Neuro-Psychiatric Symptoms in Civilian Survivors of Urban Missile Attacks

doi:10.21203/rs.3.rs-1500108/v1

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Research article

Neuro-Psychiatric Symptoms in Civilian Survivors of Urban Missile Attacks

https://doi.org/10.21203/rs.3.rs-1500108/v1

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published 13 Jun, 2023

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Background: Blast-explosion may cause traumatic brain injury (TBI), leading to post-concussion syndrome (PCS). In studies on military personnel, PCS symptoms are highly similar to those occurring in post-traumatic-stress-disorder (PTSD), questioning the overlap between these syndromes. In the current study we assessed PCS and PTSD in civilians following exposure to rocket attacks. We hypothesized that PCS symptomatology and brain connectivity will be associated with the objective physical exposure, while PTSD symptomatology will be associated with the subjective mental experience.

Methods: 289 residents of explosion-sites have participated in the current study. Participants completed self-report of PCS and PTSD. The association between objective and subjective factors of blast and clinical outcomes was assessed using multivariate analysis. White-matter (WM) alterations and cognitive abilities were assessed in a sub-group of participants (n=46) and non-exposed controls (n=16). Non-parametric analysis was used to compare connectivity and cognition between the groups.

Results: Blast-exposed individuals reported higher PTSD and PCS symptomatology. Among exposed individuals, those who were directly exposed to blast, reported higher levels of subjective feeling of danger and presented WM hypoconnectivity. Cognitive abilities did not differ between groups. Several risk-factors for the development of PCS and PTSD were identified.

Conclusions: Civilians exposed to blast present higher PCS/PTSD symptomatology as well as WM hypoconnectivity. Although symptoms are sub-clinical, they might lead to the future development of a full-blown syndrome and should be considered carefully. The similarities between PCS and PTSD suggest these are not distinct syndromes, but rather represent different ends on a spectrum of a combined disorder.

Blast

PTSD

mTBI

PCS

Blast-explosion may cause a traumatic brain injury (TBI)¹ with injury magnitude depending on factors such as blast energy and distance from the epicenter. In mild-TBI (mTBI), a variety of physical, emotional, and cognitive symptoms are reported², and when these persist over 3 months, they are referred to as post-concussion syndrome (PCS)³. The pathophysiology underlying PCS is not-yet fully understood, since similar symptomatology is reported in other trauma victims^4–5 and specifically in individuals with post-traumatic-stress-disorder (PTSD). PTSD can develop following the exposure to a life threatening event, if the individual felt in-danger, and suffers from re-experiencing, avoidance, hyper-arousal and negative alterations in cognition and mood^6–7. The peritraumatic-response (i.e., feeling in-danger, scared or helpless at the time of the event) is a potential predictor for future PTSD^8–9.

Whereas other types of brain injury can be assessed using routine neuroimaging, PCS remains a challenge for such assessment, since the damage is associated with small, diffused, brain alterations (i.e., diffuse axonal injury, DAI) that cannot be viewed on computerized tomography (CT) or Magnetic Resonance Imaging (MRI) scans. DAI reflects white-matter (WM) damage from sustained forces acting on the brain, shearing axons and microscopic changes^10–11 and can only be visualized using diffusion-tensor imaging (DTI)^12–17. Microstructural changes in the brain were evident in rats following exposure¹⁸ and repeated exposure¹⁹ to blast wave, suggesting these might underlie PCS symptomatology in humans as well. Despite inconsistencies²⁰, numerous mTBI studies in humans report abnormal diffusion in frontal association, projection and commissural fibers^{14–17, 21–24}.

Although blast-related-TBI²⁵ can occur in civilian settings, most studies in the field were conducted on military personnel leaving the etiology and prognosis of civilian blast-related-TBI unaddressed²⁶. The current study employed a multidisciplinary approach to examine PCS/PTSD unique and overlapping features in blast-exposed civilians. Physical and mental exposures were examined by studying subjective self-reported symptomatology, objective measures of cognitive abilities, and WM alterations. We hypothesized that exposure to blast would lead to PCS/PTSD symptoms. Specifically, we hypothesized that blast impact would lead to objective WM alterations and cognitive deficits manifesting as PCS symptoms; and that mere exposure to blast would lead to a subjective emotional experience manifesting as PTSD symptoms.

Methods

Standard Protocol Approvals, Registrations, and Patient Consents

The study was approved by the Soroka University Medical Center Institutional Review Board (IRB) and all participants gave their written informed consent for participation. The current study is an ecological observational evaluation of clinical symptomatology, cognitive abilities and neuroimaging in a non-clinical exposed population sample that was conducted in two phases.

Identification of recruitment sites

Following the completion of operation “Protective-Edge” in Israel (July-August 2014), rocket explosion sites were identified within the residential area of the city of Beer-Sheva using military official reports and media coverage, cross-linked, and verified with local citizens’ reports. Four explosion sites, sustaining only one BM-21 Grad missile explosion during the operation, and never sustaining similar events in the past 10 years, were chosen.

Participants’ recruitment and screening

Participants’ enrollment began three weeks after the last rocket attack in the city of Beer-Sheva (August 2014) and lasted for ~ 2 years. Recruitment was performed from all four sites in parallel. Systematic door-to-door screening was performed by study personnel in and near the impact sites, starting from the vicinity of the explosion areas and up to a radius distance of 500 meters from the explosion site. Participants above the age of 18 who agreed to participate in the study were recruited. Individuals that were unable to sign an informed consent form and/or complete a self-report questionnaire, as well as individuals who were not living in the same address or were not in their home during the missile attack, were excluded from the study. Upon meeting all inclusion criteria, participants were given an explanation about the study and signed an informed-consent form.

Overall, 301 Beer-Sheva residents living in a range of 500 meters from four impact sites were recruited to “phase 1” of the study, 12 of which had met exclusion criteria, thus a total of 289 individuals participated in this phase of the study (see CONSORT table, Fig. 1).

Blast physical exposure assessment

Measures of residence-distance from the impact site were collected from maps, air photographs and physical survey of the site. The exposure of each participant to blast was evaluated according to his/her residency address, based on two parameters:

(a) Level of exposure – residency addresses were classified as “directly-exposed” when the residency building was in open “sightline” to the explosion site allowing full blast wave exposure, or “indirectly-exposed” when such a sightline was obstructed by other structures.

(b) Distance from impact site– the physical distance (in meters) of the residence building from the impact site.

Demographic and clinical symptom reports

Participants completed the following self-report questionnaires, with the presence of study personnel:

(a) Demographic (e.g., age, gender, employment history, as well as physical and mental health record) and rocket exposure questionnaires.

(b) The Rivermead Post-concussion syndrome Questionnaire (RPQ²⁷): a self-report measure of PCS assessing symptom severity following mTBI consisting of 16 post-concussion symptoms. For each symptom, participants are asked to rate the degree to which each symptom has been absent or a mildly/moderately/severely changed over the previous 24 hours compared with the month prior to the event. Responses are scored on a 5-point Likert scale ranging from '0' = “did not change at all” to '4' = “worsen very much”. A PCS severity score is calculated by counting the number of existing symptoms. A score of 2 and above is considered as a positive PCS diagnosis. Two additional scores are derived: RPQ-3 relates to the existence of early symptom clusters and RPQ-13 which relates to later, psychosocial symptoms²⁸.

(c) The Post-Traumatic Diagnostic Scale for DSM IV (PDS-4^29–30) is a self-report measure of PTSD related to a single-identified traumatic event. The PDS assesses the presence and nature of the trauma (item-A1), the emotional subjective response during the event (item-A2), as well as symptom severity (i.e., items B-D). The subjective response (A2) includes a positive response to at least one of the following questions: “Did you feel in-danger?”, “Did you feel helpless?”, and “Did you feel scared?”. Symptom severity, on each of the 17 DSM-IV PTSD symptoms, is rated on a scale from 0 (“not at all or only one time”) to 3 (“5 or more times a week/almost always”), with total scores ranging from 0–51. In the current study we examined both the subjective response and overall severity.

Statistical analysis

Descriptive statistics of demographic and clinical characteristics for nominal variables are presented as n (%), continuous variables with normal distribution are presented as mean ± standard deviation (SD) whereas variables with non-normal distribution are presented as medians and inter-quartile range (IQR). Univariate comparison was held between exposure-groups (directly-exposed versus indirectly-exposed). Information regarding participants’ age is depicted by mean ± SD and was compared via Students’ T-test; variables that are depicted by n(%) were compared via Pearson’s Chi-square, these include demographic information (gender, marital status, education, army service, and history of head-trauma) and subjective emotional experience (i.e., DSM-IV stressor criteria A2); lastly, post-exposure symptoms’ severity (both PCS and PTSD) are depicted by Median and IQR, these were compared via Man-Whitney U test.

Multivariate analysis was then performed to assess the degree of association between physical and emotional blast-related factors (i.e., direct/indirect exposure, distance from blast and DSM-IV stressor criteria A2) and clinical outcomes – PCS and PTSD symptoms’ severity, assessed by RPQ and PDS respectively. These were adjusted to demographic characteristics, medical history of head trauma and impact site. The four neighborhoods surrounding the four impact sites differed in demographic characteristics. To account for these differences, a Generalized Linear Mixed Model (GLMM) was applied, with the impact site as a random effect. The GLMM, adjusted for clustered population by blast-site, was performed for each independent variable and each outcome. All models are adjusted for gender, age at the time of the blast, medical history of head trauma and the time passed from the explosion to the interview (in weeks). Results are presented as odds ratio (OR) with 95% confidence interval (CI).

Data were analyzed using IBM Statistical Package for Social Sciences (SPSS, version 24©).

Results

Tables 1a and 1b depict demographical and clinical characteristics of the study population, as well as experience related factors of the blast exposure and the primary outcomes.

Table 1

Population characteristics by level of blast exposure (direct vs. indirect)
A. Demographical characteristics
Population characteristics	Total 289 (100%)	Direct exposure 58 (20%)	Indirect exposure 231 (80%)	p-value
Age at time of explosion ^a	45 ± 17	49 ± 20	44 ± 16	0.060
Gender (Males) ^b	104 [36%]	21 [37%]	83 [36%]	0.900
Marital status (married) ^b	209 [72%]	31 [55%]	178 [80%]	< 0.001
Education years ^a	14.5 ± 4	13 ± 5	15 ± 4	0.030
Employed ^b	190 [66%]	30 [55%]	160 [73%]	0.010
Past military service ^b	183 [63%]	28 [50%]	155 [74%]	0.001
History of head trauma ^b	54 [19%]	10 [18%]	44 [20%]	0.740
B. Clinical characteristics
Emotional experience during explosion (A2 criteria)
Felt danger during blast ^b	83 [29%]	24 [41%]	59 [26%]	0.017
Felt helplessness during blast ^b	76 [26%]	18 [31%]	58 [25%]	0.359
Felt scared during blast ^b	92 [32%]	23 [40%]	69 [30%]	0.153
Post-exposure symptoms’ severity
PTSD (PDS score) ^c	1 [0–7]	3 [0–8]	1 [0–6]	0.076
Post-Concussion (RPQ score) ^c	2 [0–18]	2 [0–17]	2 [0–18]	0.361
RPQ3 score ^c	0 [0–2]	0 [0–3]	0 [0–2]	0.706
RPQ13 score ^c	4 [0-15.5]	2.5 [0–15]	4 [0–16]	0.359
Note. Table 1 shows population characteristics including demographic characteristics (A), parameters assessing the emotional experience of the blast and post exposure symptom severity depicted by PDS and RPQ scores (B). Univariate analysis was held to assess the difference between participants who suffered from a direct or an indirect exposure to the blast. ^a=variables are depicted by Mean ± SD and compared via Students’ T-test; ^b=variables are depicted by n(%) and compared via Pearson’s Chi-square; ^c=variables are depicted by Median and [IQR] and compared via Man-Whitney U test. Statistically significant results appear in bold.

Participants

Statistical analysis was performed on 289 subjects who met all inclusion criteria. Univariate analysis comparing the direct- versus indirect-exposure groups yielded no statistically significant differences in age, gender or history of head trauma (p > .05). The groups significantly differed in years of education (M_{indirectly−exposed}=15, SD = 4, M_{directly−exposed}=13, SD = 5, p = .03), marital status, and employment (N_{indirectly−exposed}>N_{direct−exposed}, p < .001, p < .01, respectively) (Table 1a).

Clinical symptomatology

A significant linear correlation was observed between PTSD symptom severity (as measured via the PDS questionnaire) and PCS symptom severity (as measured via the RPQ questionnaire) ,r = .714, N = 289, p = .000. This correlation remained significant when computed separately for exposure groups; r_{indirectly-exposed}=.702, N = 231, p = .000 and r_{direct-exposed}=.789, N = 58, p = .000, with no significant difference between exposure groups (z = 1.31, p = .095). As can be seen in Table 1b, PTSD symptom severity was within the lower end of the mild range. PCS symptom severity was also within the low range for early and late symptom clusters. No statistically significant differences were found between directly- and indirectly-exposed participants in subjective reports of PTSD or PCS symptom severity. Notwithstanding, the DSM-IV stressor criteria A2 corresponding to the peritraumatic experience, significantly differed between exposure-groups, with directly-exposed individuals reporting higher levels of feeling-in-danger during the explosion (41% vs. 26%, p = .017).

Multivariate analysis via GLMM showed risk factors for higher PTSD and PCS symptoms, adjusted for demographic and clinical parameters, and clustered by neighborhoods (i.e., impact-sites). Female gender was a risk factor for the development of both PTSD and PCS symptoms (OR 0.4 (95% CI 0.263–0.609), OR 0.38 (95% CI 0.243–0.609) for PTSD and PCS, respectively). Proximity to the explosion site was a risk factor for the development of PTSD symptoms (OR 0.905 (95% CI 0.822–0.998)). A history of head trauma, time passed since the explosion, and feeling scared were all risk factors for the development of PCS symptoms (OR 1.779 (95% CI 1.023–3.093), OR 1.013 (95% CI 1.005–1.021), and OR 1.707 (95% CI 1.050–2.774) for history of head trauma, time passed and subjective feeling, respectively), see Fig. 2.

To summarize, the peritraumatic experience differed between the exposure groups and was also associated with PTSD symptoms. Furthermore, we identified several risk factors for both PTSD and PCS symptomatology; these include female gender (for both syndromes); proximity to the explosion site (PTSD); and history of head trauma, time passed since the explosion, and feeling scared (PCS).

Methods

Participants’ Recruitment And Screening

Of the 289 participants who took part in “Phase 1”, participants willing to undergo cognitive and imaging tests and presented no contraindications to MRI, were invited to participate in the next phase of the study (“Phase 2”) at Soroka University Medical Center, Beer-Sheva, Israel. Overall, 46 phase 2 individuals completed a cognitive assessment battery; of those, 42 eligible participants underwent MRI (see CONSORT table, Fig. 1). In addition, a control group of 16 non-blast-exposed age, gender and education matched individuals was recruited (all participated in the imaging phase, 15 completed cognitive tests). Following definition of participants in phase 1 (i.e., directly/indirectly-exposed), control group participants were defined “unexposed”.

Cognition

Cognitive functioning was assessed using a computerized test battery (Mindstreams ® NeuroTrax Corp., Newark, NJ) in Hebrew. The Mindstreams battery is a patented, scientifically validated computerized cognitive assessment system that assesses performance across an array of cognitive domains. Participants' performance is compared to age-and-education matched controls and then normalized, yielding scores with an average of 100 and SD of 15. Scores within 1 SD of the average (the 85–115 range) represent normal or average abilities. The system has been validated with several populations such as mild-cognitive impairment patients – MCI^31− 32, Attention-Deficit Hyperactivity Disorder (ADHD^33− 34) schizophrenia³⁵ and depression³⁶ and is recognized as a standard research tool for cognitive assessment.

MRI and DTI data acquisition & processing

Scans were acquired using a 3-Tesla scanner (Ingenia, Philips Medical Systems), and included: Anatomical scans (3D-TFE T1-w, TR/TE = 8.1/3.7ms, field of view (FOV) 256 mm, 150 slices); T2-w and FLAIR sequences were acquired as part of a clinical routine. DTI data were acquired on the same scanner using a single-shot echo-planar imaging (EPI) sequence with SENSE parallel imaging (reduction factor = 2.5). 60 Axial slices of 2.0 mm (zero-gap) thickness were acquired parallel to the anterior-posterior commissure line (AC-PC). The in-plane acquisition resolution was 2.88 × 3.58 mm. The DTI data were acquired along 33 directions with b = 1000 s/mm². A TR/TE = 9000/106 milliseconds (ms) was used without cardiac gating for a total acquisition time of 6:21 min for each dataset. All fiber tracking was performed using mrDiffusion, an open source package written by the Vision, Imaging Science and Technology Activities (VISTA) lab at Stanford, CA, USA (http://web.stanford.edu/group/vista/cgi-bin/wiki/index.php/Software), and in-house Matlab (Mathworks, Natick, MA) scripts. In total, 4 average diffusion parameters (fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD)) were calculated for each tract (n = 20, automatically defined by the mrDiffusion package) and for each participant.

Statistical analysis

Descriptive statistics of demographic and clinical characteristics for nominal variables are presented as n (%), continuous variables with normal distribution are presented as mean ± SD whereas variables with non-normal distribution are presented as medians and IQR. Univariate comparison was held between exposure-groups (exposed versus non-exposed, directly-exposed versus indirectly-exposed). Information regarding participants’ age is depicted by mean ± SD and was compared via Students’ T-test; variables that are depicted by n(%) were compared via Pearson’s Chi-square (these include information regarding gender, education, army service, medical history and history of head-trauma); lastly, post-exposure symptoms’ severity (both PCS and PTSD) as well as cognitive performance are depicted by Median and IQR, these were compared via Man-Whitney U test.

Results

Table 2 depicts demographical, clinical characteristics and cognitive outcomes of participants that underwent “phase 2” and performed neuroimaging and cognitive evaluation for the exposed and unexposed (control) groups.

Table 2

Population characteristics by exposure to blast and level of exposure (direct vs. indirect) for cognition and imaging sub population
Population characteristics		Direct exposure N = 13 (22%)	Indirect exposure N = 29 (50%)	No exposure N = 16 (28%)	Exposed vs. non-exposed (p-value)	Direct vs. indirect (p-value)
Age at interview ^a		37 ± 14	49 ± 18	54 ± 16	0.083	0.024
Gender (Males) ^b		5 [38.5%]	10 [34.5%]	9 [56%]	0.156	0.804
Education ^b Elementary High school Academic		1 (8%] 5 [38.5%] 7 [53.5%]	1 [4%] 12 [43%] 15 [54%]	0 6 [40%] 9 [60%]	0.665	0.839
Past military service ^b		10 [77%]	20 [69%]	11 [85%]	0.340	0.598
Chronic medication ^b		3 [23%]	13 [48%]	3 [23%]	0.269	0.130
History of head trauma ^b		4 [31%]	6 [21%]	4 [29%]	0.722	0.478
Post-exposure symptoms’ severity
PTSD (PDS score) ^c	3 [0.5–13.5]		3 [0-15.5]	0 [0–4]	0.033	0.966
RPQ3 ^c	0 [0–4]		0 [0–2]	0 [0–0]	0.033	0.621
RPQ13 ^c	4 [0-21.5]		8 [0–11]	5.5 [0–9]	0.444	0.831
Post-Concussion (RPQ score ^c	1 [0–15]		4 [0–7]	4 [0–6]	0.564	0.940
Cognition^d
Memory ^c	103 [97–106]		99 [84–105]	102 [90–105]	0.760	0.211
Executive function ^c	107 [96–112]		104 [97–111]	98 [85–105]	0.168	0.693
Visual spatial ^c	105 [89–116]		97 [86–111]	104 [90–114]	0.448	0.219
Verbal function ^c	107 [99–113]		101 [69–110]	103 [96–109]	0.831	0.249
Attention ^c	104 [96–107]		102 [92–109]	99 [93–106]	0.737	1.000
Information ^c processing speed	105 [96–118]		105 [95–109]	97 [91–109]	0.283	0.560
Motor skills ^c	101 [97–107]		104 [100–108]	102 [96–111]	0.976	0.486
Global cognitive ^c assessment	104 [100–108]		101 [90–106]	98 [92–105]	0.556	0.154
Note. Table 2 shows demographic and clinical characteristics for sub-population divided by direct exposure, indirect exposure and no exposure to blast. Univariate comparison was held between exposed vs. non-exposed participants and direct vs. indirect levels of explosion. ^a=variables are depicted by Mean ± SD and compared via Students’ T-test; ^b=variables are depicted by n(%) and compared via Pearson’s Chi-square; ^c=variables are depicted by Median and [IQR] and compared via Man-Whitney U test. Statistically significant results are highlighted. ^d=Data for the no-exposure group is reported for 15 participants.

Participants

Statistical analysis was performed on 58 subjects who met all inclusion criteria. Univariate analysis comparing the direct (n = 13) versus indirect-exposed (n = 29) yielded a significant difference in age with the direct-exposed group being significantly younger (M_{indirectly−exposed}=49, SD = 18, M_{direct−exposed}=37, SD = 14, p = .024). No other significant differences in demographic characteristics were found.

Clinical symptomatology

Post-exposure symptom severity analysis showed significant differences between exposed and unexposed participants in both PTSD and PCS symptoms (p = .03 for both PDS and RPQ-3) with directly-exposed participants showing higher levels of symptoms’ severity compared to indirect-exposed participants.

Cognition

Directly exposed (n = 13), indirectly exposed (n = 29) and unexposed (controls, n = 15) participants completed the Mindstreams test battery. There were no significant differences in cognitive abilities between the groups (Table 2).

Imaging

We first compared DTI data between exposed (direct- and indirect-exposed, n = 42) and unexposed control (n = 16) participants. For tracts showing a significant difference in diffusion parameters between these groups, we next compared DTI parameters between direct- and indirect-exposed participants to determine the impact of blast exposure magnitude. This comparison resulted in significant differences between the two exposure groups in the following tracts and parameters: 1) The left inferior fronto-occipital fasciculus (IFOF) FA values (z=-2.08, p = .037); 2); 2) The right IFOF AD values (z=-2.42, p = .015); 3) The left and right thalamic radiation AD values (z=-2.93, p = .003; z=-2.56, p = .01, respectively); 4) The left arcuate AD values (z=-2.09, p = .036); 5) The right superior longitudinal fasciculus (SLF) AD values (z=-2.59, p = .009). Importantly, for all tracts and parameters, directly-exposed participants showed lower FA/AD values compared to indirectly-exposed suggesting exposure level affected WM integrity (Fig. 3). WM hypoconnectivity and symptom severity were not associated.

To summarize, exposed participants (direct- and indirect) showed higher subjective symptomatology compared to unexposed controls. Furthermore, when comparing direct- and indirectly-exposed individuals, directly-exposed individuals presented hypoconnectivity in specific WM tracts.

In the current study we used an ecological approach to explore the association of two major components of an explosion in an urban setting: an objective component- the physical impact of the blast; and a subjective component- the emotional experience. We combined self-reports of PCS and PTSD symptomatology with objective measurements of cognitive functioning and alterations in WM neuro-anatomical connectivity. The study population is a community based, non-clinical cohort, recruited based on place of residence and vicinity to the impact-site.

The results of phase 1 showed that PCS and PTSD self-reported symptom severity did not differ between directly- and indirectly-exposed individuals. However, the subjective component of the exposure (the peritraumatic response, DSM-IV criteria A2) was significantly elevated among directly-exposed individuals. Regardless of levels of exposure, we identified several risk factors for the development of PCS and PTSD symptoms. These included both objective (history of head injury, physical distance, time since exposure and female gender) and subjective (the peritraumatic response, A2) factors. In phase 2 we found that blast-exposure was significantly associated with both PTSD and PCS symptomatology, as both direct and indirect-exposed participants (compared to unexposed controls) reported higher symptom severity. Finally, directly-exposed individuals showed hypoconnectivity in specific WM tracts. Taken together, our findings suggest that individuals who were exposed to blast, reported higher PTSD and PCS symptomatology compared to unexposed individuals. Among exposed individuals, those who were directly exposed, reported significantly higher feeling of danger, and presented specific WM hypoconnectivity.

Our findings highlight differences between exposed and unexposed individuals in the subjective experience to the traumatic event. In studies on clinical populations, it has been shown that the subjective experience of fear during the event was associated with later development of PTSD symptoms⁸. Recent studies show that the peritraumatic response that occurs at the time, or immediately after the trauma, is a predictor of later PTSD⁹. Thus, although directly exposed individuals did not report higher PTSD symptomatology overall, one of the major predictors for later PTSD was elevated in this group.

Following our hypothesis, WM connectivity was modulated by exposure to the impact-site, with WM diffusion alterations occurring in direct-exposed participants solely. In the mTBI literature, multifocal WM lesions causing disruptions of the axolemma and neurofilament organization are considered as representations of microscopic changes that result from sustained acceleration and deceleration forces associated with blast exposure^10–11. Lower AD values are thus considered indicative of axonal injury^37–39 and may imply on differential blast-impact in residences from different exposure levels. Unlike our hypothesis, these WM diffusion alterations did not correlate with clinical symptoms or with cognitive abilities. Several meta-analyses and reviews^40–41 also demonstrated inconsistencies regarding the specificity of DTI findings and their correlation with clinical symptoms. Studies on blast exposure, primarily in military populations, also resulted in conflicting findings^42–45. Our imaging results demonstrate that WM DTI alterations can be found following the exposure to blast explosion in an urban environment. Such findings indicate that WM alterations can be evident even following the exposure to minor blast waves and are not a result of intense exposure solely.

The unique study setup and design allowed us to explore the association between PCS symptomatology and the level of exposure to the physical effect of the explosion, e.g., the blast wave. The symptoms of PCS are usually considered to be sequelae of a head injury, and if this is the case, we would have expected them to be most prevalent and severe close to the epicenter of the blast wave. Namely, that directly-exposed individuals would show higher PCS symptoms. Our data demonstrated no such association, questioning the role played by the physical blast in causing such symptoms. Several observations have previously questioned the attribution of the PCS symptom cluster to physical head trauma. For example, post-concussive symptoms were found to occur at similar rates in trauma victims who sustained mTBI and in those who did not⁴⁶. Soldiers with mTBI were significantly more likely to report a high number of somatic and post-concussive symptoms than soldiers with other injuries⁴⁷. However, the impact of these post-concussive symptoms became non-significant after PTSD and depression were considered. In a large prospective observational study⁴⁸, emotional distress and maladaptive coping experienced early after brain injury, in combination with pre-injury mental health problems, education, and age, predicted recovery at six months following mTBI. mTBI is associated with high rates of PTSD, in both military and civilian populations, and especially in blast related head injury⁴⁹. It is not clear if the physical impact or the psychological trauma is associated with the syndrome. In our cohort, female gender, history of head trauma, time passed since the exposure and the subjective feeling of being scared, all served as risk factors for PCS symptomatology. Importantly, these risk factors were identified in previous studies on PTSD/PCS symptomatology in studies on blast-explosion in military personnel^{50, 51}. The coexistence of a highly similar set of objective and subjective risk factors for both disorders, highlights the complexity in differential diagnosis between the two and may suggest that they are not distinct symptom clusters. Alternatively, the current findings suggest they represent a spectrum of a combined disorder that may develop as a result of a physical injury, or as a result of multiple objective and subjective trauma-related factors.

Advances in neuroscience, and in unraveling the brain mechanisms underlying PCS and PTSD, have made the historical discussion⁵² about “neurogenic” versus “psychogenic” etiology obsolete. Representing different models of brain activity, PCS and PTSD are neither psychogenic nor neurogenic⁵³, rather, they should be referred to as a combined biopsychological disorder. Our study attempts to approach this issue from a multidisciplinary approach, dissecting head trauma into two elements, physical (the blast) and psychological (the experience), and evaluating the contribution of both to symptomatology. This kind of dissection is difficult in most cohorts and study designs, since neither the impact nor the experience can be quantified, but when it is feasible, it may allow better understanding of the disorders.

The current study has several limitations. The study evaluates blast-related symptomatology in a unique and innovative design. Nevertheless, it is a retrospective study, and therefore its generalizability is limited. It is also limited by the fact that recruitment was performed during an extended period of time, and that imaging was performed on a single time point in a sub-group of the study cohort. Although it provides further insight into the relationship between PCS and PTSD, due to its cohort retrospective nature it cannot establish causality between PCS and PTSD to blast-exposure. Future studies enabling repeated measures of subjective and objective aspects of blast exposure, might provide further insight into the trajectory of these two syndromes over time. Such studies would also allow the establishment of biomarkers that would help guide diagnosis and prevention.

Taken together, the current findings suggest that exposure to blast affects both objective, neuro-physical (i.e., WM alterations) and subjective, mental (i.e., feeling in danger) aspects. Differences in emotional experience were limited to the peritraumatic experience and not to symptom severity overall. It is possible that these specific, but significant, differences are sub-clinical manifestations of the full-blown PCS/PTSD disorder. Furthermore, it is possible that the observed alterations in WM neuro-anatomical connectivity and mental experience will predict future escalation, as the strength of the peritraumatic response is reported as a predictor of future development of PTSD^8–9, and WM alterations in similar tracts was reported to be associated with PTSD symptom severity and cognitive deficits^54–55. Overall, our findings suggest that even if they are not clinically diagnosed, individuals who are directly exposed to explosion blast, suffer from mental and WM neuro-anatomical changes and should thus be considered a population at risk for the future development of PTSD and/or PCS. To the best of our knowledge, this is the first systematic report of the long-term effects of blast-related PCS/PTSD in civilian population. While some of the findings were similar to those reported in military populations, others were somewhat different thus highlight the importance of blast consequences in civilians²⁵ and the need to study them carefully.

Traumatic brain injury (TBI)

Mild traumatic brain injury (mTBI)

Post-concussion syndrome (PCS)

Post-traumatic-stress-disorder (PTSD)

White-matter (WM)

Diffuse axonal injury (DAI)

Computerized tomography (CT)

Magnetic Resonance Imaging (MRI)

Diffusion-tensor imaging (DTI)

Institutional Review Board (IRB)

Rivermead Post-concussion syndrome Questionnaire (RPQ)

Post-Traumatic Diagnostic Scale (PDS)

Diagnostic and statistical manual of mental disorders (DSM)

Inter-quartile range (IQR)

Generalized Linear Mixed Model (GLMM)

Odds ratio (OR)

Confidence interval (CI)

Statistical Package for Social Sciences (SPSS)

Mild-cognitive impairment patients (MCI)

Attention-Deficit Hyperactivity Disorder (ADHD)

Field of view (FOV)

Fractional anisotropy (FA)

Mean diffusivity (MD)

Radial diffusivity (RD)

Axial diffusivity (AD)

Inferior fronto-occipital fasciculus (IFOF)

Superior longitudinal fasciculus (SLF)

Ethics approval and consent to participate: The study was approved by the Soroka University Medical Center Institutional Review Board (IRB) and all participants gave their written informed consent for participation.

Consent for publication: Not applicable.

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests: The authors declare that they have no competing interests.

Funding: The study was funded by the ADELIS foundation.

Authors' contributions: Conceived and designed the experiments: GI, AF, HS, HC, IS. Performed the experiments: RS, NZ, LO, YD. Analyzed the data: RS, SN, YD, LO, VN. Contributed reagents/materials/analysis tools: GI, AF, IS, HS, VN. Wrote the paper: RS, SN, GI. All authors read and approved the final manuscript.

Acknowledgements: Not applicable.

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Editorial decision: Major revision
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You are reading this latest preprint version

Neuro-Psychiatric Symptoms in Civilian Survivors of Urban Missile Attacks

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Phase 1

Methods

Standard Protocol Approvals, Registrations, and Patient Consents

Identification of recruitment sites

Participants’ recruitment and screening

Blast physical exposure assessment

Demographic and clinical symptom reports

Statistical analysis

Results

Participants

Clinical symptomatology

Phase 2

Methods

Participants’ Recruitment And Screening

Cognition

MRI and DTI data acquisition & processing

Statistical analysis

Results

Participants

Clinical symptomatology

Cognition

Imaging

General Discussion

Conclusion

Abbreviations

Declarations

Consent for publication: Not applicable.

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Funding: The study was funded by the ADELIS foundation.

Acknowledgements: Not applicable.

References

Status:

Journal Publication

Version 1