Attenuating side effects of deep brain stimulation in the bed nucleus of the stria terminalis for obsessive compulsive disorder using current-steering strategies

Deep brain stimulation (DBS) targeting the anterior limb of the internal capsule (ALIC) is effective for severe, treatment-resistant obsessive-compulsive disorder (trOCD), with approval under a humanitarian device exemption from the U.S. FDA [[1]Shofty B. Gadot R. Viswanathan A. Provenza N.R. Storch E.A. McKay S.A. et al.Intraoperative valence testing to adjudicate between ventral capsule/ventral striatum and bed nucleus of the stria terminalis target selection in deep brain stimulation for obsessive-compulsive disorder.J Neurosurg. 2022; 1: 1-9https://doi.org/10.3171/2022.10.JNS221683Crossref Scopus (1) Google Scholar,[2]Gadot R. Najera R. Hirani S. Anand A. Storch E. Goodman W.K. et al.Efficacy of deep brain stimulation for treatment-resistant obsessive-compulsive disorder: systematic review and meta-analysis.J Neurol Neurosurg Psychiatry. 2022; (jnnp-2021-328738)https://doi.org/10.1136/JNNP-2021-328738Crossref PubMed Google Scholar]. Over the past two decades, this DBS target has evolved posteriorly, from several millimeters anterior to the anterior commissure (AC) to closer or just posterior to the AC [[2]Gadot R. Najera R. Hirani S. Anand A. Storch E. Goodman W.K. et al.Efficacy of deep brain stimulation for treatment-resistant obsessive-compulsive disorder: systematic review and meta-analysis.J Neurol Neurosurg Psychiatry. 2022; (jnnp-2021-328738)https://doi.org/10.1136/JNNP-2021-328738Crossref PubMed Google Scholar]. The subjacent gray matter anterior to the AC is the ventral striatum, designating this target as the ventral capsule/ventral striatum (VC/VS). Posterior to the AC, the subjacent gray matter is the bed nucleus of the stria terminalis (BNST). Targeting the BNST has been effective in a number of case series, with response rates of 67–100% [[1]Shofty B. Gadot R. Viswanathan A. Provenza N.R. Storch E.A. McKay S.A. et al.Intraoperative valence testing to adjudicate between ventral capsule/ventral striatum and bed nucleus of the stria terminalis target selection in deep brain stimulation for obsessive-compulsive disorder.J Neurosurg. 2022; 1: 1-9https://doi.org/10.3171/2022.10.JNS221683Crossref Scopus (1) Google Scholar,[2]Gadot R. Najera R. Hirani S. Anand A. Storch E. Goodman W.K. et al.Efficacy of deep brain stimulation for treatment-resistant obsessive-compulsive disorder: systematic review and meta-analysis.J Neurol Neurosurg Psychiatry. 2022; (jnnp-2021-328738)https://doi.org/10.1136/JNNP-2021-328738Crossref PubMed Google Scholar]. Side effects of stimulation, which can limit therapy delivery, include insomnia, hypomania, and weight gain [[3]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. 2015; 21 (2016 21:9): 1272-1280https://doi.org/10.1038/mp.2015.124Crossref PubMed Scopus (145) Google Scholar,[4]Baldermann J.C. Hahn L. Dembek T.A. Kohl S. Kuhn J. Visser-Vandewalle V. et al.Weight change after striatal/capsule deep brain stimulation relates to connectivity to the bed nucleus of the stria terminalis and hypothalamus.Brain Sci. 2019; 9https://doi.org/10.3390/BRAINSCI9100264Crossref Google Scholar]. Some side effects may result from off-target activation of surrounding tissue and functionally connected structures [[4]Baldermann J.C. Hahn L. Dembek T.A. Kohl S. Kuhn J. Visser-Vandewalle V. et al.Weight change after striatal/capsule deep brain stimulation relates to connectivity to the bed nucleus of the stria terminalis and hypothalamus.Brain Sci. 2019; 9https://doi.org/10.3390/BRAINSCI9100264Crossref Google Scholar]. Here, we report amelioration of an unusual constellation of adverse effects from off-target BNST stimulation, achieved by testing an anatomically-derived hypothesis regarding their origin using electrical current-steering with segmented DBS leads. The patient is a 23-year-old male who underwent BNST DBS for trOCD. Before DBS, the patient suffered from severe obsessive (perfectionism, symmetry, contamination) and compulsive (re-arranging, mental rituals, cleaning) symptoms that were refractory to pharmacotherapy, transcranial magnetic stimulation, and cognitive behavioral therapy (YBOCS = 34, Fig. 1a) [[5]Goodman W.K. Price L.H. Rasmussen S.A. Mazure C. Fleischmann R.L. Hill C.L. et al.The Yale-Brown obsessive compulsive scale. I. Development, use, and reliability.Arch Gen Psychiatr. 1989; 46: 1006-1011https://doi.org/10.1001/ARCHPSYC.1989.01810110048007Crossref PubMed Scopus (0) Google Scholar]. We implanted bilateral segmented DBS leads (SenSight, Medtronic, USA) via robot-assisted stereotaxy [[6]Giridharan N. Katlowitz K.A. Anand A. Gadot R. Najera R.A. Shofty B. et al.Robot-assisted deep brain stimulation: high accuracy and streamlined workflow.Oper Neurosurg (Hagerstown). 2022; 23: 254-260https://doi.org/10.1227/ONS.0000000000000298Crossref PubMed Scopus (0) Google Scholar]. Intraoperative behavioral testing revealed a positive affective response (e.g., contralateral hemi-smile) while stimulating the ventral two levels on both leads (contacts L0, L1, R8, and R9; Fig. 1b). We recently showed that this acute intraoperative response can be a good predictor of longer-term OCD improvement [[1]Shofty B. Gadot R. Viswanathan A. Provenza N.R. Storch E.A. McKay S.A. et al.Intraoperative valence testing to adjudicate between ventral capsule/ventral striatum and bed nucleus of the stria terminalis target selection in deep brain stimulation for obsessive-compulsive disorder.J Neurosurg. 2022; 1: 1-9https://doi.org/10.3171/2022.10.JNS221683Crossref Scopus (1) Google Scholar]. Two weeks post-operatively, we began our typical monopolar survey by testing various amplitudes (0–5 mA) and pulse widths (90–210 μs) across levels of the lead in ring mode with 125 Hz stimulation frequency. Consistent with the intraoperative results, activation of the deepest contacts on both leads (L0 more so than R8) elicited a mirth response characterized by spontaneous smiling, increased energy, and improved mood; we set monopolar stimulation accordingly (Fig. 1c). At the two-week follow-up assessment, OCD symptom severity dramatically improved, meeting criteria for remission with 76.5% reduction in YBOCS (YBOCS = 8, Fig. 1a). However, over the next two months, he developed heat/cold intolerance, marked weight gain (+20 lbs), increased appetite, gastrointestinal distress, restlessness and marked fatigue. We hypothesized that these symptoms, in particular the temperature intolerance and weight gain, were related to hypothalamic (specifically, lateral hypothalamic) dysfunction from off-target stimulation [[7]Marshall J.C. Eagleson C.A. McCartney C.R. Hypothalamic dysfunction.Mol Cell Endocrinol. 2021; 186: 227-230https://doi.org/10.1016/S0303-7207(02)00031-XCrossref Scopus (7) Google Scholar]. Our estimation of the electrical field produced by the stimulation parameters added further confidence to this hypothesis. To determine whether the stimulation fields overlapped with the hypothalamus, we reconstructed the volume of tissue activated (VTA; FMRIB, Oxford, UK), overlaid with a hypothalamic atlas [[8]Spindler M. Özyurt J. Thiel C.M. Automated diffusion-based parcellation of the hypothalamus reveals subunit-specific associations with obesity.Sci Rep. 2020; 10 (2020 10:1): 1-9https://doi.org/10.1038/s41598-020-79289-9Crossref PubMed Scopus (11) Google Scholar], and visualized using the MATLAB-based (MathWorks, USA) Lead-DBS toolbox [[9]Horn A. Kühn A.A. Lead-DBS: a toolbox for deep brain stimulation electrode localizations and visualizations.Neuroimage. 2015; 107: 127-135https://doi.org/10.1016/J.NEUROIMAGE.2014.12.002Crossref PubMed Scopus (0) Google Scholar]. VTA estimates of the initial settings demonstrated 131 mm3 overlap with the hypothalamus on the left (Figs. 1d) and 28.5 mm3 on the right (Fig. 1e). Based on the imaging estimates, we reasoned that steering the field in a lateral and superior/dorsal direction would avoid the hypothalamus and thereby hopefully reduce the side effects. We investigated different configurations to test this hypothesis (Fig. 1c), while striving to preserve therapeutic response. On day one, we maintained a monopolar configuration on the right but moved the cathode from the lowest level ring contact (R8-) to the segmented R9a- and R9c-contacts (Fig. 1e), thus steering the field dorsally and laterally. He tolerated this change but reported a slight decrease in mood. On day two, we attempted the same maneuver on the left side, but the patient did not tolerate this change because of deterioration in mood and increased anxiety. The next day, we attempted an intermediate move with bipolar stimulation, assigning the deepest contact level as cathode and the next one as anode (L0-, L1+) (Fig. 1d). The patient trialed these new settings for one day but reported worsening mood. Therefore, on the last day, we switched the configuration to monopolar on the right (R8-, with an option to switch to R9ac-), to better maintain therapeutic response, and bipolar on the left (L0-/L1+). Two days later, the patient continued to report unbearable fatigue and restlessness. We advised him to switch back to the R9ac-. Fortunately, he tolerated the directional stimulation and, over the course of two weeks, his sleep, temperature sensitivity, weight gain, satiety, gastrointestinal issues, restlessness, and fatigue progressively improved to near-baseline. His obsessive-compulsive symptoms remained well controlled (YBOCS = 3, Fig. 1a). VTA estimates after current-steering demonstrated 20 mm3 overlap with the hypothalamus on the left (Fig. 1d) and no overlap on the right (Fig. 1e). This case highlights the importance of considering off-target hypothalamic stimulation during surgical planning and programming for BNST DBS. The hypothalamus borders the BNST [[4]Baldermann J.C. Hahn L. Dembek T.A. Kohl S. Kuhn J. Visser-Vandewalle V. et al.Weight change after striatal/capsule deep brain stimulation relates to connectivity to the bed nucleus of the stria terminalis and hypothalamus.Brain Sci. 2019; 9https://doi.org/10.3390/BRAINSCI9100264Crossref Google Scholar], and its subnuclei regulate temperature, satiety, and circadian rhythm, among other homeostatic functions [[7]Marshall J.C. Eagleson C.A. McCartney C.R. Hypothalamic dysfunction.Mol Cell Endocrinol. 2021; 186: 227-230https://doi.org/10.1016/S0303-7207(02)00031-XCrossref Scopus (7) Google Scholar]. While current-steering cannot correct overtly malpositioned leads, it has been demonstrated to significantly increase the therapeutic window and side effect threshold when implemented for patients with Parkinson's disease in a prospective, double-blinded trial [[10]Dembek T.A. Reker P. Visser-Vandewalle V. Wirths J. Treuer H. Klehr M. et al.Directional DBS increases side-effect thresholds—a prospective, double-blind trial.Mov Disord. 2017; 32: 1380-1388https://doi.org/10.1002/MDS.27093Crossref PubMed Scopus (0) Google Scholar]. Different combinations of segmented contacts and anode/cathode configurations can be used to optimally shape the stimulation field to avoid nearby structures or white matter fibers [[10]Dembek T.A. Reker P. Visser-Vandewalle V. Wirths J. Treuer H. Klehr M. et al.Directional DBS increases side-effect thresholds—a prospective, double-blind trial.Mov Disord. 2017; 32: 1380-1388https://doi.org/10.1002/MDS.27093Crossref PubMed Scopus (0) Google Scholar]. Of note, the time course of behavioral responses to parameter adjustments may vary depending on the neural structures involved. Hypothalamic modulation can take days or weeks to manifest due to the relatively slow action of hormones [[7]Marshall J.C. Eagleson C.A. McCartney C.R. Hypothalamic dysfunction.Mol Cell Endocrinol. 2021; 186: 227-230https://doi.org/10.1016/S0303-7207(02)00031-XCrossref Scopus (7) Google Scholar], compared to the acute effects of stimulation on affect or motor function. We present a case of hypothalamic side effects associated with BNST DBS that were attenuated using current-steering strategies. Due to the proximity of the BNST to the hypothalamus, targeting this region warrants special consideration during surgical planning and programming. The current-steering capabilities of segmented leads expands the parameter space available for programming. Based on our experience, VTA reconstructions may help identify the optimal configurations. No funding was received for the creation of this case report.