Subscribe to eTOC

Stimulating the Cingulum Relieves Anxiety During Awake Neurosurgery
What Is the Therapeutic Potential?

Article In Brief

In epilepsy patients undergoing neurosurgery while awake, investigators reported that stimulating the same small area of the cingulum bundle induced strong relief of anxiety and feelings of mirth. The study authors said such stimulation could potentially help those who experience chronic pain, depression, and anxiety disorders.

Deep brain stimulation of a small region of the cingulum bundle alleviates anxiety and induces mirth, according to a new study in three patients. The finding is likely to be immediately useful in some patients who must be alert during awake brain surgery and may lead to a new form of treatment for patients with anxiety, depression, and certain kinds of pain, according to lead investigator Jon T. Willie, MD, PhD, assistant professor of neurosurgery and neurology at the Emory University School of Medicine in Atlanta, Georgia.

“What is novel here is that we have found a way to create anxiolysis without sedation, and we've never seen that pharmacologically,” Dr. Willie said. The study was published in the February 11 online edition of the Journal of Clinical Investigation.

The Study Design, Findings

The discovery emerged during pre-surgical mapping of an epilepsy patient's brain in order to discover the focus of her medically intractable seizures. One of the deep electrodes placed in her brain passed from back to front from the left parietal lobe through the cingulum bundle, a tract of white matter that courses from back to front, carrying messages to and from the cingulate cortex above it.

“We don't usually put electrodes along that trajectory,” Dr. Willie said. “We usually put them in from a trajectory that is more orthogonal,” with at most one contact passing through the bundle. In this patient, though, the electrodes made multiple contacts, allowing the team to test responses to stimulation along several centimeters of white matter. “This was a unique situation, because we had an electrode array that was particularly well aligned with the cingulum bundle, an anatomical structure that is not usually sampled well.”

Dr. Willie tested the effect of stimulation at multiple sites and with multiple contacts, finding that the contacts that gave the strongest behavioral response lay in dorsal anterior segment of the cingulum bundle. More anterior stimulation had little effect, and more posterior stimulation provoked unwanted motor responses in addition to anxiolysis.

But the effects in the middle were profound and immediate. As soon as the stimulation was turned on, the patient smiled, laughed, and described the experience as highly pleasant and inducing a feeling of calm relaxation.

“Wow, everyone should have this,” she said, adding she was “so happy I could cry.” After a few seconds, the stimulation was turned off again, and the feeling dissipated as quickly as it had appeared. It was stronger with stronger stimulation, and absent with single-blind sham stimulation.

After further characterizing the patient's response to brief stimulation, Dr. Willie examined the effects of prolonged stimulation. Over the course of 33 minutes, she again reported happiness and relaxation, and engaged in pleasant and appropriate social interactions with the clinical team. She remained alert and without either mental impairment or aberrant thoughts. When she was asked to think of a sad memory, she reported the substance of it—the death of a pet—but without experiencing the sadness of the event.

Based on EEG findings from elsewhere in her brain, surgery for her seizures was deemed advisable, but contemplation of awake neurosurgery provoked significant anxiety for the patient. Normal anxiolytic medications during surgery are problematic, Dr. Willie explained, because they induce sedation that interferes with precisely monitoring the real-time localization of the resection borders. That led Dr. Willie to propose using intraoperative cingulum stimulation to relieve her anxiety. The patient agreed. As she came out of the anesthesia needed during cranial opening, she became anxious and fearful. The stimulation was turned on, her anxiety disappeared and she rated her happiness as 10 out of 10, and the operation proceeded.

“This didn't change who the patient was or take away her will—it was just engaging one of the normal biological pathways of the brain, that elevated her mood,” Dr. Willie said.

Dr. Willie reported on two other patients in the new study and has since studied more than a dozen others. In both patients, featured in the current study, targeting the same small area of the cingulum bundle induced strong relief of anxiety and feelings of mirth, although neither patient reported the effect as being as unabashedly pleasant as the index patient had.

None of the patients to date have shown any hint of withdrawal symptoms after stopping the stimulus, Dr. Willie said, “and we wouldn't expect that to occur, since basic pathways of reward and addiction are described elsewhere in the brain.”

One patient in the new study, and multiple patients since, reported that stimulation reduced pain, a finding that is consistent with previous work in the cingulum, in which ablation has been used to treat the affective components of intractable cancer pain.

How cingulum stimulation produces its effect is unknown, Dr. Willie said. “We think it is related to an effect on the gray matter in the dorsal anterior cingulate areas, which we know to be involved with emotional regulation, social interaction, and self-assessment,” but much further work will be needed to refine this picture. He added that stimulating white matter may be better therapeutically than targeting the linked gray matter, because it seems able to produce a larger effect at relatively low thresholds of current.

Recent work in deep brain stimulation for depression supports this view; when researchers moved from the gray matter to the white matter subserving the target region, the clinical benefit was much more consistent. “This makes sense, if you think of the white matter as like the trunk of a tree, and the gray matter as the leaves. You can have a much stronger influence over a larger network by targeting the trunk,” Dr. Willie said.

It is too soon to say how practical cingulum stimulation will be for epilepsy or tumor surgery, he added, “since it would require a brain surgery to then do another brain surgery.” But for those patients who cannot tolerate awake surgery—such as children or patients with high levels of anxiety—it may be an important option. The larger potential “is likely to be for those with chronic pain, depression, and anxiety disorders. And there are no other DBS targets for anxiety at the moment, so this could be an important area to investigate.”

Expert Commentary

“These findings are extraordinarily interesting and show how complex emotional and cognitive behaviors can be activated the brain,” commented Arthur Toga, PhD, provost professor of ophthalmology, neurology, psychiatry and behavioral sciences, radiology and engineering and director of the Neuroimaging and Informatics Institute at the University of Southern California Keck School of Medicine.

“It remains to be seen if this is the best target for anxiety,” he said, “and consistently targeting it is likely to be more challenging than targeting the sites used for movement disorders, since there is likely considerable variability across individuals. We don't know yet whether this is a transient effect, which would make placement of electrodes for long-term therapy premature.”

“The importance of the study is that it demonstrates a way to produce anxiolysis without sedation, which might make surgery safer and more reliable,” commented Andres Lozano, MD, PhD, professor of surgery and chair in neurosurgery at the University of Toronto. One future possibility might be to target this area non-invasively, he added, such as with transcranial stimulation, avoiding the need to place an electrode in the cingulum for short-term anxiolysis.

Figure

“What is novel here is that we have found a way to create anxiolysis without sedation, and we've never seen that pharmacologically.”

—DR. JON T. WILLIE

“This really shines the light of attention onto this area of the brain, and suggests it is an interesting target worthy of further pursuit. Whether it will eventually turn into a therapeutically useful site, we don't know, but now the door has been cracked open, and we need to go there and see what we can derive from this intervention.”

Disclosures

Dr. Willie consults for Medtronic, Neuropace, and MRI Interventions, but has no conflicts related to the research in this study. He does have a patent pending on the use of cingulum bundle stimulation for the treatment of anxiety and pain. Dr. Toga had no disclosures.

Link Up for More Information

• Bijanki KR, Manns JR, Inman CS, et al. Cingulum stimulation enhances positive affect and anxiolysis to facilitate awake craniotomy https://www.jci.org/articles/view/120110. J Clin Invest 2019; Epub 2019 Feb 11.