To the Editor:
Deep brain stimulation (DBS) of the subcallosal cingulate has been tested in a series of studies with repeated evidence of sustained long-term effects but with a variable time course of symptom improvement across cohorts. Several randomized controlled trials of different DBS brain targets did not show differences between active and sham stimulation, and a possible cause of failure may have been the prolonged time until clinical response was seen (1-3).
Electrical stimulation of individual contacts on the implanted DBS lead is commonly used during movement disorder surgery to identify immediate improvements in tremor or rigidity and locate sites producing side effects. These effects are transient, disappearing when stimulation is off. Similarly, behavioral changes have been described with stimulation during DBS surgery for depression and include transient changes in mood, attention, and connectedness (4-6). The relation of these acute behavioral effects to postsurgical antidepressant effects has not been fully examined.
Since 2007, the experimental procedure at Emory University has evolved to implement tractography-guided target selection. Over time, intraoperative testing was extended to accommodate electrophysiological experiments and recordings with both unilateral and bilateral stimulation. This short communication reports a post hoc analysis of the increasingly sustained carryover of symptom improvement in the month following subcallosal cingulate DBS surgery for treatment-resistant depression in successive cohorts, all in the absence of ongoing stimulation.
The initial cohort of 17 patients with unipolar and bipolar depression was implanted between 2007 and 2010 (cohort 1) (Libra XP; St. Jude Medical [now Abbott Neuromodulation], Plano, TX). The determination of the surgical target was made based on a general anatomical coordinate approach, using structural T1/T2 magnetic resonance imaging image guidance, and following a similar procedure to that applied in the first cases of subcallosal cingulate DBS (6-8). Twelve of these patients were exposed to intraoperative stimulation, using parameters like the ones used for chronic stimulation (130 Hz, 90-μsec pulse width, 4–8 mA) for approximately 2 to 5 minutes per contact. The other 5 patients were implanted under full anesthesia, and no testing was conducted. Patients in this first cohort then entered a single-blind sham stimulation for a month until chronic stimulation was initiated. A retrospective analysis of this initial cohort identified a combination of white matter bundles associated with response to chronic DBS (9). Consequently, presurgical target identification using tractography became an integral part of the protocol. A second cohort of 11 patients was implanted between 2011 and 2013 with tractography-guided target selection (cohort 2). All of these patients received intraoperative stimulation, with a minimum of 3 minutes per contact (4 per side), occasionally repeating contacts associated with the most salient behavioral responses (10). A third group of 10 patients was implanted between 2014 and 2019 with a different DBS device (cohort 3) (Activa PC+S; Medtronic, Minneapolis, MN) (NCT01984710). The surgical protocol was identical to the previous cohort, applying tractography-guided target selection. The aims of the research required more prolonged intraoperative testing. These patients received the initial 3-minute stimulation per contact (as with cohort 2) but were followed by repeated bilateral stimulation at the identified optimal contacts for an additional 15 to 20 minutes.
Demographic and clinical characteristics were similar for the three cohorts. The baseline depression severity score as measured by the 17-item Hamilton Depression Rating Scale (HDRS-17) in the month prior to surgery was 23.2 ± 3.2, with no significant differences between groups (n = 38). The mean HDRS-17 score for cohort 1 was 23.8 ± 3, for cohort 2 was 23.1 ± 3, and for cohort 3 was 22.3 ± 2.6, averaged over the 4 weeks prior to surgery (Figure 1).
Figure 1.
The 17-item Hamilton Depression Rating Scale (HDRS-17) scores 4 weeks before and after subcallosal cingulate deep brain stimulation surgery. *Statistically significant difference between cohort implanted without tractography and the two cohorts implanted with tractography. **Statistically significant difference among the three cohorts (F = 12.93, p < .0001).
One week after surgery, HDRS-17 scores had decreased by 2.8 points to 21.1 ± 4.2 (11.6% decline) in cohort 1, by 6.7 points to 16.5 ± 5 (28.8% decline) in cohort 2, and by 9.8 points to of 12.5 ± 3.1 (43.9% decline) in cohort 3. A comparison among the three cohorts at 1 week postsurgery showed a statistically significant difference (analysis of variance [F = 12.93, p < .0001]), with the cohorts that used tractography-based implantation resulting in larger decreases in depression severity scores. Additionally, cohort 3 (which received additional bilateral stimulation at the therapeutic target) showed an even greater antidepressant effect 1 week postsurgery (t test, cohort 2 vs. cohort 3: p = .02). The significant difference in HDRS-17 score between cohort 1 and the other two cohorts (target selected with tractography) was maintained through the 4 weeks following surgery and prior to the initiation of chronic stimulation.
A robust carryover of DBS antidepressant effects in the first week after surgery was observed, as a function of precise targeting and the longer intraoperative stimulation. The three cohorts had comparable baseline characteristics, were recruited by the same investigators, and were implanted by the same surgeon; they differed solely in the targeting methods and the absolute exposure to stimulation in the operating room (identical stimulation parameters: 130 Hz, 90-msec pulse width, 6 mA). While the difference between cohort 1 and both cohorts 2 and 3 (implanted with tractography) accounted for the overall greater antidepressant effect over the entire postsurgical month, the added implementation of a longer intraoperative stimulation protocol was associated with a more drastic reduction in depressive symptoms in the first week after surgery. The magnitude of these first-week changes in cohort 3 is consistent with a rapid antidepressant response attributable to the exposure to therapeutic bilateral stimulation in the operating room.
These observations have several implications. Improving the surgical protocol is essential, with awake intraoperative unilateral testing providing important behavioral corroboration of the intended tractography-defined target in each hemisphere. An unexpected and important new observation is that the additional exposure to bilateral stimulation at these optimized locations results in a significant sustained antidepressant effect without ongoing stimulation. This antidepressant effect was not clinically significant in cohort 1, with its less precise targeting and shorter time of intraoperative testing. Together, these findings suggest that reproducible and sustained changes in depressive symptoms facilitated by prolonged bilateral stimulation at tractography-defined surgical targets are not merely transient phenomena, but rather reflect early antidepressant effects initiated with optimized therapeutic stimulation. Biomarkers of these first effects are an important next step to understanding DBS mechanisms for treatment-resistant depression (11).
Acknowledgments and Disclosures
This work was supported by the Hope for Depression Research Foundation (to HSM), Dana Foundation (to HSM), and National Institutes of Health Grant No. 1UH3NS103550-01 (principal investigator, HSM).
Devices were donated by St. Jude Medical (now Abbott Neuromodulation) and Medtronic.
PR-P has served as a consultant for Janssen Pharmaceuticals. ALC has received support from the National Institutes of Health Loan Repayment Program and the American Board of Psychiatry and Neurology. KW, ACW, and KC report no biomedical financial interests or potential conflicts of interest. SJG has served as a consultant to and received research support from Janssen Pharmaceuticals, and serves on the Research Grants Committee of the American Foundation for Suicide Prevention. PEH has received research support from the National Institutes of Health K23 program (Grant No. MH077869), NeoSync, the Brain and Behavior Research Foundation, and the Veterans Administration; he receives royalties from Oxford University Press and UpToDate. REG has received grants from Medtronic, Neuropace, and MRI Interventions; honoraria from Medtronic and MRI Interventions; and is a paid consultant to St. Jude Medical, Medtronic, Neuropace, MRI Interventions, Neuralstem, and SanBio. HSM has received consulting and intellectual licensing fees from St. Jude Medical (now Abbott Neuromodulation).
Footnotes
ClinicalTrials.gov: DBS for TRD Medtronic Activa PC+S; https://clinicaltrials.gov/ct2/show/NCT01984710; NCT01984710.
Contributor Information
Patricio Riva-Posse, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
Andrea L. Crowell, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia
Kathryn Wright, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
Allison C. Waters, Center for Advanced Circuit Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York
KiSueng Choi, Center for Advanced Circuit Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York.
Steven J. Garlow, Department of Psychiatry, University of Wisconsin, Madison, Wisconsin
Paul E. Holtzheimer, Departments of Psychiatry and Surgery, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
Robert E. Gross, Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia
Helen S. Mayberg, Center for Advanced Circuit Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York
References
- 1.Dougherty DD, Rezai AR, Carpenter LL, Howland RH, Bhati MT, O’Reardon JP, et al. (2015): A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression. Biol Psychiatry 78:240–248. [DOI] [PubMed] [Google Scholar]
- 2.Holtzheimer PE, Husain MM, Lisanby SH, Taylor SF, Whitworth LA, McClintock S, et al. (2017): Subcallosal cingulate deep brain stimulation for treatment-resistant depression: A multisite, randomised, sham-controlled trial. Lancet Psychiatry 4:839–849. [DOI] [PubMed] [Google Scholar]
- 3.Coenen VA, Bewernick BH, Kayser S, Kilian H, Bostrom J, Greschus S, et al. (2019): Superolateral medial forebrain bundle deep brain stimulation in major depression: A gateway trial. Neuropsychopharmacology 44:1224–1232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Choi KS, Riva-Posse P, Gross RE, Mayberg HS (2015): Mapping the “depression switch” during intraoperative testing of subcallosal cingulate deep brain stimulation. JAMA Neurol 72:1252–1260. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Riva-Posse P, Inman CS, Choi KS, Crowell AL, Gross RE, Hamann S, et al. (2019): Autonomic arousal elicited by subcallosal cingulate stimulation is explained by white matter connectivity. Brain Stimul 12:743–751. [DOI] [PubMed] [Google Scholar]
- 6.Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, et al. (2005): Deep brain stimulation for treatment-resistant depression. Neuron 45:651–660. [DOI] [PubMed] [Google Scholar]
- 7.Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, Kennedy SH (2008): Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry 64:461–467. [DOI] [PubMed] [Google Scholar]
- 8.Hamani C, Mayberg H, Snyder B, Giacobbe P, Kennedy S, Lozano AM (2009): Deep brain stimulation of the subcallosal cingulate gyrus for depression: Anatomical location of active contacts in clinical responders and a suggested guideline for targeting. J Neurosurg 111:1209–1215. [DOI] [PubMed] [Google Scholar]
- 9.Riva-Posse P, Choi KS, Holtzheimer PE, McIntyre CC, Gross RE, Chaturvedi A, et al. (2014): Defining critical white matter pathways mediating successful subcallosal cingulate deep brain stimulation for treatment-resistant depression. Biol Psychiatry 76:963–969. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Riva-Posse P, Choi KS, Holtzheimer PE, Crowell AL, Garlow SJ, Rajendra JK, et al. (2017): A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression. Mol Psychiatry 23:843–849. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Smart O, Choi KS, Riva-Posse P, Tiruvadi V, Rajendra J, Waters AC, et al. (2018): Initial unilateral exposure to deep brain stimulation in treatment-resistant depression patients alters spectral power in the subcallosal cingulate. Front Comput Neurosci 12:43. [DOI] [PMC free article] [PubMed] [Google Scholar]