Subclinical post-traumatic stress symptomology and brain structure in youth with chronic headaches

Jillian Vinall Miller, Quinn Andre, Inge Timmers, Laura Simons, Nivez Rasic, Catherine Lebel, Melanie Noel, Jillian Vinall Miller, Quinn Andre, Inge Timmers, Laura Simons, Nivez Rasic, Catherine Lebel, Melanie Noel

Abstract

Background/aims: Post-traumatic stress symptoms (PTSS) and chronic pain often co-occur at high rates in youth. PTSS may alter brain structure thereby contributing to headache chronicity. This study examined whether PTSS and altered limbic circuitry were associated with headache frequency in youth.

Methods: Thirty youth aged 10-18 years with chronic headaches and 30 age- and sex-matched controls underwent a 3T MRI scan. Volumes of the hippocampus and amygdala were obtained from T1-weighted images. Mean fractional anisotropy (FA, an index of white matter structure) axial and radial diffusivity values of the cingulum and uncinate fasciculus were extracted from diffusion-weighted images. Youth reported on their headaches daily, for one-month, and self-reported pubertal status, emotion regulation, adverse childhood experiences (ACEs) and PTSS using validated measures. Volumes of the hippocampus and amygdala and diffusivity values of the cingulum and uncinate were compared between patients and controls. Hierarchical linear regressions were used to examine the association between PTSS, subcortical volumes and/or diffusivity values and headache frequency.

Results: Mean FA values of the cingulum were higher in patients compared to controls (P = 0.02, Cohen's d = 0.69). Greater PTSS (P = 0.04), smaller amygdala volumes (P = 0.01) and lower FA of the cingulum (P = 0.04) were associated with greater headache frequency, after accounting for age, puberty, pain duration, emotion regulation, and ACEs (Adjusted R2 ≥ 0.15). Headache frequency was associated with increases in radial diffusivity (P = 0.002, Adjusted R2 = 0.59), as opposed to axial diffusivity (n.s.).

Conclusions: PTSS, smaller amygdalar volume, and poorer cingulum structural connectivity were associated with headache frequency in youth, and may underlie headache chronicity.

Keywords: Brain; Headache; PTSD; Pain; Post-traumatic stress symptoms; Trauma.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1
Fig. 1
Participant flow chart.
Fig. 2
Fig. 2
Brain regions of interest. A. Circled are the amygdala (blue) and hippocampus (orange) Freesurfer segmentations. B. FA color map and cingulum tract. C. FA color map and uncinate fasciculus tract. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

References

    1. Abdul-Rahman M.F., Qiu A., Sim K. Regionally specific white matter disruptions of fornix and cingulum in schizophrenia. PLoS One. 2011;6
    1. Adams E. Tractography-based quantitation of corticospinal tract development in premature newborns. J. Pediatr. 2010;156(6):882–888.e1.
    1. Andersson J.L.R., Graham M.S., Zsoldos E., Sotiropoulos S.N. Incorporating outlier detection and replacement into a non-parametric framework for movement and distortion correction of diffusion MR images. Neuroimage. 2016;141:556–572.
    1. Andersson J.L.R., Sotiropoulos S.N. An integrated approach to correction for off-resonance effects and subject movement in diffusion MR imaging. Neuroimage. 2016;125:1063–1078.
    1. Andersson J.L.R., Skare S., Ashburner J. How to correct susceptibility distortions in spin-echo echo-planar images: application to diffusion tensor imaging. Neuroimage. 2003;20(2):870–888.
    1. Arcaya M.C., Lowe S.R., Asad A.L., Subramanian S.V., Waters M.C., Rhodes J. Association of posttraumatic stress disorder symptoms with migraine and headache after a natural disaster. Health Psychol. 2017;36(5):411–418.
    1. Asmundson G.JG., Coons M.J., Taylor S., Katz J. PTSD and the experience of pain: research and clinical implications of shared vulnerability and mutual maintenance models. Can. J. Psychiatry. 2002;47(10):930–937.
    1. A.P. Association, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (American Psychiatric Association, Arlington, VA, 2013).
    1. A.P. Association, Diagnostic and Statistical Manual of Mental Disorders: DSM-V (American Psychiatric Association, Washington, DC, 2013).
    1. Averill L.A. Glutamate dysregulation and glutamatergic therapeutics for PTSD: evidence from human studies. Neurosci. Lett. 2017;649:147–155.
    1. Baliki M.N., Petre B., Torbey S., Herrmann K.M., Huang L., Schnitzer T.J., Fields H.L., Apkarian A.V. Corticostriatal functional connectivity predicts transition to chronic back pain. Nat. Neurosci. 2012;15(8):1117–1119.
    1. Beauchet O., Barden J., Liu-Ambrose T., Chester V.L., Szturm T., Allali G. The relationship between hippocampal volume and static postural sway: results from the GAIT study. Age (Dordr) 2016;38(1) doi: 10.1007/s11357-016-9883-4.
    1. Beaulieu C. The basis of anisotropic water diffusion in the nervous system – a technical review. NMR Biomed. 2002;15(7-8):435–455.
    1. Beckham J.C., Crawford A.L., Feldman M.E., Kirby A.C., Hertzberg M.A., Davidson J.R.T., Moore S.D. Chronic posttraumatic stress disorder and chronic pain in Vietnam combat veterans. J. Psychosom. Res. 1997;43(4):379–389.
    1. Beggs S., Currie G., Salter M.W., Fitzgerald M., Walker S.M. Priming of adult pain responses by neonatal pain experience: maintenance by central neuroimmune activity. Brain. 2012;135(2):404–417.
    1. Bitter S.M., Mills N.P., Adler C.M., Strakowski S.M., DelBello M.P. Progression of amygdala volumetric abnormalities in adolescents after their first manic episode. J. Am. Acad. Child Adolesc. Psychiatry. 2011;50(10):1017–1026.
    1. Blakemore S.J., Burnett S., Dahl R.E. The role of puberty in the developing adolescent brain. Hum. Brain Mapp. 2010;31:926–933.
    1. Brna P., Dooley J., Gordon K., Dewan T. The prognosis of childhood headache: a 20-year follow-up. Arch. Pediatr. Adolesc. Med. 2005;159(12):1157. doi: 10.1001/archpedi.159.12.1157.
    1. N. R. Burke Harris, T.;, Center for Youth Wellness ACE-Questionnaire (CYW ACE-Q Child, Teen, Teen SR) (Center for Youth Wellness, San Francisco, CA, ed. 7, 2015).
    1. Carskadon M.A., Acebo C. A self-administered rating scale for pubertal development. J. Adolesc. Health. 1993;14(3):190–195.
    1. Chen Z. Altered functional connectivity of amygdala underlying the neuromechanism of migraine pathogenesis. J. Headache Pain. 2017;18(1) doi: 10.1186/s10194-017-0722-5.
    1. Cisler J.M., Sigel B.A., Steele J.S., Smitherman S., Vanderzee K., Pemberton J., Kramer T.L., Kilts C.D. Changes in functional connectivity of the amygdala during cognitive reappraisal predict symptom reduction during trauma-focused cognitive-behavioral therapy among adolescent girls with post-traumatic stress disorder. Psychol. Med. 2016;46(14):3013–3023.
    1. I. Cooporation, IBM SPSS Statistics for Macintosh, Version 26.0 (IBM Corp., Armonk, NY, 2019).
    1. Copeland W.E., Keeler G., Angold A., Costello E.J. Traumatic events and posttraumatic stress in childhood. Arch. Gen. Psychiatry. 2007;64(5):577. doi: 10.1001/archpsyc.64.5.577.
    1. Dale A.M., Fischl B., Sereno M.I. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage. 1999;9(2):179–194.
    1. Daniels J.K., Lamke J.P., Gaebler M., Walter H., Scheel M. White matter integrity and its relationship to PTSD and childhood trauma–a systematic review and meta-analysis. Depress Anxiety. 2013;30(3):207–216.
    1. Disease G.B.D., Injury I., Prevalence C. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789–1858.
    1. Eccleston, C., et al., Psychological therapies for the management of chronic and recurrent pain in children and adolescents. Cochrane Database Syst. Rev., 10.1002/14651858.CD003968.pub4, CD003968 (2014).
    1. Erpelding N. Rapid treatment-induced brain changes in pediatric CRPS. Brain Struct. Funct. 2016;221(2):1095–1111.
    1. Farquharson S., Tournier J.-D., Calamante F., Fabinyi G., Schneider-Kolsky M., Jackson G.D., Connelly A. White matter fiber tractography: why we need to move beyond DTI. J. Neurosurg. 2013;118(6):1367–1377.
    1. Filipovic B.R., Djurovic B., Marinkovic S., Stijak L., Aksic M., Nikolic V., Starcevic A., Radonjic V. Volume changes of corpus striatum, thalamus, hippocampus and lateral ventricles in posttraumatic stress disorder (PTSD) patients suffering from headaches and without therapy. Cent. Eur. Neurosurg. 2011;72(03):133–137.
    1. Fischl, B., FreeSurfer. Neuroimage 62, 774-781 (2012).
    1. Foa E.B., Johnson K.M., Feeny N.C., Treadwell K.R.H. The child PTSD Symptom Scale: a preliminary examination of its psychometric properties. J. Clin. Child. Psychol. 2001;30(3):376–384.
    1. Galinski M., Sidhoum S., Cimerman P., Perrin O., Annequin D., Tourniaire B. Early diagnosis of migraine necessary in children: 10-year follow-up. Pediatr. Neurol. 2015;53(4):319–323.
    1. Geeraert B.L. A comparison of inhomogeneous magnetization transfer, myelin volume fraction, and diffusion tensor imaging measures in healthy children. Neuroimage. 2018;182:343–350.
    1. Geeraert B.L., Lebel R.M., Lebel C. A multiparametric analysis of white matter maturation during late childhood and adolescence. Hum. Brain Mapp. 2019;40(15):4345–4356.
    1. Geha P.Y. The brain in chronic CRPS pain: abnormal gray-white matter interactions in emotional and autonomic regions. Neuron. 2008;60(4):570–581.
    1. Gerber M.R., Fried L.E., Pineles S.L., Shipherd J.C., Bernstein C.A. Posttraumatic stress disorder and intimate partner violence in a women's headache center. Women Health. 2012;52(5):454–471.
    1. Goddings A.-L., Mills K.L., Clasen L.S., Giedd J.N., Viner R.M., Blakemore S.-J. The influence of puberty on subcortical brain development. Neuroimage. 2014;88:242–251.
    1. Gullone E., Taffe J. The Emotion Regulation Questionnaire for Children and Adolescents (ERQ-CA): a psychometric evaluation. Psychol. Assess. 2012;24(2):409–417.
    1. Harnett N.G., Goodman A.M., Knight D.C. PTSD-related neuroimaging abnormalities in brain function, structure, and biochemistry. Exp. Neurol. 2020;330:113331. doi: 10.1016/j.expneurol.2020.113331.
    1. Hernandez-Latorre M.A., Roig M. Natural history of migraine in childhood. Cephalalgia. 2000;20(6):573–579.
    1. Hershey A.D., Powers S.W., Coffey C.S., Eklund D.D., Chamberlin L.A., Korbee L.L. Childhood and Adolescent Migraine Prevention (CHAMP) study: a double-blinded, placebo-controlled, comparative effectiveness study of amitriptyline, topiramate, and placebo in the prevention of childhood and adolescent migraine. Headache. 2013;53(5):799–816.
    1. Herting M.M., Sowell E.R. Puberty and structural brain development in humans. Front. Neuroendocrinol. 2017;44:122–137.
    1. Holley A.L., Wilson A.C., Noel M., Palermo T.M. Post-traumatic stress symptoms in children and adolescents with chronic pain: a topical review of the literature and a proposed framework for future research. Eur. J. Pain. 2016;20(9):1371–1383. doi: 10.1002/ejp.879.
    1. Hubbard C.S., Khan S.A., Xu S.u., Cha M., Masri R., Seminowicz D.A. Behavioral, metabolic and functional brain changes in a rat model of chronic neuropathic pain: a longitudinal MRI study. Neuroimage. 2015;107:333–344.
    1. Jensen K.B., Regenbogen C., Ohse M.C., Frasnelli J., Freiherr J., Lundström J.N. Brain activations during pain: a neuroimaging meta-analysis of patients with pain and healthy controls. Pain. 2016;157(6):1279–1286.
    1. Jiang Y., Oathes D., Hush J., Darnall B., Charvat M., Mackey S., Etkin A. Perturbed connectivity of the amygdala and its subregions with the central executive and default mode networks in chronic pain. Pain. 2016;157(9):1970–1978.
    1. Kalmakis K.A., Meyer J.S., Chiodo L., Leung K. Adverse childhood experiences and chronic hypothalamic-pituitary-adrenal activity. Stress. 2015;18(4):446–450.
    1. Kienbacher C., Wöber C., Zesch H.E., Hafferl-Gattermayer A., Posch M., Karwautz A., Zormann A., Berger G., Zebenholzer K., Konrad A., Wöber-Bingöl Ç. Clinical features, classification and prognosis of migraine and tension-type headache in children and adolescents: a long-term follow-up study. Cephalalgia. 2006;26(7):820–830.
    1. King S., Chambers C.T., Huguet A., MacNevin R.C., McGrath P.J., Parker L., MacDonald A.J. The epidemiology of chronic pain in children and adolescents revisited: a systematic review. Pain. 2011;152(12):2729–2738.
    1. Kirkland A.E., Sarlo G.L., Holton K.F. The role of magnesium in neurological disorders. Nutrients. 2018;10(6):730. doi: 10.3390/nu10060730.
    1. Láinez M.J.A., Domínguez M., Rejas J., Palacios G., Arriaza E., Garcia-Garcia M., Madrigal M. Development and validation of the Migraine Screen Questionnaire (MS-Q) Headache. 2005;45(10):1328–1338.
    1. Larroza A., Moratal D., D'Ocon Alcaniz V., Arana E. I. por la Alzheimer's Disease Neuroimaging, [Tractography of the uncinate fasciculus and the posterior cingulate fasciculus in patients with mild cognitive impairment and Alzheimer disease] Neurologia. 2014;29:11–20.
    1. Lebel C., Beaulieu C. Longitudinal development of human brain wiring continues from childhood into adulthood. J. Neurosci. 2011;31(30):10937–10947.
    1. Lebel C., Walker L., Leemans A., Phillips L., Beaulieu C. Microstructural maturation of the human brain from childhood to adulthood. Neuroimage. 2008;40(3):1044–1055.
    1. Lebel C., Treit S., Beaulieu C. A review of diffusion MRI of typical white matter development from early childhood to young adulthood. NMR Biomed. 2019;32(4):e3778. doi: 10.1002/nbm.v32.410.1002/nbm.3778.
    1. Lieberman G. White matter involvement in chronic musculoskeletal pain. J. Pain. 2014;15(11):1110–1119.
    1. Mansour A.R., Farmer M.A., Baliki M.N., Apkarian A.V. Chronic pain: the role of learning and brain plasticity. Restor. Neurol. Neurosci. 2014;32:129–139.
    1. Mark L.P. Pictorial review of glutamate excitotoxicity: fundamental concepts for neuroimaging. AJNR Am. J. Neuroradiol. 2001;22:1813–1824.
    1. McDonald, J.H., Handbook of Biological Statistics (Sparky House Publishing, Baltimore, Maryland, ed. 3rd Edition, 2014).
    1. McWilliams L.A., Cox B.J., Enns M.W. Mood and anxiety disorders associated with chronic pain: an examination in a nationally representative sample. Pain. 2003;106:127–133.
    1. Messina R. White matter microstructure abnormalities in pediatric migraine patients. Cephalalgia. 2015;35(14):1278–1286.
    1. Mody I., MacDonald J.F. NMDA receptor-dependent excitotoxicity: the role of intracellular Ca2+ release. Trends Pharmacol. Sci. 1995;16:356–359.
    1. Mutso A.A., Petre B., Huang L., Baliki M.N., Torbey S., Herrmann K.M., Schnitzer T.J., Apkarian A.V. Reorganization of hippocampal functional connectivity with transition to chronic back pain. J. Neurophysiol. 2014;111(5):1065–1076.
    1. Nahman-Averbuch H. Identification of neural and psychophysical predictors of headache reduction following cognitive behavioral therapy in adolescents with migraine. Pain. 2020 doi: 10.1097/j.pain.0000000000002029.
    1. Nelson S.M., Cunningham N.R., Kashikar-Zuck S. A conceptual framework for understanding the role of adverse childhood experiences in pediatric chronic pain. Clin. J. Pain. 2017;33:264–270.
    1. Neville A., Jordan A., Beveridge J.K., Pincus T., Noel M. Diagnostic uncertainty in youth with chronic pain and their parents. J. Pain. 2019;20(9):1080–1090.
    1. Neville A., Griep Y., Palermo T.M., Vervoort T., Schulte F., Yeates K.O., Sumpton J.E., Mychasiuk R., Noel M. A “dyadic dance”: pain catastrophizing moderates the daily relationships between parent mood and protective responses and child chronic pain. Pain. 2020;161(5):1072–1082.
    1. Noel M., Wilson A.C., Holley A.L., Durkin L., Patton M., Palermo T.M. Posttraumatic stress disorder symptoms in youth with vs without chronic pain. Pain. 2016;157(10):2277–2284.
    1. O'Doherty D.C.M., Tickell A., Ryder W., Chan C., Hermens D.F., Bennett M.R., Lagopoulos J. Frontal and subcortical grey matter reductions in PTSD. Psychiatry Res. Neuroimaging. 2017;266:1–9.
    1. O'Doherty D.C.M., Ryder W., Paquola C., Tickell A., Chan C., Hermens D.F., Bennett M.R., Lagopoulos J. White matter integrity alterations in post-traumatic stress disorder. Hum. Brain Mapp. 2018;39(3):1327–1338.
    1. Orr S.L., Kabbouche M.A., O’Brien H.L., Kacperski J., Powers S.W., Hershey A.D. Paediatric migraine: evidence-based management and future directions. Nat. Rev. Neurol. 2018;14(9):515–527.
    1. Özge A., Termine C., Antonaci F., Natriashvili S., Guidetti V., Wöber-Bingöl Ç. Overview of diagnosis and management of paediatric headache. Part I: diagnosis. J. Headache Pain. 2011;12(1):13–23.
    1. Pavlova M., Kopala-Sibley D.C., Nania C., Mychasiuk R., Christensen J., McPeak A., Tomfohr-Madsen L., Katz J., Palermo T.M., Noel M. Sleep disturbance underlies the co-occurrence of trauma and pediatric chronic pain: a longitudinal examination. Pain. 2020;161(4):821–830.
    1. Perosa V., Priester A., Ziegler G., Cardenas-Blanco A., Dobisch L., Spallazzi M., Assmann A., Maass A., Speck O., Oltmer J., Heinze H.-J., Schreiber S., Düzel E. Hippocampal vascular reserve associated with cognitive performance and hippocampal volume. Brain. 2020;143(2):622–634.
    1. B. L. Peterlin et al., Posttraumatic stress disorder in migraine. Headache 49, 541-551 (2009).
    1. Plaisier A., Pieterman K., Lequin M.H., Govaert P., Heemskerk A.M., Reiss I.K.M., Krestin G.P., Leemans A., Dudink J. Choice of diffusion tensor estimation approach affects fiber tractography of the fornix in preterm brain. AJNR Am. J. Neuroradiol. 2014;35(6):1219–1225.
    1. Reynolds, J.G., M.; Lebel, C., White Matter Tractography Guides. doi: 10.6084/m9.figshare.7603271.v1 (2019).
    1. Rocca M.A. Structural brain MRI abnormalities in pediatric patients with migraine. J. Neurol. 2014;261(2):350–357.
    1. Rosso I.M., Crowley D.J., Silveri M.M., Rauch S.L., Jensen J.E. Hippocampus glutamate and N-acetyl aspartate markers of excitotoxic neuronal compromise in posttraumatic stress disorder. Neuropsychopharmacology. 2017;42(8):1698–1705.
    1. Salberg S., Noel M., Burke N.N., Vinall J., Mychasiuk R. Utilization of a rodent model to examine the neurological effects of early life adversity on adolescent pain sensitivity. Dev. Psychobiol. 2020;62(3):386–399. doi: 10.1002/dev.v62.310.1002/dev.21922.
    1. Santoro J.D. Brain diffusion abnormalities in children with tension-type and migraine-type headaches. AJNR Am. J. Neuroradiol. 2018;39(5):935–941.
    1. Schilling K. Reproducibility and variation of diffusion measures in the squirrel monkey brain, in vivo and ex vivo. Magn. Reson. Imaging. 2017;35:29–38.
    1. Smith S.M., Jenkinson M., Woolrich M.W., Beckmann C.F., Behrens T.E.J., Johansen-Berg H., Bannister P.R., De Luca M., Drobnjak I., Flitney D.E., Niazy R.K., Saunders J., Vickers J., Zhang Y., De Stefano N., Brady J.M., Matthews P.M. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage. 2004;23:S208–S219.
    1. Soltani S., van Ryckeghem D.M.L., Vervoort T., Heathcote L.C., Yeates K., Sears C., Noel M. Attentional biases in pediatric chronic pain: an eye-tracking study assessing the nature of the bias and its relation to attentional control. Pain. 2020;161(10):2263–2273. doi: 10.1097/j.pain.0000000000001916.
    1. Suarez-Jimenez B. Neural signatures of conditioning, extinction learning, and extinction recall in posttraumatic stress disorder: a meta-analysis of functional magnetic resonance imaging studies. Psychol. Med. 2020;50(9):1442–1451. doi: 10.1017/S0033291719001387.
    1. Timmers I., Quaedflieg C.W.E.M., Hsu C., Heathcote L.C., Rovnaghi C.R., Simons L.E. The interaction between stress and chronic pain through the lens of threat learning. Neurosci. Biobehav. Rev. 2019;107:641–655.
    1. Tripathi G.M., Kalita J., Misra U.K. Role of glutamate and its receptors in migraine with reference to amitriptyline and transcranial magnetic stimulation therapy. Brain Res. 2018;1696:31–37.
    1. Vinall J., Miller S.P., Bjornson B.H., Fitzpatrick K.P.V., Poskitt K.J., Brant R., Synnes A.R., Cepeda I.L., Grunau R.E. Invasive procedures in preterm children: brain and cognitive development at school age. Pediatrics. 2014;133(3):412–421.
    1. Vinall J., Pavlova M., Asmundson G.J., Rasic N., Noel M. Mental health comorbidities in pediatric chronic pain: a narrative review of epidemiology, models, neurobiological mechanisms and treatment. Children (Basel) 2016;3
    1. Wakana S., Jiang H., Nagae-Poetscher L.M., van Zijl P.C.M., Mori S. Fiber tract-based atlas of human white matter anatomy. Radiology. 2004;230(1):77–87.
    1. Wrase J., Makris N., Braus D.F., Mann K., Smolka M.N., Kennedy D.N., Caviness V.S., Hodge S.M., Tang L., Albaugh M., Ziegler D.A., Davis O.C., Kissling C., Schumann G., Breiter H.C., Heinz A. Amygdala volume associated with alcohol abuse relapse and craving. Am. J. Psychiatry. 2008;165(9):1179–1184.
    1. Zarei M.R., Shabani M., Chamani G., Abareghi F., Razavinasab M., Nazeri M. Migraine patients have a higher prevalence of PTSD symptoms in comparison to chronic tension-type headache and healthy subjects: a case-control study. Acta Odontol. Scand. 2016;74(8):633–635.
    1. Zhang Y., Zhang J., Zhu S., Du C., Zhang W. Prevalence and predictors of somatic symptoms among child and adolescents with probable posttraumatic stress disorder: a cross-sectional study conducted in 21 primary and secondary schools after an earthquake. PLoS One. 2015;10

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