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. 2025 Apr 10;58(2):220–228. doi: 10.5115/acb.24.200

Age-dependent brain subcortical white and gray matter disruptions in patients with posttraumatic stress disorder

Kambiz Kangarlou 1, Samira Raminfard 2, Jayran Zebardast 2, Elham Faghihzadeh 3, Bahman Jalali Kondori 4,5,
PMCID: PMC12178690  PMID: 40204642

Abstract

Posttraumatic stress disorder (PTSD) is a psychiatric condition that can develop after experiencing a traumatic event, and it is associated with a range of functional and structural brain abnormalities. This study aimed to investigate age-related differences in subcortical gray and white matter in veterans with PTSD. This study recruited 44 patients with PTSD and 48 healthy controls. Participants were divided into two age groups to evaluate structural magnetic resonance imaging analysis. The results showed that individuals with PTSD had significantly smaller subcortical gray matter volumes, including the bilateral thalamus, hippocampus, amygdala, left pallidum, and right accumbens-area (P<0.05). Diffusion tensor imaging analyses revealed lower fractional anisotropy in several white matter structures, including the anterior limb of the internal capsule, anterior corona radiata, and cingulum in both hemispheres (P<0.05). Additionally, the mean diffusivity was higher in the anterior limb of the internal capsule, anterior corona radiata and the right external capsule (P<0.05). A comparative analysis between two age groups, over 50 and under 50 years old, showed that younger PTSD patients had a reduction in volume and abnormality in the corresponding white matter in more regions compared to the control group. These findings suggest that PTSD is associated with significant structural alterations in the brain, which may contribute to the pathophysiology of the disorder. So, patient age is an effective factor in exposure to traumatic events and an older age is continuously associated with a worsening traumatic brain injury outcome.

Keywords: Posttraumatic stress disorder, Gray matter, White matter, Diffusion tensor imaging

Introduction

Posttraumatic stress disorder (PTSD) is a cognitive disorder that is characterized by recurrent symptoms such as nightmares, flashbacks, hyperarousal or numbing, and avoidance of trauma-related situations. It is associated with problems in concentration, attention, and memory, as well as difficulty in recalling the details of the traumatic event [1]. In military veterans, the prevalence of PTSD is almost double that of the general population [2]. The clinical presentation of PTSD can vary depending on age, and it is likely that these differences may be seen in the types of symptoms experienced by different age groups [3, 4]. Neuroimaging studies have revealed changes in functional neuroanatomy such as executive function, emotional regulation, and contextual processing, as well as abnormalities in multiple frontal-limbic system structures [5]. One of the common methods for investigating neuroanatomical changes in PTSD is an estimation of gray matter volume [6, 7]. Magnetic resonance imaging (MRI) scans have shown focal atrophy of gray matter [8, 9], altered fractional anisotropy (FA) [10], and altered connectivity [11]. The hippocampus and amygdala are thought to play a critical role in PTSD due to their involvement in learning and memory processes as well as stress regulation [12].

Other MRI studies have implicated that different brain regions and the white matter tracts connecting these regions are associated with PTSD pathophysiology [13]. Diffusion tensor imaging (DTI) measures water diffusion in white matter, quantifying the integrity of structural networks, and can be used to identify changes associated with disease [14, 15]. FA and mean diffusivity (MD) are two diffusion parameters related to white matter integrity [16]. Studies have used tractography to investigate the organization of white matter in people with PTSD [17]. Results from these studies have indicated decreased FA and possible MD elevation in certain brain regions, such as the cingulum bundle, frontal tracts, and superior longitudinal fasciculus. It is thought that these alterations may be reflective of differences in emotional processing, memory, and learning. The aim of this study was to evaluate age-related differences in subcortical gray matter and corresponding white matter in veterans with PTSD.

Materials and Methods

Participants

In this study, 44 male patients (mean age of 39.72±11.96 SD) with blast-exposure associated PTSD, as well as 48 healthy controls (mean age of 35.45±10.57 SD), were recruited for evaluation of age-specific alterations in the volume of deep brain nuclei and corresponding white matter structure. To this end, two age groups were established: those under 50 and those over 50, based on previous research indicating that reductions in subcortical structure volume begin around the age of 50 [18]. Demographic data were shown in Table 1. All cases provided written informed consent before the study. This study was approved by review board of the Iran University of Medical Sciences (Ethical ID: IR.IUMS.REC.1398.158).

Table 1.

Demographic data of participants

Mean±SD
Age (yr)
PTSD (n=44) 39.72±11.96
Control (n=48) 35.45±10.57
Age group over 50 (yr)
PTSD (n=14) 54.58±2.69
Control (n=9) 53.44±2.58
Age group under 50 (yr)
PTSD (n=30) 32.56±6.70
Control (n=39) 30.84±6.35

PTSD, posttraumatic stress disorder.

All participants were assessed using the structured clinical interview for DSM-IV. PTSD symptom severity was administered by a clinical psychologist and rated with the Clinician-Administered PTSD Scale (mean score=70, SD=37).

We acquired structural data for the evaluation of brain regions volume and then employed the DTI technique to reconstruct the white matter integrity and structural network with nodes defined as 90 brain regions. Finally, graph theory and nonparametric tests were applied to analyze topological properties and perform group comparisons of the topological metrics.

Magnetic resonance imaging acquisition

All imaging was performed on a 3T MRI machine (Siemens) in the National Brain Mapping Lab (Iran) with the following protocols:

Sagittal 3D-MPRage (TR=1,800 ms, TE=3.53 ms, TI=1,100 ms, acquisition matrix=256×256×160 mm, FOV=25.6, and voxel size=1×1×1 mm3).

DTI acquired using a pulsed-gradient spin-echo sequence (TR=9,900 ms, TE=90 ms, acquisition matrix=128×128×65 mm, FOV=25.6, voxel size=2×2×2 mm3, b-factor=0, and 1,000 s/mm2 with 5 and 64 gradient directions respectively).

Image analysis

Volumetry

Automated segmentation and cortical and subcortical gray matter volume calculation and estimation of total intracranial volume (TIV) from T1 images were performed using the FreeSurfer image analysis suite, which is documented and freely available for download online (https://surfer.nmr.mgh.harvard.edu/) [19]. Preprocessing of the raw T1-weighted images using recon-all command was performed to preprocess all images through standard steps, including motion correction and averaging, removal of non-brain tissue and skull-stripping, automated talairach transformation, segmentation of subcortical white and gray matter, transformation to MNI305 atlas space, intensity normalization, and volumetric registration.

Diffusion tensor imaging

All DTI were preprocessed using Explore DTI 4.8.6 analysis package (Image Sciences Institute) [20]. Preprocessing was performed for the correction of eddy-current-induced distortion, head motion, and echoplanar imaging susceptibility distortion by co-registering. Whole-brain tractography was executed by fitting a diffusion tensor model to DTI data using a deterministic streamline approach. The criteria were as follows, seed point resolution of 1 mm3, step size 1, angle threshold of >30, and FA value of <0.2. Diffusion metrics including FA and MD were calculated for 48 white matter tracts in two hemispheres using the International Consortium of Brain Mapping (ICBM) white matter atlas which was acquired under an initiative of the ICBM.

Statistical analysis

All statistical analyses were performed in SPSS version 21 (IBM Co.) software. The two-sample t-test showed significant differences in subcortical gray volume between the two groups and age-adjusted groups, respectively. The independent t-test and two-sample t-test revealed significant differences in DTI parameters between the two groups and age-adjusted groups, respectively. The results indicated smaller subcortical gray matter volumes and lower FA and higher MD in certain white matter structures in individuals with PTSD compared to controls, with P-values less than 0.05.

Results

Subcortical gray volume

The statistical results for subcortical gray volume without age adjustment are shown in Table 2. There are significant differences in brain structure between individuals with PTSD and normal controls. Specifically, individuals with PTSD had significantly smaller subcortical gray matter volumes than those in the control group. Additionally, the mean volumes of the bilateral thalamus, hippocampus, amygdala, left pallidum, and right accumbens-area were also significantly smaller in individuals with PTSD than those in the control group (Fig. 1).

Table 2.

Subcortical gray volume between posttraumatic stress disorder patients and control

Subcortical gray volume
Region Group Volume P-value
Left-thalamus Control 8,417.577±732.0050 0.001
PTSD 7,809.800±880.9861
Left-pallidum Control 2,196.435±198.2683 0.028
PTSD 2,103.375±200.8944
Left-hippocampus Control 4,471.440±431.0384 0.000
PTSD 4,125.943±447.2402
Left-amygdala Control 1,696.073±179.2565 0.150
PTSD 1,603.991±176.4120
Right-thalamus Control 8,128.575±634.1157 0.001
PTSD 7,646.036±775.3228
Right-hippocampus Control 4,698.829±431.1111 0.000
PTSD 4,351.991±428.8777
Right-amygdala Control 1,890.606±171.4803 0.004
PTSD 1,778.109±189.8123
Right-accumbens-area Control 607.788±101.3822 0.034
PTSD 561.566±105.6302
Subcortical gray volume Control 62,808.83±4,864.708 0.001
PTSD 59,435.86±4,757.594

Values are presented as mean±SD. PTSD, posttraumatic stress disorder.

Fig. 1.

Fig. 1

The regions with volume reduction in posttraumatic stress disorder patients. Bilateral thalamus (Th), hippocampus (Hipp), amygdala (Amy), right accumbens-area (Acc) and left pallidum (Pall).

Subcortical gray volume between two age groups

The statistical results for subcortical gray volume between the two age groups are shown in Table 3. There are significant differences in left thalamus volume in the age group over 50, between PTSD (mean±SD 7,742.078±666.0446) and normal controls (mean±SD 7,067.007±784.6620). In the age group of under 50, we show a significant reduction in the volume of the bilateral thalamus, caudate, hippocampus, amygdala, left pallidum, and right accumbens area (Fig. 2).

Table 3.

Subcortical gray volume between age-adjusted groups

Region Group Volume P-value
Volume between groups >50 (yr)
Left-thalamus Control 7,742.078±666.0446 0.045
PTSD 7,067.007±784.6620
Volume between groups <50 (yr)
Left-thalamus Control 8,573.462±660.5571 0.013
PTSD 8,156.437±695.8189
Left-caudate Control 3,761.923±502.9450 0.040
PTSD 3,510.180±482.6031
Left-pallidum Control 2,241.390±181.8835 0.033
PTSD 2,140.463±200.9493
Left-hippocampus Control 4,537.338±405.3977 0.001
PTSD 4,200.490±360.1487
Left-amygdala Control 1,729.872±165.9505 0.036
PTSD 1,644.680±160.1835
Right-thalamus Control 8,259.415±558.4764 0.011
PTSD 7,862.020±700.7490
Right-caudate Control 3,743.313±506.0341 0.032
PTSD 3,484.013±465.4479
Right-hippocampus Control 4,750.462±429.5512 0.002
PTSD 4,436.040±369.4460
Right-amygdala Control 1,918.715±156.3686 0.009
PTSD 1,814.413±164.7256
Right-accumbens-area Control 631.259±90.8417 0.008
PTSD 568.017±101.5126

Values are presented as mean±SD. PTSD, posttraumatic stress disorder.

Fig. 2.

Fig. 2

The regions with volume reduction in the age group of under 50 years old posttraumatic stress disorder patients. Bilateral thalamus (Th), hippocampus (Hipp), amygdala (Amy), caudate (Cau), right accumbens-area (Acc) and left pallidum (Pall).

Diffusion tensor imaging parameters

The significant result of DTI parameters (FA and MD) between total cases of PTSDs and normal controls are shown in Table 4. Significant differences were observed in the several white matter structures. The FA of certain brain white matters, including the anterior limb of the internal capsule, anterior corona radiata, external capsule in both hemispheres, left cingulum, and fornix, is lower in individuals with PTSD compared to controls. Additionally, the MD of the anterior limb of the internal capsule, anterior corona radiata, and cingulum in both hemispheres and the right external capsule are higher in individuals with PTSD compared to normal controls.

Table 4.

Fractional anisotropy between posttraumatic stress disorder and control

Region Group Values P-value
FA total
Anterior limb of internal capsule L Control 0.51±0.023 0.000
PTSD 0.49±0.029
Anterior limb of internal capsule R Control 0.51±0.031 0.100
PTSD 0.50±0.028
Anterior corona radiata L Control 0.41±0.024 0.001
PTSD 0.39±0.024
Anterior corona radiata R Control 0.42±0.024 0.000
PTSD 0.40±0.025
External capsule L Control 0.38±0.020 0.380
PTSD 0.37±0.022
External capsule R Control 0.39±0.020 0.210
PTSD 0.38±0.026
Cingulum (cingulate gyrus) L Control 0.27±0.033 0.100
PTSD 0.26±0.031
Fornix (cres) striaterminalis R Control 0.36±0.034 0.032
PTSD 0.35±0.039
MD total
Anterior limb of internal capsule L Control 0.00070±0.000022 0.020
PTSD 0.00073±0.000081
Anterior limb of internal capsule R Control 0.00070±0.000023 0.032
PTSD 0.00072±0.000074
Anterior corona radiata L Control 0.00072±0.000033 0.012
PTSD 0.00075±0.000052
Anterior corona radiata R Control 0.00072±0.000032 0.018
PTSD 0.00074±0.000058
External capsule R Control 0.00075±0.000022 0.040
PTSD 0.00077±0.000065
Cingulum (cingulate gyrus) L Control 0.00074±0.000023 0.002
PTSD 0.00077±0.000050
Cingulum (cingulate gyrus) R Control 0.00074±0.000024 0.014
PTSD 0.00076±0.000046

Values are presented as mean±SD. FA, fractional anisotropy; MD, mean diffusivity; R, right; L, left; PTSD, posttraumatic stress disorder.

Diffusion tensor imaging parameters between two age groups

The colored FA map of brain tracts in PTSDs groups (0ver and under 50 years old) are shown in Fig. 3. The statistical result between the age groups of over 50 and under 50 years old have been demonstrated in Table 5. The result shows that veterans with PTSD in the age group of over 50 years old have significant lower FA in the left anterior limb of the internal capsule in comparison to normal people in the same age range. PTSDs in the age group of under 50 years show significant changes in the number of fiber tracts. The left anterior limb of the internal capsule, bilateral anterior corona radiata, superior corona radiata, and right external capsule in the veterans with PTSD had a significant lower amount than those in the normal controls.

Fig. 3.

Fig. 3

The whitened area in each slices show fractional anisotropy reduction of brain tracts in two age groups posttraumatic stress disorder patients (over and under 50 years old). From left to tight, bilateral anterior corona radiata, external capsule, and anterior limb of internal capsule.

Table 5.

The result of diffusion tensor imaging parameters between age-adjusted groups

Region Group Values P-value
FA between groups >50 (yr)
Anterior limb of internal capsule Control 0.51±0.019 0.006
PTSD 0.47±0.034
Anterior corona radiata L Control 0.40±0.032 0.522
PTSD 0.38±0.031
Anterior corona radiata R Control 0.40±0.024 0.214
PTSD 0.39±0.025
Superior corona radiata L Control 0.44±0.022 0.214
PTSD 0.43±0.021
External capsule R Control 0.38±0.020 0.680
PTSD 0.37±0.019
FA between groups <50 (yr)
Anterior limb of internal capsule Control 0.51±0.024 0.047
PTSD 0.49±0.024
Anterior corona radiata L Control 0.41±0.022 0.003
PTSD 0.40±0.021
Anterior corona radiata R Control 0.42±0.024 0.004
PTSD 0.40±0.025
Superior corona radiata L Control 0.47±0.019 0.000
PTSD 0.45±0.017
Superior corona radiata R Control 0.46±0.022 0.000
PTSD 0.44±0.022
External capsule R Control 0.39±0.021 0.019
PTSD 0.37±0.024
MD between groups >50 (yr)
Anterior limb of internal capsule L Control 0.00070±0.00019 0.522
PTSD 0.00071±0.00022
Anterior corona radiata L Control 0.00074±0.00025 0.256
PTSD 0.00076±0.00024
Anterior corona radiata R Control 0.00074±0.00022 0.680
PTSD 0.00075±0.00023
External capsule R Control 0.00077±0.00019 0.522
PTSD 0.00079±0.00020
Cingulum L Control 0.00092±0.00010 0.039
PTSD 0.00102±0.00011
MD between groups <50 (yr)
Anterior limb of internal capsule L Control 0.00070±0.00014 0.004
PTSD 0.00072±0.00021
Anterior corona radiata L Control 0.00072±0.00027 0.004
PTSD 0.00074±0.00018
Anterior corona radiata R Control 0.00071±0.00027 0.019
PTSD 0.00073±0.00034
External capsule R Control 0.00075±0.00017 0.022
PTSD 0.00076±0.00020
Cingulum L Control 0.00087±0.00023 0.000
PTSD 0.00091±0.00017

Values are presented as mean±SD. FA, fractional anisotropy; MD, mean diffusivity; R, right; L, left; PTSD, posttraumatic stress disorder.

Discussion

The present study explored the subcortical gray matter volume alteration and corresponding white matter abnormalities derived from diffusion metrics in veterans who had PTSD in comparison with healthy controls. Additionally, as age is one of the factors that affect the structure of the brain such as subcortical gray matter volume and white matter integrity, in this study we examined the impact of age and structural changes in two age groups of over and under 50 years old veterans with PTSD compared to normal individuals.

The results of this study clearly suggest that there are significant differences in brain structure between total and age-adjusted individuals with PTSD and normal controls. Volumetric analysis on subcortical structures shows that individuals with PTSD have a significantly smaller subcortical gray matter, than those in the control group. Additionally, the mean volumes of the bilateral thalamus, hippocampus, amygdala, left pallidum, and right accumbens-area were also significantly smaller in individuals with PTSD than those in the control group.

These findings are consistent with previous research that has suggested that individuals with PTSD have structural changes in their brains compared to those without the disorder. Most brain regions that have been extensively studied concerning PTSD are the amygdala and the hippocampus. Smaller amygdala [5, 21] and hippocampal volume [6, 22] in adults with PTSD compared to both healthy and trauma-exposed controls were reported. These two areas are involved in learning and memory, as well as emotional regulation. Fear-based learning that involves the amygdala has been viewed as a main factor in PTSD. Studies have found that individuals with PTSD may have alterations in the volume and function of the hippocampus, which may contribute to the development and maintenance of PTSD symptoms [6] as reported that individuals with PTSD have poor performance on memory tasks [23] and the alterations in hippocampal activity during memory processing tasks [24]. Understanding the role of the hippocampus in PTSD is important for the development of new treatments. Interventions that target this brain region may be able to improve symptoms of PTSD. However, it is important to note that PTSD is a complex disorder that involves multiple brain regions and pathways. Previous studies have revealed that alteration in the other deep brain gray matters also correlated to PTSD symptoms [25]. In the present study, we reported volume reduction in the thalamus, caudate, pallidum, and nucleus accumbens in PTSD patients. Brain volume reduction in the thalamus is not commonly observed in studies focused on PTSD. Although thalamus is a hub for relying sensory information, but it has many other functions in the controlling and processing brain activity. Volumetric change induced by stress in the thalamus, have been observed by Yoshii et al. [26]. It has been investigated that the fearful stimulation activated the thalamus [27]. The role of thalamic sensory processing in fear-based learning has been studied primarily in relation to its influence on the functioning and output of the amygdala, rather than as a significant psychological or pathological factor that contributes to the development of PTSD [28]. The caudate and pallidum, part of basal nuclei, are involved in the reward anticipation and response. Lower caudate volume has been associated with disruption of reward processing and can be seen in PTSD, depression, and substance abuse [25]. Abnormal activity within these nucleihas been documented in other imaging studies for PTSD [29]. The nucleus accumbens is linked to the brain reward system. Decreased functioning within this structure has been reported in PTSD patients previously [30]. This could be due to several factors such as chronic stress or trauma exposure which can lead to changes in brain structure. Additionally, it is possible that these structural changes may be associated with the symptoms of PTSD such as intrusive memories and avoidance behaviors. These findings have important implications for understanding the underlying mechanisms of PTSD and for developing effective treatments for this disorder. Future research should focus on further exploring these structural differences between individuals with PTSD and normal controls to better understand how they may contribute to the development and maintenance of this disorder. Additionally, further research should investigate how these structural differences may be related to treatment outcomes so that more effective interventions can be developed for those suffering from PTSD.

For evaluation of the white matter abnormalities and connections corresponding to deep brain nuclei, we used DTI imaging to evaluate changes in subcortical gray matter fiber tracts, which were previously described as volumetric changes. DTI measures showed the abnormality as a reduction in FA and elevation in MD, in internal, and external capsule, corona radiata, cingulum and fornix that are part of alimbic-thalamo-cortical pathway that is involved in the occurrence of the PTSD symptoms. However, there are controversies in the white matter integrity results. Some of the studies regarding DTI measurements in nonmilitary PTSDs have reported decreased FA in particular brain tracts such as anterior corona radiata and cingulum [11, 31, 32] as we reported in this study, whereas, some other studies have reported increase FA [17, 33, 34]. Anterior corona radiata directly connect the cingulate and prefrontal cortex and indirectly amygdala with the thalamus. Evidence has resulted that the anterior corona radiata plays a distinct role in emotion regulation, and attention, the functions that impaired in PTSD [35]. Cingulum, a reciprocal connection of amygdala and the cingulate cortex, associated with memory, attention, and executive function. We find elevation in MD of cingulum which correspond to the impaired fibers. In contrary to our finding, reduction in MD with trend for elevation in FA of cingulate in war veterans with PTSD have been reported by Bierer et al. [36]. They discussed that this finding is a likely result of neuroplastic changes in this tract [36]. Furthermore, we investigated significant elevation in MD of all other thalamocortical and limbic tracts (Table 4). This evidence suggests that the integrity of fiber tracts is more likely to be damaged and have decreased functionality.

A comparative analysis between two age groups, over 50 and under 50 years old, showed that PTSD patients who were younger had a reduction in volume and abnormality in the corresponding white matter in more regions compared to the control group. This is while individuals over 50 only showed this reduction in volume of the left thalamus. These findings suggest that age may be an important factor to consider when examining brain structure in PTSD patients. It is possible that younger individuals may be more vulnerable to developing PTSD due to their increased gray matter volume or that their brains may be more susceptible to changes associated with PTSD. Young age is one of the potential risk factors that play a role in PTSD and it has been suggested that the younger age increase vulnerability for PTSD [37]. The result of a symptom-based study by Konnert and Wong [3] have proposed the less severe symptoms for older veterans instead of young veterans with PTSD. As compare to our study, blast-exposed veterans have been found to experience an age-associated decrease in the integrity of their white matter, which may contribute to the neurodegenerative effects of the blast. In this study comparing veterans who had been exposed to close-range blasts (within 410 meters) to peers matched for age and severity of PTSD symptoms, it was found that there was a significant relationship between the amount of time since the veterans’ most severe blast and FA in certain regions of the brain. These same regions had previously shown an interaction between blast exposure and age on FA [38]. Although, normal aging and changes in white matter diffusivity across the lifespan have been reported in prior studies [39] but, changes seen in the FA and MD in the young blast-exposed PTSDs indicate that blast exposure may disrupt normal aging processes, causing a deviation from the typical trajectory.

According to a previous longitudinal study, there is no evidence of recovery in veterans who have been exposed to explosions and traumatic brain injuries [40]. Additionally, another study has shown that traumatic brain injuries sustained at younger ages result in more serious changes in the brain compared to those sustained at older ages [41]. Therefore, these structural changes in the brain are likely related to age, which also occurs in the control group and has led to only one subcortical gray matter of left thalamus, and one fiber tract of left anterior limb of internal capsule showing significant differences compared to individuals with PTSD.

Further research is needed to explore this relationship between age and brain structure in PTSD patients. Additionally, it would be interesting to examine how other factors such as gender or ethnicity may influence these results.

In conclusion, the findings of our study suggest that the volume of deep brain gray matter structures, including the hippocampus, amygdala, thalamus, and basal nuclei, and the corresponding white matter tracts, such as the anterior corona radiata, anterior limb of the internal capsule, cingulum, and fornix may be altered in individuals who suffer from PTSD symptoms. This finding is consistent with other studies. Additionally, we investigated age-specific alterations in brain structure among young veterans (under 50 years old) with PTSD compared to controls in the same age range.

Funding Statement

Funding None.

Footnotes

Author Contributions

Conceptualization: BJK. Data acquisition: KK, JZ. Data analysis or interpretation: SR, EF. Drafting of the manuscript: KK, SR. Critical revision of the manuscript: BJK. Approval of the final version of the manuscript: all authors.

Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

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