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Free water diffusion magnetic resonance imaging differentiates suicidal ideation from suicide attempt in treatment-resistant depression

Open AccessPublished:December 20, 2022DOI:https://doi.org/10.1016/j.bpsc.2022.12.007

      Abstract

      Background

      Suicide attempt is highly prevalent in treatment-resistant depression (TRD), however, the neurobiological profile of suicidal ideation versus suicide attempt is unclear. Neuroimaging methods including diffusion magnetic resonance imaging based free water imaging may identify neural correlates underlying suicidal ideation and attempts in individuals with TRD.

      Methods

      Diffusion magnetic resonance imaging data were obtained from 64 male and female participants (mean age 44.5±14.2), including 39 patients with TRD (n=21 with lifetime history of suicidal ideation but no attempts (SI-group); n=18 with lifetime history of suicide attempt (SA-group)), and 25 age- and sex-matched healthy controls. Depression and suicidal ideation severity were examined using clinician-rated and self-report measures. Whole-brain neuroimaging analysis was conducted using tract-based spatial statistics via FMRIB Software Library to identify differences in white matter microstructure in SI- versus SA-groups, and in patients versus controls.

      Results

      Free water imaging revealed elevated axial diffusivity and extracellular free water in fronto-thalamo-limbic white matter tracts of the SA-group compared to SI-group. In a separate comparison, patients with TRD had widespread reductions in fractional anisotropy and axial diffusivity, and elevated radial diffusivity compared to controls (thresholded p<0.05, family-wise error corrected).

      Conclusions

      A unique neural signature consisting of elevated axial diffusivity and free water is identified in patients with TRD and suicide attempt history. Findings of reduced fractional anisotropy, axial diffusivity, and elevated radial diffusivity in patients versus controls are consistent with previously published studies. Multimodal and prospective investigations are recommended to better understand biological correlates of suicide attempt.

      Keywords

      Introduction

      Treatment-resistant depression (TRD) is conceptualized as significant unresolved symptoms following multiple attempted pharmacotherapy trials for major depressive disorder (MDD) (
      • Limandri B.J.
      Treatment-resistant depression: Identification and treatment strategies.
      ). Patients with TRD have a higher burden of illness compared to treatment responsive patients with poorer quality of life, occupational and social outcomes (

      Mrazek DA, Hornberger JC, Altar CA, Degtiar I (2014):A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013. Psychiatr Serv 65: 977-987.

      ), and greater risk of mortality (

      Brenner P, Reutfors J, Nijs M, Andersson TM-L (2021): Excess deaths in treatment-resistant depression. Ther Adv Psychopharmacol 11: 20451253211006508.

      ). TRD may increase an individual’s likelihood of engaging in suicidal behaviors (

      Mrazek DA, Hornberger JC, Altar CA, Degtiar I (2014):A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013. Psychiatr Serv 65: 977-987.

      ) and an estimated 30% of patients with TRD will have a suicide attempt in their lifetime (
      • Bergfeld I.O.
      • Mantione M.
      • Figee M.
      • Schuurman P.R.
      • Lok A.
      • Denys D.
      Treatment-resistant depression and suicidality.
      ).
      Clinical prediction of suicide has not improved significantly over the last 50 years (
      • O’Connor R.C.
      • Kirtley O.J.
      The integrated motivational-volitional model of suicidal behaviour.
      ), and many cited risk factors for suicide are strongly predictive of ideation rather than attempts (

      Klonsky ED, May AM, Saffer BY (2016): Suicide, suicide attempts, and suicidal ideation. Annu Rev Clin Psychol 12: 307-330.

      ). A crucial avenue for suicide prevention is understanding the independent roles of suicidal thoughts, behaviors, and attempts (
      • Klonsky E.D.
      • Dixon-Luinenburg T.
      • May A.M.
      The critical distinction between suicidal ideation and suicide attempts.
      ), and the neurobiological progression from passive suicidal thoughts to highly lethal suicide attempts.
      In vivo neuroimaging techniques may help to distinguish between suicidal ideation and attempts on a neurobiological level (
      • Schmaal L.
      • van Harmelen A.L.
      • Chatzi V.
      • Lippard E.T.C.
      • Toenders Y.J.
      • Averill L.A.
      • et al.
      Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies.
      ). Previous magnetic resonance imaging (MRI) studies have identified both regional and whole-brain differences in patients with and without a suicide attempt history (
      • Bani-Fatemi A.
      • Tasmim S.
      • Graff-Guerrero A.
      • Gerretsen P.
      • Strauss J.
      • Kolla N.
      • et al.
      Structural and functional alterations of the suicidal brain: An updated review of neuroimaging studies.
      ), such as reduced structural gray matter volume and abnormal fronto-thalamo-limbic functional connectivity (
      • Campos A.I.
      • Thompson P.M.
      • Veltman D.J.
      • Pozzi E.
      • van Veltzen L.S.
      • Jahanshad N.
      • et al.
      Brain correlates of suicide attempt in 18,925 participants across 18 international cohorts.
      ,
      • Kang S.G.
      • Na K.S.
      • Choi J.W.
      • Kim J.H.
      • Son Y.D.
      • Lee Y.J.
      Resting-state functional connectivity of the amygdala in suicide attempters with major depressive disorder.
      ). However, the directionality of structural and functional changes have been inconsistent. For example, structural volumes of the parietal lobe in MDD patients with a history of suicidal thoughts and/or attempts are reduced in some studies but elevated in others (
      • Domínguez-Baleón C.
      • Gutiérrez-Mondragón L.F.
      • Campos-González A.I.
      • Rentería M.E.
      Neuroimaging studies of suicidal behavior and non-suicidal self-injury in psychiatric patients: A systematic review.
      ). Similarly, both increased and decreased functional connectivity of the dorsal prefrontal cortex have been reported in relation to suicidal thoughts and behaviors in MDD (
      • Schmaal L.
      • van Harmelen A.L.
      • Chatzi V.
      • Lippard E.T.C.
      • Toenders Y.J.
      • Averill L.A.
      • et al.
      Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies.
      ).
      Diffusion MRI (dMRI) could allow for detection of more subtle morphological differences between suicidal ideation and suicide attempts, due to its ability to resolve sub-voxel microstructural information (
      • Grieve S.M.
      • Maller J.J.
      High-resolution diffusion imaging: Ready to become more than just a research tool in psychiatry?.
      ). dMRI quantifies the magnetic resonance signal of the random dispersion of water molecules through white matter fiber tracts which vary based on tissue architecture (
      • Alexander D.C.
      • Dyrby T.B.
      • Nilsson M.
      • Zhang H.
      Imaging brain microstructure with diffusion MRI: practicality and applications.
      ). Diffusion tensor imaging (DTI) analysis involves mathematical modeling of the direction and magnitude of diffusion via calculation of a 3x3 tensor at each voxel, from which microscopic tissue features can be inferred (
      • Chanraud S.
      • Zahr N.
      • Sullivan E.V.
      • Pfefferbaum A.
      MR diffusion tensor imaging: A window into white matter integrity of the working brain.
      ). The measurement of fractional anisotropy (FA; directional preference of water diffusion) is the most commonly reported, in addition to mean diffusivity (MD; overall mobility of water molecules in each voxel), axial diffusivity (AD; rate of diffusion parallel to the primary diffusion direction), and radial diffusivity (RD; rate of diffusion perpendicular to the primary diffusion direction) (
      • Podwalski P.
      • Szczygieł K.
      • Tyburski E.
      • Sagan L.
      • Misiak B.
      • Samochowiec J.
      Magnetic resonance diffusion tensor imaging in psychiatry: a narrative review of its potential role in diagnosis.
      ).
      To date, few published DTI studies have examined white matter microstructure in MDD in relation to suicide ideation (
      • Taylor W.D.
      • Boyd B.
      • McQuoid D.R.
      • Kudra K.
      • Saleh A.
      • MacFall J.R.
      Widespread white matter but focal gray matter alterations in depressed individuals with thoughts of death.
      ,
      • Myung W.
      • Han C.E.
      • Fava M.
      • Mischoulon D.
      • Papakostas G.I.
      • Heo J.Y.
      • et al.
      Reduced frontal-subcortical white matter connectivity in association with suicidal ideation in major depressive disorder.
      ,
      • Reis J.V.
      • Vieira R.
      • Portugal-Nunes C.
      • Coelho A.
      • Magalhães R.
      • Moreira P.
      • et al.
      Suicidal ideation is associated with reduced functional connectivity and white matter integrity in drug-naïve patients with major depression.
      ) or attempt (
      • Jia Z.
      • Wang Y.
      • Huang X.
      • Kuang W.
      • Wu Q.
      • Lui S.
      • et al.
      Impaired frontothalamic circuitry in suicidal patients with depression revealed by diffusion tensor imaging at 3.0 T.
      ,
      • Olvet D.M.
      • Peruzzo D.
      • Thapa-Chhetry B.
      • Sublette M.E.
      • Sullivan G.M.
      • Oquendo M.A.
      • et al.
      A diffusion tensor imaging study of suicide attempters.
      ,
      • Cyprien F.
      • de Champfleur N.M.
      • Deverdun J.
      • Olié E.
      • Le Bars E.
      • Bonafé A.
      • et al.
      Corpus callosum integrity is affected by mood disorders and also by the suicide attempt history: A diffusion tensor imaging study.
      ,
      • Wei S.
      • Womer F.Y.
      • Edmiston E.K.
      • Zhang R.
      • Jiang X.
      • Wu F.
      • et al.
      Structural alterations associated with suicide attempts in major depressive disorder and bipolar disorder: A diffusion tensor imaging study.
      ). Collectively, these studies report abnormalities in white matter tracts including the inferior-frontal occipital fasciculus, uncinate fasciculus, insula, corona radiata, and anterior thalamic radiation. However, only two studies examined suicide attempt; one of which was uncorrected for multiple comparisons (
      • Olvet D.M.
      • Peruzzo D.
      • Thapa-Chhetry B.
      • Sublette M.E.
      • Sullivan G.M.
      • Oquendo M.A.
      • et al.
      A diffusion tensor imaging study of suicide attempters.
      ). While these investigations provide a foundation for further characterization of brain microstructure associated with suicide-related outcomes, no previous DTI studies have directly compared patients with suicidal ideation only to those with a suicide attempt history.
      DTI is most often conceptualized as a single diffusion tensor, where a 3x3 matrix depicts the strength and directionality of diffusion alongside microstructural white matter tracts (
      • O'Donnell L.J.
      • Westin C.F.
      An introduction to diffusion tensor image analysis.
      ). However, representation of diffusion using a single matrix is overly simplistic, as it may not fully characterize underlying neuropathological changes (
      • Alexander D.C.
      • Dyrby T.B.
      • Nilsson M.
      • Zhang H.
      Imaging brain microstructure with diffusion MRI: practicality and applications.
      ). For example, partial-volume effects occur when voxels are contaminated by signal from extracellular fluid in addition to brain tissue; DTI metrics are no longer tissue-specific, as the diffusion signal will represent the weighted average of both white matter and free water (
      • Alexander D.C.
      • Dyrby T.B.
      • Nilsson M.
      • Zhang H.
      Imaging brain microstructure with diffusion MRI: practicality and applications.
      ). Post-processing techniques such as free water imaging can estimate the independent contribution of free water and brain tissue in individual voxels. Signal contamination from extracellular fluid is removed, and the fractional volume of the free water compartment can be approximated (
      • Pasternak O.
      • Sochen N.
      • Gur Y.
      • Intrator N.
      • Assaf Y.
      Free water elimination and mapping from diffusion MRI.
      ). Previous studies have suggested that free water volume may provide insight into the pathology underlying isotropic changes (
      • Lyall A.E.
      • Pasternak O.
      • Robinson D.G.
      • Newell D.
      • Trampush J.W.
      • Gallego J.A.
      • et al.
      Greater extracellular free-water in first-episode psychosis predicts better neurocognitive functioning.
      ). Although free water dMRI has been used in recent studies with various neurological and psychiatric disorders, the application of free water imaging in TRD and suicide is unique.
      The objective of this study was to characterize standard diffusion metrics (i.e., FA, AD, and RD), free water corrected FA (FAT), AD (ADT), and RD (RDT), and the free water index (FW) using tract-based spatial statistics (TBSS) and a Matlab-based free water imaging script. In our primary analysis, patients with a lifetime history of suicidal ideation but no suicide attempt (SI-group) were compared to those with lifetime history of suicide attempt (SA-group). A second analysis compared the entire patient group to age- and sex-matched healthy controls. Differences in microstructural white matter and free water corrected diffusion metrics were expected in the SA-group relative to the SI-group and in patients compared to controls.

      Methods and Materials

      Participants

      Participants included male and female outpatients with TRD (age range, 18-65 years) recruited through referrals to the Mood Disorders Research Unit at the University of Ottawa Institute of Mental Health Research and the Mood and Anxiety Program at the Royal Ottawa Mental Health Centre in Ottawa, Canada. Age (±2 years) and sex-matched healthy control participants were recruited through community advertisement. For participants with TRD, a primary diagnosis of MDD and lack of excluding comorbid psychiatric disorders was confirmed using the Structured Clinical Interview for the DSM-5 Research Version (SCID-5-RV) (

      First MB (2015): Structured Clinical Interview for the DSM-V research version (SCID). In: The Encyclopedia of Clinical Psychology. Arlington, VA: American Psychiatric Association.

      ). Treatment resistance was defined as lack of response to two or more consecutive medications for depression with different mechanisms of action in the current major depressive episode (
      • Sackeim H.A.
      The definition and meaning of treatment-resistant depression.
      ). Inclusion criteria for patients were presence of a major depressive episode of at least 6 months in length, a score of ≥25 on the Montgomery Åsberg Depression Rating Scale (MADRS) (
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ), and endorsement of lifetime presence of suicidal ideation according to the Columbia Suicide Severity Rating Scale (C-SSRS suicide ideation severity score ≥1) (
      • Posner K.
      • Brown G.K.
      • Stanley B.
      • Brent D.A.
      • Yershova K.V.
      • Oquendo M.A.
      • et al.
      The Columbia-suicide severity rating scale: Initial validity and internal consistency findings from three multisite studies with adolescents and adults.
      ). A history of manic, hypomanic, or mixed episode(s), comorbid post-traumatic stress disorder, obsessive-compulsive disorder, substance- or alcohol-use disorder, eating disorder(s), and/or psychotic disorder(s) were exclusion criteria. Control participants had no Axis I diagnoses, confirmed through the SCID-5-RV, and no history of suicidal ideation or attempts. For all participants, positive urine toxicology screen, pregnancy, body mass index ≥35, history of head injury with a loss of consciousness, major medical or neurological illness, and contraindications to MRI scanning were exclusion criteria. The study protocol was approved by the Royal Ottawa Mental Health Centre Research Ethics Board. All participants provided written informed consent.

      Clinical Data Collection and Analysis

      Self-report and clinician-rated assessments of depression and suicidal ideation severity were completed using the MADRS, Patient Health Questionnaire 9 (PHQ-9) (
      • Kroenke K.
      • Spitzer R.L.
      • Williams J.B.W.
      The PHQ-9: Validity of a brief depression severity measure.
      ), C-SSRS, and Beck Suicide Ideation Scale (BSS) (
      • Beck A.T.
      • Kovacs M.
      • Weissman A.
      Assessment of suicidal intention: The Scale for Suicide Ideation.
      ). Suicide attempt history was assessed using the C-SSRS, with suicide attempt defined as a self-injurious act enacted with at least some intent/wish to die. Demographic and medical information, as well as family history of depression and suicide attempt were obtained through self-report. Handedness was determined using the Edinburgh Handedness Inventory (
      • Oldfield R.C.
      The assessment and analysis of handedness: The Edinburgh inventory.
      ). For naturally cycling females, to minimize the effects of endogenous ovarian hormone fluctuations on MRI data (
      • Dubol M.
      • Epperson C.N.
      • Sacher J.
      • Pletzer B.
      • Derntl B.
      • Lanzenberger R.
      • et al.
      Neuroimaging the menstrual cycle: A multimodal systematic review.
      ), the date of start of last menstrual cycle was obtained and used to schedule MRI scans during the estimated follicular phase (approximately cycle days 1-10). Analysis of clinical and demographic information was performed using IBM SPSS Statistics (SPSS Inc., Chicago, Illinois, USA, Version 27). Independent samples t-tests and chi-square tests were used to explore continuous and categorical demographic and clinical variables as appropriate. Results were considered significant at p<0.05.

      Imaging Data Acquisition

      Magnetic resonance images were acquired on a 3T Siemens PET-MR system (Siemens Biograph mMR, Siemens, Erlangen, Germany) using a 32-channel head coil. dMRI data were obtained using a single shot two-dimensional epi-planar imaging (EPI) pulse sequence in the axial plane. At the expense of susceptibility-induced distortions (resulting in potential signal loss or signal pile up in the phase encoding (PE) direction), EPI allows for reduced scanning time (
      • Poustchi-Amin M.
      • Mirowitz S.A.
      • Brown J.J.
      • McKinstry R.C.
      • Li T.
      Principles and applications of echo-planar imaging: a review for the general radiologist.
      ). Diffusion weighted images (DWIs) were acquired in the anterior-to-posterior direction (64 volumes of b=1000 s/mm2), and a single non-diffusion volume was acquired (b=0s/mm2). To correct for susceptibility-induced distortions, a posterior-to-anterior volume was also acquired (b=0s/mm2). DWI parameters included repetition time=10900ms, echo time= 105.0ms, field of view=256mm, slice thickness=2.0mm, voxel size=2.0mm x 2.0mm x 2.0mm, bandwidth=1776Hz/Px, and EPI factor=128. Prior to inclusion of the ninth participant, the PET-MR system underwent a software upgrade from VB20 to VE11P, however, an exploratory TBSS comparison of matched participants pre-post scanner upgrade revealed no significant differences. Therefore, data from participants collected prior to the scanner upgrade were retained.

      Image Preprocessing and Analysis

      DWIs were pre-processed according to a Python-based framework (pnlNipype) (

      Billah T, Bouix S, Rathi Y (2019): NIFTI MRI processing pipeline. Available from: https://github.com/pnlbwh/pnlNipype.

      ). Briefly, brain masks were created using a Convolutional Neural Network (CNN) based segmentation tool (

      Dey R, Hong Y (2018): Compnet: Complementary segmentation network for brain MRI extraction. In: Frangi J, Schnabel C, Davatzikos C, Alberola-Lopez, Gichtinger G, editors. Medical Image Computing and Computer Assisted Intervention. MICCAI 2018, pp 213-276.

      ,
      • Guha Roy A.
      • Conjeti S.
      • Navab N.
      • Wachinger C.
      QuickNAT: A fully convolutional network for quick and accurate segmentation of neuroanatomy.
      ). Topup, as well as eddy-current and motion-induced distortion correction were performed using FMRIB Software Library (FSL; RRID:SCR_003070) (
      • Andersson J.L.R.
      • Sotiropoulos S.N.
      An integrated approach to correction for off-resonance effects and subject movement in diffusion MR imaging.
      ,
      • Andersson J.L.R.
      • Skare S.
      • Ashburner J.
      How to correct susceptibility distortions in spin-echo echo-planar images: application to diffusion tensor imaging.
      ), followed by the fit of a diffusion tensor at each voxel across the whole brain. Free water imaging was applied through an in-house MatLab-based script (
      • Pasternak O.
      • Sochen N.
      • Gur Y.
      • Intrator N.
      • Assaf Y.
      Free water elimination and mapping from diffusion MRI.
      ). Using this method, conventional diffusion tensors were computed via a least-squares fit, after which diffusion maps (including FA, AD, and RD) were calculated from the tensors. Furthermore, by fitting the two-compartment free water imaging model to the diffusion images using a regularized non-linear fit, FW maps and FW corrected diffusion maps (including FAT, ADT, and RDT) were derived. MD was not examined as MD and FW have an approximate 1:1 relationship, therefore, elevations in MD are conceptualized as elevations in free water in this context. Further, free water corrected MD (MDT) was not included in this analysis as its contrast is approximately uniform and therefore not biologically meaningful (
      • Golub M.
      • Neto Henriques R.
      • Gouveia Nunes R.
      Free-water DTI estimates from single b-value data might seem plausible but must be interpreted with care.
      ).
      Voxel-wise statistics of diffusion data were accomplished using TBSS from FSL (
      • Smith S.M.
      • Jenkinson M.
      • Woolrich M.W.
      • Beckmann C.F.
      • Behrens T.E.J.
      • Johansen-Berg H.
      • et al.
      Advances in functional and structural MR image analysis and implementation as FSL.
      ,
      • Smith S.M.
      • Jenkinson M.
      • Johansen-Berg H.
      • Rueckert D.
      • Nichols T.E.
      • Mackay C.E.
      • et al.
      Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data.
      ,

      Billah T, Bouix S, Pasternak O (2019): Generalized Tract Based Spatial Statistics (TBSS) pipeline. Available from: https://github.com/pnlbwh/tbss.

      ). The general linear model (GLM) was set to perform two independent sample t-tests using mean-centered age and sex as covariates, including SI- versus SA- groups, and patients versus controls. Threshold-free cluster enhancement (TFCE) was used (
      • Smith S.M.
      • Nichols T.E.
      Threshold-free cluster enhancement: Addressing problems of smoothing, threshold dependence and localisation in cluster inference.
      ), with the number of randomized permutations set to 5000. The FSL cluster tool was used to define independent white matter clusters (

      Jenkinson M (2013) FSL Cluster. Available from: https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/Cluster

      ). Results were corrected for multiple comparisons through family-wise error (FWE) (
      • Smith S.M.
      • Nichols T.E.
      Threshold-free cluster enhancement: Addressing problems of smoothing, threshold dependence and localisation in cluster inference.
      ) and reported at a significance threshold of p<0.05.

      Results

      Sample Characteristics and Clinical Measures

      Between July 2017 and December 2021, 84 participants were consented and screened. 68 participants underwent an MRI scan, and 64 participants had analyzable dMRI data (Figure S1). Four patients were excluded from the analyses: 1 stopped the scan prematurely due to anxiety, 2 were excluded due to incidental findings, and 1 was excluded due to motion artefacts. The final dMRI dataset comprised 39 patients with TRD (including 21 in the SI-group, and 18 in the SA-group), and 25 age- and sex-matched healthy controls.
      Table 1 characterizes the demographic and clinical information for participants. Comparing SA- and SI-groups and patients to controls, there were no significant between-group differences in age, sex, handedness, body mass index, or marital status (all p>0.05). Patient and control groups differed on highest level of education (p=0.001) and smoking history (p=0.038). For all clinical scales, patients had significantly higher scores than controls (all p<0.001). A larger proportion of patients had a family history of depression compared to controls (p=0.001).
      Table 1Demographic and clinical characteristics of study participants (N=64).
      SA-GroupSI-GroupGroupPatientsControlsGroup
      (n=18)(n=21)Comparisons(n=39)(n=25)Comparisons
      Age, Years, Mean (SD)46.5 (16.3)44.6 (12.9)t37 = 0.41, p = 0.6845.5 (14.3)43.0 (14.5)t62 = 0.66, p = 0.52
      Sex, Males/Females, %44/5667/33X21 = 1.84, p = 0.1856/4460/40X21 = 0.08, p = 0.78
      Handedness, Right/Ambidextrous/Left, na15/2/016/4/1X22 = 0.93, p = 0.6331/6/121/3/1X22 = 0.25, p = 0.88
      Smoking status, Non-smoker/Former/Smoker, n10/5/315/6/0X22 = 9.62, p = 0.00825/11/323/2/0X22 = 6.67, p = 0.038
      Education, High school/College/University, %237/19/4429/19/52X22 = 6.77, p = 0.03432/19/490/0/100X22 = 18.51, p = 0.001
      Body Mass Index, kg/m2, Mean (SD)27.6 (5.5)27.5 (5.3)t37 = 0.09, p = 0.9327.5 (5.3)25.1 (3.9)t62 = 1.99, p = 0.051
      Marital status, Not married, n (%)11(61)7(33)X21 = 3.07, p = 0.0818 (

      Jenkinson M (2013) FSL Cluster. Available from: https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/Cluster

      )
      10(40)X21 = 0.23, p = 0.63
      Family history depression, n (%)a12(71)13(62)X21 = 4.26, p = 0.0425 (
      • Brundin L.
      • Bryleva E.Y.
      • Thirtamara Rajamani K.
      Role of inflammation in suicide: From mechanisms to treatment.
      )
      6(24)X21 = 10.54, p = 0.001
      Family history suicide attempt, n (%)a5(29)1(5)X21 = 7.90, p = 0.0056 (
      • Podwalski P.
      • Szczygieł K.
      • Tyburski E.
      • Sagan L.
      • Misiak B.
      • Samochowiec J.
      Magnetic resonance diffusion tensor imaging in psychiatry: a narrative review of its potential role in diagnosis.
      )
      1(4)X21 = 2.12, p = 0.15
      MADRS total score, Mean (SD)35.9 (4.1)33.1 (4.9)t37 = 1.95, p = 0.05934.4 (4.7)0.3 (0.5)t62 = 36.0, p < 0.001
      C-SSRS SI severity past week, Mean (SD)2.4 (1.5)1.8 (1.5)t37 = 1.28, p = 0.212.1 (1.5)0 (0)t62 = 6.65, p < 0.001
      Beck Scale for Suicide Ideation, Mean (SD)c16.5 (7.5)10.0 (8.0)t35 = 2.55, p = 0.01513.0 (8.3)0.1 (0.4)t60 = 7.70, p < 0.001
      Patient Health Questionnaire 9, Mean (SD) b20.7 (4.5)20.8 (3.3)t35 = 0.06, p = 0.9520.7 (3.8)0.6 (1.1)t60 = 25.70, p < 0.001
      Beck Hopelessness Scale, Mean (SD) a16.8 (3.9)15.9 (3.6)t36 = 0.70, p = 0.4916.3 (3.7)1.2 (1.5)t61 = 19.0, p < 0.001
      Age of onset of MDD, Years, Mean (SD)27.4 (12.3)30.9 (13.6)t33 = 0.77, p = 0.45
      Major depressive episodes, Single/Recurrent, %21/7924/76X21 = 0.03, p = 0.87
      Length of current episode, Years, Mean (SD)4.2 (5.1)4.4 (3.7)t32 = 0.09, p = 0.93
      Currently on disability leave, n (%)7(39)11(52)X21 = 0.71, p = 0.40
      History of lifetime inpatient hospitalization, n (%)15(88)5(24)X21 = 34.29, p < 0.001
      History of past year inpatient hospitalization, n (%)8(47)1(5)X21 = 9.30, p = 0.002
      Current Comorbid Diagnoses
      Persistent depressive disorder, n (%)16(89)17(81)X21 = 1.01, p = 0.61
      Panic disorder, n (%)2(11)0(0)X21 = 2.46, p = 0.12
      Social anxiety disorder, n (%)6(33)4(19)X21 = 1.04, p = 0.31
      Generalized anxiety disorder, n (%)8(44)11(52)X21 = 0.24, p = 0.62
      Specific phobia, n (%)1(5)1(6)X21 = 0.01, p = 0.91
      Attention deficit hyperactivity disorder, n (%)1(6)2(10)X21 = 0.22, p = 0.90
      aData missing for 1 participant
      bData missing for 2 participants
      cData missing for 3 participants.
      Abbreviations: SA, suicide attempt; SI, suicidal ideation; SD, standard deviation; MADRS, Montgomery-Åsberg Depression Rating Scale; C-SSRS, Columbia Suicide Rating Scale; MDD, major depressive disorder.
      Comparing course of illness and clinical status, SI- and SA- groups, did not differ significantly on age of MDD onset, single versus recurrent major depressive episodes, length of current major depressive episode, prevalence of comorbid psychiatric diagnoses, or current disability leave status (all p>0.05; Table 1). At the time of imaging, the groups did not differ significantly on past-week depression severity (MADRS and PHQ-9) or suicidal ideation severity on the C-SSRS. The SA-group had significantly higher self-reported past-week suicidal ideation severity on the BSS compared to the SI- group (p=0.015). Medications taken at the time of MRI scan were similar between patient groups (Table S1).
      Compared to the SI-group, a significantly higher proportion of patients in the SA-group had lifetime and past-year history of inpatient psychiatric hospitalization (p<0.001 and p=0.002, respectively, Table 1). The SA-group had significantly higher lifetime suicidal ideation severity (p<0.001). More patients in the SA-group had a family history of suicide attempt compared to the SI-group (p=0.005). For the SA-group, 44% had an attempt within the past year, and the mean time since the most recent attempt was 7.9 (±11.9) years. Table S2 characterizes the frequency, timeframe, method, and lethality of previous suicide attempts for the SA-group.

      Neuroimaging

      TBSS analyses comparing SI- versus SA-groups revealed significant differences in AD, ADT, and FW in fronto-thalamo-limbic white matter tracts as described below (FWE p<0.05; Table 2; Figure S2). Compared to the SI-group, the SA-group had elevated AD in the bilateral inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, left uncinate fasciculus, and anterior thalamic radiation (Figure 1a). With free water correction applied, the SA-group had increased ADT in the left anterior limb of the internal capsule, anterior thalamic radiation, posterior limb of the internal capsule, and superior corona radiata, as well as the body of the corpus callosum, and bilateral corticospinal tract (Figure 1b). Finally, the SA-group had elevated FW in the left uncinate fasciculus and left sagittal striatum, including the inferior fronto-occipital fasciculus and inferior longitudinal fasciculus (Figure 1c). No significant differences were identified for any other diffusion metrics, including FA, RD, FAT, or RDT.
      Table 2Elevated AD, ADT, and FW in patients with history of suicide attempt (N=18) compared to suicide ideation (N=21) identified by TBSS.
      Diffusion MetricClusterNumber of VoxelsMaximum Intensity Voxel CoordinatesHemisphereCorresponding TractPFWE-valueEffect

      Size (Cohen’s d)
      95% Confidence

      Interval
      AD110455[-36, 7, -28]LUF/ILF0.0301.480.76-2.19
      284[28, -49, 19]RIFOF0.0471.590.86-2.31
      374[39. -43, -5]RILF0.0481.150.46-1.82
      444[-38, 27, 10]LATR0.0491.080.39-1.76
      436[-22, -78, -1]LIFOF0.0500.950.28-1.61
      ADT15655[12, -28, -26]RCST0.0201.370.66-2.06
      21277[3, 1, 25]-Body of corpus callosum0.0301.070.39-1.74
      3586[-16, 8, 2]LALIC/ATR0.0301.110.43-1.79
      4188[-25, 4, 20]LSCR0.0401.160.47-1.83
      571[-23, -15, 13]LPLIC/CST0.0480.720.07-1.37
      FW1190[-37, 6, -26]LUF0.0401.450.74-2.16
      290[-37, -14, -13]LILF/IFOF0.0471.590.86-2.31
      Abbreviations: AD, axial diffusivity; ADT, free water corrected axial diffusivity; FW, fractional volume of the free water compartment; TBSS, tract-based spatial statistics; pFEW, family-wise error-corrected p value; L, left; R, right; UF, uncinate fasciculus; ILF, inferior longitudinal fasciculus; IFOF, inferior fronto-occipital fasciculus; ATR, anterior thalamic radiation; CST, corticospinal tract; ALIC, anterior limb of the internal capsule; SCR, superior corona radiata; PLIC, posterior limb of the internal capsule.
      Figure thumbnail gr1
      Figure 1Elevated AD, ADT, and FW in patients with history of suicide attempt compared to suicidal ideation: White matter tracts showing clusters of significantly elevated A) axial diffusivity (AD), B) free water corrected axial diffusivity (ADT), and C) free water index (FW) in patients with suicide attempt history compared to suicidal ideation history (pFWE<0.05, corrected for multiple comparisons). Voxels with significant elevations in diffusion metrics are depicted in warm colors. Statistical images were projected onto a mean skeleton (green), and FSL’s TBSS-fill tool was used for visualization.
      The TBSS analysis comparing patients and controls did not reveal significant differences in FW; however, between-group differences in both standard and free water corrected diffusion metrics were widespread. Significant differences were found for FA, AD, FAT, ADT, and RDT (FWE p<0.05; Table 3; Figure S3). Relative to controls, patients had clusters of reduced FA in the middle cerebellar peduncle, bilateral corticospinal tract, right inferior fronto-occipital fasciculus, superior cerebellar peduncle, and left anterior thalamic radiation (Figure 2a). Further, patients had reduced AD in the right corticospinal tract, uncinate fasciculus, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and forceps minor (Figure 2a). With free water correction, patients had reductions in FAT in the bilateral inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, left superior longitudinal fasciculus, and posterior thalamic radiation (Figure 2b). Reductions in ADT were also noted in patients in the right inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, posterior limb of the internal capsule, anterior thalamic radiation, bilateral corticospinal tract, and middle cerebellar peduncle (Figure 2b). Elevations in RDT, but not RD, were identified in the bilateral anterior thalamic radiation, superior longitudinal fasciculus, posterior thalamic radiation, inferior longitudinal fasciculus, and inferior fronto-occipital fasciculus of patients relative to controls (Figure 2b).
      Table 3Reduced FA, AD, FAT, ADT, and elevated RDT in patients with TRD and suicidal ideation (N=39) versus healthy control participants (N=25) identified by TBSS.
      Diffusion MetricClusterNumber of VoxelsMaximum Intensity Voxel CoordinatesHemisphereCorresponding

      Tract
      pFWE-valueEffect

      Size (Cohen’s d)
      95% Confidence

      Interval
      FA141781[33, -48, 12]RIFOF0.0031.611.03-2.18
      2414[9, -49, -30]RSCP0.0411.420.85-1.97
      3121[-4, -37, -33]LCST/ATR0.0461.300.74-1.85
      427[4, -22, -35]RCST0.0490.33-0.20-0.87
      524[21, -41, -35]-MCP0.0490.760.23-1.27
      AD125682[5, -32, -41]RCST<0.0012.001.38-2.61
      2410[24, 16, -10]RUF/IFOF0.0041.260.71-1.81
      3114[45, -5, 23]RSLF0.0041.470.91-2.04
      424[14, 31, 1]-Forceps minor0.0041.280.73-1.83
      FAT124300[40, -35, -13]RILF/IFOF<0.0011.951.34-2.56
      220845[-36, -51, -1]LPTR/IFOF/ILF<0.0011.781.18-2.37
      377[-47, -55, 0]LSLF0.0071.440.88-2.00
      ADT17342[41, -36, -11]RILF/IFOF<0.0012.321.67-2.96
      2469[26, -26, 18]RCST/PLIC0.0041.260.71-1.80
      3133[28, -32, -2]]RATR0.0041.210.66-1.76
      4113[-13, -34, -38]L/-CST/MCP0.0040.920.39-1.44
      RDT120575[-34, -55, 7]LPTR/ILF/IFOF/SLF/ATR0.001-1.72-2.3- -1.13
      217714[37, -51, -2]RPTR/IFOF/ILF0.001-1.83-2.42- -1.23
      3661[15, 57, -4]RATR0.020-1.70-2.23- -1.11
      4114[44, -4, 28]RSLF0.040-1.19-1.73- -0.64
      595[-9, -9, 8]LATR0.045-1.46-2.02- -0.89
      Abbreviations: FA, fractional anisotropy; AD, axial diffusivity; FAT, free water corrected fractional anisotropy; ADT, free water corrected axial diffusivity; RDT, free water corrected radial diffusivity; TRD, treatment-resistant depression; TBSS, tract-based spatial statistics; pFWE, family-wise error-corrected p value; L, left; R, right; IFOF, inferior fronto-occipital fasciculus; SCP, superior cerebellar peduncle; CST, corticospinal tract; ATR, anterior thalamic radiation; MCP, middle cerebellar peduncle; UF, uncinate fasciculus; SLF, superior longitudinal fasciculus; ILF, inferior longitudinal fasciculus; PTR, posterior thalamic radiation; PLIC, posterior limb of the internal capsule.
      Figure thumbnail gr2
      Figure 2Reduced FA, AD, FAT, ADT, and elevated RDT in patients with TRD and suicidal ideation compared to healthy controls: White matter tracts showing areas of significantly reduced A) fractional anisotropy (FA), axial diffusivity (AD), B) free water corrected fractional anisotropy (FAT), free water corrected axial diffusivity (ADT), and elevated free water corrected radial diffusivity (RDT) in patients with TRD compared to healthy controls (pFWE<0.05, corrected for multiple comparisons). Voxels with significant elevations in diffusion metrics are depicted in warm colors, and voxels with significant reductions in diffusion metrics are depicted in cool colors. Statistical images were projected onto a mean skeleton (green), and FSL’s TBSS-fill tool was used for visualization.

      Discussion

      Herein, we report a unique neural correlate of suicide attempt in TRD, consisting of elevated AD (both standard and free water corrected) and FW in fronto-thalamo-limbic white matter tracts. Further, we confer support for previously published DTI studies reporting widespread microstructural alterations in patients with depression compared to healthy controls, as reflected by findings of reduced FA and AD (both standard and free water corrected), and elevated RD (free water corrected). To date, these results provide the first indication of elevated extracellular free water specifically associated with history of suicide attempt in depression.
      From a clinical perspective, the SI- and SA-groups did not differ in terms of age of MDD onset, length and recurrence of major depressive episodes, severity of depressive symptoms, comorbid diagnoses, or current medications. Such findings highlight the homogeneity of the patient sample and underscore the difficulty in predicting suicide attempt risk among patients with TRD experiencing suicidal ideation. Indeed, past literature on the association between suicidal ideation and attempt is inconsistent. For example, in a meta-analysis of 81 studies, presence of suicidal ideation increased risk of suicide death four-fold, however, this finding was insignificant in the context of mood disorder (
      • Hubers A.A.M.
      • Moaddine S.
      • Peersmann S.H.M.
      • Stijnen T.
      • Van Duijn E.
      • Van Der Mast R.C.
      • et al.
      Suicidal ideation and subsequent completed suicide in both psychiatric and non-psychiatric populations: A meta-analysis.
      ). Nevertheless, the patient groups differed on several suicide-related outcomes including self-reported past-week suicidal ideation severity (BSS scores), lifetime and past-year psychiatric inpatient hospitalization, and family history of suicide attempt. Psychiatric inpatient admission often occurs at times of crisis when individuals might pose a threat of harm to themselves (
      • Ziegenbein M.
      • Anreis C.
      • Brüggen B.
      • Ohlmeier M.
      • Kropp S.
      Possible criteria for inpatient psychiatric admissions: Which patients are transferred from emergency services to inpatient psychiatric treatment?.
      ). The acute period following inpatient psychiatric care is one of the highest-risk periods for subsequent suicide attempt and death, and individuals hospitalized for suicidal ideation and behaviors appear to be at highest risk (
      • Jordan J.T.
      • McNiel D.E.
      Characteristics of a suicide attempt predict who makes another attempt after hospital discharge: A decision-tree investigation.
      ). Greater family history of suicide attempt in the SA-group is also in line with previous reports (
      • Rihmer Z.
      • Gonda X.
      • Torzsa P.
      • Kalabay L.
      • Akiskal H.S.
      • Eory A.
      Affective temperament, history of suicide attempt and family history of suicide in general practice patients.
      ,
      • Lopez-Castroman J.
      • Guillaume S.
      • Olié E.
      • Jaussent I.
      • Baca-García E.
      • Courtet P.
      The additive effect on suicidality of family history of suicidal behavior and early traumatic experiences.
      ). Personal history of suicide attempt and family history of suicidal behavior represent two of the most important non-modifiable risk factors for suicide, suggesting a potential biological vulnerability (
      • Turecki G.
      • Brent D.A.
      Suicide and suicidal behaviour.
      ).
      Neuroimaging studies may help elucidate neurobiological substrates differentiating suicidal ideation and attempt (
      • Schmaal L.
      • van Harmelen A.L.
      • Chatzi V.
      • Lippard E.T.C.
      • Toenders Y.J.
      • Averill L.A.
      • et al.
      Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies.
      ). In the present study, TBSS and free water imaging revealed several relevant white matter tracts associated with suicidal ideation and suicide attempt in the context of TRD. In line with these findings, previous DTI investigations in depression have identified the importance of the uncinate fasciculus (
      • Bhatia K.D.
      • Henderson L.A.
      • Hsu E.
      • Yim M.
      Reduced integrity of the uncinate fasciculus and cingulum in depression: A stem-by-stem analysis.
      ), a large white matter association tract connecting frontal and temporal cortices (

      Ocklenburg S, Güntürkün O (2018): The lateralized brain: The neuroscience and evolution of hemispheric asymmetries. Academic Press.

      ). Closely associated with the uncinate fasciculus are the inferior longitudinal fasciculus and inferior fronto-occipital fasciculus, associative temporal-limbic tracts joining the frontal, parietal, and temporal lobes (
      • Wu Y.
      • Sun D.
      • Wang Y.
      • Wang Y.
      Subcomponents and connectivity of the inferior fronto-occipital fasciculus revealed by diffusion spectrum imaging fiber tracking.
      ). Together, all three fiber tracts have been hypothesized to contribute to a cortical-subcortical microstructural disconnection syndrome in MDD (
      • Liao Y.
      • Huang X.
      • Wu Q.
      • Yang C.
      • Kuang W.
      • Du M.
      • et al.
      Is depression a disconnection syndrome? Meta- analysis of diffusion tensor imaging studies in patients with MDD.
      ). Among patients with suicide attempt history in the present study, clusters of elevated free water were localized primarily to these three tracts, as were AD findings (without free water correction). With conventional DTI analyses, altered uncinate fasciculus white matter microstructure has been specifically implicated in unipolar and bipolar depression with suicide attempt history (
      • Wei S.
      • Womer F.Y.
      • Edmiston E.K.
      • Zhang R.
      • Jiang X.
      • Wu F.
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      Structural alterations associated with suicide attempts in major depressive disorder and bipolar disorder: A diffusion tensor imaging study.
      ,
      • Johnston J.A.Y.
      • Wang F.
      • Liu J.
      • Blond B.N.
      • Wallace A.
      • Liu J.
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      Multimodal neuroimaging of frontolimbic structure and function associated with suicide attempts in adolescents and young adults with bipolar disorder.
      ,
      • Fan S.
      • Lippard E.T.C.
      • Sankar A.
      • Wallace A.
      • Johnston J.A.Y.
      • Wang F.
      • et al.
      Gray and white matter differences in adolescents and young adults with prior suicide attempts across bipolar and major depressive disorders.
      ). As elimination of noise caused by partial volume effects significantly impacted DTI analyses, future studies using DTI techniques should be aware of partial volume effects and address them if possible.
      The largest clusters showing altered tissue microstructure in the SA-group in our free water corrected analyses were localized to the corticospinal tract, body of the corpus callosum, and anterior limb of the internal capsule. Reduced FA has been reported in patients with mood disorders and suicide attempt history in the body of the corpus callosum (
      • Cyprien F.
      • de Champfleur N.M.
      • Deverdun J.
      • Olié E.
      • Le Bars E.
      • Bonafé A.
      • et al.
      Corpus callosum integrity is affected by mood disorders and also by the suicide attempt history: A diffusion tensor imaging study.
      ,
      • Wei S.
      • Womer F.Y.
      • Edmiston E.K.
      • Zhang R.
      • Jiang X.
      • Wu F.
      • et al.
      Structural alterations associated with suicide attempts in major depressive disorder and bipolar disorder: A diffusion tensor imaging study.
      ) and anterior limb of the internal capsule (
      • Jia Z.
      • Huang X.
      • Wu Q.
      • Zhang T.
      • Lui S.
      • Zhang J.
      • et al.
      High-field magnetic resonance imaging of suicidality in patients with major depressive disorder.
      ). Tractography has also shown reduced fiber projections between the anterior limb of the internal capsule and the medial frontal cortex, orbitofrontal cortex, and thalamus in patients with MDD and suicide attempt history (
      • Jia Z.
      • Wang Y.
      • Huang X.
      • Kuang W.
      • Wu Q.
      • Lui S.
      • et al.
      Impaired frontothalamic circuitry in suicidal patients with depression revealed by diffusion tensor imaging at 3.0 T.
      ). This finding may suggest disrupted cognitive and emotional processing due to cortical-thalamic interruptions in suicide attempt (
      • Jia Z.
      • Wang Y.
      • Huang X.
      • Kuang W.
      • Wu Q.
      • Lui S.
      • et al.
      Impaired frontothalamic circuitry in suicidal patients with depression revealed by diffusion tensor imaging at 3.0 T.
      ). Past work has also reported widespread white matter microstructural differences in patients with depression and suicidal ideation (
      • Taylor W.D.
      • Boyd B.
      • McQuoid D.R.
      • Kudra K.
      • Saleh A.
      • MacFall J.R.
      Widespread white matter but focal gray matter alterations in depressed individuals with thoughts of death.
      ). Consistent with our findings in patients versus controls, reduced FA and AD in the anterior thalamic radiation may lead to cognitive and affective dysfunction in depression (
      • Lai C.H.
      • Wu Y.T.
      Alterations in white matter micro-integrity of the superior longitudinal fasciculus and anterior thalamic radiation of young adult patients with depression.
      ), and is correlated with reduced FA in the superior longitudinal fasciculus (
      • Jenkins L.M.
      • Barba A.
      • Campbell M.
      • Lamar M.
      • Shankman S.A.
      • Leow A.D.
      • Ajilore O.
      • Langenecker S.A.
      Shared white matter alterations across emotional disorders: A voxel-based meta-analysis of fractional anisotropy.
      ). . The superior longitudinal fasciculus has a role in perception of emotion through bidirectional connections with the frontal, parietal, and temporal cortices (
      • Nakajima R.
      • Kinoshita M.
      • Shinohara H.
      • Nakada M.
      The superior longitudinal fascicle: reconsidering the fronto-parietal neural network based on anatomy and function.
      ). Taken together, overlapping findings from our study and previous reports strengthen our understanding of the microstructural correlates of suicidal ideation and suicide attempt in TRD.
      Diffusion measurements were significantly influenced by free water, as evidenced by differing patterns of significantly altered white matter voxels between standard and free water corrected diffusion metrics. This replicates previous reports highlighting the ability of free water correction to ameliorate erroneous diffusion signal and unmask results hidden by free water contamination (
      • Berlot R.
      • Metzler-Baddeley C.
      • Jones D.K.
      • O’Sullivan M.J.
      CSF contamination contributes to apparent microstructural alterations in mild cognitive impairment.
      ). Beyond this, the free water index was significantly elevated in the SA-group compared to the SI-group, which may provide evidence toward the source of isotropic changes identified. For example, elevations in extracellular free water have been hypothesized to reflect neuroinflammation-associated edema (
      • Pasternak O.
      • Kubicki M.
      • Shenton M.E.
      In vivo imaging of neuroinflammation in schizophrenia.
      ,
      • Oestreich L.K.L.
      • Lyall A.E.
      • Pasternak O.
      • Kikinis Z.
      • Newell D.T.
      • Savadjiev P.
      • et al.
      Characterizing white matter changes in chronic schizophrenia: A free-water imaging multi-site study.
      ). Multiple methodological approaches have provided supporting evidence for increased central and peripheral inflammation in relation to suicidal behavior (
      • Brundin L.
      • Bryleva E.Y.
      • Thirtamara Rajamani K.
      Role of inflammation in suicide: From mechanisms to treatment.
      ). Increased microgliosis has been reported in the post-mortem brain of individuals who died by suicide (
      • Brisch R.
      • Steiner J.
      • Mawrin C.
      • Krzyżanowska M.
      • Jankowski Z.
      • Gos T.
      Microglia in the dorsal raphe nucleus plays a potential role in both suicide facilitation and prevention in affective disorders.
      ), a finding that appears specific to suicide rather than psychiatric diagnosis (
      • Suzuki H.
      • Ohgidani M.
      • Kuwano N.
      • Chrétien F.
      • Lorin de la Grandmaison G.
      • Onaya M.
      • et al.
      Suicide and microglia: Recent findings and future perspectives based on human studies.
      ). Additionally, positron emission tomography (PET) studies have identified elevated microglial translocator protein (TSPO) binding in vivo in the anterior cingulate cortex, prefrontal cortex, and insula in patients with depression (
      • Setiawan E.
      • Wilson A.A.
      • Mizrahi R.
      • Rusjan P.M.
      • Miler L.
      • Rajkowska G.
      • et al.
      Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes.
      ), with preliminary data suggesting increased TSPO binding specifically in those experiencing suicidal thoughts relative to patients without suicidal ideation (
      • Holmes S.E.
      • Hinz R.
      • Conen S.
      • Gregory C.J.
      • Matthews J.C.
      • Anton-Rodriguez J.M.
      • et al.
      Elevated translocator protein in anterior cingulate in major depression and a role for inflammation in suicidal thinking: A positron emission tomography study.
      ). Finally, higher pro-inflammatory cytokine concentrations in blood and cerebrospinal fluid have been reported in individuals with depression and previous suicide attempt (

      Janelidze S, Mattei D, Westrin Å, Träskman-Bendz L, Brundin L (2011): Cytokine levels in the blood may distinguish suicide attempters from depressed patients. Brain Behav Immun 25: 335-339.

      ,
      • Lindqvist D.
      • Janelidze S.
      • Erhardt S.
      • Träskman-Bendz L.
      • Engström G.
      • Brundin L.
      CSF biomarkers in suicide attempters - a principal component analysis.
      ). Importantly, two previous studies conducted free water imaging in non-resistant MDD (
      • Bergamino M.
      • Pasternak O.
      • Farmer M.
      • Shenton M.E.
      • Paul Hamilton J.
      Applying a free-water correction to diffusion imaging data uncovers stress-related neural pathology in depression.
      ,
      • Bergamino M.
      • Kuplicki R.
      • Victor T.A.
      • Cha Y.H.
      • Paulus M.P.
      Comparison of two different analysis approaches for DTI free-water corrected and uncorrected maps in the study of white matter microstructural integrity in individuals with depression.
      ), and neither identified FW changes in patients relative to matched controls. Therefore, our results replicate these findings while suggesting that elevated free water may be specific to suicide attempt history in this cohort.
      This study has several limitations which warrant consideration. First, the study was cross-sectional and suicide attempt history was retrospectively assessed However, we thoroughly differentiated between suicide ideation and attempt history using the C-SSRS, which is critical to understanding the independent roles of these constructs (

      Klonsky ED, May AM, Saffer BY (2016): Suicide, suicide attempts, and suicidal ideation. Annu Rev Clin Psychol 12: 307-330.

      ,
      • Posner K.
      • Brown G.K.
      • Stanley B.
      • Brent D.A.
      • Yershova K.V.
      • Oquendo M.A.
      • et al.
      The Columbia-suicide severity rating scale: Initial validity and internal consistency findings from three multisite studies with adolescents and adults.
      ). Nevertheless, the cross-sectional design does not allow for assessment of the potential predictive value of our results in identifying those who will progress from ideation to attempt, and we did not control for the severity of suicidal ideation at the time of the scan. Second, our sample size was modest. Despite this, significant results were obtained even with strict correction for multiple comparisons, which emphasizes the robustness of our results. Further, the inclusion of clinically well-characterised patients and well-matched control participants strengthens the findings. For example, all previously published DTI investigations of suicide and depression focused on MDD rather than TRD (
      • Taylor W.D.
      • Boyd B.
      • McQuoid D.R.
      • Kudra K.
      • Saleh A.
      • MacFall J.R.
      Widespread white matter but focal gray matter alterations in depressed individuals with thoughts of death.
      ,
      • Myung W.
      • Han C.E.
      • Fava M.
      • Mischoulon D.
      • Papakostas G.I.
      • Heo J.Y.
      • et al.
      Reduced frontal-subcortical white matter connectivity in association with suicidal ideation in major depressive disorder.
      ,
      • Jia Z.
      • Wang Y.
      • Huang X.
      • Kuang W.
      • Wu Q.
      • Lui S.
      • et al.
      Impaired frontothalamic circuitry in suicidal patients with depression revealed by diffusion tensor imaging at 3.0 T.
      ,
      • Olvet D.M.
      • Peruzzo D.
      • Thapa-Chhetry B.
      • Sublette M.E.
      • Sullivan G.M.
      • Oquendo M.A.
      • et al.
      A diffusion tensor imaging study of suicide attempters.
      ), however, patients with TRD are at elevated suicide risk (

      Mrazek DA, Hornberger JC, Altar CA, Degtiar I (2014):A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013. Psychiatr Serv 65: 977-987.

      ). Third, patients were taking various medications at the time of imaging and potential medication effects on imaging correlates could not be analyzed. Fourth, our sample size did not allow for meaningful sex- and gender-based analyses. Regardless, all groups were well matched for sex, mean-centred sex was included as a covariate in imaging analyses, and menstrual cycle phase was considered during MRI scheduling (albeit without measurement of circulating hormone levels). Fifth, patient and control groups differed significantly on highest level of education. The control sample may have been biased toward higher education as much of the recruitment was completed in a research hospital setting. Future studies may consider matching patients and controls based on education. Sixth, history of psychiatric hospitalizations was proportionately higher in the SA-group compared to the SI-group. Previous literature has reported an association between psychiatric hospitalization and diffusion metrics (
      • Meinert S.
      • Leehr E.J.
      • Grotegerd D.
      • Repple J.
      • Förster K.
      • Winter N.R.
      • et al.
      White matter fiber microstructure is associated with prior hospitalizations rather than acute symptomatology in major depressive disorder.
      ). The effects of psychiatric hospitalizations on dMRI were not investigated separately from suicide attempts due to their high correlation. With regards to neuroimaging methods, there are inherent limitations with TBSS including the potential for rotational variance (
      • Bach M.
      • Laun F.B.
      • Leemans A.
      • Tax C.M.W.
      • Biessels G.J.
      • Stieltjes B.
      • Maier-Hein K.H.
      Methodological considerations on tract-based spatial statistics (TBSS).
      ). TBSS does not account for the impact of edema and crossing fibers, which could impact the interpretation of FA (
      • Ye Z.
      • Gary S.E.
      • Sun P.
      • Mustafi S.M.
      • Glenn G.R.
      • Yeh F.C.
      • et al.
      The impact of edema and fiber crossing on diffusion MRI metrics assessed in an ex vivo nerve phantom: Multi-tensor model vs. diffusion orientation distribution function.
      ). We addressed the former through free water imaging, however, the impact of crossing fibers should be considered in future studies. More accurate estimation of the free-water measure could be achieved with multi-shell dMRI data, which was not available in this study. Lastly, the addition of supplementary analyses such as tractography may further quantify fiber bundle characteristics (
      • Wang D.
      • Luo Y.
      • Mok V.C.T.
      • Chu W.C.W.
      • Shi L.
      Tractography atlas-based spatial statistics: Statistical analysis of diffusion tensor image along fiber pathways.
      ).
      In summary, suicide attempt is highly prevalent in the context of TRD, however, factors underlying the progression from suicidal ideation to suicide attempt are incompletely understood. In this study, standard and free water corrected diffusion metrics differed between SI- and SA-groups, and patients with TRD and suicidal ideation versus controls. Using TBSS, altered white matter microstructure and elevated extracellular free water were identified in patients with TRD and suicide attempt history in key fronto-thalamo-limbic tracts. As a group, patients with TRD and suicidal ideation had widespread alterations in white matter microstructure compared to healthy controls across multiple diffusion metrics. Notably, the effect of free water correction on diffusion metrics and the elevation of free water itself suggest a potential neurobiological mechanism leading to both anisotropic and isotropic white matter changes. To conclude, the findings reported herein strengthen the foundation for further characterization of neurobiological correlates of suicide-related outcomes in TRD.

      Acknowledgements

      The authors thank Taylor Hatchard, PhD, Meagan Birmingham, MBA, Adel Farah, MD, and Cyrus Maurice Sani, MD for participant screening, Jeanne Talbot, MD, Sandhaya Norris, MD, and Charles Desfossés, MD for medical support, and Natalia Jaworska, PhD for technical support, and we acknowledge the contributions to data collection by former lab members Hassan Khan, BA, Femi Carrington, MSc, Vanessa Zayed, MC, Alyssa Stowe, BSc, and Dominique Vasudev, BSc.

      Supplementary Material

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