Several years ago, Dr. Diana Martinez, of Columbia University Health Center in New York City, decided to investigate transcranial magnetic stimulation (TMS) as a potential noninvasive treatment for cocaine addiction. She hypothesized, based on her own lengthy experience of imaging the brains of drug users, as well as work by others, that using TMS to raise activity levels in the forebrain of long-time cocaine users might reduce their desire for the stimulant.
Dr. Martinez borrowed a newly developed type of TMS apparatus, called the H coil, from its manufacturer, Brainsway, Ltd., and developed a 3-week protocol of repeated TMS. She initiated an exploratory study, which showed the protocol to be unworkable. Volunteers found the TMS electromagnetic pulses to be extremely disturbing and refused to continue after their first exposure.
To Dr. Martinez, the volunteers’ powerfully negative reaction suggested that their long-term cocaine use had rendered them highly sensitive to TMS, and she adjusted her protocol accordingly. After trial and error, she successfully administered a complete course of treatment to a small group of volunteers. As she hoped, they took less of the drug post-treatment.
The Peer Review Experience
Encouraged, Dr. Martinez applied to the NIH in August 2015 for funding to test whether a larger study would affirm her promising results. She proposed the same study design as in her initial work, with minor changes based on what she had learned so far. As before, she would recruit volunteers who were cocaine users and not interested in quitting the drug. The volunteers would check into the hospital for a month, during which they would undergo TMS daily for 3 weeks. Before they started and after they finished the TMS course, they would attend a session, in a controlled laboratory setting, where they could, at intervals, choose to receive either a sum of money or a dose of cocaine. If TMS reduced cocaine craving, the volunteers would opt for cocaine less often after treatment than before.
Applicants for NIH funding must describe their proposed project and its scientific rationale in 12 single-spaced pages, and append biographical sketches and letters of commitment from team members who will play key roles, letters certifying that the necessary resources and lab space will be available, a budget with justification for the projected costs, and other materials.
Dr. Martinez says, “Putting together an application seems to take forever. The pages on the science are the easy part. The other stuff takes much longer.”
Like every grant application to the NIH, Dr. Martinez’s went first to a study group of NIH-funded scientists with expertise in the topic area—in this case, “interventions to prevent and treat addictions”. Study groups review each proposed study’s goals and design, and assign a score based on:
- How likely it is to produce clear findings.
- How much potential its findings will have to advance science and improve health.
Applications that receive low scores (1=excellent, 9=poor) are passed on for further stages of peer review, and may ultimately receive funding.
Dr. Martinez’s study group gave her application a score well above the fundable range. The main reason, Dr. Martinez says, was that they questioned her use of the H-type TMS coil: “They didn’t like the fact that this coil reaches deeper into the brain and is more diffuse than other coils. You can’t precisely target specific brain regions with it, as you can with other coils.”
Such concerns have a well-established rationale. An intervention into the brain ideally is aimed at a precise region that theory and empirical evidence have linked to a problem. A more diffuse intervention will alter brain function throughout a wider area, making it harder to interpret whatever effects may be observed. There is a greater risk of producing extraneous effects that mask the intervention’s beneficial effects or are harmful.
Dr. Martinez revised her application and resubmitted it in December 2015. In the revision, she explained why she believed that the relatively scattershot H coil is appropriate for TMS treatment of cocaine addiction. She says, “Brain imaging has shown that cocaine users have low neuronal activity throughout their frontal cortex, rather than in any one small region. For that reason, we want the TMS pulses to hit broad swatches of cortex, and we chose a coil that’s less selective, but goes deeper and wider than other coils.”
The study group returned the revised application with additional queries. They asked whether Dr. Martinez might better set the TMS machine to a higher intensity than she proposed—to 120 percent of the subjects’ motor threshold, rather than 90 to 100 percent. The higher intensity is commonly used in TMS applications where the objective is to activate sluggish neurons. Noting that Dr. Martinez proposed to deliver high-frequency TMS to one group of participants and sham TMS to a second group, the reviewers suggested that she consider adding a third group that would receive low-frequency TMS. Including such a group, theoretically, might help the researchers close in on the best TMS dose for treatment.
Dr. Martinez says, “The second time around there were a number of criticisms, but we definitely had answers for all of them. With regard to the pulse intensity, we originally tried using 120 percent, but patients found it distressing and walked out of the study. We lowered the intensity to 90 to 100 percent, and showed that it could reduce cocaine use at least in a small number of patients.” As to expanding the study to include a third group of patients who would receive low-frequency TMS, Dr. Martinez says, “We had shown in our pilot work that low frequency didn’t work, so we didn’t see a point to including it in the follow-up study.”
Dr. Martinez says, “We also wanted to conduct some [functional magnetic resonance] imaging on the participants, and the reviewers weren’t 100 percent thrilled with that. I’m not sure why. I thought it was cool.”
Dr. Martinez and her team considered responding to the study group’s comments in a new revised application. Ultimately, they decided not to, for the time being.
“The study group’s comments the second time around weren’t that big a deal, but they still gave us a score that was well outside the fundable range. When that happens, you feel that they just don’t have enthusiasm for the project,” says Dr. Martinez.
She adds, “After two submissions, we decided to take a break and step back. Writing applications is a lot of work, and you have other things to work on. When you do NIH research you must have a lot of things going on, because you never know what’s going to [make it through the review process and receive funding].”
“We Will Come Back to This”
Dr. Martinez says, “So that’s where it stands, unfortunately. Funding seems to be difficult all around.”
She continues, “I definitely don’t want to give up on this TMS work. One reason is that it could have clinical impact in the short term. We’re not talking about research where, for example if we were trying a new class of medications, we would try it in animals, and then we would have to do a human safety study, and then a phase 2 study, and so on. With TMS, we’re not talking about something that will take 10 years to get to the clinic.”
For the present, Dr. Martinez is pursuing other projects which, along with their value in and of themselves, may strengthen the case for investigating the H coil in cocaine addiction. She says, “We’ve done another study, similar to our cocaine study, using the H coil to reduce cannabis use. The results showed some decrease in cannabis self-administration. We’re debating submitting an application in the fall to follow up on that study. We’re also thinking of submitting a grant to the Department of Defense using TMS in chronic pain, which is sort of the inverse of addiction—neurons are hyperactive, rather than hypoactive.
“We’ll also keep watching the literature. Maybe some other lab will come out with data that reinforce the worthiness of what we want to do.
“We will come back to this. I’m going to have to take a deep breath, regroup, get the troops back together, and resubmit.”