Potential Neurophysiological Markers of Combat-Related Post-Traumatic Stress Disorder: A Cross-Sectional Diagnostic Study

Abstract

BACKGROUND: Studies suggest that the components of brain-evoked potentials (EPs) may serve as biomarkers of the post-traumatic stress disorder (PTSD) caused by participation in combat operations; however, to date, research remains fragmented, with no studies that have attempted to combine different paradigms. In addition, the mismatch negativity component has not been studied in a Russian sample of veterans with PTSD.

AIM: To identify objective neurophysiological markers of combat-related PTSD using the method of auditory-evoked potentials in active and passive listening paradigms.

METHODS: The study included a recording of auditory EPs in an oddball paradigm in three settings: 1) directed attention to auditory stimuli, 2) passive listening while viewing a neutral video sequence, and 3) viewing a video sequence associated with a traumatic event. Combatants diagnosed with PTSD (18 people) were compared with mentally healthy civilian volunteers (22 people).

RESULTS: An increase in the latency period of the early components of auditory EP (N100 and P200), an increase in the amplitude of the P200 component to a deviant stimulus, and a decrease to a standard one in the active listening

paradigm were established in the PTSD group. There were no significant differences in the parameters of the P300 component. The characteristics of mismatch negativity in the passive paradigm were revealed: an increase in the phenomenon amplitude, both when shown a video sequence associated with a traumatic event and when shown a neutral video sequence. A binary logistic regression model constructed using the selected parameters showed that the identified characteristics can potentially be considered as diagnostic markers of PTSD in combatants, as the classification accuracy stood at 87% (sensitivity — 81%, specificity — 91%).

CONCLUSION: Potential neurophysiological markers of PTSD are the following: the amplitude and latency of early components of auditory EPs in the paradigm of directed attention to stimuli and the amplitude of mismatch negativity during passive attention.

Keywords

post-traumatic stress disorder / auditory evoked potentials / N100 / P200 / P300 / mismatch negativity / combatants

References

[1] Butt M, Espinal E, Aupperle RL, et al. The electrical aftermath: Brain signals of posttraumatic stress disorder filtered through a clinical lens. Front Psychiatry. 2019;10:368. doi: 10.3389/fpsyt.2019.00368

[2] Post-traumatic stress disorder. In: Soldatkina VA, editor. Rostov-on-Don: Rostov State Medical University; 2015. 624 p. Russian.

[3] Sukiasyan S. Posttraumatic or pеritraumatic disorders: A diagnostic dilemma. Current Therapy of Mental Disorders. 2022;(3):3–13. doi: 10.21265/PSYPH.2022.69.67.001

[4] Reznik AM, Kostyuk GP. Mental disorders in participants and veterans of military operations (conditions and mechanisms of development, clinical manifestations, approaches to psychiatric care, treatment). Moscow: “KDU”, “Doborsvet”; 2023. 176 p. doi: 10.31453/kdu.ru.978-5-7913-1284-6-2023-176

[5] Lytkin VM, Shamrey VK, Kostyuk GP. Concerning mental health problems of combatants. Russian Journal of Psychiatry. 2007;6:63–68.

[6] Zukerman G, Pinhas M, Icht M. Hypervigilance or shutdown? Electrophysiological processing of trauma-unrelated aversive stimuli after traumatic life events. Exp Brain Res. 2023;241(4):1185–1197. doi: 10.1007/s00221-023-06578-w

[7] Theodoratou M, Kougioumtzis GA, Yotsidi V, et al. Neuropsychological consequences of massive trauma: Implications and clinical interventions. Medicina (Kaunas). 2023;59(12):2128. doi: 10.3390/medicina59122128

[8] Nicholson AA, Densmore M, Frewen PA, et al. The dissociative subtype of Posttraumatic stress disorder: Unique resting-state functional connectivity of basolateral and centromedial amygdala complexes. Neuropsychopharmacol. 2015;40(10):2317–2326. doi: 10.1038/npp.2015.79

[9] Haris EM, Bryant RA, Williamson T, Korgaonkar MS. Functional connectivity of amygdala subnuclei in PTSD: A narrative review. Mol Psychiatry. 2023;28(9):3581–3594. doi: 10.1038/s41380-023-02291-w

[10] Khanna MM, Badura-Brack AS, McDermott TJ, et al. Veterans with post-traumatic stress disorder exhibit altered emotional processing and attentional control during an emotional Stroop task. Psychol Med. 2017;47(11):2017–2027. doi: 10.1017/S0033291717000460

[11] Volodarskaya AA, Lobachev AV, Marchenko AA, Habarov IJ. Prospects of using event-related potentials in medical examination of military mental disorders. Medicо-Biological and Socio-Psychological Problems of Safety in Emergency Situations. 2023;(2):75–88. doi: 10.25016/2541-7487-2023-0-2-75-88

[12] Morris DJ, Steinmetzger K, Tøndering J. Auditory event-related responses to diphthongs in different attention conditions. Neurosci Lett. 2016;626:158–163. doi: 10.1016/j.neulet.2016.05.002

[13] Zweerings J, Sarkheil P, Keller M, et al. Rt-fMRI neurofeedback-guided cognitive reappraisal training modulates amygdala responsivity in posttraumatic stress disorder. Neuroimage Clin. 2020;28:102483. doi: 10.1016/j.nicl.2020.102483

[14] Adenauer H, Pinösch S, Catani C, et al. Early processing of threat cues in posttraumatic stress disorder-evidence for a cortical vigilance-avoidance reaction. Biol Psychiatry. 2010;68(5):451–458. doi: 10.1016/j.biopsych.2010.05.015

[15] Zukerman G, Fostick L, Ben-Itzchak E. Early automatic hyperarousal in response to neutral novel auditory stimuli among trauma-exposed individuals with and without PTSD: An ERP study. Psychophysiology. 2018;55(11):e13217. doi: 10.1111/psyp.13217

[16] Löw A, Frey JD, Gorzka R, et al. Multifeature mismatch negativity in patients with posttraumatic stress disorder. Clin EEG Neurosci. 2019;50(3):147–153. doi: 10.1177/1550059418814976

[17] Marquardt CA, Pokorny VJ, Kang SS, et al. Posttraumatic stress symptom dimensions and brain responses to startling auditory stimuli in combat veterans. J Abnorm Psychol. 2021;130(5):455–467. doi: 10.1037/abn0000552

[18] Felmingham KL, Stewart LF, Kemp AH, Carr AR. The impact of high trait social anxiety on neural processing of facial emotion expressions in females. Biol Psychol. 2016;117:179–186. doi: 1010.1016/j.biopsycho.2016.04.001

[19] Wang HY, Li LZ, Chang Y, et al. Impaired implicit emotion regulation in patients with panic disorder: An event-related potential study on affect labeling. World J Psychiatry. 2024;14(2):234–244. doi: 10.5498/wjp.v14.i2.234

[20] Barkar AA, Markina LD. Cognitive evoked potentials, as additional criterion in the estimation of functional interhispare asymmetry. Asymmetry. 2019;13(2);17–23. doi: 10.25692/ASY.2019.13.2.003

[21] Felmingham KL, Bryant RA, Kendall C, Gordon E. Event-related potential dysfunction in posttraumatic stress disorder: the role of numbing. Psychiatry Res. 2002;15;109(2):171–179. doi: 10.1016/S0165-1781(02)00003-3

[22] Wang C, Rapp P, Darmon D, et al. Utility of P300 ERP in monitoring post-trauma mental health: A longitudinal study in military personnel returning from combat deployment. J Psychiatr Res. 2018;101:5–13. doi: 10.1016/j.jpsychires.2018.02.027

[23] Kimura M, Ueda M, Takeda Y, et al. Aftermath of 3/11: earthquakes and involuntary attentional orienting to sudden ambient sounds. Biol Psychol. 2013;94(2):419–425. doi: 10.1016/j.biopsycho.2013.08.008

[24] Shim M, Jin MJ, Im CH, Lee SH. Machine-learning-based classification between post-traumatic stress disorder and major depressive disorder using P300 features. Neuroimage Clin. 2019;24:102001. doi: 10.1016/j.nicl.2019.102001

[25] Näätänen R, Kujala T, Winkler I. Auditory processing that leads to conscious perception: a unique window to central auditory processing opened by the mismatch negativity and related responses. Psychophysiology. 2011;48(1):4–22. doi: 10.1111/j.1469-8986.2010.01114.x

[26] Menning H, Renz A, Seifert J, Maercker A. Reduced mismatch negativity in posttraumatic stress disorder: a compensatory mechanism for chronic hyperarousal? Int J Psychophysiol. 2008;68(1):27–34. doi: 10.1016/j. ijpsycho.2007.12.003

[27] Ge Y, Wu J, Sun X, Zhang K. Enhanced mismatch negativity in adolescents with posttraumatic stress disorder (PTSD). Int J Psychophysiol. 2011;79(2):231–235. doi: 10.1016/j.ijpsycho.2010.10.012

[28] Bangel KA, van Buschbach S, Smit DJA, et al. Aberrant brain response after auditory deviance in PTSD compared to trauma controls: An EEG study. Sci Rep. 2017;7(1):16596. doi: 10.1038/s41598-017-16669-8

[29] Ioakeimidis V, Lennuyeux-Comnene L, Khachatoorian N, et al. Trait and State Anxiety Effects on Mismatch Negativity and Sensory Gating Event-Related Potentials. Brain Sci. 2023;13(10):1421. doi: 10.3390/brainsci13101421

[30] Wang C, Costanzo ME, Rapp PE, et al. Identifying Electrophysiological Prodromes of Post-traumatic Stress Disorder: Results from a pilot study. Front Psychiatry. 2017;8:71. doi: 10.3389/fpsyt.2017.00071

[31] Yurtaev SS. The methodology of instrumental (psychophysiological) diagnostics of post-traumatic stress disorder. Psychology. Historical-critical Reviews and Current Researches. 2019;8(3A):81–90.

[32] Quillivic R, Gayraud F, Auxéméry Y, et al. Interdisciplinary approach to identify language markers for post-traumatic stress disorder using machine learning and deep learning. Sci Rep. 2024;14(1):12468. doi: 10.1038/s41598-024-61557-7

[33] Chernyavsky EA, Zelenina NV, Yusupov VV, Grigorov AV. The application of modern psychophysiological hardware and software complexes in prediction of resistance to combat psychological stress. Russian Military Medical Academy Reports. 2022;41(3):277–282. doi: 10.17816/rmmar83952

[34] Li Q, Coulson Theodorsen M, Konvalinka I, et al. Resting-state EEG functional connectivity predicts post-traumatic stress disorder subtypes in veterans. J Neural Eng. 2022;19(6). doi: 10.1088/1741-2552/ac9aaf

[35] Eda TA, Fusun DM, Sakir G, et al. The effect of disease severity and chronic CPAP-therapy on cognitive functions and event related potentials in OSAS. Ideggyogy Sz. 2023;30;76(3–4):129–139. doi: 10.18071/isz.76.0129

[36] Miller LN, Simmons JG, Whittle S, et al. The impact of posttraumatic stress disorder on event-related potentials in affective and non-affective paradigms: A systematic review with meta-analysis. Neurosci Biobehav Rev. 2021;122:120–142. doi: 10.1016/j.neubiorev.2020.12.027

[37] Mitrofanov A, Kichuk I, Rusalova M, et al. The development of the automated discriminant analysis of the EEG to Distinguish Two Classes. Психология. Psychology. Journal of the Higher School of Economics. 2020:17(2):223–249. doi: 10.17323/1813-8918-2020-2-223-249

[38] Annanmaki T, Palmu K, Murros K, Partanen J. Altered N100-potential associates with working memory impairment in Parkinson’s disease. J Neural Transm (Vienna). 2017;124(10):1197–1203. doi: 10.1007/s00702-017-1758-z

[39] Tarawneh HY, Mulders WHAM, Sohrabi HR, et al. Investigating auditory electrophysiological measures of participants with mild cognitive impairment and Alzheimer’s disease: A systematic review and meta-analysis of event-related potential studies. J Alzheimers Dis. 2021;84(1):419–448. doi: 10.3233/JAD-210556

[40] Wang B, Otten LJ, Schulze K, et al. Is auditory processing measured by the N100 an endophenotype for psychosis? A family study and a meta-analysis. Psychol Med. 2024;54(8):1559–1572. doi: 10.1017/S0033291723003409

[41] Fickling SD, Smith AM, Stuart MJ, et al. Subconcussive brain vital signs changes predict head-impact exposure in ice hockey players. Brain Commun. 2021;3(2):fcab019. doi: 10.1093/braincomms/fcab019

[42] Schramm M, Goregliad Fjaellingsdal T, Aslan B, et al. Electrophysiological evidence for increased auditory crossmodal activity in adult ADHD. Front Neurosci. 2023;17:1227767. doi: 10.3389/fnins.2023.1227767

Funding

Moscow Center for Innovative Technologies in HealthcareМосковский центр инновационных технологий в здравоохранении(0903-7/23)

RIGHTS & PERMISSIONS

Telesheva K., Savenkova V., Morozova I., Ochneva A., Zeltser A., Andreyuk D., Reznik A., Mukhin V., Melkonian G., Lytkina K., Mitrofanov A., Morozova A.