Abstract
Background
Posttraumatic stress disorder (PTSD) is a debilitating disorder, and there is no current
accurate prediction of who develops it after trauma. Neurobiologically, individuals
with chronic PTSD exhibit aberrant resting-state functional connectivity (rsFC) between
the hippocampus and other brain regions (e.g., amygdala, prefrontal cortex, posterior
cingulate), and these aberrations correlate with severity of illness. Previous small-scale
research (n < 25) has also shown that hippocampal rsFC measured acutely after trauma is predictive
of future severity using a region-of-interest–based approach. While this is a promising
biomarker, to date, no study has used a data-driven approach to test whole-brain hippocampal
FC patterns in forecasting the development of PTSD symptoms.
Methods
A total of 98 adults at risk of PTSD were recruited from the emergency department
after traumatic injury and completed resting-state functional magnetic resonance imaging
(8 min) within 1 month; 6 months later, they completed the Clinician-Administered
PTSD Scale for DSM-5 for assessment of PTSD symptom severity. Whole-brain rsFC values
with bilateral hippocampi were extracted (using CONN) and used in a machine learning
kernel ridge regression analysis (PRoNTo); a k-folds (k = 10) and 70/30 testing versus training split approach were used for cross-validation
(1000 iterations to bootstrap confidence intervals for significance values).
Results
Acute hippocampal rsFC significantly predicted Clinician-Administered PTSD Scale for
DSM-5 scores at 6 months (r = 0.30, p = .006; mean squared error = 120.58, p = .006; R2 = 0.09, p = .025). In post hoc analyses, hippocampal rsFC remained significant after controlling
for demographics, PTSD symptoms at baseline, and depression, anxiety, and stress severity
at 6 months (B = 0.59, SE = 0.20, p = .003).
Conclusions
Findings suggest that functional connectivity of the hippocampus across the brain
acutely after traumatic injury is associated with prospective PTSD symptom severity.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological Psychiatry: Cognitive Neuroscience and NeuroimagingAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Diagnostic and Statistical Manual of Mental Disorders.5th ed. American Psychiatric Association, Arlington, VA2013
- Trauma-Informed Care in Behavioral Health Services. Rockville, (MD): Substance Abuse and Mental Health Services Administration.(Available at:)
- Screening and treating hospitalized trauma survivors for posttraumatic stress disorder and depression.J Trauma Acute Care Surg. 2019; 87: 440-450
- Posttraumatic stress disorder after injury: Does admission to intensive care unit increase risk?.J Trauma. 2010; 69: 627-632
- Early intervention may prevent the development of posttraumatic stress order: A randomized pilot civilian study with modified prolonged exposure.Biol Psychiatry. 2012; 72: 957-963
- Early intervention following trauma may mitigate genetic risk for PTSD in civilians: A pilot prospective emergency department study.J Clin Psychiatry. 2014; 75: 1380-1387
- Pre-deployment risk factors for PTSD in active-duty personnel deployed to Afghanistan: A machine-learning approach for analyzing multivariate predictors.Mol Psychiatry. 2020;
- A validated predictive algorithm of post-traumatic stress course following emergency department admission after a traumatic stressor.Nat Med. 2020; 26: 1084-1088
- Computational causal discovery for post-traumatic stress in police officers.Transl Psychiatry. 2020; 10: 233
- Amygdala functional connectivity in the acute aftermath of trauma prospectively predicts severity of posttraumatic stress symptoms.Neurobiol Stress. 2020; 12: 100217
- Neural indices of emotional reactivity and regulation predict course of PTSD symptoms in combat-exposed veterans.Prog Neuropsychopharmacol Biol Psychiatry. 2018; 82: 255-262
- Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma.Nat Neurosci. 2002; 5: 1242-1247
- Default mode network connectivity as a predictor of post-traumatic stress disorder symptom severity in acutely traumatized subjects.Acta Psychiatr Scand. 2010; 121: 33-40
- Structural connectivity of the posterior cingulum is related to reexperiencing symptoms in posttraumatic stress disorder.Chronic Stress (Thousand Oaks). 2018; 2 (2470547018807134)
- Multi-voxel pattern analysis of amygdala functional connectivity at rest predicts variability in posttraumatic stress severity.Brain Behav. 2020; 10e01707
- Amygdala response to negative stimuli predicts PTSD symptom onset following a terrorist attack.Depress Anxiety. 2014; 31: 834-842
- Genetic predictors of hippocampal subfield volume in PTSD cases and trauma-exposed controls.Eur J Psychotraumatol. 2020; 11: 1785994
- Altered resting-state functional connectivity of basolateral and centromedial amygdala complexes in posttraumatic stress disorder.Neuropsychopharmacology. 2014; 39: 351-359
- A review of hippocampal activation in post-traumatic stress disorder.Psychophysiology. 2020; 57e13357
- Functional neuroanatomy of emotion and its regulation in PTSD.Harv Rev Psychiatry. 2018; 26: 116-128
- A cognitive model of posttraumatic stress disorder.Behav Res Ther. 2000; 38: 319-345
- Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder.Biol Psychiatry. 2009; 66: 1075-1082
- Amygdala, medial prefrontal cortex, and hippocampal function in PTSD.Ann N Y Acad Sci. 2006; 1071: 67-79
- Emotion and episodic memory in neuropsychiatric disorders.Behav Brain Res. 2010; 215: 162-171
- Reduced hippocampal and amygdala activity predicts memory distortions for trauma reminders in combat-related PTSD.J Psychiatr Res. 2011; 45: 660-669
- Traumatic stress: Effects on the brain.Dialogues Clin Neurosci. 2006; 8: 445-461
- Suppression of adult neurogenesis impairs population coding of similar contexts in hippocampal CA3 region.Nat Commun. 2012; 3: 1253
- Effects of traumatic stress on brain structure and function: Relevance to early responses to trauma.J Trauma Dissociation. 2005; 6: 51-68
- Hippocampal function during associative learning in patients with posttraumatic stress disorder.J Psychiatr Res. 2009; 43: 309-318
- Increased activation of the left hippocampus region in Complex PTSD during encoding and recognition of emotional words: A pilot study.Psychiatry Res. 2009; 171: 44-53
- Post-traumatic stress disorder and declarative memory functioning: A review.Dialogues Clin Neurosci. 2011; 13: 346-351
- Episodic and semantic components of autobiographical memories and imagined future events in post-traumatic stress disorder.Memory. 2014; 22: 595-604
- Neural substrates of overgeneralized conditioned fear in PTSD.Am J Psychiatry. 2017; 174: 125-134
- Impaired contextual modulation of memories in PTSD: An fMRI and psychophysiological study of extinction retention and fear renewal.J Neurosci. 2014; 34: 13435-13443
- Exposure-based therapy changes amygdala and hippocampus resting-state functional connectivity in patients with posttraumatic stress disorder.Depress Anxiety. 2018; 35: 974-984
- Abnormalities in whole-brain functional connectivity observed in treatment-naive post-traumatic stress disorder patients following an earthquake.Psychol Med. 2014; 44: 1927-1936
- Default mode network subsystems are differentially disrupted in posttraumatic stress disorder.Biol Psychiatry Cogn Neurosci Neuroimaging. 2017; 2: 363-371
- Altered default mode network configuration in posttraumatic stress disorder after earthquake: A resting-stage functional magnetic resonance imaging study.Medicine. 2017; 96: e7826
- Neural dysregulation in posttraumatic stress disorder: Evidence for disrupted equilibrium between salience and default mode brain networks.Psychosom Med. 2012; 74: 904-911
- Hippocampal network connectivity and activation differentiates post-traumatic stress disorder from generalized anxiety disorder.Neuropsychopharmacology. 2013; 38: 1889-1898
- MRI findings in posttraumatic stress disorder.J Magn Reson Imaging. 2020; 52: 380-396
- The functional neuroanatomy of PTSD: A critical review.Prog Brain Res. 2008; 167: 151-169
- Functional neuroimaging of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia.Am J Psychiatry. 2007; 164: 1476-1488
- Context processing and the neurobiology of post-traumatic stress disorder.Neuron. 2016; 92: 14-30
- Brain network disturbance related to posttraumatic stress and traumatic brain injury in veterans.Biol Psychiatry. 2015; 78: 210-216
- Functional connectivity of hippocampal subregions in PTSD: Relations with symptoms.BMC Psychiatry. 2018; 18: 129
- Anterior hippocampal dysconnectivity in posttraumatic stress disorder: A dimensional and multimodal approach.Transl Psychiatry. 2017; 7: e1045
- Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD.Am J Psychiatry. 2001; 158: 1248-1251
- Hippocampal volume in psychiatric diagnoses: Should psychiatry biomarker research account for comorbidities?.Chronic Stress (Thousand Oaks). 2020; 4 (2470547020906799)
- Stability of hippocampal subfield volumes after trauma and relationship to development of PTSD symptoms.Neuroimage. 2021; 236: 118076
- Volume and shape analysis of the hippocampus and amygdala in veterans with traumatic brain injury and posttraumatic stress disorder.Brain Imaging Behav. 2020; 14: 1850-1864
- MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder.Am J Psychiatry. 2003; 160: 924-932
- Stress effects on neuronal structure: Hippocampus, amygdala, and prefrontal cortex.Neuropsychopharmacology. 2016; 41: 3-23
- Hippocampal-amygdala resting state functional connectivity serves as resilience factor for short- and long-term stress exposure.Biol Psychiatry. 2020; 87: S88-S89
- Early altered resting-state functional connectivity predicts the severity of post-traumatic stress disorder symptoms in acutely traumatized subjects.PLoS One. 2012; 7e46833
- Prognostic neuroimaging biomarkers of trauma-related psychopathology: Resting-state fMRI shortly after trauma predicts future PTSD and depression symptoms in the AURORA study.Neuropsychopharmacology. 2021; 46: 1263-1271
- Psychological burden of PTSD, depression, and their comorbidity in the U.S. veteran population: Suicidality, functioning, and service utilization.J Affect Disord. 2019; 256: 633-640
- Comorbidity between post-traumatic stress disorder and major depressive disorder: Alternative explanations and treatment considerations.Dialogues Clin Neurosci. 2015; 17: 141-150
- The use of machine learning techniques in trauma-related disorders: A systematic review.J Psychiatr Res. 2020; 121: 159-172
- Decoding the traumatic memory among women with PTSD: Implications for neurocircuitry models of PTSD and real-time fMRI neurofeedback.PLoS One. 2015; 10e0134717
- Quantitative prediction of individual psychopathology in trauma survivors using resting-state fMRI.Neuropsychopharmacology. 2014; 39: 681-687
- Prediction of illness severity in patients with major depression using structural MR brain scans.J Magn Reson Imaging. 2012; 35: 64-71
- Abnormal brain activation during directed forgetting of negative memory in depressed patients.J Affect Disord. 2016; 190: 880-888
- Whole-brain resting-state functional connectivity identified major depressive disorder: A multivariate pattern analysis in two independent samples.J Affect Disord. 2017; 218: 346-352
- Prediction of individual clinical scores in patients with Parkinson’s disease using resting-state functional magnetic resonance imaging.J Neurol Sci. 2016; 366: 27-32
- What do differences between multi-voxel and univariate analysis mean? How subject-, voxel-, and trial-level variance impact fMRI analysis.Neuroimage. 2014; 97: 271-283
- Detecting neuroimaging biomarkers for depression: A meta-analysis of multivariate pattern recognition studies.Biol Psychiatry. 2017; 82: 330-338
- Neural decoding and “inner” psychophysics: A distance-to-bound approach for linking mind, brain, and behavior.Front Neurosci. 2016; 10: 190
- Hippocampal subfield alterations in pediatric patients with post-traumatic stress disorder.Soc Cogn Affect Neurosci. 2021; 16: 334-344
- Diagnostic potential of multimodal neuroimaging in posttraumatic stress disorder.PLoS One. 2017; 12e0177847
- The validity of the PTSD checklist as a measure of symptomatic change in combat-related PTSD.Behav Res Ther. 2001; 39: 977-986
- The differential diagnostic accuracy of the PTSD Checklist among men versus women in a community sample.Psychiatry Res. 2014; 220: 679-686
- The Glasgow Coma Scale.J Emerg Med. 2000; 19: 67-71
- The Glasgow Coma Scale at 40 years: Standing the test of time.Lancet Neurol. 2014; 13: 844-854
- The PTSD Checklist for DSM-5 (PCL-5) – Standard [Measurement instrument].(Available at:)
- The Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5): Development and initial psychometric evaluation..J Trauma Stress. 2015; 28: 489-498
- The Clinician-Administered PTSD Scale for DSM–5 (CAPS-5): Development and initial psychometric evaluation in military veterans.Psychol Assess. 2018; 30: 383-395
- Manual for the Depression Anxiety Stress Scales.2nd ed. Psychology Foundation, Sydney1995
- Psychometric properties of the 21-item Depression Anxiety Stress Scale (DASS-21).Afr Res Rev. 2018; 12: 135
- Conn: A functional connectivity toolbox for correlated and anticorrelated brain networks.Brain Connect. 2012; 2: 125-141
- Modeling geometric deformations in EPI time series.Neuroimage. 2001; 13: 903-919
- The slice-timing problem in event-related fMRI.Wellcome Department of Cognitive Neurology, Institute of Neurology, London, United Kingdom1999 (Available at:)https://www.fil.ion.ucl.ac.uk/spm/doc/papers/rnah_slicetime.pdfDate accessed: March 14, 2021
- Methods to detect, characterize, and remove motion artifact in resting state fMRI.Neuroimage. 2014; 84: 320-341
- Recent progress and outstanding issues in motion correction in resting state fMRI.Neuroimage. 2015; 105: 536-551
- Unified segmentation.Neuroimage. 2005; 26: 839-851
- Smoothing and cluster thresholding for cortical surface-based group analysis of fMRI data.Neuroimage. 2006; 33: 1093-1103
- An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets.Neuroimage. 2003; 19: 1233-1239
- Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain.Neuroimage. 2002; 15: 273-289
- PRoNTo: Pattern recognition for neuroimaging toolbox.Neuroinformatics. 2013; 11: 319-337
- A comparative study of pairwise learning methods based on kernel ridge regression.Neural Comput. 2018; 30: 2245-2283
- Adaptive identification of cortical and subcortical imaging markers of early life stress and posttraumatic stress disorder.J Neuroimaging. 2019; 29: 335-343
- PRoNTo Manual.University of College London, London2018
Schrouff J, Cremers J, Garraux G, Baldassare L, Mourao-Miranda J, Phillips C (2013): Localizing and comparing weight maps generated from linear kernel machine learning models. Presented at the International Workshop on Pattern Recognition in Neuroimaging (PRNI), June 22–24, Philadelphia, Pennsylvania.
- PTSD and its dissociative subtype through the lens of the insula: Anterior and posterior insula resting-state functional connectivity and its predictive validity using machine learning.Psychophysiology. 2020; 57e13472
- On the interpretation of weight vectors of linear models in multivariate neuroimaging.Neuroimage. 2014; 87: 96-110
- Psychometric properties of nine scoring rules for the Clinician-Administered Posttraumatic Stress Disorder Scale.Psychol Assess. 1999; 11: 124-133
- Feature adjustment in kernel space when using cross-validation.(Available at)http://www.cs.ucl.ac.uk/fileadmin/UCL-CS/research/Research_Notes/RN_17_09_ARJMM.pdfDate: 2017Date accessed: March 14, 2021
- Individualized prediction of PTSD symptom severity in trauma survivors from whole-brain resting-state functional connectivity.Front Behav Neurosci. 2020; 14: 563152
- Using structural neuroanatomy to identify trauma survivors with and without post-traumatic stress disorder at the individual level.Psychol Med. 2014; 44: 195-203
- Exploring memory function in earthquake trauma survivors with resting-state fMRI and machine learning.BMC Psychiatry. 2020; 20: 43
- Identifying disease foci from static and dynamic effective connectivity networks: Illustration in soldiers with trauma.Hum Brain Mapp. 2018; 39: 264-287
- New roles for the cerebellum in health and disease.Front Syst Neurosci. 2013; 7: 83
- Structural alterations within cerebellar circuitry are associated with general liability for common mental disorders.Mol Psychiatry. 2018; 23: 1084-1090
- The emerging importance of the cerebellum in broad risk for psychopathology.Neuron. 2019; 102: 17-20
- Altered large-scale functional brain organization in posttraumatic stress disorder: A comprehensive review of univariate and network-level neurocircuitry models of PTSD.Neuroimage Clin. 2020; 27: 102319
- Posttraumatic stress disorder in the national comorbidity survey.Arch Gen Psychiatry. 1995; 52: 1048-1060
- The nature and course of subthreshold PTSD.J Anxiety Disord. 2010; 24: 918-923
- Rates of subthreshold PTSD among U.S. military veterans and service members: A literature review.Mil Psychol. 2017; 29: 117-127
- Characterization of post-traumatic stress disorder using resting-state fMRI with a multi-level parametric classification approach.Brain Topogr. 2015; 28: 221-237
- Classifying heterogeneous presentations of PTSD via the default mode, central executive, and salience networks with machine learning.Neuroimage Clin. 2020; 27: 102262
- Predicting sample size required for classification performance.BMC Med Inform Decis Mak. 2012; 12: 8
- Center for Epidemiologic Studies Depression Scale: Review and Revision (CESD and CESD-R).in: Maruish M.E. The Use of Psychological Testing for Treatment Planning and Outcomes Assessment: Instruments for Adults. 3rd ed. Lawrence Erlbaum, Mahwah, NJ2004: 363-377
Article info
Publication history
Published online: August 31, 2021
Accepted:
August 22,
2021
Received in revised form:
July 18,
2021
Received:
March 14,
2021
Identification
Copyright
© 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Identifying Neurobiological Markers of Posttraumatic Stress Disorder Using Resting-State Functional Magnetic Resonance Imaging Data: The Promise of Data-Driven Computational ApproachesBiological Psychiatry: Cognitive Neuroscience and NeuroimagingVol. 7Issue 2
- PreviewCurrent psychiatric research, evaluation, and treatment rely on a diagnostic system based almost exclusively on subjective data, such as self-reported experiences and questionnaires, rather than on more objective markers. Recent advances in computational power have enabled the increasing use of data-driven computational approaches aiming to identify objective neural markers for diagnosing psychopathology (i.e., classifying subjects as either patients or healthy control subjects), predicting illness onset and development, and predicting treatment response.
- Full-Text
- Preview
