Fully Automated Habenula Segmentation Provides Robust and Reliable Volume Estimation Across Large Magnetic Resonance Imaging Datasets, Suggesting Intriguing Developmental Trajectories in Psychiatric Disease.

Studies of habenula (Hb) function and structure provided evidence of its involvement in psychiatric disorders, including schizophrenia and bipolar disorder. Previous studies using magnetic resonance imaging (manual/semiautomated segmentation) have reported conflicting results. Aiming to improve Hb segmentation reliability and the study of large datasets, we describe a fully automated protocol that was validated against manual segmentations and applied to 3 datasets (childhood/adolescence and adult bipolar disorder and schizophrenia). It achieved reliable Hb segmentation, providing robust volume estimations across a large age range and varying image acquisition parameters. Applying it to clinically relevant datasets, we found smaller Hb volumes in the adult bipolar disorder dataset and larger volumes in the adult schizophrenia dataset compared with healthy control subjects. There are indications that Hb volume in both groups shows deviating developmental trajectories early in life. This technique sets a precedent for future studies, as it allows for fast and reliable Hb segmentation and will be publicly available.

[1]  R. Murray,et al.  Grey matter abnormalities in Brazilians with first-episode psychosis. , 2007, The British journal of psychiatry. Supplement.

[2]  H. Wey,et al.  PET Neurochemical Imaging Modes. , 2016, Seminars in nuclear medicine.

[3]  Chandrasekharan Kesavadas,et al.  Resting state fMRI: A review on methods in resting state connectivity analysis and resting state networks , 2017, The neuroradiology journal.

[4]  D Louis Collins,et al.  Warping an atlas derived from serial histology to 5 high-resolution MRIs , 2018, Scientific Data.

[5]  M. Mallar Chakravarty,et al.  Derivation of high-resolution MRI atlases of the human cerebellum at 3T and segmentation using multiple automatically generated templates , 2014, NeuroImage.

[6]  D. H. Root,et al.  Review of the cytology and connections of the lateral habenula, an avatar of adaptive behaving , 2017, Pharmacology Biochemistry and Behavior.

[7]  Essa Yacoub,et al.  Human habenula segmentation using myelin content , 2016, NeuroImage.

[8]  Peter Kirsch,et al.  Remission of Major Depression Under Deep Brain Stimulation of the Lateral Habenula in a Therapy-Refractory Patient , 2010, Biological Psychiatry.

[9]  I. Lucki,et al.  Dysregulation of the Lateral Habenula in Major Depressive Disorder , 2018, Front. Synaptic Neurosci..

[10]  Tiffany M Chaim-Avancini,et al.  State-dependent microstructural white matter changes in drug-naïve patients with first-episode psychosis , 2017, Psychological Medicine.

[11]  S. Frangou,et al.  Imaging Habenula Volume in Schizophrenia and Bipolar Disorder , 2018, Front. Psychiatry.

[12]  M. McHugh.  Interrater reliability: the kappa statistic , 2012, Biochemia medica.

[13]  S. Rauch,et al.  Structural brain magnetic resonance imaging of limbic and thalamic volumes in pediatric bipolar disorder. , 2005, The American journal of psychiatry.

[14]  J. Roiser,et al.  Habenula Volume in Bipolar Disorder and Major Depressive Disorder: A High-Resolution Magnetic Resonance Imaging Study , 2011, Biological Psychiatry.

[15]  Benjamin A. Ely,et al.  Resting‐state functional connectivity of the human habenula in healthy individuals: Associations with subclinical depression , 2016, Human brain mapping.

[16]  M. Mallar Chakravarty,et al.  Multi-atlas segmentation of the whole hippocampus and subfields using multiple automatically generated templates , 2014, NeuroImage.

[17]  T. Jhou,et al.  The mesopontine rostromedial tegmental nucleus: A structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta , 2009, The Journal of comparative neurology.

[18]  Arno Klein,et al.  Large-scale evaluation of ANTs and FreeSurfer cortical thickness measurements , 2014, NeuroImage.

[19]  Arno Klein,et al.  A reproducible evaluation of ANTs similarity metric performance in brain image registration , 2011, NeuroImage.

[20]  Benedikt A. Poser,et al.  Multi-echo fMRI: A review of applications in fMRI denoising and analysis of BOLD signals , 2017, NeuroImage.

[21]  W. Drevets,et al.  Habenula volume in post-traumatic stress disorder measured with high-resolution MRI , 2011, Biology of Mood & Anxiety Disorders.

[22]  J. Near,et al.  Validation of in vivo MRS measures of metabolite concentrations in the human brain , 2019, NMR in biomedicine.

[23]  R. Kupka,et al.  Circuits Regulating Pleasure and Happiness in Bipolar Disorder , 2017, Front. Neural Circuits.

[24]  Jinhui Wang,et al.  Altered Volume and Functional Connectivity of the Habenula in Schizophrenia , 2017, Front. Hum. Neurosci..

[25]  Brian B. Avants,et al.  The optimal template effect in hippocampus studies of diseased populations , 2010, NeuroImage.

[26]  Nikos Makris,et al.  Diagnostic and sex effects on limbic volumes in early-onset bipolar disorder and schizophrenia. , 2007, Schizophrenia bulletin.

[27]  M. Mallar Chakravarty,et al.  Evaluating accuracy of striatal, pallidal, and thalamic segmentation methods: Comparing automated approaches to manual delineation , 2017, NeuroImage.

[28]  V. Voon,et al.  Habenula deep brain stimulation for refractory bipolar disorder , 2019, Brain Stimulation.

[29]  D. Collins,et al.  Performing label‐fusion‐based segmentation using multiple automatically generated templates , 2013, Human brain mapping.

[30]  Erick Jorge Canales-Rodríguez,et al.  Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group , 2017, Molecular Psychiatry.

[31]  H. Holcomb,et al.  Schizophrenia in translation: the presence of absence: habenular regulation of dopamine neurons and the encoding of negative outcomes. , 2005, Schizophrenia bulletin.

[32]  O. Hikosaka,et al.  Lateral habenula as a source of negative reward signals in dopamine neurons , 2007, Nature.

[33]  D. Louis Collins,et al.  MINC 2.0: A Flexible Format for Multi-Modal Images , 2016, Front. Neuroinform..

[34]  S. Grillner,et al.  Evolutionary conservation of the habenular nuclei and their circuitry controlling the dopamine and 5-hydroxytryptophan (5-HT) systems , 2011, Proceedings of the National Academy of Sciences.

[35]  S. Floresco,et al.  Dopaminergic circuitry and risk/reward decision making: implications for schizophrenia. , 2015, Schizophrenia bulletin.

[36]  O. Hikosaka.  The habenula: from stress evasion to value-based decision-making , 2010, Nature Reviews Neuroscience.

[37]  M. Fakhoury,et al.  The habenula in psychiatric disorders: More than three decades of translational investigation , 2017, Neuroscience & Biobehavioral Reviews.

[38]  David Borsook,et al.  Habenula functional resting-state connectivity in pediatric CRPS. , 2014, Journal of neurophysiology.

[39]  J. A. Dani,et al.  The medial habenula and interpeduncular nucleus circuitry is critical in addiction, anxiety, and mood regulation , 2017, Journal of neurochemistry.

[40]  David N. Kennedy,et al.  CANDIShare: A Resource for Pediatric Neuroimaging Data , 2011, Neuroinformatics.

[41]  M. Mallar Chakravarty,et al.  A novel in vivo atlas of human hippocampal subfields using high-resolution 3T magnetic resonance imaging , 2013, NeuroImage.