Friday, December 31, 2021

Your Own Personal DBS

The second calendar year of COVID surges to a close, and hospital personnel continue their frenetic pace of caring for the infected (most of whom are defiantly unvaccinated). For the rest of us, Vaccine Scientists are the 2021 Heroes of the Year... surely they will outsmart the latest variant of the sneaky virus. Their astonishing achievements built on less glamorous (and less recognized) work conducted over the course of 20 years. As told by Time magazine:

In 2005, [Dr. Katalin] Kariko and [Dr. Drew] Weissman reported their findings in what they thought would be a landmark paper in the journal Immunity, then waited for the accolades to flood in. “I told Kati the night before the paper was published, Tomorrow our phones are going to ring off the hook,” says Weissman. No one called.

Clinical Neuroscience Heroes of the Year

Another remarkable achievement in 2021 was the demonstration of a “closed-loop” deep brain stimulation (DBS) protocol in a patient with refractory depression (Scangos et al., 2021a, 2021b). This new personalized treatment modality was based on devices and procedures first used in patients with intractable epilepsy. An implanted responsive neurostimulation (RNS) system detects brain waves that predict the onset of a seizure and then delivers pulses to quell the aberrant electrical activity. The device provides stimulation only when needed, thereby “closing the loop” on a self-contained, personalized neurotherapy.

NeuroPace Next Gen RNS® System


Application of this concept to major depressive disorder (MDD) was based on years of research in basic neurophysiology, neural circuits and biomarkers, electrocorticography (ECoG), cognitive neuroscience, neuroengineering, and machine learning. Some of this work was funded by the 2013 BRAIN Initiative, specifically DARPA's SUBNETS program. The goals of DARPA were rather lofty and unattainable (as they usually are) and outlined in a detailed funding announcement. Or, as I quipped at the time:

To elaborate, over a 5 year period, the successful applicants must conduct clinical trials in human patients with 7 specified psychiatric and neurological disorders (not including PD), some of which have never been treated with DBS. The successful teams will use devices that both stimulate and record neural activity, and provide real-time data that can be decoded as reflecting a particular behavioral state... basically, a futuristic implant that can adjust its own stimulation parameters based on how the patient is doing.


O ye of little faith!

“Someone to hear your prayers
Someone who cares”

Bypassing the “paradigm shift” of another brand of precision psychiatry, a group of scientists and clinicians at UCSF actually achieved this goal in a proof-of-concept n=1 clinical trial, taking personalized psychiatry to its ultimate (albeit prohibitively expensive) destination (Scangos et al., 2021a, 2021b).


The first step in establishing a personalized deep brain stimulation protocol in a single patient with treatment-resistant depression involved 10 days of “mood mapping” while EEG activity was recorded from 160 contacts in 10 target brain regions (Fig 1a, Scangos et al. 2021a).

Electrodes were implanted bilaterally in orbitofrontal cortex, amygdala, hippocampus, ventral capsule/ventral striatum (VC/VS), and subgenual cingulate for 10 days to map mood and identify a “depressive state” biomarker that correlated with symptom ratings. Cross-validated supervised machine learning models identified gamma power in left and right amygdala as the most reliable indicators. Additional results from the mapping of brain stimulation → emotional response are shown below in a schematic figure (click on image for a larger view).

Fig. 1 (Scangos et al. 2021b). Mapping mood across the corticolimbic circuit. (a) Examples of the clinical responses to ~90 s of stimulation. Electrodes that demonstrated a positive or negative mood response to stimulation are enlarged for emphasis and shaded with color of respective region.

Three positive protocols were identified: ‘tingles of pleasure’ with 100-Hz VC/VS stimulation, ‘neutral alertness … less cobwebs and cotton’ with 100-Hz SGC stimulation, and calm pleasure ‘like … reading a good book’ with 1-Hz OFC stimulation.

The team's earlier work on mood mapping was initiated in patients with epilepsy, who were under neurosurgical observation to localize seizure foci using recordings from intracranial electrodes (Kirby et al., 2018; Rao et al., 2018). This actually follows the path outlined by DARPA in their Systems-Based Neurotechnology for Emerging Therapies (SUBNETS) précis:
Through measuring pathways involved in complex systems-based brain disorders [such as MDD] ... SUBNETS will pursue the capability to record and model how these systems function in both normal and abnormal conditions, among volunteers seeking treatment for unrelated neurologic disorders [such as epilepsy] and impaired clinical research participants. SUBNETS will then use these models to determine safe and effective therapeutic stimulation methodologies. These models will be adapted onto next-generation, closed-loop neural stimulators that exceed currently developed capacities for simultaneous stimulation and recording...

Ultimately, stimulation of the right VC/VS was associated with the most consistent and sustained improvement in symptoms (Scangos et al. 2021a). A combination of techniques (evoked potential mapping, graph theory, and deterministic tractography) identified the connectivity between right VC/VS and the amygdala sites. Further sessions suggested that right VC/VS stimulation may be associated with a reduction in gamma activity on trials that saw an improvement in mood. 

After all these mapping sessions, the DBS sites were selected: the NeuroPace RNS System was placed with stimulating leads in right VC/VS and recording leads in right amygdala. Most impressive of all is that detection of the “depressive” gamma biomarker in the amygdala would trigger six seconds of 1 mA intermittent stimulation in VC/VS.

The authors found that the number of detections, defined as gamma power crossing a threshold of 0.8% of full amplitude scale within 10-min recording periods was 87% predictive of symptom severity state and highly correlated with [the patient's self-report on standardized scales]” (Scangos et al. 2021a). The patient's depression improved dramatically within 12 days, and full remission was reached several months later.

The 2021 papers presented an overview of procedures and the results obtained from one patient (Sarah), who was identified by first name and masked photo in press releases and news articles. The n=1 trial was the culmination of hundreds of millions of dollars of federal research funding, so I was kinda fascinated by why the clinical team chose this particular patient (which is protected health information, of course). In an interview, Sarah said, “I was at the end of the line. 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.”

The inclusion criteria for the trial required that the current depressive episode is two or more years in length and treatment-resistant (failure to respond to four adequate trials (including ECT), three classes of medications, one augmentation strategy, and psychotherapy). In the present case, her most recent 4-year episode did not adequately respond to four antidepressants, augmentation with five other meds, electroconvulsive therapy, transcranial magnetic stimulation, or psychotherapy. In other words, closed-loop DBS is only appropriate for the most severe unrelenting cases of depression.

The Future of Depression Treatment is here, but will it work in other patients? And at what cost?
. . .


DARPA has mandated that all depressed Americans must be implanted with its CyberNeuroTron WritBit device, which cost $100 billion to develop. CNTWB is a closed-loop DBS system that automatically adjusts the stimulation parameters at 12 different customized target locations. It uses state-of-the-art syringe-injectable mesh electronics, incorporating silicon nanowires and microvoltammetry. Electrical and chemical signals are continuously recorded and uploaded to a centralized data center, where machine learning algorithms determine with high accuracy whether a given pattern of activity signals a significant change in mood.

The data are compiled, analyzed, and stored by the global search engine conglomerate BlueBook, which in 2032 swallowed up Google, Facebook, Apple, and every other internet data mining company.

Further Reading


And the DARPA deep brain stimulation awards go to...

New Deep Brain Stimulation System Measures Neurotransmitter Release

Who Will Pay for All the New DBS Implants?

BROADEN Trial of DBS for Treatment-Resistant Depression Halted by the FDA

Will machine learning create new diagnostic categories, or just refine the ones we already have?


Scangos KW, Khambhati AN, Daly PM, Makhoul GS, Sugrue LP, Zamanian H, Liu TX, Rao VR, Sellers KK, Dawes HE, Starr PA, Krystal AD, Chang EW. (2021a). Closed-loop neuromodulation in an individual with treatment-resistant depression. Nature Medicine 27(10):1696-700.

Scangos KW, Makhoul GS, Sugrue LP, Chang EF, Krystal AD. (2021b). State-dependent responses to intracranial brain stimulation in a patient with depression. Nature Medicine 27(2):229-31.

"Reach out, touch faith"

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