Brain Stimulation Techniques All Target Same Network

Pauline Anderson

October 07, 2014

Across the same neurologic and psychiatric diseases, target sites for both invasive deep brain stimulation (DBS) and noninvasive approaches, such as transcranial magnetic stimulation, fall within the same brain network, a new study shows.

The results suggest that it may be possible to translate the success of DBS used in diseases such as Parkinson's disease (PD) into new and improved noninvasive treatments, said lead author, Michael D. Fox, MD, PhD, assistant professor, Harvard Medical School, director, Laboratory for Brain Network Imaging and Modulation, and associate director, Deep Brain Stimulation Program, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

If the researchers are on the right track, it could even eventually spell the end of DBS, he told Medscape Medical News.

"I would love to see the day when we don't need deep brain stimulation," said Dr Fox. "It would be nice for patients to be able to avoid undergoing brain surgery if they don't have to, but we are nowhere near that point right now."

The study is published online September 29 in the Proceedings of the National Academy of Sciences of the United States of America.

Deep in the Brain

In DBS, an electrode is surgically implanted deep in the brain and used to deliver electrical pulses at high frequency. DBS systems are approved by the US Food and Drug Administration for treating essential tremor and PD; have exemptions for use in dystonia and obsessive compulsive disorder (OCD); and are being explored for depression, Alzheimer's disease (AD), and minimally conscious states.

Noninvasive alternatives to DBS include transcranial magnetic stimulation (TMS), which uses a rapidly changing magnetic field to induce currents, and transcranial direct current stimulation (iDCS), which involves application of weak electrical currents to modulate neuronal membrane potential.

Researchers have theorized that invasive and noninvasive stimulation of different brain regions might actually modify the same brain network to provide therapeutic benefit. For example, the primary indication for TMS is depression and the primary indication for DBS is PD, but DBS is being investigated as a treatment for depression and TMS is being investigated as a treatment for PD.

To get a better handle on how various brain stimulation sites are connected, researchers first searched PubMed for neurologic and psychiatric diseases that were treated with invasive and noninvasive stimulation. These included addiction, AD, anorexia, depression, dystonia, epilepsy, essential tremor, gait dysfunction, Huntington disease, minimally conscious state, OCD, pain, PD, and Tourette syndrome.

They then listed the targets for both invasive (DBS) and noninvasive (TMS, iDCS) stimulation for each of these 14 conditions.

To test the hypothesis that these sites are different nodes within the same brain network, the researchers used resting-state functional-connectivity MRI (rs-fcMRI). This technique allows for visualization of brain networks based on correlated fluctuations in blood oxygenation.

Road Map

The researchers reanalyzed a unique rs-fcMRI dataset collected from 1000 healthy persons (mean age, 21.3 years). The database, said Dr Fox, "is like a road map of how the normal brain is wired up."

They used this "map" to look for correlations between invasive and noninvasive brain stimulation sites.

In 13 of the 14 diseases (all except epilepsy), the best site for DBS was significantly more correlated with the best site for noninvasive stimulation than with random sites.

After inclusion all stimulation sites (some diseases have more than one target stimulation site), the link between the sites of invasive and noninvasive brain stimulation remained significantly greater than chance in 10 of the 14 diseases.

The finding that both invasive and noninvasive brain stimulation affects nodes in the same network supports a growing belief that network-level effects may be as important as local effects in understanding the therapeutic response, said the authors.

There are several possible explanations for why different types of stimulation applied to different nodes of a network could result in similar symptomatic relief. It could, for example, be related to anatomic connections, or the symptoms could be caused by the balance of activity between brain regions rather than by activity in a single region.

The researchers also found that the sites where brain stimulation was ineffective were characterized by a lack of functional connectivity.

To ensure that the results weren't dependent on clinical data from any particular disease, the researchers randomly omitted any three diseases from the group of 14 and found that the relationship between the best sites for invasive and noninvasive brain stimulation remained significant at the group level (P < .05).

They also replicated the analyses in 56 patients with PD (mean age, 60.3 years) and in 23 patients with medication-refractory depression (age, 52 years). For the most part, the results in healthy persons were replicable in these patients.

This suggests that the brain wiring in these populations varies only a little from the norm, said Dr Fox. "With these diseases, there's a slight change in the normal wiring pattern but not a completely different wiring pattern."

While rs-fcMRI has the potential be an important clinical tool, it does have some restrictions, said Dr Fox. For one thing, it has limited resolution, and because it depends on fluctuations in brain activity and in blood flow, it can only infer brain connectivity.

"It's not a direct measure, so it's different from anatomical connectivity," said Dr Fox.

Practical Implication

Perhaps the most important practical implication of the study is that it provides a testable method for translating the success of DBS into better noninvasive treatments. "We already know that brain stimulation works really well for movement disorders," said Dr Fox. "We know that it works for Parkinson disease, tremor and dystonia. We want to find a way to make non-invasive brain stimulation work that well."

Dr Fox and his research colleagues are already looking into this, but it's still in the very early stages. "We're at a point where it looks like we can probably get an effect, but now we have to figure out why we're getting that effect, how we're getting that effect, and how we can get a better and more consistent effect."

The new brain connectivity information should help. "If we optimize stimulation based on looking at brain connectivity, maybe the noninvasive approach will get a lot better," said Dr Fox. Down the road, patients with PD may just need to put on a cap when they go to bed and have a targeted brain area stimulated while they sleep.

Looking to the future, Dr Fox predicts that within a few decades, patients with a neurologic disorder will be able to choose among drugs, brain stimulation, or a combination of these treatments. Today, pharmaceutical approaches now represent about 99% of neurologic treatments, but that will likely drop to 50%, with brain stimulation becoming increasingly important, he said.

This focus on brain stimulation could be accelerated if the hypothesis that links neurologic diseases to abnormal rhythms in brain circuits proves to be true. Just like patients with a heart arrhythmia get a pacemaker or defibrillator to shock their heart back to beating normally, perhaps in future, patients with PD, or epilepsy, or pain might get their brain stimulated to shock the circuits back into a normal rhythm, said Dr Fox.

This study was supported in part by grants from the National Institutes of Health and from the American Academy of Neurology/American Brain Foundation; Harvard Clinical and Translational Science Center/Harvard Catalyst; the Michael J. Fox Foundation; the Sidney R. Baer, Jr. Foundation; and the National Football League Players Association. Dr Fox is listed as inventor in issued patents or patent applications on functional connectivity and guidance of transcranial magnetic stimulation.

Proc Natl Acad Sci U S A. Published online September 29, 2014. Abstract


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