Deep Brain Stimulation for Treatment-Refractory Mood and Obsessive-Compulsive Disorders

Deep brain stimulation (DBS) is an invasive therapy in which electrodes are surgically placed into the brain and deliver continuous electrical stimulation. It was originally developed for Parkinson’s disease and other movement disorders. As evidence emerged that certain mental disorders involved abnormal function of specific brain nuclei, multiple investigators launched trials of DBS for mental disorders, particularly major depression (MDD) and obsessive-compulsive disorder (OCD). While open-label results were promising, recent large well-designed clinical trials in MDD have failed. We review the result of major DBS studies to date in psychiatry and what they have taught us about DBS’ safety and efficacy. We further review a variety of animal and human neuroscience studies that have started to shed light on DBS’ mechanisms of action at multiple brain targets. From these, we identify major trends that are likely to drive psychiatric DBS development in the coming decade, including “closed-loop” responsive stimulation, biomarker-based patient selection, and a better modeling of phenotypic heterogeneity within mental disorders. We conclude that on balance, DBS remains promising as a psychiatric treatment, but recent evidence highlights a clear need for further development and a better understanding of mechanisms.

[1]  J. Gybels,et al.  Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder , 1999, The Lancet.

[2]  Sheng Zhang,et al.  Global Resting-State Functional Magnetic Resonance Imaging Analysis Identifies Frontal Cortex, Striatal, and Cerebellar Dysconnectivity in Obsessive-Compulsive Disorder , 2014, Biological Psychiatry.

[3]  K. Deisseroth,et al.  Illuminating circuitry relevant to psychiatric disorders with optogenetics , 2015, Current Opinion in Neurobiology.

[4]  Brendon O. Watson,et al.  Brain rhythms and neural syntax: implications for efficient coding of cognitive content and neuropsychiatric disease. , 2012, Dialogues in clinical neuroscience.

[5]  Jens Kuhn,et al.  Deep brain stimulation of the nucleus accumbens and its usefulness in severe opioid addiction , 2014, Molecular Psychiatry.

[6]  D. Denys,et al.  Deep Brain Stimulation Induces Striatal Dopamine Release in Obsessive-Compulsive Disorder , 2014, Biological Psychiatry.

[7]  P. House,et al.  Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Unipolar and Bipolar Depression , 2012 .

[8]  Karl J. Friston,et al.  Computational psychiatry , 2012, Trends in Cognitive Sciences.

[9]  P. Sachdev,et al.  Deep brain stimulation of anteromedial globus pallidus interna for severe Tourette's syndrome. , 2012, The American journal of psychiatry.

[10]  D W Moran,et al.  A chronic generalized bi-directional brain–machine interface , 2011, Journal of neural engineering.

[11]  Yusuf Tufail,et al.  Ultrasonic neuromodulation by brain stimulation with transcranial ultrasound , 2011, Nature Protocols.

[12]  B. Mädler,et al.  Rapid Effects of Deep Brain Stimulation for Treatment-Resistant Major Depression , 2013, Biological Psychiatry.

[13]  V. Sturm,et al.  Long-Term Effects of Nucleus Accumbens Deep Brain Stimulation in Treatment-Resistant Depression: Evidence for Sustained Efficacy , 2012, Neuropsychopharmacology.

[14]  D. Denys,et al.  Rebound of Affective Symptoms Following Acute Cessation of Deep Brain Stimulation in Obsessive-compulsive Disorder , 2014, Brain Stimulation.

[15]  S. Haber,et al.  Closed-Loop Deep Brain Stimulation Is Superior in Ameliorating Parkinsonism , 2011, Neuron.

[16]  Eric L. Denovellis,et al.  Synchronous Oscillatory Neural Ensembles for Rules in the Prefrontal Cortex , 2012, Neuron.

[17]  E. Eskandar,et al.  Deep Brain Stimulation for Treatment-Resistant Psychiatric Illnesses: What Has Gone Wrong and What Should We Do Next? , 2016, Biological Psychiatry.

[18]  S. Rauch,et al.  Prospective long-term follow-up of 44 patients who received cingulotomy for treatment-refractory obsessive-compulsive disorder. , 2002, The American journal of psychiatry.

[19]  S. Haber,et al.  Enhancement of Fear Extinction with Deep Brain Stimulation: Evidence for Medial Orbitofrontal Involvement , 2015, Neuropsychopharmacology.

[20]  M. Morrell Responsive cortical stimulation for the treatment of medically intractable partial epilepsy , 2011, Neurology.

[21]  E. Eskandar,et al.  Lesion analysis for cingulotomy and limbic leucotomy: comparison and correlation with clinical outcomes. , 2014, Journal of neurosurgery.

[22]  V. Sturm,et al.  DBS in the basolateral amygdala improves symptoms of autism and related self-injurious behavior: a case report and hypothesis on the pathogenesis of the disorder , 2013, Front. Hum. Neurosci..

[23]  Jong-Hwan Lee,et al.  Focused ultrasound modulates region-specific brain activity , 2011, NeuroImage.

[24]  A. Grace,et al.  Long-Term High Frequency Deep Brain Stimulation of the Nucleus Accumbens Drives Time-Dependent Changes in Functional Connectivity in the Rodent Limbic System , 2013, Brain Stimulation.

[25]  H. Ballantine,et al.  Treatment of psychiatric illness by stereotactic cingulotomy , 1987, Biological Psychiatry.

[26]  Sidney H. Kennedy,et al.  Deep brain stimulation for treatment-resistant depression: follow-up after 3 to 6 years. , 2011, The American journal of psychiatry.

[27]  K. Deisseroth,et al.  Repeated Cortico-Striatal Stimulation Generates Persistent OCD-Like Behavior , 2013, Science.

[28]  C. Winter,et al.  Medial Forebrain Bundle Deep Brain Stimulation has Symptom-specific Anti-depressant Effects in Rats and as Opposed to Ventromedial Prefrontal Cortex Stimulation Interacts With the Reward System , 2015, Brain Stimulation.

[29]  Sarah H. Lisanby,et al.  Fundamentals of transcranial electric and magnetic stimulation dose: Definition, selection, and reporting practices , 2012, Brain Stimulation.

[30]  Christina L. Boisseau,et al.  Unified Protocol for the Transdiagnostic Treatment of Emotional Disorders: Protocol Development and Initial Outcome Data. , 2010, Cognitive and behavioral practice.

[31]  N. Logothetis,et al.  Scaling Brain Size, Keeping Timing: Evolutionary Preservation of Brain Rhythms , 2013, Neuron.

[32]  Thomas V. Wiecki,et al.  Subthalamic nucleus stimulation reverses mediofrontal influence over decision threshold , 2011, Nature Neuroscience.

[33]  Gwenn S. Smith,et al.  Deep Brain Stimulation Influences Brain Structure in Alzheimer's Disease , 2015, Brain Stimulation.

[34]  N. Alpert,et al.  A functional neuroimaging investigation of deep brain stimulation in patients with obsessive-compulsive disorder. , 2006, Journal of neurosurgery.

[35]  Peter A. Tass,et al.  A model of desynchronizing deep brain stimulation with a demand-controlled coordinated reset of neural subpopulations , 2003, Biological Cybernetics.

[36]  B. Greenberg,et al.  Gamma ventral capsulotomy for obsessive-compulsive disorder: a randomized clinical trial. , 2014, JAMA psychiatry.

[37]  G. Quirk,et al.  Neural Structures Mediating Expression and Extinction of Platform-Mediated Avoidance , 2014, The Journal of Neuroscience.

[38]  B. Aouizerate,et al.  Pathophysiology of obsessive–compulsive disorder A necessary link between phenomenology, neuropsychology, imagery and physiology , 2004, Progress in Neurobiology.

[39]  Emery N. Brown,et al.  Characterization of fear conditioning and fear extinction by analysis of electrodermal activity , 2015, 2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC).

[40]  Y. Temel,et al.  Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms , 2015, Translational Psychiatry.

[41]  Christian Hauptmann,et al.  Coordinated reset neuromodulation for Parkinson's disease: Proof-of-concept study , 2014, Movement disorders : official journal of the Movement Disorder Society.

[42]  Mu-Yi Hua,et al.  Enhanced therapeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruption for brain tumor treatment: an overview of the current preclinical status. , 2012, Neurosurgical focus.

[43]  C. McIntyre,et al.  Electric field and stimulating influence generated by deep brain stimulation of the subthalamic nucleus , 2004, Clinical Neurophysiology.

[44]  G. Fink,et al.  Decision-making under risk is improved by both dopaminergic medication and subthalamic stimulation in Parkinson's disease , 2014, Experimental Neurology.

[45]  Joshua A. Gordon,et al.  Fear and Safety Engage Competing Patterns of Theta-Gamma Coupling in the Basolateral Amygdala , 2014, Neuron.

[46]  W. van den Brink,et al.  Deep brain stimulation increases impulsivity in two patients with obsessive–compulsive disorder , 2011, International clinical psychopharmacology.

[47]  Darin D Dougherty,et al.  Cerebral metabolic correlates as potential predictors of response to anterior cingulotomy for obsessive compulsive disorder , 2001, Biological Psychiatry.

[48]  Christian Hauptmann,et al.  Therapeutic modulation of synaptic connectivity with desynchronizing brain stimulation. , 2007, International journal of psychophysiology : official journal of the International Organization of Psychophysiology.

[49]  B. Greenberg,et al.  Deep Brain Stimulation for Intractable Obsessive Compulsive Disorder: Pilot Study Using a Blinded, Staggered-Onset Design , 2010, Biological Psychiatry.

[50]  Karl Deisseroth,et al.  Recent advances in optogenetics and pharmacogenetics , 2013, Brain Research.

[51]  D. Denys,et al.  Cognitive–behavioural therapy augments the effects of deep brain stimulation in obsessive–compulsive disorder , 2014, Psychological Medicine.

[52]  M. Carceller‐Sindreu,et al.  Immediate cerebral metabolic changes induced by discontinuation of deep brain stimulation of subcallosal cingulate gyrus in treatment-resistant depression. , 2015, Journal of affective disorders.

[53]  Emad N. Eskandar,et al.  Package architecture and component design for an implanted neural stimulator with closed loop control , 2015, 2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC).

[54]  K. Tye Neural Circuit Reprogramming: A New Paradigm for Treating Neuropsychiatric Disease? , 2014, Neuron.

[55]  Johannes J. Letzkus,et al.  Neuronal circuits of fear extinction , 2010, The European journal of neuroscience.

[56]  T. Insel,et al.  Toward the future of psychiatric diagnosis: the seven pillars of RDoC , 2013, BMC Medicine.

[57]  Jean-Marie Aerts,et al.  Conceptualization and validation of an open-source closed-loop deep brain stimulation system in rat , 2015, Scientific Reports.

[58]  Emad N. Eskandar,et al.  Cognitive state prediction using an EM algorithm applied to Gamma distributed data , 2015, 2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC).

[59]  S. Rauch,et al.  Deficits in conditioned fear extinction in obsessive-compulsive disorder and neurobiological changes in the fear circuit. , 2013, JAMA psychiatry.

[60]  Emery N. Brown,et al.  Estimating a dynamic state to relate neural spiking activity to behavioral signals during cognitive tasks , 2015, 2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC).

[61]  B. Penninx,et al.  Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N=9484) , 2014, Molecular Psychiatry.

[62]  Ann M Graybiel,et al.  Toward a Neurobiology of Obsessive-Compulsive Disorder , 2000, Neuron.

[63]  S. Rauch,et al.  Obsessive-compulsive disorder: beyond segregated cortico-striatal pathways , 2012, Trends in Cognitive Sciences.

[64]  K. Zilles,et al.  Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer’s dementia , 2014, Molecular Psychiatry.

[65]  Max Wintermark,et al.  A pilot study of focused ultrasound thalamotomy for essential tremor. , 2013, The New England journal of medicine.

[66]  Frank Padberg,et al.  Transcranial Magnetic Stimulation of Deep Brain Regions: Principles and Methods , 2007 .

[67]  Sarah H. Lisanby,et al.  Coil design considerations for deep transcranial magnetic stimulation , 2014, Clinical Neurophysiology.

[68]  B. Greenberg,et al.  Who qualifies for deep brain stimulation for OCD? Data from a naturalistic clinical sample. , 2014, The Journal of neuropsychiatry and clinical neurosciences.

[69]  Michael S Okun,et al.  Deep brain stimulation in the internal capsule and nucleus accumbens region: responses observed during active and sham programming , 2006, Journal of Neurology, Neurosurgery & Psychiatry.

[70]  A. Mazaheri,et al.  No Impact of Deep Brain Stimulation on Fear-Potentiated Startle in Obsessive–Compulsive Disorder , 2014, Front. Behav. Neurosci..

[71]  Gregory J. Quirk,et al.  Deep brain stimulation of the ventral striatum increases BDNF in the fear extinction circuit , 2013, Front. Behav. Neurosci..

[72]  Alik S. Widge,et al.  Baseline and Treatment-Emergent EEG Biomarkers of Antidepressant Medication Response Do Not Predict Response to Repetitive Transcranial Magnetic Stimulation , 2013, Brain Stimulation.

[73]  D. Dougherty,et al.  Managing patients with psychiatric conditions treated with deep brain stimulation , 2015 .

[74]  J. Gordon,et al.  Circuits in Sync: Decoding Theta Communication in Fear and Safety , 2014, Neuropsychopharmacology.

[75]  Nicole C. Swann,et al.  Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson's disease , 2015, Nature Neuroscience.

[76]  N. Makris,et al.  A Virtual Patient Simulator Based on Human Connectome and 7 T MRI for Deep Brain Stimulation. , 2014, International journal on advances in life sciences.

[77]  S. Rauch,et al.  Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Treatment-Resistant Depression , 2009, Biological Psychiatry.

[78]  S. Lisanby,et al.  Electric field depth–focality tradeoff in transcranial magnetic stimulation: Simulation comparison of 50 coil designs , 2013, Brain Stimulation.

[79]  D. Dougherty,et al.  DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS , 2015, Depression and anxiety.

[80]  P. Fox,et al.  Identification of a common neurobiological substrate for mental illness. , 2015, JAMA psychiatry.

[81]  Pedram Afshar,et al.  A translational platform for prototyping closed-loop neuromodulation systems , 2013, Front. Neural Circuits.

[82]  R. Bittar,et al.  The anteromedial GPi as a new target for deep brain stimulation in obsessive compulsive disorder , 2014, Journal of Clinical Neuroscience.

[83]  Justin K. Rajendra,et al.  Defining Critical White Matter Pathways Mediating Successful Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression , 2014, Biological Psychiatry.

[84]  T. Insel,et al.  Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it? , 2012, Molecular Psychiatry.

[85]  Polina Anikeeva,et al.  Wireless magnetothermal deep brain stimulation , 2015, Science.

[86]  Sarah R. Heilbronner,et al.  Translational Research in OCD: Circuitry and Mechanisms , 2013, Neuropsychopharmacology.

[87]  C. Koch,et al.  Ephaptic coupling to endogenous electric field activity: why bother? , 2015, Current Opinion in Neurobiology.

[88]  R. Hales,et al.  J Neuropsychiatry Clin Neurosci , 1992 .

[89]  K. Schleifer,et al.  Targeted enhancement of cortical-hippocampal brain networks and associative memory , 2014 .

[90]  Clement Hamani,et al.  Deep Brain Stimulation Reverses Anhedonic-Like Behavior in a Chronic Model of Depression: Role of Serotonin and Brain Derived Neurotrophic Factor , 2012, Biological Psychiatry.

[91]  Michael X. Cohen,et al.  Nucleus Accumbens Deep Brain Stimulation Decreases Ratings of Depression and Anxiety in Treatment-Resistant Depression , 2010, Biological Psychiatry.

[92]  C. Moritz,et al.  Affective Brain-Computer Interfaces As Enabling Technology for Responsive Psychiatric Stimulation. , 2014, Brain computer interfaces.

[93]  C. Hamani,et al.  Chronic deep brain stimulation of the rat ventral medial prefrontal cortex disrupts hippocampal–prefrontal coherence , 2015, Experimental Neurology.

[94]  Steve M. Potter,et al.  Closed-Loop, Open-Source Electrophysiology , 2010, Front. Neurosci..

[95]  H. Mayberg Targeted electrode-based modulation of neural circuits for depression. , 2009, The Journal of clinical investigation.

[96]  G. Quirk,et al.  Fear extinction as a model for translational neuroscience: ten years of progress. , 2012, Annual review of psychology.

[97]  A. Benabid,et al.  Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus , 1991, The Lancet.

[98]  Jakob Voigts,et al.  Neural ensemble communities: open-source approaches to hardware for large-scale electrophysiology , 2015, Current Opinion in Neurobiology.

[99]  S. Krahl,et al.  Deep brain stimulation of the basolateral amygdala for treatment-refractory combat post-traumatic stress disorder (PTSD): study protocol for a pilot randomized controlled trial with blinded, staggered onset of stimulation , 2014, Trials.

[100]  J. Pritchard,et al.  Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology , 2022 .

[101]  E. Miller,et al.  Frequency-specific hippocampal-prefrontal interactions during associative learning , 2015, Nature Neuroscience.

[102]  S. Rauch,et al.  Magnetic Resonance Imaging-guided Stereotactic Limbic Leukotomy for Treatment of Intractable Psychiatric Disease , 2002, Neurosurgery.

[103]  Andrea A Kühn,et al.  Lead-DBS: A toolbox for deep brain stimulation electrode localizations and visualizations , 2015, NeuroImage.

[104]  Helen S. Mayberg,et al.  Multimodal Approaches to Define Network Oscillations in Depression , 2015, Biological Psychiatry.

[105]  L. Parsons,et al.  Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. , 1999, The American journal of psychiatry.

[106]  M. Vink,et al.  Deep brain stimulation restores frontostriatal network activity in obsessive-compulsive disorder , 2013, Nature Neuroscience.

[107]  Thomas R Insel,et al.  Rethinking mental illness. , 2010, JAMA.

[108]  Nir Lipsman,et al.  Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial , 2013, The Lancet.

[109]  Joel L. Voss,et al.  Targeted enhancement of cortical-hippocampal brain networks and associative memory , 2014, Science.

[110]  Jaimie M. Henderson,et al.  Patient-specific analysis of the volume of tissue activated during deep brain stimulation , 2007, NeuroImage.

[111]  Scott R. Stanslaski,et al.  Brain Stimulation for Epilepsy – Local and Remote Modulation of Network Excitability , 2014, Brain Stimulation.

[112]  G. Friehs,et al.  Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience , 2010, Molecular Psychiatry.

[113]  K. Hasan,et al.  The medial forebrain bundle as a deep brain stimulation target for treatment resistant depression: A review of published data , 2015, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[114]  A. Lozano,et al.  Deep Brain Stimulation for Treatment-Resistant Depression , 2005, Neuron.

[115]  Clement Hamani,et al.  The Subcallosal Cingulate Gyrus in the Context of Major Depression , 2011, Biological Psychiatry.

[116]  Clement Hamani,et al.  A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression. , 2012, Journal of neurosurgery.

[117]  R. Paz,et al.  Amygdala–prefrontal interactions in (mal)adaptive learning , 2015, Trends in Neurosciences.

[118]  D. Kondziolka,et al.  A Randomized Sham-Controlled Trial of Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Chronic Treatment-Resistant Depression , 2015, Biological Psychiatry.

[119]  Alik S Widge,et al.  Pre-frontal control of closed-loop limbic neurostimulation by rodents using a brain–computer interface , 2014, Journal of neural engineering.

[120]  G. Quirk,et al.  Deep brain stimulation of the ventral striatum enhances extinction of conditioned fear , 2012, Proceedings of the National Academy of Sciences.

[121]  R. Friedlander,et al.  Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. , 2014, Neurosurgery.

[122]  Paul M. Corballis,et al.  Effects of Subcallosal Cingulate Deep Brain Stimulation on Negative Self-bias in Patients With Treatment-resistant Depression , 2015, Brain Stimulation.

[123]  Chantal E. Stern,et al.  Theta rhythm and the encoding and retrieval of space and time , 2014, NeuroImage.

[124]  Carlos Segura,et al.  An implantable 64-channel neural interface with reconfigurable recording and stimulation , 2015, 2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC).

[125]  H. Westenberg,et al.  Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder. , 2010, Archives of general psychiatry.

[126]  Brian Patenaude,et al.  Neurobiological Signatures of Anxiety and Depression in Resting-State Functional Magnetic Resonance Imaging , 2015, Biological Psychiatry.

[127]  K. Foote,et al.  Deep Brain Stimulation for Treatment-resistant Depression: Systematic Review of Clinical Outcomes , 2014, Neurotherapeutics.

[128]  Bruce R. Rosen,et al.  Optogenetically Induced Behavioral and Functional Network Changes in Primates , 2012, Current Biology.

[129]  C. Hamani,et al.  Deep brain stimulation in rats: Different targets induce similar antidepressant-like effects but influence different circuits , 2014, Neurobiology of Disease.

[130]  S. Houle,et al.  Stimulation of the subthalamic nucleus and impulsivity: Release your horses , 2009, Annals of neurology.