Medial forebrain bundle stimulation after failed subcallosal cingulate deep brain stimulation for treatment-resistant depression: Efficacy of a dual deep brain stimulation system for depression

•The use of MFB DBS for depression can be efficacious even in those patients who fail DBS at a separate target.•Having both MFB and SCC DBS seems to augment the treatment response in terms of patient-reported HAM-D score.•The increased efficacy of both systems together is likely due to combinatorial targeting of underlying disease networks. Treatment-resistant depression (TRD) occurs in up to one-third of patients with major depressive disorder (MDD) [[1]Rush A.J. Trivedi M.H. Wisniewski S.R. Stewart J.W. Nierenberg A.A. Thase M.E. Ritz L. Biggs M.M. Warden D. Luther J.F. Shores-Wilson K. Niederehe G. Fava M. STAR*D Study Team. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression.N Engl J Med. 2006 Mar 23; 354: 1231-1242Crossref PubMed Scopus (920) Google Scholar]. Several DBS targets have been identified, including the subcallosal cingulate cortex (SCC), nucleus accumbens, anterior limb of internal capsule, lateral habenula, red nucleus of the stria terminalis and medial forebrain bundle (MFB) [[2]Drobisz D. Damborská A. Deep brain stimulation targets for treating depression.Behav Brain Res. 2019 Feb 1; 359: 266-273Crossref PubMed Scopus (102) Google Scholar]. MFB is an emerging target showing efficacy for stimulation in TRD6-8 and might be the best target for anhedonic depression [[3]Widge A.S. Malone Jr., D.A. Dougherty D.D. Closing the loop on deep brain stimulation for treatment-resistant depression.Front Neurosci. 2018 Mar 21; 12: 175Crossref PubMed Scopus (86) Google Scholar]. There are no reports of multiple stimulator systems for TRD. It is suspected that MDD is a network disorder rather than a disorder of a single locus [[4]Zhu Z. Hubbard E. Guo X. Barbosa D.A.N. Popal A.M. Cai C. Jiang H. Zheng Z. Lin J. Gao W. Zhang J. Bartas K. Macchia D. Derdeyn P. Halpern C.H. Mayberg H.S. Beier K.T. Zhu J. Wu H. A connectomic analysis of deep brain stimulation for treatment-resistant depression.Brain Stimul. 2021 Sep-Oct; 14: 1226-1233Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. As different components of the network play separate roles, the potential exists to modulate separate sub-circuits. We present two patients in whom prior SCC DBS was performed without sustained symptom relief who then had MFB DBS and had improved symptom relief with both systems activated. In both cases, the effects of having both systems exceed the effect of either system individually. Procedure: Pre-operative diffusion tensor imaging (DTI) (Fig. 1A) was fused with the pre-operative MRI (Fig. 1B). MFB was tracked using a region of interest (5 × 5 × 5 mm^3) placed in the white matter lateral to the ventral tegmental area (VTA). Anterior border was the ipsilateral mammillary body and the mammillothalamic tract. Laterally border was the medial border of the subthalamic nucleus/substantia nigra complex. Standardized coordinates were entered into neuro-navigation and cross-referenced with DTI. Test stimulation with the microelectrode was done up to an amplitude of 4.0V. We placed the permanent electrode (Medtronic 3387) with intra-operative x-ray verification. We used antibacterial envelopes on our IPG units [[5]Persad A.R. Ahmed S.U. Mercure-Cyr R. Waterhouse K. Vitali A.M. Use of antibacterial envelopes for prevention of infection in neuromodulation implantable pulse generators.Oper Neurosurg (Hagerstown). 2022 Nov 1; 23: 413-419Crossref PubMed Scopus (3) Google Scholar]. Example post-operative images are shown (Fig. 1C).Case 1: A 58-year-old female with 18-year history of depression treated pharmacologically with fluoxetine, clonidine, amitriptyline and clonazepam who had bilateral SCC DBS 9 years prior. She initially had some subjective benefit but felt she had plateaued. Following several escalations in pharmacotherapy, her psychiatrist advocated for MFB DBS. There were no intra-operative consequences of stimulation. The patient reported subjective improvement at 1 week follow-up. Her SCC DBS was turned off, but at 5-month follow-up her psychiatrist determined that she was better with both units on. Her SCC DBS was turned back on and her clinical status improved further. She has 56 months of follow-up.Case 2: A 39-year-old male patient with 15-year history of depression, treated with aripiprazole and clozapine. The patient received SCC DBS unit 5 years prior due to recurrent suicidal ideation (SI). Had electroconvulsive therapy with minimal results. Following SCC DBS, initially felt mild improvement but this was transient. Three years following SCC DBS, the patient was admitted to hospital with a suicide attempt. His psychiatrist recommended MFB DBS. There were no intra-operative consequences of stimulation. The patient reported subjective improvement at 1-week follow-up. His SCC DBS started off, but was turned on at 5-month follow-up. He had further clinical improvement with both systems on. His family immediately noticed change after MFB DBS battery stopped working at 18 months follow-up, but took longer to notice differences after the SCC DBS battery failed. The patient had no suicide or self-harm attempts since MFB DBS. He was able to stop aripiprazole on dual stimulation. He has 45 months of follow-up. MFB target coordinates (Fig. 1D), stimulation parameters (Fig. 1E) and clinical improvement (Fig. 1F) are demonstrated. There were no major or minor adverse events in either patient. While the most common target for TRD is SCC, MFB has emerged as a promising target [6Sobstyl M. Kupryjaniuk A. Prokopienko M. Rylski M. Subcallosal cingulate cortex deep brain stimulation for treatment-resistant depression: a systematic review.Front Neurol. 2022 Apr 1; 13780481Crossref PubMed Scopus (5) Google Scholar, 7Coenen V.A. Bewernick B.H. Kayser S. Kilian H. Boström J. Greschus S. Hurlemann R. Klein M.E. Spanier S. Sajonz B. Urbach H. Schlaepfer T.E. Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial.Neuropsychopharmacology. 2019 Jun; 44: 1224-1232Crossref PubMed Scopus (102) Google Scholar, 8Bewernick B.H. Kayser S. Gippert S.M. Switala C. Coenen V.A. Schlaepfer T.E. Deep brain stimulation to the medial forebrain bundle for depression-long-term outcomes and a novel data analysis strategy.Brain Stimul. 2017; 10: 664-671Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar]. MFB contains the dopaminergic fibres of the meso-limbic and meso-cortical reward fibres and can be targeted by pre-operative planning integrating DTI. Outcomes of DBS targeting the SCC [[6]Sobstyl M. Kupryjaniuk A. Prokopienko M. Rylski M. Subcallosal cingulate cortex deep brain stimulation for treatment-resistant depression: a systematic review.Front Neurol. 2022 Apr 1; 13780481Crossref PubMed Scopus (5) Google Scholar] and MFB [[7]Coenen V.A. Bewernick B.H. Kayser S. Kilian H. Boström J. Greschus S. Hurlemann R. Klein M.E. Spanier S. Sajonz B. Urbach H. Schlaepfer T.E. Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial.Neuropsychopharmacology. 2019 Jun; 44: 1224-1232Crossref PubMed Scopus (102) Google Scholar,[8]Bewernick B.H. Kayser S. Gippert S.M. Switala C. Coenen V.A. Schlaepfer T.E. Deep brain stimulation to the medial forebrain bundle for depression-long-term outcomes and a novel data analysis strategy.Brain Stimul. 2017; 10: 664-671Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar] are good. Remission rates with SCC range from 27 to 66.7 % [[6]Sobstyl M. Kupryjaniuk A. Prokopienko M. Rylski M. Subcallosal cingulate cortex deep brain stimulation for treatment-resistant depression: a systematic review.Front Neurol. 2022 Apr 1; 13780481Crossref PubMed Scopus (5) Google Scholar]. MFB stimulation demonstrated improvement at short- and medium-term follow-up in 6/7 patients [[8]Bewernick B.H. Kayser S. Gippert S.M. Switala C. Coenen V.A. Schlaepfer T.E. Deep brain stimulation to the medial forebrain bundle for depression-long-term outcomes and a novel data analysis strategy.Brain Stimul. 2017; 10: 664-671Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar]. A recent trial on MFB DBS showed a positive symptomatic response in all patients [[7]Coenen V.A. Bewernick B.H. Kayser S. Kilian H. Boström J. Greschus S. Hurlemann R. Klein M.E. Spanier S. Sajonz B. Urbach H. Schlaepfer T.E. Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial.Neuropsychopharmacology. 2019 Jun; 44: 1224-1232Crossref PubMed Scopus (102) Google Scholar]. MFB might be the target of choice for anhedonic depression [[3]Widge A.S. Malone Jr., D.A. Dougherty D.D. Closing the loop on deep brain stimulation for treatment-resistant depression.Front Neurosci. 2018 Mar 21; 12: 175Crossref PubMed Scopus (86) Google Scholar]. We demonstrated clinical improvement in our patients following tandem activation of the SCC DBS system following MFB DBS. Both patients underwent MFB DBS as a delayed salvage following inadequate response to SCC DBS. We demonstrate for the first time that (a) implantation of DBS at a different target than the index stimulator may work for salvage, and (b) there is synergy between stimulation systems in improving patient clinical status. A recent study [[4]Zhu Z. Hubbard E. Guo X. Barbosa D.A.N. Popal A.M. Cai C. Jiang H. Zheng Z. Lin J. Gao W. Zhang J. Bartas K. Macchia D. Derdeyn P. Halpern C.H. Mayberg H.S. Beier K.T. Zhu J. Wu H. A connectomic analysis of deep brain stimulation for treatment-resistant depression.Brain Stimul. 2021 Sep-Oct; 14: 1226-1233Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar] classified depression targets into four clusters: cortical, striatal, thalamic and MFB. The SCC is a cortical target. The white matter tracts targeted by SCC DBS are the cingulate bundle, forceps minor and uncinate fasciculus, whereas the MFB and other non-cortical targets are primarily involved in the anterior thalamic radiation and the MFB. As the conduit of the dopaminergic meso-limbic and meso-cortical fibres, the MFB is a powerful regulator of mood, predominantly joy [[9]Coenen V.A. Panksepp J. Hurwitz T.A. Urbach H. Mädler B. Human medial forebrain bundle (MFB) and anterior thalamic radiation (ATR): imaging of two major subcortical pathways and the dynamic balance of opposite affects in understanding depression.J Neuropsychiatry Clin Neurosci. 2012; 24 (Spring): 223-236Crossref PubMed Google Scholar]. The primary effect of the MFB is through reward circuitry [[10]Coenen V.A. Schumacher L.V. Kaller C. Schlaepfer T.E. Reinacher P.C. Egger K. Urbach H. Reisert M. The anatomy of the human medial forebrain bundle: ventral tegmental area connections to reward-associated subcortical and frontal lobe regions.Neuroimage Clin. 2018 Mar 18; 18: 770-783Crossref PubMed Scopus (81) Google Scholar], rather than by mood, which potentially allows it to play a modulatory role in mood disorders. In summary, the depression circuitry targeted downstream of the SCC and MFB stimulator are distinct. As such, the synergy seen in our case is likely due to more holistic modulation of depression connectome. We favor that while the second system improved the effect of the first system, the effects are not simply additive but instead the effect of modulating more of the underlying connectome. Both patients endorsed an initial improvement following their index SCC stimulator placement that normalized. Taking this together with the improvement seen with the standalone MFB stimulator, and the synergistic improvement with the dual stimulation, we suggest that this outcome suggests habituation of depression circuitry following SCC stimulation. A dual stimulator system therefore offers two advantages: (a) it approaches a different portion of the depression circuit than the SCC stimulator [[4]Zhu Z. Hubbard E. Guo X. Barbosa D.A.N. Popal A.M. Cai C. Jiang H. Zheng Z. Lin J. Gao W. Zhang J. Bartas K. Macchia D. Derdeyn P. Halpern C.H. Mayberg H.S. Beier K.T. Zhu J. Wu H. A connectomic analysis of deep brain stimulation for treatment-resistant depression.Brain Stimul. 2021 Sep-Oct; 14: 1226-1233Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar], and (b) it offers expanded coverage of the depression circuit in concert with the SCC stimulator. We present the first report of a dual stimulator system in TRD. Our patients did well and had benefit from the dual system at 4-year follow-up. Our results suggest synergic effect of neuromodulation for TRD. None.

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