Correspondence
Psychiatry
Deep Brain Stimulation of the Substantia Nigra Pars
Reticulata for Treatment-Resistant Schizophrenia: A
Case Report
To the Editor:
Deep brain stimulation (DBS) is an effective treatment for
Parkinson’s disease (1) via modulation of motor cortico-
striatothalamic circuits (CSTs) (2,3). CST connections to motor,
limbic, and associative cortices are also promising DBS targets
for Tourette syndrome, obsessive-compulsive disorder (4), and
major depression (5–8). Schizophrenia (SZ) is a disorder with
disruptions in limbic and associative CSTs (9,10). One-fifth to
one-half of SZ patients are treatment resistant (TR). DBS tar-
geted at basal ganglia structures within limbic and associative
CSTs could have the potential to alleviate TR SZ symptoms.
The substantia nigra pars reticulata (SNr) functions as a major
basal ganglia output of limbic and associative CSTs via
ascending projections to the mediodorsal nucleus of the
thalamus and limbic and associative cortices, ultimately clos-
ing the loop via descending inhibitory GABAergic (gamma-
aminobutyric acidergic) projections to the ventral basal ganglia
and SNr (11–13). We postulated that the SNr may serve as a
common node, modulating limbic and associative cortices
through a projection to the mediodorsal nucleus of the thal-
amus. If so, this would make it a potentially effective target for
DBS in TR SZ.
Here, we present the first known use of bilateral SNr DBS in
TR SZ. We report the first 6-month stimulation data. The study
was registered on ClinicalTrials.gov (NCT02361554).
The subject is a 35-year-old Caucasian woman with TR SZ,
paranoid type, with comorbid obsessive-compulsive disorder.
Her positive symptoms consisted of persistent auditory and
visual hallucinations, thought broadcasting, and persecutory
delusions that emerged when she was 19 years of age. Anti-
psychotic medications, including clozapine, failed to signifi-
cantly reduce her symptoms. Electroconvulsive therapy was
never used. She volunteered in a study using repetitive
Figure 1. Relationship between symptoms and deep brain stimulation voltage following placement of the deep brain stimulation contacts. (A) Improvement
in hallucinations between 0.5 and 1.0 V. Mild development of ocular deviation near 1.0 V and dysarthria by 1.3–1.4 V. Stable tremor without clear alteration (x:
voltage; y: Likert scale 0–10). (B) Improvement in hallucinations at .0.5 V. The subject experienced paresthesia transiently (heat sensation) at 1.0 V, which
recurred at higher voltages. Some increase in hand/leg cramping movements also occurred at higher voltages (x: voltage; y: Likert scale 0–10).
https://doi.org/10.1016/j.biopsych.2021.03.007
ISSN: 0006-3223
Biological
transcranial magnetic stimulation for TR hallucinations several
years before DBS.
Her baseline Brief Psychiatric Rating Scale (BPRS) (14) total
score was 42, with extremely severe (7) hallucinatory behavior
and severe (6) unusual thought content subscale scores but
without conceptual disorganization. On the Scale for the
Assessment of Negative Symptoms (15), she was rated as
showing marked avolition/apathy and mild anhedonia/
asociality.
Prior to enrollment, the subject’s capacity to give written
informed consent was independently assessed by a psychia-
trist not involved in the study and reviewed by a Data Safety
Monitoring Board, as required by the Johns Hopkins Hospital
Institutional Review Board. Two DBS leads (3387; Medtronic)
were stereotactically implanted via ROSA (Zimmer Biomet)
robotic-assisted technique under general anesthesia. Co-
ordinates of the electrode placement in the left and right SNr
were the following: x (mm lateral to anterior commissure-
posterior commissure: left 28.42, right 17.66), y (mm poste-
rior to midcommissural point: left 27.67, right 28.40), z (mm
inferior to anterior commissure–posterior commissure:
left 215.19, right 213.09).
The system was activated 5 weeks after DBS leads place-
ment. The patient was assessed weekly until the stimulation
started and after using the BPRS and Scale for the Assess-
ment of Negative Symptoms. Cognitive testing was obtained
at baseline and after 24 weeks of stimulation.
Activation of the second ventral DBS contact produced
acute resolution of hallucinations at low voltages of 1.0 V and
0.8 V in the left (Figure 1A) and right (Figure 1B) SNr, respec-
tively (monopolar stimulation, pulse width 60 ms, frequency
130 Hz). Temporarily discontinuing the stimulation or
decreasing the amplitude, unknown to the patient, was asso-
ciated with immediate return of hallucinations. Changes in
medications made during DBS were the following: haloperidol
was decreased from 30 mg to 25 mg daily, oxcarbazepine
600 mg twice daily was discontinued, quetiapine was
increased from 200 mg to 400 mg (for sleep), sertraline
ª 2021 Society of Biological Psychiatry. e57
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Biological
Psychiatry Correspondence

Figure 2. Time course of symptoms before and after onset of deep brain stimulation. (A, B) The time course from baseline until 24 weeks after onset of
stimulation for hallucinations and unusual thought content (any type of delusions) as by the Brief Psychiatric Rating Scale (BPRS). (C, D) Time course for
negative symptoms from the Scale for the Assessment of Negative Symptoms (SANS). The blue dotted vertical line corresponds to the time of implantation,
while the green dotted vertical line corresponds to the onset of stimulation. Each dot corresponds to an evaluation (dates on the x-axis).

increased from 50 mg to 100 mg, and dextroamphetamine-
amphetamine 30 mg twice daily was unchanged.
After 24 weeks of stimulation, BPRS ratings for unusual
thought content and hallucinations (Figure 2A, B) had both
decreased to 1 (not present). Suspiciousness up to a delu-
sional level was also down to 1 from a baseline score of 6
(severe). Her total BPRS score decreased from 42 at baseline
to 20. Her Scale for the Assessment of Negative Symptoms
anhedonia/asociality and avolition/apathy ratings were
improved slightly (Figure 2C, D). The patient remains stably
improved at 1-year follow-up.
The subject experienced no significant complications or
adverse events related to the DBS device implantation except
for increased appetite for the first 3 months, gaining 33 lb,
taking her weight to 314 lb (142 kg) with a body mass index of
54 kg/m2. Contrary to many studies of DBS for Parkinson’s
disease reporting decreased verbal fluency on tests of
speeded lexical retrieval, our subject showed the exact
opposite pattern. Her phonemic and semantic verbal fluency
increased markedly. Conversely, her performance on tests of
verbal and visuospatial learning/memory declined. The cause
of these shifts is unclear, and whether they persist following
further treatment will require longer follow-up.
This is the first reported case of SNr DBS for TR SZ. The
subject reported immediate and complete resolution of chronic
hallucinations in an amplitude dose-responsive fashion upon
selective SNr stimulation initiation. Remission of delusions
occurred within 12 weeks (Figure 2). There are few trials of DBS
in TR SZ. Two cases of habenular DBS have been reported
with initial improvements followed by deterioration within the
year (16). Seven TR SZ patients were randomized to the nu-
cleus accumbens or subgenual anterior cingulate cortex (17).
The subgenual anterior cingulate cortex cohort showed only
modest improvement compared with the nucleus accumbens
cohort. High stimulation parameters were necessary in the
nucleus accumbens group, with peak settings of 7.5 V, 210 Hz,
and 210 ms. We report antipsychotic effects with low-
amplitude SNr stimulation, suggesting high specificity of this
target and minimal risk of adverse effects owing to limited
stimulation of neighboring structures. While long-term efficacy
remains to be seen, these results could suggest that SNr DBS
may be more effective for SZ than response rates noted in
multiple antipsychotic clinical trials (18). Placebo effects
related to expectation and extra attention provided to the pa-
tient should be considered, as these have been demonstrated
to occur in DBS for Parkinson’s disease and obsessive-
compulsive disorder (19,20). However, in our subject, the
symptoms responded in a highly specific and reproducible way
to stimulation location and amplitude.
In summary, we have shown in this first case that SNr DBS
in TR SZ can be safely used and can provide relief from
symptoms that did not respond to pharmacologic treatment.
Nicola Cascella
Ankur A. Butala
Kelly Mills
Min Jae Kim

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Correspondence
Yousef Salimpour
Teresa Wojtasievicz
Brian Hwang
Bernadette Cullen
Martijn Figee
Lauren Moran
Fred Lenz
Akira Sawa
David J. Schretlen
William Anderson
Acknowledgments and Disclosures
This work was supported by the National Institutes of Health (Grant No. MH-
094268, Silvio O. Conte Center, Grant No. MH-092443, Grant No. MH-
105660, and Grant No. MH-107730 [to AS]).
We extend our gratitude to the participant and her family. We thank
Gianluca Ursini, M.D., Ph.D., and Giovanna Punzi, M.D., Ph.D., for critical
reading and editorial help. We also thank Ms. Yukiko Lema for suggestions
for formatting the figures and her role in research management.
WA is a member of the advisory board for Longeviti Neurosolutions and
is a compensated consultant for Globus Medical. Under an agreement be-
tween Psychological Assessment Resources, Inc. and DJS, DJS is entitled
to a share of royalty on sales of a test used in the study described in this
article. The terms of this arrangement are being managed by the Johns
Hopkins University in accordance with its conflict-of-interest policies. All
other authors report no biomedical financial interests or potential conflicts of
interest.
Article Information
From the Johns Hopkins Schizophrenia Center (NC, AS), Department of
Psychiatry (NC, AAB, BC, AS, DJS), Department of Neurology (AAB, KM,
MJK, YS), Department of Neurosurgery (TW, BH, FL, WA), Department of
Neuroscience (AS), Department of Biomedical Engineering (AS), and
Department of Mental Health (AS), the Johns Hopkins Hospital, the Johns
Hopkins University School of Medicine and Bloomberg School of Public
Health, Baltimore, Maryland; the Nash Family Center for Advanced Circuit
Therapeutics (MF), Icahn School of Medicine, New York, New York; and the
Division of Psychotic Disorders (LM), McLean Hospital, Belmont,
Massachusetts.
Address correspondence to Nicola Cascella, M.D., at ncascel1@jhmi.edu.
Received Feb 24, 2021; accepted Mar 2, 2021.
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