Deborah Brauser

June 01, 2012

June 1, 2012 (Philadelphia, Pennsylvania) — Using functional magnetic resonance imaging (fMRI) to guide transcranial magnetic stimulation (TMS) may boost efficacy of the procedure for various disorders, including nicotine dependence, new research suggests.

TMS is a noninvasive method approved for treating major depression. Although research is currently under way for its use in treating additional psychiatric and neurological disorders, researchers here at the American Psychiatric Association's 2012 Annual Meeting said that its efficacy "depends on accurate targeting of TMS pulses to the physiologically responsive brain regions."

In a small proof-of-concept pilot study testing the feasibility of the fMRI process before assessing the efficacy of TMS for treating nicotine dependence, the investigators enrolled 10 healthy nonsmoking volunteers who performed a visually cued finger-tapping task. TMS energy pulses were then randomly applied to individually targeted brain regions (identified earlier by fMRI) during half the sessions.

Those who were randomly assigned to receive a 30-minute session of active TMS showed a significant difference in mean task reaction times between trials that did and did not use the pulses. The participants who received a half-hour "sham TMS" session did not show significant differences in reaction times.

"These findings show that TMS can influence brain function sufficiently to alter performance on a visual-motor coordination task, and suggest that substantial individual differences in functional brain neuroanatomy relevant to the task could weaken the efficacy of TMS if done without neuronavigation," write the investigators.

"In other words, TMS could manipulate motor response; and individualized single-subject fMRI-guided pulses gave us a significant effect," lead author David A. Gorelick, MD, PhD, physician-scientist in the Intramural Research Program at the National Institute on Drug Abuse (NIDA) in Baltimore, Maryland, told Medscape Medical News.

Dr. David Gorelick

Although he noted that fMRI is an expensive process and that these results "have no clinical significance" and are only relevant for research purposes at this time, "this is a good reminder to clinicians about the importance of accurately targeting the desired brain regions, especially if your patient is not currently responding to TMS."

Skull Landmarks Diminish Efficacy

According to the researchers, skull landmarks are currently used for TMS targeting in patients with depression in clinical settings.

However, "individual differences in brain neuroanatomy lead to diminished efficacy for TMS treatment when external topography is used for targeting," they write.

Dr. Gorelick noted during his presentation that past research has shown that relying on skull landmarks may contribute to "missing the mark" in up to one half of the patients being treated with TMS.

He went on to explain that targeting is not as important with electroconvulsive therapy (ECT), because that process generates electro-disturbance throughout the whole brain.

"Advantages that TMS has over other stimulation treatments, such as ECT, in treating depression include that TMS is noninvasive and well tolerated," said Dr. Gorelick.

"There are no seizures or loss of consciousness, no medication or anesthesia is required, and it can be done in a simple outpatient visit. There are also no cognitive side effects, and it's cheaper," he added.

Dr. Gorelick noted that TMS also does not affect the entire brain. Instead, "it's targeted to the brain area you think will have the best therapeutic effect."

For this study, the targeted brain site was identified by fMRI scans prior to the trials. The site was determined on the basis of which area showed the maximum activation during the cued tapping task.

"Brain-sight neuronavigation was used to position the TMS coil over the target region, and its location varied among the subjects," reported the investigators.

Three of the participants had the coil positioned over the right middle frontal gyrus, 2 had it positioned over the left superior parietal lobe, 2 had it over the right precuneus, and 1 each had it over the inferior parietal lobe, the left precentral gyrus, and the right precentral gyrus.

The amplitude of the TMS pulses was at "120% of resting motor threshold." The sham TMS group experienced the same type of loud noise while wearing the coils and the same amount of pressure against the scalp as the active TMS group.

All tapping tasks were performed using the right index finger, and all participants were right-handed.

Faster Reaction Times

Results showed that the active TMS group had a significantly shorter mean reaction time between the trials with and without pulses (236.1 ms vs 276 ms; P = .02).

"We were very pleased to see that in trials where pulses were delivered, all 5 subjects had faster reaction times, did better at the task, than when a pulse was not delivered," said Dr. Gorelick.

There were no significant differences in reactions times between the 2 types of trials for the sham TMS group (264.7 vs 284; P = .18).

"Again, admittedly there was no clinical significance to this, but it's a proof of concept that this process works," said Dr. Gorelick.

"If you're starting a patient in TMS treatment for depression, use the approved method, which is based on scalp landmarks. But if the patient doesn't respond, I'd consider a more targeted approach. There are different levels of targeting, and the fMRI is the most intensive and most expensive. But past studies have shown that there are other things you can do to improve the targeting, including using the EEG [electroencephalography] mapping system on the scalp."

Still, Dr. Gorelick reported that NIDA is now conducing a double-blind study assessing the efficacy of using fMRI-guided TMS in reducing nicotine craving.

At the recent Society of Biological Psychiatry annual meeting in Philadelphia, he presented a poster examining this targeting process.

"We did show individual variability in the target region of the brain for the TMS pulses, suggesting very clearly that if you didn't individualize fMRI guidance, you would be missing the target in a fair proportion of the people," he said.

"So far, it's kind of circumstantial evidence that individual guidance with fMRI could improve the efficacy of the TMS treatment. Whether it actually does in the full study with cigarette smokers, I can't say until we finish and break the blind."

Potentially Significant Advance

"I think that combining TMS with localization based on functional imaging provides an elegant way of exploring the role of brain regions in certain cognitive tasks and functions," Paul B. Fitzgerald, PhD, professor of psychiatry at Monash Alfred Psychiatry Research Center at Monash University in Melbourne, Australia, told Medscape Medical News.

Dr. Paul Fitzgerald

"It also provides a substantially more valid way of targeting treatment based on the confirmed location of activation associated with specific brain functions. This is potentially a significant advance on the relatively primitive methods used in most [repetitive] TMS treatment applications, especially in depression," added Dr. Fitzgerald, who was not involved with this study

Nevertheless, he noted that these methods are very complex, "and it is difficult to see how they will directly translate into clinical practice."

"They are likely to, however, identify novel targets for treatment localization; and it may well be that methods can be developed to ensure coil placement at new treatment sites without the necessity for all subjects to undergo complex localization procedures," he said.

In 2009, Dr. Fitzgerald and colleagues published results from a study in Neuropsychopharmacology that examined the efficacy of TMS targeted with structural MRI for treatment-resistant depression.

"Our previous research has shown that improved antidepressant responses may be produced by localizing treatment using neuronavigation methods similar to those described by Dr Gorelick, but using structural anatomy rather than functional brain activation," said Dr. Fitzgerald.

"It may be that improvements in treatment response can be produced just by simple measurement methods that take into account head size, such as the use of EEG localization points. In the future, we may also look for sites based on structural connectivity using diffusion tensor imaging scanning."

Overall, Dr. Fitzgerald said that "clearly," optimal response will likely rise when a treatment is optimally targeted.

"In depression, we need to establish more accurately exactly what the best target actually is. A nice aspect of Dr. Gorelick's approach is the way it directly links stimulation site to specific task activation," he concluded.

The study was supported by NIDA's Intramural Research Program and by its Residential Research Support Services. Dr. Gorelick has disclosed no relevant financial relationships. Dr. Fitzgerald reported no financial relationships relevant to this study. However, he did report being supported by an NHMRC Practitioner Fellowship; having received equipment for research from Brainsway Ltd, Medtronic Ltd, and MagVenture A/S; receiving research funding from Cervel Neurotech; and receiving consultancy fees as a scientific advisor for Bionomics.

The American Psychiatric Association's 2012 Annual Meeting. Abstract SCR18-1. Presented May 7, 2012.

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