Treating severe depression with on-demand brain stimulation
Immediate, long-term relief for patient's symptoms

Date:
October 4, 2021
Source:
University of California - San Francisco
Summary:
Physicians have successfully treated a patient with severe
depression by tapping into the specific brain circuit involved in
depressive brain patterns and resetting them using the equivalent
of a pacemaker for the brain.



FULL STORY ==========================================================================
The study, which appears in the Oct. 4, 2021, issue of Nature Medicine, represents a landmark success in the years-long effort to apply advances
in neuroscience to the treatment of psychiatric disorders.


========================================================================== "This study points the way to a new paradigm that is desperately needed
in psychiatry," said Andrew Krystal, PhD, professor of psychiatry and
member of the UCSF Weill Institute for Neurosciences. "We've developed a precision- medicine approach that has successfully managed our patient's treatment- resistant depression by identifying and modulating the circuit
in her brain that's uniquely associated with her symptoms." Previous
clinical trials have shown limited success for treating depression with traditional deep brain stimulation (DBS), in part because most devices
can only deliver constant electrical stimulation, usually only in one
area of the brain. A major challenge for the field is that depression
may involve different brain areas in different people.

What made this proof-of-principle trial successful was the discovery of a neural biomarker -- a specific pattern of brain activity that indicates
the onset of symptoms -- and the team's ability to customize a new DBS
device to respond only when it recognizes that pattern. The device then stimulates a different area of the brain circuit, creating on-demand,
immediate therapy that is unique to both the patient's brain and the
neural circuit causing her illness.

This customized approach alleviated the patient's depression symptoms
almost immediately, Krystal said, in contrast to the four- to eight-week
delay of standard treatment models and has lasted over the 15 months
she has had the implanted device. For patients with long-term, treatment-resistant depression, that result could be transformative.

"I was at the end of the line," said the patient, who asked to be known
by her first name, Sarah. "I was severely depressed. I could not see
myself continuing if this was all I'd be able to do, if I could never
move beyond this. It was not a life worth living." Applying Proven
Advances in Neuroscience to Mental Health


==========================================================================
The path to this project at UCSF began with a large, multicenter effort sponsored under President Obama's BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative in 2014.

Through that initiative, UCSF neurosurgeon Edward Chang, MD, and
colleagues conducted studies to understand depression and anxiety in
patients undergoing surgical treatment for epilepsy, for whom mood
disorders are also common. The research teamdiscovered patterns of
electrical brain activity that correlated with mood states and identified
new brain regions that could be stimulated to relieve depressed mood.

With results from the previous research as a guide, Chang, Krystal,
and first author Katherine Scangos, MD, PhD, all members of the Weill Institute, developed a strategy relying on two steps that had never been
used in psychiatric research: mapping a patient's depression circuit
and characterizing her neural biomarker.

"This new study puts nearly all the critical findings of our previous
research together into one complete treatment aimed at alleviating
depression," said Chang, who is co-senior author with Krystal on the
paper and the Joan and Sanford Weill Chair of Neurological Surgery.

The team evaluated the new approach in June 2020 under an FDA
investigational device exemption, when Chang implanted a responsive neurostimulation device that he has successfully used in treating
epilepsy.



==========================================================================
"We were able to deliver this customized treatment to a patient with depression, and it alleviated her symptoms," said Scangos. "We haven't
been able to do this the kind of personalized therapy previously in psychiatry." To personalize the therapy, Chang put one of the device's electrode leads in the brain area where the team had found the biomarker
and the other lead in the region of Sarah's depression circuit where stimulation best relieved her mood symptoms. The first lead constantly monitored activity; when it detected the biomarker, the device signaled
the other lead to deliver a tiny (1mA) dose of electricity for 6 seconds,
which caused the neural activity to change.

"The effectiveness of this therapy showed that not only did we
identify the correct brain circuit and biomarker, but we were able to
replicate it at an entirely different, later phase in the trial using the implanted device," said Scangos. "This success in itself is an incredible advancement in our knowledge of the brain function that underlies mental illness." Translating Neural Circuits into New Insights For Sarah,
the past year has offered an opportunity for real progress after years
of failed therapies.

"In the early few months, the lessening of the depression was so
abrupt, and I wasn't sure if it would last," she said. "But it has
lasted. And I've come to realize that the device really augments the
therapy and self-care I've learned while being a patient here at UCSF."
The combination has given her perspective on emotional triggers and
irrational thoughts on which she used to obsess. "Now," she said,
"those thoughts still come up, but it's just...poof...the cycle stops."
While the approach appears promising, the team cautions that this is
just the first patient in the first trial.

"There's still a lot of work to do," said Scangos, who has enrolled two
other patients in the trial and hopes to add nine more. "We need to look
at how these circuits vary across patients and repeat this work multiple
times. And we need to see whether an individual's biomarker or brain
circuit changes over time as the treatment continues." FDA approval
for this treatment is still far down the road, but the study points
toward new paths for treating severe depression. Krystal said that understanding the brain circuits underlying depression is likely to
guide future non-invasive treatments that can modulate those circuits.

Added Scangos, "The idea that we can treat symptoms in the moment, as
they arise, is a whole new way of addressing the most difficult-to-treat
cases of depression." Co-authors include Ankit Khambhati, Patrick Daly, Ghassan Makhoul, Leo Sugrue, Hashem Zamanian, Tony Liu, Vikram Rao,
Kristin Sellers, Heather Dawes and Philip Starr, all of UCSF.The work
was supported by the National Institutes of Health (K23NS110962), the
Ray and Dagmar Dolby Family Fund, and other philanthropy.

========================================================================== Story Source: Materials provided by
University_of_California_-_San_Francisco. Original written by Robin
Marks. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Scangos, K.W., Khambhati, A.N., Daly, P.M. et al. Closed-loop
neuromodulation in an individual with treatment-resistant
depression. Nat Med, 2021 DOI: 10.1038/s41591-021-01480-w ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211004115125.htm

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