Lack of clinical response to deep brain stimulation of the medial forebrain bundle in depression

Deep brain stimulation (DBS) is a promising treatment option for severe refractory major depressive disorder (MDD) [[1]Riva-Posse P. Choi K.S. Holtzheimer P.E. Crowell A.L. Garlow S.J. Rajendra J.K. et al.A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression.Mol Psychiatr. 2018; 23: 843-849Crossref PubMed Scopus (224) Google Scholar,[2]Bergfeld I.O. Mantione M. Hoogendoorn M.L. Ruhe 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: a randomized clinical trial.JAMA Psychiatry. 2016; 73: 456-464Crossref PubMed Scopus (185) Google Scholar]. The most common neural targets for DBS in MDD are the subcallosal cingulate cortex (SCC) and the ventral capsule/ventral striatum (VC/VS) [3van der Wal J.M. Bergfeld I.O. Lok A. Mantione M. Figee M. Notten P. et al.Long-term deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression.J Neurol Neurosurg Psychiatry. 2020 Feb; 91: 189-195Crossref PubMed Scopus (26) Google Scholar, 4Crowell A.L. Riva-Posse P. Holtzheimer P.E. Garlow S.J. Kelley M.E. Gross R.E. et al.Long-term outcomes of subcallosal cingulate deep brain stimulation for treatment-resistant depression.Am J Psychiatr. 2019; 176: 949-956Crossref PubMed Scopus (69) Google Scholar, 5Hamani C. Nobrega J.N. Deep brain stimulation in clinical trials and animal models of depression.Eur J Neurosci. 2010; 32: 1109-1117Crossref PubMed Scopus (58) Google Scholar]. The long-term clinical response after DBS to these targets has been characterized as a gradual improvement in mood, with >40% of patients reaching a responder status by 1 year [[3]van der Wal J.M. Bergfeld I.O. Lok A. Mantione M. Figee M. Notten P. et al.Long-term deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression.J Neurol Neurosurg Psychiatry. 2020 Feb; 91: 189-195Crossref PubMed Scopus (26) Google Scholar,[4]Crowell A.L. Riva-Posse P. Holtzheimer P.E. Garlow S.J. Kelley M.E. Gross R.E. et al.Long-term outcomes of subcallosal cingulate deep brain stimulation for treatment-resistant depression.Am J Psychiatr. 2019; 176: 949-956Crossref PubMed Scopus (69) Google Scholar]. Recently, the superolateral branch of the medial forebrain bundle (slMFB) was identified as a novel DBS target for MDD [[6]Schlaepfer T.E. Bewernick B.H. Kayser S. Madler B. Coenen V.A. Rapid effects of deep brain stimulation for treatment-resistant major depression.Biol Psychiatr. 2013; 73: 1204-1212Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar]. Unlike the SCC and VC/VS, the slMFB can only be identified using diffusion magnetic resonance imaging (dMRI) [[7]Coenen V.A. Sajonz B. Reisert M. Bostroem J. Bewernick B. Urbach H. et al.Tractography-assisted deep brain stimulation of the superolateral branch of the medial forebrain bundle (slMFB DBS) in major depression.Neuroimage Clin. 2018; 20: 580-593Crossref PubMed Scopus (50) Google Scholar]. The slMFB is an ascending white-matter tract containing the dopaminergic fibers of the meso-limbic and meso-cortical reward pathways [[8]Fenoy A.J. Schulz P.E. Selvaraj S. Burrows C.L. Zunta-Soares G. Durkin K. et al.A longitudinal study on deep brain stimulation of the medial forebrain bundle for treatment-resistant depression.Transl Psychiatry. 2018; 8: 111Crossref PubMed Scopus (63) Google Scholar]. Two centers have reported extremely favourable rapid results following DBS of the slMFB (≥50% responder status within 1 week, ≥80% responder status by 1 year) [[8]Fenoy A.J. Schulz P.E. Selvaraj S. Burrows C.L. Zunta-Soares G. Durkin K. et al.A longitudinal study on deep brain stimulation of the medial forebrain bundle for treatment-resistant depression.Transl Psychiatry. 2018; 8: 111Crossref PubMed Scopus (63) Google Scholar,[9]Coenen V.A. Bewernick B.H. Kayser S. Kilian H. Bostrom J. Greschus S. et al.Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial.Neuropsychopharmacology. 2019; 44: 1224-1232Crossref PubMed Scopus (74) Google Scholar]. In this report, we outline our failed attempt to replicate these findings. Two patients with severe MDD underwent DBS to the slMFB (for inclusion/exclusion criteria see trial registry: NCT04009928). Both patients were males (ages 55,62) with a long-standing history of anhedonic MDD, who had failed numerous trials of pharmacotherapy, psychotherapy, and electroconvulsive therapy. The slMFB was targeted using pre-operative structural and diffusion-weighted MRI scans, as previously reported [[8]Fenoy A.J. Schulz P.E. Selvaraj S. Burrows C.L. Zunta-Soares G. Durkin K. et al.A longitudinal study on deep brain stimulation of the medial forebrain bundle for treatment-resistant depression.Transl Psychiatry. 2018; 8: 111Crossref PubMed Scopus (63) Google Scholar,[9]Coenen V.A. Bewernick B.H. Kayser S. Kilian H. Bostrom J. Greschus S. et al.Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial.Neuropsychopharmacology. 2019; 44: 1224-1232Crossref PubMed Scopus (74) Google Scholar]. A 3mm spherical region of interest (ROI) was placed in the midbrain, used as a seed to perform tractography (http://dsi-studio.labsolver.org/), and manually adjusted to maximize contact with the slMFB (Fig. 1). Coordinates of the inferior-medial aspect of the ROI was used as the target for DBS. DBS electrodes (Medtronic, 3389) were implanted with the patients awake but sedated. Intraoperative stimulation at the deepest contacts revealed diplopia but no autonomic changes. Patient 1 experienced a transient arousal/appetitive response during right sided test-stimulation, but this could not be re-captured on repeat testing. Under general anesthetic, the electrodes were connected to the implantable pulse generator (Medtronic, Activa PC). Electrode placement was verified with a postoperative MRI. Stimulation was initiated at 2 weeks postoperatively and adjusted biweekly. Programming began at 1.5V, 60μs, and 130Hz (bipolar) and was increased systematically by 0.5V biweekly, until persistent diplopia necessitated moving to other contacts. After 2-4-week trials of bipolar stimulation at each contact, monopolar stimulation was also tested. In a few instances, patients reported transient improvements in mood following stimulation change, which prompted increasing the stimulation intensity during the following visit. At 6 months postoperatively, patients entered a double-blind crossover phase. They were randomized to 2 weeks of OFF or ON stimulation followed by the inverse treatment. The primary outcomes of the study were safety, and antidepressant efficacy, as measured by the 17-item Hamilton Depression Rating Scale (HAMD-17) at 6 months vs. baseline. Response was defined a priori as a ≥50% reduction in HAMD-17 compared to the pre-surgery baseline. As a secondary outcome, we compared HAMD-17 scores during ON vs OFF stimulation for each patient. Percent improvement in HAMD-17 scores between baseline and 6mo follow-up and ON/OFF scores was calculated as (1–6mo/baseline)x100 or (1-ON/OFF)x100. There were no serious adverse events, including hospitalizations or suicide attempts. During the titration phase, tested amplitudes varied from 1.5V to 3.0V. Both patients reported reproducible dizziness and/or oculomotor side effects at amplitudes ≥3.0V, which were more pronounced during monopolar stimulation and at deeper electrode contacts. Independent of the selected settings, patients did not reach responder status at any point over the study period. Patient 1 observed a reduction in anxiety as measured by the Beck Anxiety Inventory (BAI), although this did not result in a change in mood or quality of life, as measured by the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). During the blinded crossover phase, neither patient was able to differentiate between ON or OFF stimulation and there were minimal changes in mood as measured by HAMD-17 scores (Fig. 1). In patients 1 and 2, percent improvement in HAM-17 scores recorded at 6mo vs baseline were 5% and 0%, respectively. When ON/OFF scores were considered, changes were in the order of 11% and −17%. In our study, two patients with refractory MDD underwent dMRI-guided DBS of the MFB. The procedure was well-tolerated and was not associated with any serious adverse events. As expected, transient diplopia and dizziness were observed during DBS programming, especially at higher voltages, deeper contacts, and monopolar stimulation. Although one patient did experience a reduction in anxiety following stimulation, the acute and durable response reported by other investigators was not observed in our two patients. Aside from a few technical differences (i.e. we did not use microelectrode recordings), our treatment strategy was similar to previous reports. Postoperative MRI and the expected clinical findings of stimulation-related diplopia at the deepest contacts confirmed the correct positioning of electrodes. As such, the reason for the discrepancy between our findings and previous reports remains unclear. It may relate to the relatively small sample size, although this is not in keeping with a recent report of nearly 100% response rate [[9]Coenen V.A. Bewernick B.H. Kayser S. Kilian H. Bostrom J. Greschus S. et al.Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial.Neuropsychopharmacology. 2019; 44: 1224-1232Crossref PubMed Scopus (74) Google Scholar]. Our findings may further emphasize the important of personalizing DBS targets to each patient. It has previously been suggested that the slMFB target might be best suited for anhedonic depression [[10]Widge A.S. Malone Jr., D.A. Dougherty D.D. Closing the loop on deep brain stimulation for treatment-resistant depression.Front Neurosci. 2018; 12: 175Crossref PubMed Scopus (71) Google Scholar]. Although both of our patients presented with primarily anhedonic features, more nuanced target selection may be necessary, incorporating additional clinical features and neuroimaging biomarkers. Future studies by independent groups are required to address the potential role of slMFB DBS in MDD. The authors gratefully acknowledge support from the Sunnybrook Foundation and the Harquail Centre for Neuromodulation.

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