In the continuing search for new and more effective methods of treating addiction, researchers in the U.S. and around the world have been testing various modes of non-invasive brain stimulation, reporting mixed success.

In a newly published paper, a team led by a BBRF grantee reports encouraging preliminary results in a randomized, blinded clinical trial of a non-invasive brain stimulation method called theta-frequency transcranial alternating current (tACS), in a people with opioid use disorder (OUD).

In tACS, a weak oscillating electrical current (2mA, provided by a small 9-volt battery) is applied through electrodes placed on the scalp to target specific brain wave frequencies. In the past, researchers have used it to study and potentially modify cognitive processes like memory, attention, and mood, by calibrating the stimulation to natural brain rhythms. In the new study, reported in Molecular Psychiatry, Hamed Ekhtiari, M.D., Ph.D., a 2018 BBRF Young Investigator, and colleagues, delivered tACS to synchronize activity in a focused area at the brain’s theta frequency, which reflects slow neural oscillations (4 Hz - 8 Hz).

The team also included Martin P. Paulus, M.D., a member of BBRF’s Scientific Council and recipient of a BBRF Young Investigator grant in 2000. He is President and Scientific Director of the Laureate Institute for Brain Research. Dr. Ekhtiari, mentored by Dr. Paulus, is at the University of Texas Southwestern, Dallas.

The team noted results of prior fMRI brain scanning research indicating that drug cues activate neural circuits that overlap with reward and emotion processing systems, including the striatum and amygdala. Other circuits have been identified that are involved in managing cravings and preventing relapse. Central to this process, the team explains, is top-down regulation by the brain’s executive control network, especially frontoparietal regions that include the dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex (PPC). The latter two structures exert regulatory control over parts of the brain “beneath” the cortex—including the amygdala, striatum, and other areas involved in emotional regulation.

Non-invasive brain stimulation is a well proven technology that has been brought to bear in trying to modulate drug cue-induced brain activation in people with addiction. The key question involves identifying and effectively targeting neural mechanisms that underlie treatment response. TMS (transcranial magnetic stimulation), which has become a mainstream treatment for depression, has also been approved by the FDA for smoking cessation—thus addressing one form of addictive substance use. Results in TMS treatments for other forms of addiction, including OUD, have been mixed at best.

Drs. Ekhtiari, Paulus and colleagues wanted to test tACS, a type of transcranial electrical stimulation (tES), for a variety of reasons. Among these are its comparatively low cost and accessibility: last December, the FDA approved the first at-home tES device for depression. tACS was particularly appealing to the team, since it can be used to promote network synchronization. (Prior research suggests effective communication between brain regions relies on the synchronized oscillatory activity of neurons.) In the newly reported trial, they used a high-definition electrode configuration to achieve more precise focus of the stimulation on targeted brain areas than is possible with either conventional tES or TMS.

A total of 60 individuals with opioid use disorder—all of them male, average age in the mid-30s—who were being treated in a residential drug addiction treatment center took part in the trial, in which 30 were randomized to receive a single 20-minute tACS stimulation session and 30 received a single placebo stimulation session designed to be indistinguishable from active stimulation. Two pairs of high-definition electrodes were placed on the scalp to focus the stimulation in the right frontoparietal network. Stimulation of this network in other research has been shown to have pronounced effects on executive functions.

Each participant received an fMRI brain scan 8 minutes before and 8 minutes after the stimulation (or placebo) session. This was followed by a screen-based task that presented drug cues and tested drug-cue reactivity. Participants rated their level of drug craving at intervals during this task, but also before the trial began and after each fMRI session, as well as while they were inside the scanner and one day after the stimulation session.

The most important result in this trial concerned how well theta frequency-tuned tACS engaged the frontoparietal circuitry that plays such an important role in the modulation by the executive control network of subcortical areas like the amygdala and striatum, implicated in addiction. The researchers found that active tACS stimulation reduced drug cue-induced reactivity in the striatum. To the team, this is consistent with the premise of their trial: that theta-band tACS targeted to promote frontoparietal synchrony can indeed help modulate circuits connecting the cortex and subcortical areas like the amygdala and striatum.

Across the active and placebo groups, self-reported differences in drug craving were not significant after a single stimulation session (it was lower in both groups). “In future studies, multi-session interventions may be necessary to achieve durable changes in craving and drug-use behavior,” the team suggested. It would also be useful, they said, if in future trials researchers performed long-term follow-up assessments to examine whether neural changes precipitated by active tACS translate into improved cognitive control, changes in stress markers, and reductions in relapse rates.

For now, the key result of the trial, the team stressed, was the demonstration that tACS with high-definition electrode placement targeting the right frontoparietal circuitry “can modulate neural systems involved in craving regulation.” The team has developed an optimized version of tACS based on results of this study that it hopes to test in addiction treatment. The current study thus opens a path to other tests of highly focused low-power electrical stimulation to alter neural activity underlying the symptoms that make drug addiction so powerful a modifier of behavior and of the individual’s ability to exercise judgment and restraint when faced with craving as well as cues to use addictive substances.