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Reduced limbic microstructural integrity in functional neurological disorder

Published online by Cambridge University Press:  26 November 2019

Ibai Diez
Affiliation:
Department of Neurology, Functional Neurology Research Group, Behavioral Neurology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA Department of Nuclear Medicine, Gordon Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Neurotechnology Laboratory, Tecnalia Health Department, Derio, Spain
Benjamin Williams
Affiliation:
Department of Neurology, Functional Neurology Research Group, Behavioral Neurology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Marek R. Kubicki
Affiliation:
Department of Psychiatry, Center for Morphometric Analysis, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Department of Psychiatry, Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Nikos Makris
Affiliation:
Department of Psychiatry, Center for Morphometric Analysis, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Department of Radiology, Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
David L. Perez*
Affiliation:
Department of Neurology, Functional Neurology Research Group, Behavioral Neurology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA Department of Psychiatry, Neuropsychiatry Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
*
Author for correspondence: David L. Perez, E-mail: [email protected]

Abstract

Background

Functional neurological disorder (FND) is a condition at the intersection of neurology and psychiatry. Individuals with FND exhibit corticolimbic abnormalities, yet little is known about the role of white matter tracts in the pathophysiology of FND. This study characterized between-group differences in microstructural integrity, and correlated fiber bundle integrity with symptom severity, physical disability, and illness duration.

Methods

A diffusion tensor imaging (DTI) study was performed in 32 patients with mixed FND compared to 36 healthy controls. Diffusion-weighted magnetic resonance images were collected along with patient-reported symptom severity, physical disability (Short Form Health Survey-36), and illness duration data. Weighted-degree and link-level graph theory and probabilistic tractography analyses characterized fractional anisotropy (FA) values across cortico-subcortical connections. Results were corrected for multiple comparisons.

Results

Compared to controls, FND patients showed reduced FA in the stria terminalis/fornix, medial forebrain bundle, extreme capsule, uncinate fasciculus, cingulum bundle, corpus callosum, and striatal-postcentral gyrus projections. Except for the stria terminalis/fornix, these differences remained significant adjusting for depression and anxiety. In within-group analyses, physical disability inversely correlated with stria terminalis/fornix and medial forebrain bundle FA values; illness duration negatively correlated with stria terminalis/fornix white matter integrity. A FND symptom severity composite score did not correlate with FA in patients.

Conclusions

In this first DTI study of mixed FND, microstructural differences were observed in limbic and associative tracts implicated in salience, defensive behaviors, and emotion regulation. These findings advance our understanding of neurocircuit pathways in the pathophysiology of FND.

Type
Original Articles
Copyright
Copyright © Cambridge University Press 2019

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References

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (DSM-5). Washington, DC: American Psychiatric Pub.Google Scholar
Atmaca, M., Baykara, S., Mermi, O., Yildirim, H., & Akaslan, U. (2016). Pituitary volumes are changed in patients with conversion disorder. Brain Imaging and Behavior, 10, 9295.CrossRefGoogle ScholarPubMed
Avbersek, A., & Sisodiya, S. (2010). Does the primary literature provide support for clinical signs used to distinguish psychogenic nonepileptic seizures from epileptic seizures? Journal of Neurology Neurosurgery & Psychiatry, 81, 719725.CrossRefGoogle ScholarPubMed
Aybek, S., Nicholson, T. R., Draganski, B., Daly, E., Murphy, D. G., David, A. S., & Kanaan, R. A. (2014a). Grey matter changes in motor conversion disorder. Journal of Neurology Neurosurgery & Psychiatry, 85, 236238.CrossRefGoogle Scholar
Aybek, S., Nicholson, T. R., O'Daly, O., Zelaya, F., Kanaan, R. A., & David, A. S. (2015). Emotion-motion interactions in conversion disorder: an FMRI study. PLoS One, 10, e0123273.CrossRefGoogle Scholar
Aybek, S., Nicholson, T. R., Zelaya, F., O'Daly, O. G., Craig, T. J., David, A. S., & Kanaan, R. A. (2014b). Neural correlates of recall of life events in conversion disorder. JAMA Psychiatry, 71, 5260.CrossRefGoogle Scholar
Baek, K., Donamayor, N., Morris, L. S., Strelchuk, D., Mitchell, S., Mikheenko, Y.Voon, V. (2017). Impaired awareness of motor intention in functional neurological disorder: implications for voluntary and functional movement. Psychological Medicine, 47, 16241636.CrossRefGoogle ScholarPubMed
Bakvis, P., Spinhoven, P., & Roelofs, K. (2009). Basal cortisol is positively correlated to threat vigilance in patients with psychogenic nonepileptic seizures. Epilepsy & Behavior: E&B, 16, 558560.CrossRefGoogle ScholarPubMed
Bannerman, D. M., Rawlins, J. N., McHugh, S. B., Deacon, R. M., Yee, B. K., Bast, T.Feldon, J. (2004). Regional dissociations within the hippocampus–memory and anxiety. Neuroscience & Biobehavioral Reviews, 28, 273283.CrossRefGoogle ScholarPubMed
Barsky, A. J., Orav, E. J., & Bates, D. W. (2005). Somatization increases medical utilization and costs independent of psychiatric and medical comorbidity. Archives of General Psychiatry, 62, 903910.CrossRefGoogle ScholarPubMed
Begue, I., Adams, C., Stone, J., & Perez, D. L. (2019). Structural alterations in functional neurological disorder and related conditions: a software and hardware problem? NeuroImage: Clinical.CrossRefGoogle ScholarPubMed
Bolen, R. D., Koontz, E. H. & Pritchard, P. B. III (2016). Prevalence and distribution of MRI abnormalities in patients with psychogenic nonepileptic events. Epilepsy & Behavior: E&B 59, 7376.CrossRefGoogle ScholarPubMed
Bubb, E. J., Metzler-Baddeley, C., & Aggleton, J. P. (2018). The cingulum bundle: anatomy, function, and dysfunction. Neuroscience & Biobehavioral Reviews, 92, 104127.CrossRefGoogle ScholarPubMed
Choi, J., Jeong, B., Rohan, M. L., Polcari, A. M., & Teicher, M. H. (2009). Preliminary evidence for white matter tract abnormalities in young adults exposed to parental verbal abuse. Biological Psychiatry, 65, 227234.CrossRefGoogle ScholarPubMed
Colby, J. B., Soderberg, L., Lebel, C., Dinov, I. D., Thompson, P. M., & Sowell, E. R. (2012). Along-tract statistics allow for enhanced tractography analysis. NeuroImage, 59, 32273242.CrossRefGoogle ScholarPubMed
Daum, C., Hubschmid, M., & Aybek, S. (2014). The value of ‘positive’ clinical signs for weakness, sensory and gait disorders in conversion disorder: a systematic and narrative review. Journal of Neurology Neurosurgery & Psychiatry, 85, 180190.CrossRefGoogle ScholarPubMed
Denk, F., McMahon, S. B., & Tracey, I. (2014). Pain vulnerability: a neurobiological perspective. Nature Neuroscience, 17, 192200.CrossRefGoogle ScholarPubMed
Devinsky, O. (2000). Right cerebral hemisphere dominance for a sense of corporeal and emotional self. Epilepsy & Behavior, 1, 6073.CrossRefGoogle Scholar
Diez, I., Ortiz-Teran, L., Williams, B., Jalilianhasanpour, R., Ospina, J. P., Dickerson, B. C.Perez, D. L. (2019). Corticolimbic fast-tracking: enhanced multimodal integration in functional neurological disorder. Journal of Neurology Neurosurgery & Psychiatry 90, 929938.CrossRefGoogle ScholarPubMed
Ding, J., An, D., Liao, W., Wu, G., Xu, Q., Zhou, D., & Chen, H. (2014). Abnormal functional connectivity density in psychogenic non-epileptic seizures. Epilepsy Research, 108, 11841194.CrossRefGoogle ScholarPubMed
Ding, J. R., An, D., Liao, W., Li, J., Wu, G. R., Xu, Q.Chen, H. (2013). Altered functional and structural connectivity networks in psychogenic non-epileptic seizures. PLoS One, 8, e63850.CrossRefGoogle ScholarPubMed
Espay, A. J., Aybek, S., Carson, A., Edwards, M. J., Goldstein, L. H., Hallett, M.Morgante, F. (2018a). Current concepts in diagnosis and treatment of functional neurological disorders. JAMA Neurology 75, 11321141.CrossRefGoogle Scholar
Espay, A. J., Maloney, T., Vannest, J., Norris, M. M., Eliassen, J. C., Neefus, E.Szaflarski, J. P. (2018b). Dysfunction in emotion processing underlies functional (psychogenic) dystonia. Movement Disorders, 33, 136145.CrossRefGoogle Scholar
Espay, A. J., Maloney, T., Vannest, J., Norris, M. M., Eliassen, J. C., Neefus, E.Szaflarski, J. P. (2018c). Impaired emotion processing in functional (psychogenic) tremor: a functional magnetic resonance imaging study. NeuroImage: Clinical, 17, 179187.CrossRefGoogle Scholar
Ezra, M., Faull, O. K., Jbabdi, S., & Pattinson, K. T. (2015). Connectivity-based segmentation of the periaqueductal gray matter in human with brainstem optimized diffusion MRI. Human Brain Mapping, 36, 34593471.CrossRefGoogle ScholarPubMed
Fani, N., King, T. Z., Brewster, R., Srivastava, A., Stevens, J. S., Glover, E. M.Jovanovic, T. (2015). Fear-potentiated startle during extinction is associated with white matter microstructure and functional connectivity. Cortex, 64, 249259.CrossRefGoogle ScholarPubMed
Hallett, M. (2006). Psychogenic movement disorders: a crisis for neurology. Current Neurology and Neuroscience Reports, 6, 269271.CrossRefGoogle ScholarPubMed
Hanson, J. L., Knodt, A. R., Brigidi, B. D., & Hariri, A. R. (2015). Lower structural integrity of the uncinate fasciculus is associated with a history of child maltreatment and future psychological vulnerability to stress. Development and Psychopathology, 27, 16111619.CrossRefGoogle ScholarPubMed
Hassa, T., Sebastian, A., Liepert, J., Weiller, C., Schmidt, R., & Tüscher, O. (2017). Symptom-specific amygdala hyperactivity modulates motor control network in conversion disorder. NeuroImage: Clinical, 15, 143150.CrossRefGoogle ScholarPubMed
Hernando, K. A., Szaflarski, J. P., Ver Hoef, L. W., Lee, S., & Allendorfer, J. B. (2015). Uncinate fasciculus connectivity in patients with psychogenic nonepileptic seizures: a preliminary diffusion tensor tractography study. Epilepsy & Behavior, 45, 6873.CrossRefGoogle ScholarPubMed
Iglesias, J. E., Van Leemput, K., Bhatt, P., Casillas, C., Dutt, S., Schuff, N.Alzheimer's Disease Neuroimaging, I. (2015). Bayesian segmentation of brainstem structures in MRI. NeuroImage 113, 184195.CrossRefGoogle ScholarPubMed
Inamura, K., Shinagawa, S., Nagata, T., Tagai, K., Nukariya, K., & Nakayama, K. (2015). White matter hyperintensities are associated with the severity of late-life somatoform disorders and executive functions. Nordic Journal of Psychiatry, 24, 18.CrossRefGoogle Scholar
Jenkins, L. M., Barba, A., Campbell, M., Lamar, M., Shankman, S. A., Leow, A. D.Langenecker, S. A. (2016). Shared white matter alterations across emotional disorders: a voxel-based meta-analysis of fractional anisotropy. NeuroImage: Clinical, 12, 10221034.CrossRefGoogle ScholarPubMed
Kamali, A., Yousem, D. M., Lin, D. D., Sair, H. I., Jasti, S. P., Keser, Z.Hasan, K. M. (2015). Mapping the trajectory of the stria terminalis of the human limbic system using high spatial resolution diffusion tensor tractography. Neuroscience Letters, 608, 4550.CrossRefGoogle ScholarPubMed
Keuken, M. C., Bazin, P. L., Crown, L., Hootsmans, J., Laufer, A., Muller-Axt, C.Forstmann, B. U. (2014). Quantifying inter-individual anatomical variability in the subcortex using 7T structural MRI. NeuroImage, 94, 4046.CrossRefGoogle Scholar
Keynejad, R. C., Frodl, T., Kanaan, R., Pariante, C., Reuber, M., & Nicholson, T. R. (2018). Stress and functional neurological disorders: mechanistic insights. Journal of Neurology Neurosurgery & Psychiatry, 90, 813821.CrossRefGoogle ScholarPubMed
Konigs, M., van Heurn, L. W. E., Bakx, R., Vermeulen, R. J., Goslings, J. C., Poll-The, B. T.Pouwels, P. J. W. (2017). The structural connectome of children with traumatic brain injury. Human Brain Mapping, 38, 36033614.Google ScholarPubMed
Kozlowska, K., Griffiths, K. R., Foster, S. L., Linton, J., Williams, L. M., & Korgaonkar, M. S. (2017). Grey matter abnormalities in children and adolescents with functional neurological symptom disorder. NeuroImage: Clinical, 15, 306314.CrossRefGoogle ScholarPubMed
Kroenke, K., Spitzer, R. L., & Williams, J. B. (2002). The PHQ-15: validity of a new measure for evaluating the severity of somatic symptoms. Psychosomatic Medicine, 64, 258266.CrossRefGoogle ScholarPubMed
Labate, A., Cerasa, A., Mula, M., Mumoli, L., Gioia, M. C., Aguglia, U.Gambardella, A. (2011). Neuroanatomic correlates of psychogenic nonepileptic seizures: a cortical thickness and VBM study. Epilepsia, 53, 377385.CrossRefGoogle ScholarPubMed
Lee, S., Allendorfer, J. B., Gaston, T. E., Griffis, J. C., Hernando, K. A., Knowlton, R. C.Ver Hoef, L. W. (2015). White matter diffusion abnormalities in patients with psychogenic non-epileptic seizures. Brain Research, 1620, 169176.CrossRefGoogle ScholarPubMed
Ludwig, L., Pasman, J. A., Nicholson, T., Aybek, S., David, A. S., Tuck, S.Stone, J. (2018). Stressful life events and maltreatment in conversion (functional neurological) disorder: systematic review and meta-analysis of case-control studies. The Lancet. Psychiatry, 5, 307320.CrossRefGoogle ScholarPubMed
Makris, N., & Pandya, D. N. (2009). The extreme capsule in humans and rethinking of the language circuitry. Brain Structure & Function, 213, 343358.CrossRefGoogle ScholarPubMed
Maurer, C. W., LaFaver, K., Ameli, R., Epstein, S. A., Hallett, M., & Horovitz, S. G. (2016a). Impaired self-agency in functional movement disorders: a resting-state fMRI study. Neurology, 87, 564570.Google Scholar
Maurer, C. W., LaFaver, K., Limachia, G. S., Capitan, G., Ameli, R., Sinclair, S.Horovitz, S. G. (2018). Gray matter differences in patients with functional movement disorders. Neurology, 91, e1870e1879.CrossRefGoogle ScholarPubMed
Maurer, C. W., Liu, V. D., LaFaver, K., Ameli, R., Wu, T., Toledo, R.Hallett, M. (2016b). Impaired resting vagal tone in patients with functional movement disorders. Parkinsonism & Related Disorders, 30, 1822.CrossRefGoogle Scholar
McIntosh, A. M., Bastin, M. E., Luciano, M., Maniega, S. M., Del, C. V. H. M., Royle, N. A.Deary, I. J. (2013). Neuroticism, depressive symptoms and white-matter integrity in the Lothian Birth Cohort 1936. Psychological Medicine, 43, 11971206.CrossRefGoogle ScholarPubMed
Nicholson, T. R., Aybek, S., Kempton, M. J., Daly, E. M., Murphy, D. G., David, A. S., & Kanaan, R. A. (2014). A structural MRI study of motor conversion disorder: evidence of reduction in thalamic volume. Journal of Neurology Neurosurgery & Psychiatry, 85, 227229.CrossRefGoogle ScholarPubMed
Perez, D. L., Dworetzky, B. A., Dickerson, B. C., Leung, L., Cohn, R., Baslet, G., & Silbersweig, D. A. (2015). An integrative neurocircuit perspective on psychogenic nonepileptic seizures and functional movement disorders: neural functional unawareness. Clinical EEG and Neuroscience, 46, 415.CrossRefGoogle ScholarPubMed
Perez, D. L., Matin, N., Barsky, A., Costumero-Ramos, V., Makaretz, S. J., Young, S. S.Dickerson, B. C. (2017a). Cingulo-insular structural alterations associated with psychogenic symptoms, childhood abuse and PTSD in functional neurological disorders. Journal of Neurology Neurosurgery & Psychiatry 88, 491497.CrossRefGoogle Scholar
Perez, D. L., Matin, N., Williams, B., Tanev, K., Makris, N., LaFrance, W. C. Jr. & Dickerson, B. C. (2018). Cortical thickness alterations linked to somatoform and psychological dissociation in functional neurological disorders. Human Brain Mapping 39, 428439.CrossRefGoogle ScholarPubMed
Perez, D. L., Williams, B., Matin, N., LaFrance, W. C. Jr., Costumero-Ramos, V., Fricchione, G. L.Dickerson, B. C. (2017b). Corticolimbic structural alterations linked to health status and trait anxiety in functional neurological disorder. Journal of Neurology Neurosurgery & Psychiatry 88, 10521059.CrossRefGoogle Scholar
Pick, S., Goldstein, L. H., Perez, D. L., & Nicholson, T. R. (2019). Emotional processing in functional neurological disorder: a review, biopsychosocial model and research agenda. Journal of Neurology Neurosurgery & Psychiatry, 90, 704711.CrossRefGoogle ScholarPubMed
Pick, S., Mellers, J. D., & Goldstein, L. H. (2016). Explicit facial emotion processing in patients with dissociative seizures. Psychosomatic Medicine, 78, 874885.CrossRefGoogle ScholarPubMed
Ploner, M., Lee, M. C., Wiech, K., Bingel, U., & Tracey, I. (2011). Flexible cerebral connectivity patterns subserve contextual modulations of pain. Cerebral Cortex, 21, 719726.CrossRefGoogle ScholarPubMed
Rief, W., & Hiller, W. (2003). A new approach to the assessment of the treatment effects of somatoform disorders. Psychosomatics, 44, 492498.CrossRefGoogle ScholarPubMed
Roelofs, K. (2017). Freeze for action: neurobiological mechanisms in animal and human freezing. Philosophical Transactions of the Royal Society of London B Biological Sciences, 372.Google ScholarPubMed
Rubinov, M., & Sporns, O. (2010). Complex network measures of brain connectivity: uses and interpretations. NeuroImage, 52, 10591069.CrossRefGoogle ScholarPubMed
Sampaio-Baptista, C., & Johansen-Berg, H. (2017). White matter plasticity in the adult brain. Neuron, 96, 12391251.CrossRefGoogle ScholarPubMed
Seignourel, P. J., Miller, K., Kellison, I., Rodriguez, R., Fernandez, H. H., Bauer, R. M.Okun, M. S. (2007). Abnormal affective startle modulation in individuals with psychogenic [corrected] movement disorder. Movement Disorders, 22, 12651271.CrossRefGoogle ScholarPubMed
Stone, J., Carson, A., Duncan, R., Roberts, R., Warlow, C., Hibberd, C.Sharpe, M. (2010a). Who is referred to neurology clinics? – the diagnoses made in 3781 new patients. Clinical Neurology and Neurosurgery, 112, 747751.CrossRefGoogle Scholar
Stone, J., LaFrance, W. C. Jr., Levenson, J. L. & Sharpe, M. (2010b). Issues for DSM-5: conversion disorder. American Journal of Psychiatry 167, 626627.CrossRefGoogle Scholar
Tomic, A., Agosta, F., Sarasso, E., Petrovic, I., Basaia, S., Pesic, D.Filippi, M. (2018). Are there two different forms of functional dystonia? A multimodal brain structural MRI study. Molecular Psychiatry.Google ScholarPubMed
van den Heuvel, M. P., & Sporns, O. (2011). Rich-club organization of the human connectome. Journal of Neuroscience, 31, 1577515786.CrossRefGoogle ScholarPubMed
van der Kruijs, S. J., Bodde, N. M., Vaessen, M. J., Lazeron, R. H., Vonck, K., Boon, P.Jansen, J. F. (2012). Functional connectivity of dissociation in patients with psychogenic non-epileptic seizures. Journal of Neurology Neurosurgery & Psychiatry, 83, 239247.CrossRefGoogle ScholarPubMed
Vasta, R., Cerasa, A., Sarica, A., Bartolini, E., Martino, I., Mari, F.Labate, A. (2018). The application of artificial intelligence to understand the pathophysiological basis of psychogenic nonepileptic seizures. Epilepsy and Behavior, 87, 167172.CrossRefGoogle ScholarPubMed
Von Der Heide, R. J., Skipper, L. M., Klobusicky, E., & Olson, I. R. (2013). Dissecting the uncinate fasciculus: disorders, controversies and a hypothesis. Brain, 136, 16921707.CrossRefGoogle ScholarPubMed
Voon, V., Brezing, C., Gallea, C., Ameli, R., Roelofs, K., LaFrance, W. C. Jr. & Hallett, M. (2010a). Emotional stimuli and motor conversion disorder. Brain 133, 15261536.CrossRefGoogle Scholar
Voon, V., Brezing, C., Gallea, C., & Hallett, M. (2011). Aberrant supplementary motor complex and limbic activity during motor preparation in motor conversion disorder. Movement Disorders, 26, 23962403.CrossRefGoogle ScholarPubMed
Voon, V., Cavanna, A. E., Coburn, K., Sampson, S., Reeve, A. & LaFrance, W. C. Jr. (2016). Functional neuroanatomy and neurophysiology of functional neurological disorders (conversion disorder). The Journal of Neuropsychiatry and Clinical Neurosciences 28, 168190.CrossRefGoogle Scholar
Voon, V., Gallea, C., Hattori, N., Bruno, M., Ekanayake, V., & Hallett, M. (2010b). The involuntary nature of conversion disorder. Neurology, 74, 223228.CrossRefGoogle Scholar
Ware, J. E. Jr. & Sherbourne, C. D. (1992). The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Medical Care 30, 473483.CrossRefGoogle ScholarPubMed
Wassermann, D., Makris, N., Rathi, Y., Shenton, M., Kikinis, R., Kubicki, M., & Westin, C. F. (2016). The white matter query language: a novel approach for describing human white matter anatomy. Brain Structure & Function, 221, 47054721.CrossRefGoogle ScholarPubMed
Williams, B., Jalilianhasanpour, R., Matin, N., Fricchione, G. L., Sepulcre, J., Keshavan, M. S.Perez, D. L. (2018). Individual differences in corticolimbic structural profiles linked to insecure attachment and coping styles in motor functional neurological disorders. Journal of Psychiatric Research, 102, 230237.CrossRefGoogle ScholarPubMed
Yendiki, A., Koldewyn, K., Kakunoori, S., Kanwisher, N., & Fischl, B. (2014). Spurious group differences due to head motion in a diffusion MRI study. NeuroImage, 88, 7990.CrossRefGoogle Scholar
Zito, G. A., Apazoglou, K., Paraschiv-Ionescu, A., Aminian, K., & Aybek, S. (2018). Abnormal postural behavior in patients with functional movement disorders during exposure to stress. Psychoneuroendocrinology, 101, 232239.CrossRefGoogle ScholarPubMed
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