging brain can be selectively and sustainably exploited using repetitive and highly focalized neuromodulation grounded in spatiospectral parameters of memory-specific cortical circuitry,” the researchers concluded.