Anhedonia and Reward-Circuit Connectivity Distinguish Nonresponders from Responders to Dorsomedial Prefrontal Repetitive Transcranial Magnetic Stimulation in Major Depression

BACKGROUND Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeting specific nodes within the brain's emotion-regulation network, may be useful both as therapies and as probes for identifying clinically relevant depression subtypes. METHODS Here, we applied 20 sessions of magnetic resonance imaging-guided repetitive transcranial magnetic stimulation (rTMS) to the dorsomedial prefrontal cortex in 47 unipolar or bipolar patients with a medication-resistant major depressive episode. RESULTS Treatment response was strongly bimodal, with individual patients showing either minimal or marked improvement. Compared with responders, nonresponders showed markedly higher baseline anhedonia symptomatology (including pessimism, loss of pleasure, and loss of interest in previously enjoyed activities) on item-by-item examination of Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology ratings. Congruently, on baseline functional magnetic resonance imaging, nonresponders showed significantly lower connectivity through a classical reward pathway comprising ventral tegmental area, striatum, and a region in ventromedial prefrontal cortex. Responders and nonresponders also showed opposite patterns of hemispheric lateralization in the connectivity of dorsomedial and dorsolateral regions to this same ventromedial region. CONCLUSIONS The results suggest distinct depression subtypes, one with preserved hedonic function and responsive to dorsomedial rTMS and another with disrupted hedonic function, abnormally lateralized connectivity through ventromedial prefrontal cortex, and unresponsive to dorsomedial rTMS. Future research directly comparing the effects of rTMS at different targets, guided by neuroimaging and clinical presentation, may clarify whether hedonia/reward circuit integrity is a reliable marker for optimizing rTMS target selection.

[1]  P. Pahapill,et al.  Deep brain stimulation for Parkinson's disease dissociates mood and motor circuits: A functional MRI case study , 2003, Movement disorders : official journal of the Movement Disorder Society.

[2]  J. Krystal,et al.  Trajectories of depression severity in clinical trials of duloxetine: insights into antidepressant and placebo responses. , 2011, Archives of general psychiatry.

[3]  Olivier Ledoit,et al.  A well-conditioned estimator for large-dimensional covariance matrices , 2004 .

[4]  J. Price,et al.  Neural circuits underlying the pathophysiology of mood disorders , 2012, Trends in Cognitive Sciences.

[5]  D. De Ridder,et al.  TMS by double-cone coil prefrontal stimulation for medication resistant chronic depression: A case report , 2014, Neurocase.

[6]  G. Glover,et al.  Resting-State Functional Connectivity in Major Depression: Abnormally Increased Contributions from Subgenual Cingulate Cortex and Thalamus , 2007, Biological Psychiatry.

[7]  A. Rush,et al.  The dexamethasone suppression test in patients with mood disorders. , 1996, The Journal of clinical psychiatry.

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

[9]  M. Thase,et al.  Assessing the ‘true’ effect of active antidepressant therapy v. placebo in major depressive disorder: use of a mixture model , 2011, British Journal of Psychiatry.

[10]  Mark Hallett,et al.  Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression , 1995, Neuroreport.

[11]  Z. Daskalakis,et al.  New Targets for rTMS in Depression: A Review of Convergent Evidence , 2013, Brain Stimulation.

[12]  K. Leonhard.  [Pathogenesis of manic-depressive disease]. , 1957, Der Nervenarzt.

[13]  Yuan Zhou,et al.  Abnormal Cortical Networks in Mild Cognitive Impairment and Alzheimer's Disease , 2010, PLoS Comput. Biol..

[14]  M. Mintun,et al.  Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus , 2010, Proceedings of the National Academy of Sciences.

[15]  Stephan Hamann,et al.  Sex differences in brain activation to emotional stimuli: A meta-analysis of neuroimaging studies , 2012, Neuropsychologia.

[16]  C. Hamani,et al.  Deep brain stimulation for treatment-resistant depression. , 2010, The American journal of psychiatry.

[17]  Orrin Devinsky,et al.  Right ventromedial prefrontal lesions result in paradoxical cardiovascular activation with emotional stimuli. , 2006, Brain : a journal of neurology.

[18]  Anthony R. McIntosh,et al.  Limbic–frontal circuitry in major depression: a path modeling metanalysis , 2004, NeuroImage.

[19]  William W. McDonald,et al.  Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: A Multisite Randomized Controlled Trial , 2007, Biological Psychiatry.

[20]  E. Bullmore,et al.  Hierarchical Organization of Human Cortical Networks in Health and Schizophrenia , 2008, The Journal of Neuroscience.

[21]  Franco Benazzi,et al.  Various forms of depression , 2006, Dialogues in clinical neuroscience.

[22]  Jordan Grafman,et al.  The functional neuroanatomy of depression: Distinct roles for ventromedial and dorsolateral prefrontal cortex , 2009, Behavioural Brain Research.

[23]  Heather L. Urry,et al.  Failure to Regulate: Counterproductive Recruitment of Top-Down Prefrontal-Subcortical Circuitry in Major Depression , 2007, The Journal of Neuroscience.

[24]  B. Harrison,et al.  Regionally specific alterations in functional connectivity of the anterior cingulate cortex in major depressive disorder. , 2012, Psychological medicine.

[25]  P. Gorwood.  Neurobiological mechanisms of anhedonia , 2008, Dialogues in clinical neuroscience.

[26]  A. Beck,et al.  An inventory for measuring clinical anxiety: psychometric properties. , 1988, Journal of consulting and clinical psychology.

[27]  J. Davidson,et al.  A history of the concept of atypical depression. , 2007, The Journal of clinical psychiatry.

[28]  Pablo Villoslada,et al.  A computational analysis of protein-protein interaction networks in neurodegenerative diseases , 2008, BMC Systems Biology.

[29]  Brent L. Hughes,et al.  Prefrontal-Subcortical Pathways Mediating Successful Emotion Regulation , 2008, Neuron.

[30]  E. Bora,et al.  Gray matter abnormalities in Major Depressive Disorder: a meta-analysis of voxel based morphometry studies. , 2012, Journal of affective disorders.

[31]  Jordan Grafman,et al.  Distinct Regions of Prefrontal Cortex Mediate Resistance and Vulnerability to Depression , 2008, The Journal of Neuroscience.

[32]  Simon J Graham,et al.  Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe. , 2005, Archives of general psychiatry.

[33]  Jun-Sung Park,et al.  Whole-brain Functional Networks in Cognitively Normal, Mild Cognitive Impairment, and Alzheimer’s Disease , 2013, PloS one.

[34]  Sarah H Lisanby,et al.  Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. , 2010, Archives of general psychiatry.

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

[36]  C. Martin-Soelch.  Is depression associated with dysfunction of the central reward system? , 2009, Biochemical Society transactions.

[37]  O. Sporns,et al.  Complex brain networks: graph theoretical analysis of structural and functional systems , 2009, Nature Reviews Neuroscience.

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

[39]  C. Naranjo,et al.  Probing brain reward system function in major depressive disorder: altered response to dextroamphetamine. , 2002, Archives of general psychiatry.

[40]  Jen-Chuen Hsieh,et al.  Antidepressant mechanism of add-on repetitive transcranial magnetic stimulation in medication-resistant depression using cerebral glucose metabolism. , 2010, Journal of affective disorders.

[41]  D. Sheehan,et al.  The Anxiety Disease , 1984 .

[42]  Haifang Li,et al.  Machine learning classifier using abnormal brain network topological metrics in major depressive disorder , 2012, Neuroreport.

[43]  P. Falkai,et al.  The role of the human ventral striatum and the medial orbitofrontal cortex in the representation of reward magnitude – An activation likelihood estimation meta-analysis of neuroimaging studies of passive reward expectancy and outcome processing , 2012, Neuropsychologia.

[44]  A. Beck,et al.  Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients. , 1996, Journal of personality assessment.

[45]  Gaël Varoquaux,et al.  Learning and comparing functional connectomes across subjects , 2013, NeuroImage.

[46]  Thomas T. Liu,et al.  A component based noise correction method (CompCor) for BOLD and perfusion based fMRI , 2007, NeuroImage.

[47]  Axel Schäfer,et al.  Gender differences in the processing of disgust- and fear-inducing pictures: an fMRI study , 2005, Neuroreport.

[48]  Z. Daskalakis,et al.  Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials , 2013, Psychological Medicine.

[49]  D. Zald,et al.  Reconsidering anhedonia in depression: Lessons from translational neuroscience , 2011, Neuroscience & Biobehavioral Reviews.

[50]  M. Sim,et al.  Pessimism, worthlessness, anhedonia, and thoughts of death identify DSM-IV major depression in hospitalized, medically ill patients. , 2010, Psychosomatics.

[51]  Kristen A. Lindquist,et al.  The brain basis of emotion: A meta-analytic review , 2012, Behavioral and Brain Sciences.

[52]  Lubos Buzna,et al.  Robustness of trans-European gas networks. , 2009, Physical review. E, Statistical, nonlinear, and soft matter physics.

[53]  R Cameron Craddock,et al.  A whole brain fMRI atlas generated via spatially constrained spectral clustering , 2012, Human brain mapping.

[54]  J. Markowitz,et al.  The 16-Item quick inventory of depressive symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression , 2003, Biological Psychiatry.

[55]  A. Der-Avakian,et al.  The neurobiology of anhedonia and other reward-related deficits , 2012, Trends in Neurosciences.

[56]  Leor N. Katz,et al.  Differential effects of deep TMS of the prefrontal cortex on apathy and depression , 2011, Brain Stimulation.

[57]  George Zouridakis,et al.  Functional connectivity networks in the autistic and healthy brain assessed using Granger causality , 2010, 2010 Annual International Conference of the IEEE Engineering in Medicine and Biology.

[58]  A single motor unit recording technique for studying the differential activation of corticospinal volleys by transcranial magnetic stimulation. , 2001, Brain research. Brain research protocols.

[59]  Á. Pascual-Leone,et al.  Lateralized effect of rapid-rate transcranial magnetic stimulation of the prefrontal cortex on mood , 1996, Neurology.

[60]  Xiaoqi Huang,et al.  Disrupted Brain Connectivity Networks in Drug-Naive, First-Episode Major Depressive Disorder , 2011, Biological Psychiatry.

[61]  A. Lozano,et al.  Subcallosal Cingulate Gyrus Deep Brain Stimulation for Treatment-Resistant Depression , 2008, Biological Psychiatry.

[62]  P. Falkai,et al.  Functional neuroimaging of reward processing and decision-making: A review of aberrant motivational and affective processing in addiction and mood disorders , 2008, Brain Research Reviews.

[63]  I. Kanazawa,et al.  Predominant activation of I1-waves from the leg motor area by transcranial magnetic stimulation , 2000, Brain Research.

[64]  L. Hiller,et al.  The Warwick-Edinburgh Mental Well-being Scale (WEMWBS): development and UK validation , 2007, Health and quality of life outcomes.

[65]  E. Nestler,et al.  The Mesolimbic Dopamine Reward Circuit in Depression , 2006, Biological Psychiatry.

[66]  Mark Gerstein,et al.  The Importance of Bottlenecks in Protein Networks: Correlation with Gene Essentiality and Expression Dynamics , 2007, PLoS Comput. Biol..

[67]  M. Hamilton.  A RATING SCALE FOR DEPRESSION , 1960, Journal of neurology, neurosurgery, and psychiatry.

[68]  J. Endicott,et al.  Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure. , 1993, Psychopharmacology bulletin.