Identification of a personalized intracranial biomarker of depression and response to DBS therapy

Abstract

Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) has shown promise as a therapy for refractory obsessive-compulsive disorder (OCD) [[1]Luyten L. Hendrickx S. Raymaekers S. Gabriëls L. Nuttin B. Electrical stimulation in the bed nucleus of the stria terminalis alleviates severe obsessive-compulsive disorder.Mol Psychiatr. 2016; 21: 1272-1280https://doi.org/10.1038/mp.2015.124Crossref PubMed Scopus (103) Google Scholar,[2]Mosley P.E. Windels F. Morris J. Coyne T. Marsh R. Giorni A. et al.A randomised, double-blind, sham-controlled trial of deep brain stimulation of the bed nucleus of the stria terminalis for treatment-resistant obsessive-compulsive disorder.Transl Psychiatry. 2021; : 11https://doi.org/10.1038/s41398-021-01307-9Crossref PubMed Scopus (8) Google Scholar] and major depressive disorder (MDD) [[3]Bergfeld I.O. Mantione M. Hoogendoorn M.L.C. Ruhé H.G. Notten P. Van Laarhoven J. et al.Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression.JAMA Psychiatr. 2016; 73: 456-464https://doi.org/10.1001/jamapsychiatry.2016.0152Crossref PubMed Scopus (148) Google Scholar]. DBS currently is ‘open-loop’ with stimulation parameters remaining fixed over time. In contrast, ‘closed-loop’ DBS delivers stimulation only when a biomarker of the target symptom state indicates it is needed, decreasing stimulation time-thereby potentially reducing the risk of side effects, prolonging battery life, and potentially improving efficacy by mitigating neural adaptation. This method has shown efficacy in treating epilepsy [[4]Morrell M.J. RNS System in Epilepsy Study Group. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy.Neurology. 2011; 77: 1295-1304https://doi.org/10.1212/WNL.0b013e3182302056Crossref PubMed Scopus (707) Google Scholar] and promise in treating Parkinson's disease [[5]Little S. Pogosyan A. Neal S. Zavala B. Zrinzo L. Hariz M. et al.Adaptive deep brain stimulation in advanced Parkinson disease.Ann Neurol. 2013; 74: 449-457https://doi.org/10.1002/ana.23951Crossref PubMed Scopus (652) Google Scholar]. One challenge to the development of closed-loop DBS for psychiatric indications is the dearth of biomarkers of symptom state [[6]Sani O.G. Yang Y. Lee M.B. Dawes H.E. Chang E.F. Shanechi M.M. Mood variations decoded from multi-site intracranial human brain activity.Nat Biotechnol. 2018; 36: 954https://doi.org/10.1038/nbt.4200Crossref PubMed Scopus (67) Google Scholar]. Here, we report identification of an electrophysiological depression biomarker in a patient receiving DBS in the ALIC and nearby bed nucleus of the stria terminalis (BNST). This case represents a proof-of-concept that personalized biomarkers can be detected using existing commercially available DBS devices, marking a step towards the development of closed-loop systems. The patient is a 51-year-old man with a history of severe, treatment-refractory OCD (Yale-Brown Obsessive Compulsive Scale: Y-BOCS of 31) and co-morbid severe MDD. The patient's harm-based OCD began in his teenage years and was formally diagnosed at the age of 28 years. His OCD and depression did not adequately respond to trials of 5 SSRIs, 1 SNRI, augmentation strategies (2 antipsychotics, clomipramine, stimulant, IV ketamine), and transcranial magnetic stimulation. The patient had extensive trials of exposure-response prevention and psychodynamic therapy with limited benefit. Given this history of treatment refractoriness and significant functional impairment related to severe OCD and MDD, the patient was deemed an appropriate candidate for DBS targeting the ALIC, which has been shown to be helpful for both disorders [1Luyten L. Hendrickx S. Raymaekers S. Gabriëls L. Nuttin B. Electrical stimulation in the bed nucleus of the stria terminalis alleviates severe obsessive-compulsive disorder.Mol Psychiatr. 2016; 21: 1272-1280https://doi.org/10.1038/mp.2015.124Crossref PubMed Scopus (103) Google Scholar, 2Mosley P.E. Windels F. Morris J. Coyne T. Marsh R. Giorni A. et al.A randomised, double-blind, sham-controlled trial of deep brain stimulation of the bed nucleus of the stria terminalis for treatment-resistant obsessive-compulsive disorder.Transl Psychiatry. 2021; : 11https://doi.org/10.1038/s41398-021-01307-9Crossref PubMed Scopus (8) Google Scholar, 3Bergfeld I.O. Mantione M. Hoogendoorn M.L.C. Ruhé H.G. Notten P. Van Laarhoven J. et al.Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression.JAMA Psychiatr. 2016; 73: 456-464https://doi.org/10.1001/jamapsychiatry.2016.0152Crossref PubMed Scopus (148) Google Scholar]. DBS leads (3387; Medtronic, Minneapolis, MN) were stereotactically implanted within the ALIC and surrounding BNST bilaterally and were connected to an Activa PC (Medtronic, Minneapolis, MN) internal pulse generator. The patient underwent standard stimulation programming with partial response in OCD symptoms (reduction in Y-BOCS from 36 to 25; 31% improvement) and notable improvement in depression (reduction in PHQ-9 from 25 to 15; 40% improvement) from pre-op to one year follow up. Subsequently, the patient underwent IPG exchange due to battery depletion with the Percept PC (Medtronic, Minneapolis, MN) at approximately 15 months post-implantation. This new device is the first clinically approved device to have the ability to perform local field potential (LFP) recordings from the DBS leads in addition to stimulation. Ultimately, stimulation from the right lead was discontinued given lack of benefit, and the patient was primarily treated with DBS from the left ALIC contacts, while recordings were performed from the right contacts. We localized electrode placement using pre- and post-operative MRI and found the right dorsal three contacts were in the BNST while all contacts on the stimulating lead were located in the ventral ALIC (Fig. 1A, supplemental methods) [[7]Horn A. Li N. Dembek T.A. Kappel A. Boulay C. Ewert S. et al.Lead-DBS v2: towards a comprehensive pipeline for deep brain stimulation imaging.Neuroimage. 2019; 184: 293-316https://doi.org/10.1016/j.neuroimage.2018.08.068Crossref PubMed Scopus (203) Google Scholar]. Pre-operative diffusion-tensor imaging was used to determine putative fiber tracts being modulated by DBS from the left, stimulating lead (Fig. 1B and C). and identified prominent connections to the frontal cortex, temporal lobe, and contralateral BNST, which are tracts that have been associated with mood improvements in prior studies [[8]Baldermann J.C. Melzer C. Zapf A. Kohl S. Timmermann L. Tittgemeyer M. et al.Connectivity profile predictive of effective deep brain stimulation in obsessive-compulsive disorder.Biol Psychiatr. 2019; 85: 735-743https://doi.org/10.1016/j.biopsych.2018.12.019Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar]. We tracked the patient's symptom state using validated visual analogue scales (VAS) across several domains (obsessions, compulsions, anxiety, energy, and depression). LFP recordings were simultaneously acquired from the patient's right-sided sensing lead using the Percept IPG's patient-triggered power spectra recording mode. We collected a set of power spectral density (PSD) recordings derived from 30 sec of LFP (Fig. 1C). Power in 6 frequency bands (delta: 1–4Hz; theta: 4–8Hz; alpha: 8–12Hz; beta: 12–25Hz; low gamma: 25–50Hz; high gamma: 50–97Hz) was correlated with VAS scores of symptom state. We found a significant inverse correlation between low and high gamma power and VAS-Depression ratings (Fig. 1D and E). We then monitored power in a low gamma range (25Hz ± 2.5Hz) continuously over ∼6 weeks using the timeline mode (Fig. 1F) in parallel with the VAS symptom ratings. We found that low gamma power preceding VAS depression scoring was again inversely correlated with VAS depression ratings (Fig. 1G and H), and this correlation became stronger by averaging over a longer time window (Fig. 1G). The strength of the low gamma correlation with VAS-D was strongest immediately prior to the rating, demonstrating a strong temporal relationship between the biomarker and depressive symptoms (Fig. 1G, inset). These results were validated using leave-on-out cross-validation analysis (R2 = 0.72, p = 5.8 × 10−5). To test whether the putative biomarker of depression severity was responsive to stimulation, we also recorded streamed LFP traces from the right lead while DBS of the left ALIC was cycled on and off in-office. We found that left DBS stimulation in the left ALIC generated a broadband increase in power in the right BNST (Fig. 1I and J, supplemental methods), including significant increases in low and high gamma power (Fig. 1K) accompanied by a general improvement in symptoms (see supplemental video). In summary, we describe a case where we identified BNST gamma power to be a putative personalized biomarker that is both associated with depression symptoms and responsive to therapeutic DBS. Gamma enhancement with stimulation may be mediated by structural connectivity between our stimulation contacts in the left ALIC and our recording contact in the right BNST (Fig. 1B). The correlation between BNST gamma activity and mood is consistent with studies demonstrating the BNSTs role in reward motivation pathways [[9]Jennings J.H. Sparta D.R. Stamatakis A.M. Ung R.L. Pleil K.E. Kash T.L. et al.Distinct extended amygdala circuits for divergent motivational states.Nature. 2013; 496: 224-228https://doi.org/10.1038/nature12041Crossref PubMed Scopus (432) Google Scholar,[10]Giardino W.J. Eban-Rothschild A. Christoffel D.J. Li S Bin Malenka R.C. de Lecea L. Parallel circuits from the bed nuclei of stria terminalis to the lateral hypothalamus drive opposing emotional states.Nat Neurosci. 2018; 21: 1084-1095https://doi.org/10.1038/s41593-018-0198-xCrossref PubMed Scopus (85) Google Scholar]. We utilized a personalized method for discovering biomarkers of symptom state by correlating spectral features from intracranial recordings with longitudinal self-reports. The interindividual variability of this marker across subjects remains unknown. However, we speculate that different biomarkers may be unique to individuals, disorders, and brain locations, highlighting the importance of developing individualized closed-loop DBS that can adapt to patients’ symptoms in real-time. Further work will be needed to extend this work other patients with OCD and co-morbid severe MDD; patients with MDD without OCD; and to ultimately implement and test closed-loop DBS therapy targeting depression. This work is supported by the National Institute of Mental Health (Grant No. K23MH125018 ), P&S Fund from the Brain and Behavior Foundation (Grant No. A136828 ), and Foundation for OCD Research (Grant No. P0548058 ).

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