Brain morphological changes and functional neuroanatomy related to cognitive and emotional distractors during working memory maintenance in post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is associated with abnormalities in the processing and regulation of emotion as well as cognitive deficits. This study evaluated the differential brain activation patterns associated with cognitive and emotional distractors during working memory (WM) maintenance for human faces between patients with PTSD and healthy controls (HCs) and assessed the relationship between changes in the activation patterns by the opposing effects of distraction types and gray matter volume (GMV). Twenty-two patients with PTSD and twenty-two HCs underwent T1-weighted magnetic resonance imaging (MRI) and event-related functional MRI (fMRI), respectively. Event-related fMRI data were recorded while subjects performed a delayed-response WM task with human face and trauma-related distractors. Compared to the HCs, the patients with PTSD showed significantly reduced GMV of the inferior frontal gyrus (IFG) ( p < 0.05, FWE-corrected). For the human face distractor trial, the patients showed significantly decreased activities in the superior frontal gyrus and IFG compared with HCs ( p < 0.05, FWE-corrected). The patients showed lower accuracy scores and slower reaction times for the face recognition task with trauma-related distractors compared with HCs as well as significantly increased brain activity in the STG during the trauma-related distractor trial was observed ( p < 0.05, FWE-corrected). Such differential brain activation patterns associated with the effects of distraction in PTSD patients may be linked to neural mechanisms associated with impairments in both cognitive control for confusable distractors and the ability to control emotional distraction.


Introduction
Post-traumatic stress disorder (PTSD) emerges following the experience of traumatic events, and it manifests in symptoms such as intrusion, avoidance, and alterations in cognition, mood, and arousal reactivity (Lu et al., 2023;Martin et al., 2021;Sun et al., 2021;Xian-Yu et al., 2022;Zuo et al., 2023).These symptoms underscore the complex interplay between emotional and cognitive domains.Notably, individuals with PTSD affect both cognitive functions and emotion regulation (Hayes et al., 2012;Kaplan et al., 2022;Yuan et al., 2023).
Over recent years, there has been growing knowledge of the deficits in inhibitory control present in PTSD patients.Inhibitory control, as a pivotal type of executive function, encompasses the higher-order cognitive processes that are essential for one to engage in goal-directed behavior (D 'Souza et al., 2018;Diamond, 2013).Such deficits have been correlated with the severity of PTSD symptoms, particularly re-experiencing symptoms (Leskin and White, 2007;Swick et al., 2012).Neuroimaging studies have used various measures to evaluate inhibitory control in PTSD, including the go/no-go task (Falconer et al., 2013(Falconer et al., , 2008;;Kim et al., 2018;Sadeh et al., 2015), stop signal task (Harle et al., 2020;Powers et al., 2022;van Rooij et al., 2014), Stroop task (White et al., 2015), and antisaccade task (Nieuwenhuis et al., 2001); the results of these methods have indicated the presence of functional abnormalities in the prefrontal cortex (PFC) of PTSD patients.For example, a functional magnetic resonance imaging (fMRI) study with the Stroop task reported that greater PTSD symptom severity scores were associated with increased activation in the PFC in response to emotional relative to neutral stimuli (White et al., 2015).In a stop-signal anticipation task, patients with PTSD showed a reduced inferior frontal gyrus (IFG) response during proactive inhibition compared with healthy controls (van Rooij et al., 2014).Moreover, an electroencephalography study using the go/no-go task suggested that individuals with childhood trauma have inhibitory failure and frontal lobe dysfunction (Kim et al., 2018).PTSD has also been shown to be associated with inhibitory control deficits, but these effects depend on which task was used and how it was implemented (Swick and Ashley, 2020).
Working memory (WM) is a system of cognitive processes that store and process information currently being used in a cognitive task (Izmalkova et al., 2022).Goal-directed behavior depends on cognitive control such as WM, which allows one to maintain and manipulate information relevant to one's current task over a short period of time (Kim et al., 2015).In PTSD patients, WM impairment significantly affects daily functioning by compromising their ability to filter out irrelevant stimuli and focus on task-relevant information.This impairment leads to difficulties in concentrating, planning, and executing tasks, exacerbating PTSD symptoms by increasing susceptibility to distractions and overgeneralization of traumatic memories.The disruptions caused by psychological trauma, particularly those occurring in individuals with PTSD, interfere with goal-oriented behaviors.Emotionally-charged distractions pose a particular challenge for cognitive operations, thus making it vital to comprehend their underlying mechanisms (Dolcos and McCarthy, 2006).A prior fMRI study that used a similar delay-response WM task to our study revealed that the amygdala, ventrolateral PFC, and fusiform gyrus were associated with trauma distractors in PTSD patients (Morey et al., 2009).A similar study suggested that tolcapone increased cortical responses to fear, relative to neutral stimuli, in higher-severity PTSD subjects, and that it reduced cortical responses to fearful stimuli in lower-severity PTSD subjects (Westphal et al., 2021).Effects of distraction by presenting task-irrelevant distractors during delay interval of a WM task have received much attention.Patients with PTSD may be linked to a deficit of their ability to maintain focus on goal-relevant information for confusing distractors.Therefore, elucidating the effects of emotional and non-emotional distractors on goal-directed cognitive processes is crucial for understanding the cognitive-affective interactions of PTSD patients.
In addition to functional abnormality, there have been numerous structural neuroimaging studies (Kroes et al., 2011;Liu et al., 2012;O'Doherty et al., 2017;Woodward et al., 2009;Zhang et al., 2018) conducted to identify the neural centers related to structural dysfunction.One such structural study (Zhang et al., 2018) reported that, compared to a trauma-exposed control group, patients with PTSD had a larger gray matter volumes (GMVs) in the middle temporal gyrus (MTG) and medial PFC, along with a smaller GMV in the region of the temporal pole.A similar study (Nardo et al., 2013) reported that PTSD subjects showed reduced GMV in the PFC compared to traumatized controls.It is possible that these structural differences are involved in the cognitive and affective processing dysfunctions that have been shown to occur while engaging in delay-response WM tasks with distractors.
Drawing from insights provided by previous functional and structural abnormalities, this study endeavors to offer a deeper neurobiological understanding of difficulties in cognitive and emotional regulation experienced by individuals with PTSD.Thus, this study aims to assess the differential brain activation patterns associated with the human face and trauma-related distractors during WM maintenance for human faces between PTSD patients and healthy controls.Moreover, as a secondary analysis, this study evaluated the relationship between changes in the activation patterns by the opposing effects of distraction types and the increase or reduction in the volumes of the corresponding brain areas.

Subjects
Twenty-two patients diagnosed with PTSD (mean age = 34.2± 13.3 years; 12 males and 10 females) and twenty-two healthy controls (HCs; mean age = 33.6 ± 9.9 years; 12 males and 10 females) underwent magnetic resonance imaging (MRI).The patients with PTSD had been diagnosed with PTSD at the Jeonbuk National University Hospital, while the HCs without psychiatric illnesses were recruited via advertisement.Both groups were matched for age, gender, and handedness (Table 1).
The inclusion criteria for the patients with PTSD were as follows: 1) a diagnosis of PTSD according to DSM-IV-TR (Association AP, 2000); 2) no history of other neurological or psychiatric illnesses; 3) a score above 26 on the Korean version of the Mini-Mental State Examination (K-MMSE); and 4) a score of 33 or above on the Clinically Administered PTSD Scale (CAPS) total scores (Murphy et al., 2017).The CAPS was used to assess symptoms of PTSD.A Hamilton Rating Scale for Depression (HAMD, 0 -7 = normal, 8 -16 = mild depression, 17 -23 = moderate depression, >24 = severe depression) was used to evaluate depression levels of patients (Sharp, 2015).All patients fell within the mild depression range.Eighteen patients with PTSD received prescription for multiple psychotropic medications, while four patients with PTSD were prescribed one psychotropic medication (Supplementary Table.S1).The patients experienced psychological trauma as follows: sexual abuse (n=2), bullying (n=7), traffic accidents (n=10), natural disasters (n=1), community violence (n=1), and domestic violence (n=1).The average duration of illness for the patients was 3.5 ± 3.0 years, and the K-MMSE score was 28.9 ± 0.9.
Healthy controls were selected based on the following criteria: 1) no diagnosis of PTSD according to DSM-IV-TR, and 2) no history of any drug treatment or neurological or psychiatric disorder.Symptom severity was assessed by Clinical Global Impression-Severity Scale (CGI-S, 1 = normal -7 = amongst the most severely ill patients) (Busner and Targum, 2007) and Global Assessment of Functioning (GAF, 0 = severe psychopathology and functional disability -100 = positive mental health) (Startup et al., 2002).
This study was approved by the Institutional Review Board of Jeonbuk National University Hospital (IRB-JBUH).All experimental procedures and methods were performed in accordance with the relevant guidelines and regulations approved by IRB-JBUH.Informed consent was obtained from each participant.
For the encoding task, three different human faces sequentially appear once (1.66 s each) on a quartile coordinate.During the WM maintenance trial following the encoding, the subjects were asked to maintain the WM for the encoded faces.Then, the distractors were presented for a total time of 6 s (3 s each), and the subjects were instructed to look at the distractors while maintaining the WM.The distractors consisted of 1) human faces, 2) scrambled faces, 3) traumarelated pictures, and 4) neutral pictures.The controls for the human face and trauma-related distractors were the scrambled faces and neutral distractors, respectively.
The human faces were selected from a high school yearbook of one of the authors, which were converted into black-and-white pictures of an oval shape featuring eyes, nose, mouth, and eyebrows.The human faces consisted of males and females in an equal ratio.The scrambled faces were generated from normal-shaped human faces by rotating the image − 200 • using Adobe Photoshop.Before the fMRI examination, a pool of 100 pictures comprising 50 trauma-related pictures and 50 neutral pictures was collected from the International Affective Picture System and various websites (Lang and Cuthbert, 2005).A psychologist, two psychiatrists, and seven graduate students then selected trauma-related and 20 neutral pictures from this pool.The trauma-related pictures included photographs of car accidents, natural disasters, crime, violence, and terror, while the 20 neutral pictures included scenic views of environments such as forests, parks, and gardens to induce a comfortable feeling.
In the retrieval trial, either the face presented in the encoding trial or a new face was presented to the participants (50% were presented with an encoding face and 50% were presented with a new face).The subjects were asked to make a recognition decision for the retrieval of the human face by pressing one of two response keys.That is, the subjects were instructed to press the right-hand button if they recognized the probe face in the retrieval trial as one of the three faces that was previously viewed in the trial, while they were instructed to press the left-hand button if they viewed the probe face as a new face that they did not recognize from the three previously viewed faces.The accuracy of the face recognition task was evaluated under the criterion that the subject's response was within two seconds in the retrieval task.The gender of the face distractors and retrieval probe always matched the gender of the three human faces in the encoding trial.Each probe was followed by a Fig. 1.Diagram for the delayed-response working memory (WM) tasks with human face distractors.For the encoding task, three different human faces sequentially appear once on a quartile coordinate.During the WM maintenance trial following the encoding, the subjects were asked to maintain the WM for the encoded faces.Then, the distractors were presented, and the subjects were instructed to look at the distractors while maintaining the WM.The distractors consisted of 1) human faces, 2) scrambled faces, 3) trauma-related pictures, and 4) neutral pictures.The controls for the human face and trauma-related distractors were scrambled faces and neutral distractors, respectively.In the retrieval trial, either the face presented in the encoding trial or a new face was presented.The subjects were asked to make a recognition decision for the retrieval of the human face by pressing one of two response keys.ITI: intertrial interval.
12 s ITI to allow the hemodynamic response to return to the baseline (the total length of each trial was 32 s) (Dolcos et al., 2008).The retrieval task consisted of 10 trials with human face distractors, 10 trials with scrambled face distractors, 10 trials with trauma-related distractors, and 10 trials with neutral distractors.In the 40 trials, four different types of distractors were randomly presented.The accuracy (%) and reaction time (ms) for the face recognition tasks for each subject in the retrieval trial was measured by the SuperLab software (Cedrus Corporation, San Pedro, CA).After completion of the fMRI exams, each subject was asked to rate their emotional status when viewing the trauma-related and neutral pictures as distractors on an eleven-point scale: 0 = not unpleasant and 10 = maximal unpleasant.Before MR scanning, subjects were provided with sufficient practice to become accustomed to the activation paradigm.
The average illuminance levels of the pictures for all human face and scrambled face distractors were equivalent to each other, as were the average illuminance levels of the pictures for all trauma-related and neutral distractors.The illuminance levels were measured with a digital illuminance meter (Illuminance Meter, Tektronix, USA).The visual stimuli were presented using the SuperLab software.

MRI processing and analysis
Anatomical and functional MR images were analyzed using Statistical Parametric Mapping (SPM8, Wellcome Department of Cognitive Neurology, University College London, London, UK).The Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) protocol was used for outlier detection and visual inspection (Kim et al., 2024(Kim et al., , 2023)).In the fMRI data, the analyses included a head motion value of < 2 mm.

Structural analyses
Prior to data processing, all individual data were aligned to the anterior-to-posterior commissure line on the transverse plane.After the correction of bias in the images due to field non-uniformity, the images were segmented into GM, white matter, and cerebrospinal fluid (CSF) using tissue probability maps based on the International Consortium of Brain Mapping space template for the East Asian brain type.The mean templates for GM and white matter were created using individual GM and white matter images.All the images were normalized to the Montreal Neurological Institute template and subsequently separated into GM and white matter images.The images were then smoothed with an 8-mm full-width-at-half-maximum (FWHM) isotropic Gaussian kernel.Based on previous review papers related to PTSD (Cesari et al., 2023;Fenster et al., 2018;Hayes et al., 2012;Ju et al., 2020), the 18 brain regions of interest (ROIs) were defined using WFU Pickatlas software (Maldjian et al., 2003) as follows: the superior/middle/inferior frontal gyrus, anterior/posterior cingulate gyrus, medial/lateral orbitofrontal gyrus, supplementary motor area, superior/middle/inferior temporal gyrus, insula, amygdala, caudate nucleus, globus pallidus, hippocampus, putamen, and thalamus.To quantify the whole-brain volumes, a total intracranial volume (TICV) was calculated for each subject by summing the corresponding GM, white matter, and CSF volumes (mL).

Functional MRI analysis
Among the twenty-two patients with PTSD, two were excluded from the fMRI analysis due to excessive head motion (> 2 mm).Meanwhile, one of the 22 HCs was excluded from the fMRI analysis with excessive head motion (> 2 mm).For the statistical analysis, incorrectly performed trials for the face recognition task in both HCs and PTSD patients were excluded.The fMRI data were analyzed by postprocessing and data analysis using Statistical Parametric Mapping (SPM8; Wellcome Department of Cognitive Neurology, University College London, London, UK) following the procedure described in our previous study (Kim et al., 2015).Post-processing of fMRI data included the following steps: slice-timing correction, rigid body correction for head movement, spatial normalization, and spatial smoothing.After slice-timing correction, the images were realigned to match each functional volume to the reference volume as well as spatially normalized to the standard EPI template in Montreal Neurological Institute (MNI) space, which is a template created from 152 brain data sets, using a 12-parameter affine transformation followed by a nonlinear deformation.Lastly, the images were smoothed with an 8-mm full-width-half-maximum Gaussian filter.After that, brain activities were identified using multiple regression analysis of the time series of MR signal intensities in each voxel for contrasts of distractors (human face vs. scrambled face", "trauma-related picture vs. neutral picture", "human face > scrambled face vs. trauma-related picture > neutral picture", or "trauma-related picture > neutral picture vs. human face > scrambled face").

Statistical analyses 2.5.1. Demographic and clinical characteristics
A two-sample t-test was used to compare the age, education, and HAM-D of patients with PTSD and the HCs, and a chi-square (χ2) test was used to compare the gender and handedness of the two groups using SPSS (version 28.0, IBM, Armonk, NY, USA).

Structural analyses
For the group comparison analysis, a multivariate analysis of variance, with age, sex, and TICV as covariates, was used to compare the GMVs of the two groups (family-wise error (FWE)-corrected, p < 0.05).The cluster size included more than 20 contiguous voxels.Correlations between the CAPS scores and brain volumes were computed using a partial correlation, with age, sex, and TICV as covariates, with SPSS.

Functional MRI analysis
The two sample t-test was used to compare the accuracy (%) and reaction time (ms) for the face recognition task, and subjective response to distractors between the two groups.Given that our data were found to be not normally distributed, a Mann-Whitney U test was used to compare the two groups.The Shapiro-Wilk test was used to assess the normality of the data.Multivariate analyses of variance, with age and sex as covariates, were conducted to compare the differential brain activation patterns between the two groups for WM maintenance and distractor ("human face > scrambled face", "trauma-related picture > neutral picture", "human face > scrambled face -trauma-related picture > neutral picture", or "trauma-related picture > neutral picture -human face > scrambled face") trials using Statistical nonParametric Mapping (SnPM13).The results were thresholded at a cluster-level corrected threshold of p<0.05 for n=5000 permutations (FWE-corrected), with a cluster-determining threshold set at the voxel level <0.001.The cluster size included more than 20 contiguous voxels.Correlations between the BOLD signal changes and GMVs were computed using the partial correlation, with age and sex as covariates.

Clinical evaluation
Table 1 presents the demographic and clinical characteristics of the PTSD patients and HCs.No significant differences were found between the two groups in age (t(42) = − 0.14, p = 0.888), gender (p = 1.000), handedness (p = 1.000), and education (t(42) = 1.62, p = 0.114).There were significant differences in the HAM-D (t(42) = − 19.69, p < 0.001) between 2 groups.The average score of the CAPS in the patients with PTSD was 56.8 ± 13.6.The average scores of the CGI-S and GAF in the HCs were 1.0 ± 0.0 and 93.6 ± 3.5, respectively.

Brain volume changes
The PTSD patients showed significant decreases in the GMV of the right IFG compared with the HCs (t(42) = 5.60, p < 0.05, FWEcorrected; Fig. 2).The GMV of the right IFG in the PTSD patients were negatively correlated with CAPS scores (r = − 0.51, p = 0.027; Fig. 2).There were no significant differences between the two groups in the GMVs of the other ROIs (p > 0.05).There were also no significant differences in the white matter volumes of the ROIs between the two groups (p > 0.05).

Subjective response to distractors
The average perceived negative emotion scores for the traumarelated pictures were 8.1 ± 1.5 and 8.2 ± 1.1 in the HCs (n = 21) and PTSD patients (n = 20) (p = 0.883), respectively, whereas the corresponding scores for the neutral pictures were 0.5 ± 1.1 and 0.5 ± 1.2 (p = 0.614), respectively, and showed no significant differences (Supplementary Table S2).
The accuracy scores for the face recognition task with trauma-related distractors were 67.9 ± 11.0% and 60.5 ± 10.0% for the HCs and PTSD patients (p = 0.046), respectively, while the corresponding scores for the neutral distractors were 64.5±12.2% and 66.5±13.1% (p = 0.561), respectively (Fig. 3, Supplementary Table S3).The reaction times for the face recognition task with trauma-related distractors were 1332.2 ± 208.6 ms and 1496.1 ± 280.4 ms for the HCs and PTSD patients (t(39) = − 2.13, p = 0.039), respectively, while the reaction times for the scrambled face distractors were 1211.4 ± 200.2 ms and 1354.5 ± 285.5 ms (t(39) = − 1.87, p = 0.070), respectively (Fig. 3, Supplementary Table S3).Compared to the HCs, the patients with PTSD showed Fig. 2. Reduced gray matter (GM) volumes in patients with PTSD relative to healthy controls (HCs).The color-coded pixels were scaled to the range (t-value) more than the cut-off threshold (FWE-corrected, p < 0.05).The patients with PTSD showed reduced inferior frontal gyrus volume compared with HCs (a, b).The GM volumes of the right IFG in the PTSD patients were negatively correlated with CAPS scores (r = − 0.51, p = 0.027).lower accuracy scores and slower reaction times during WM maintenance with trauma-related distractors.The reaction times for the face recognition task with trauma-related distractors in PTSD patients were positively correlated with the CAPS scores (r = 0.47, p = 0.047) (Supplementary Fig. S1).

Differential activation patterns related to the distractor between the two groups
For the human face distractor trial, the patients showed significantly decreased activities in the superior frontal gyrus (SFG) (t(39) = 4.72, p = 0.042) and IFG (t(39) = 4.58, p = 0.033) compared with the HCs (FWEcorrected; Fig. 5, Table 2, Supplementary Fig. S3 and Table S5).The BOLD signal changes of the right IFG during the human face distractor trial in the patients were positively correlated with the GMVs of the right IFG (r = 0.48, p = 0.043; Fig. 5).In addition, the patients showed lower accuracy scores and slower reaction times for the face recognition task with trauma-related distractors compared with HCs as well as significantly increased brain activity in the STG (t(39) = 4.53, p = 0.009) during the trauma-related distractor trial was observed (FWE-corrected; Fig. 6, Table 2, Supplementary Fig. S4 and Table S6).Lastly, there were no significant differences between the two groups in terms of contrasts of distractors (human face > scrambled face vs. trauma-related picture > neutral picture) (p > 0.05).

Discussion
Compared to the HCs, the patients with PTSD showed significantly reduced GMV of the right IFG.The CAPS scores in the PTSD patients were negatively correlated with GMVs of the right IFG.Further, in the delayed-response WM tasks, the patients with PTSD showed significantly decreased activities in the SFG and IFG compared with HCs Fig. 3. Accuracy (a) and reaction time (b) for the face recognition task in PTSD patients and healthy controls (HCs).The patients performed worse with traumarelated distractors compared with HCs (p < 0.04).In addition, the patients showed slower reaction times for the face recognition task with the scrambled face distractor (p < 0.04) and trauma-related distractor (p < 0.03) compared with HCs, respectively.Fig. 4. Increased activities in PTSD patients than healthy controls (HCs) during WM maintenance of the target faces.The color-coded pixels were scaled to the range (t-value) more than the cut-off threshold (FWE-corrected, p < 0.05).The patients with PTSD showed significantly increased activities in the left MTG and bilateral STG during the WM maintenance compared to the HCs.during the human face distractor trial, and they also showed significantly increased activity in the STG during the trauma-related distractor trial.Given that abnormalities in the PFC have previously been linked to symptoms of PTSD (Clausen et al., 2017;Geuze et al., 2008;Hampshire et al., 2010;Kim et al., 2018;Powers et al., 2022), these results suggest that reduced GMV and decreased brain activity in the PFC may be associated with cognitive dysfunction in PTSD.
The patients with PTSD showed reduced GMV in the IFG compared with the HCs, which is consistent with the prior findings of reduced IFG volume in patients with PTSD (Kroes et al., 2011).Reduced IFG volume may be associated with PTSD symptom severity.A structural study found that cortical thickness of the IFG has a significant negative correlation with CAPS in patients with PTSD (Liu et al., 2012).A similar study suggested that patients with PTSD showed a smaller volume in the IFG (Woodward et al., 2009).Other works found deficit in the IFG in patients with chronic PTSD, along with thinner cortical thickness of the IFG in veterans with PTSD (Geuze et al., 2008;Liu et al., 2012;Woodward et al., 2009).Moreover, the CAPS scores in PTSD patients were negatively correlated with the GMVs of the right IFG.Our results further support the notion that reduced GMV in the IFG may be a key biomarker for PTSD detection.
During the WM maintenance for the faces presented in the encoding trial, the patients with PTSD showed significantly increased activities in the STG and MTG compared with HCs, which is consistent with prior evidence associating these regions with impaired WM maintenance performance (Park et al., 2011;Sato et al., 2018).Our findings suggest that patients with PTSD have deficits in the STG and MTG, both of which are associated closely with impairment of cognitive processing for WM  maintenance.WM maintenance is associated with dominant frontotemporal connections, and the STG and MTG have both been specifically implicated in WM maintenance (Park et al., 2011;Sato et al., 2018).The STG and MTG are each part of a neural network that is responsible for the processing of WM maintenance.For example, one fMRI study reported that increasing PTSD severity was associated with increased activity in the MTG (Falconer et al., 2008).A similar study also suggested that the STG is a hub region during WM maintenance (Park et al., 2011).Therefore, the increased activities in the MTG and STG of the patients with PTSD may be attributable to the impairment of cognitive processing during WM maintenance with the encoded faces.This study found that patients with the PTSD showed significantly decreased activities in the IFG and SFG during WM maintenance with the human face distractors.This finding is consistent with the results of an fMRI study that found that decreased activities in the IFG and SFG during response inhibition are implicated in PTSD symptoms (Powers et al., 2022).The IFG and SFG play important roles in rational recognition and decision-making ability during inhibitory processes (Aron et al., 2004;Hampshire et al., 2010;Kim et al., 2015).Veterans with PTSD have shown reduced activation in the IFG during proactive inhibition trials, where this impairment did not improve with successful treatment, thus suggesting a more trait-like or pre-existing risk factor (Powers et al., 2022;van Rooij et al., 2014).Similarly, an fMRI study reported that patients with PTSD showed decreased activities in the SFG and IFG in inhibitory control (Falconer et al., 2008).Worse PTSD severity and neuropsychological performance are related to reduced SFG activity during interference processing (Clausen et al., 2017).Moreover, the GMVs of the right IFG in the PTSD patients were positively correlated with BOLD signal changes in the right IFG during WM maintenance with the human face distractors.Based on these literature findings and the proposed role of the SFG and IFG in PTSD, we speculate that decreased activities of the SFG and IFG in patients with PTSD may reflect impairment of the cognitive processing for confusable face distractors.
Interestingly, the patients with PTSD showed lower scores and slower reaction times for the face recognition task with trauma-related distractors compared with the HCs.This suggests that they may have difficulties in WM maintenance for trauma-related distractors in the delayed-response WM task, but there were no significant differences between the two groups for other distractors.Further, the STG was more highly activated during the trauma-related distractor trial in the patients than in the HCs.The findings of lower scores for the face recognition task of the trauma-related distractor concomitant with increased activity in the STG are potentially attributable to potent emotional distractors that can capture attention and reallocate processing resources, thus impairing effective function (Dolcos and McCarthy, 2006).For example, an fMRI study reported that patients with PTSD showed hyperactivity in the STG during a retrieval memory task (Lanius et al., 2005).A similar study also found that patients with PTSD showed increased activity in the STG during extinction learning (Milad et al., 2009).The higher activity of the STG observed in this study may be associated with the deficit in the inhibition of the emotional distractor.In particular, the STG was commonly activated during WM maintenance and trauma-related distractor trials, which is a specific role that it plays in WM maintenance and retrieval.STG abnormality may be particularly useful for identifying PTSD.Based on these findings, we speculate that increased activity of the STG and decreased activities of the IFG and SFG observed in PTSD patients may be associated with increased emotional distractibility and impaired ability for emotional and non-emotional distractors during the delay-response WM task.These differential patterns of brain activities may be particularly useful for identifying emotion and cognition interactions in PTSD.
Considering these findings, implications for current and future PTSD treatment approaches are profound.Targeted therapeutic interventions could focus on enhancing neural plasticity and connectivity in the PFC potentially through cognitive rehabilitation or neuromodulation techniques such as transcranial magnetic stimulation (TMS) or neurofeedback (Cools and Arnsten, 2022;Mehta et al., 2024;Thomson et al., 2020).Furthermore, understanding specific neural circuits involved in PTSD, including STG's role in processing emotional distractors, could inform more personalized and effective clinical practices.
This study has some limitations.First, a primary limitation of our study is its relatively small sample size.Therefore, we used a statistical threshold of a p-value of less than 0.05 using FWE correction to compensate for this disadvantage, giving a statistically reliable significance level.Larger studies with independent samples are needed to corroborate the findings and provide a more objective target for interventions aimed at reducing PTSD.Second, we did not investigate specific effects of these medications on brain volume or brain activation patterns associated with WM maintenance.Third, this study does not account for the differential impact of distinct types of psychological traumas.Given that trauma can manifest in numerous ways and has heterogeneous effects, the broad grouping might overlook nuanced neurobiological differences based on trauma type.Fourth, inherent biases in our study design, particularly selection bias, could have influenced our results.For instance, the recruitment of PTSD patients primarily from clinical settings might not fully represent the broader PTSD population.Acknowledging this, future research should include more diverse and representative samples.Finally, more studies with functional and structural connectivity are needed in the future to compare individuals who were exposed to trauma but did not develop PTSD to individuals who did develop PTSD.

Conclusion
This study demonstrated altered brain volume and brain activation patterns associated with the effects of human face and trauma-related distractors in patients with PTSD during the delay interval of the WM task.The differential brain activation patterns associated with the effects of distraction may be linked to neural mechanisms with impairment of cognitive and emotional controls for distractors.These findings are expected to contribute to the understanding of the neural mechanism associated with severe symptoms in connection with functional and structural abnormalities.

Fig. 5 .
Fig. 5. Decreased activities in PTSD patients than healthy controls (HCs) during the delayed-response WM task with human face distractors.The color-coded pixels were scaled to the range (t-value) more than the cut-off threshold (FWE-corrected, p < 0.05).(a) The patients showed significantly decreased activities in the SFG and IFG compared with HCs for the human face distractor trial.(b) The BOLD signal changes of the right IFG during the human face distractor trial in the patients were positively correlated with the GM volumes of the right IFG (r = 0.48, p = 0.043).

Fig. 6 .
Fig. 6.Increased activities in PTSD patients than healthy controls (HCs) during the delayed-response WM task with trauma-related distractors.The color-coded pixels were scaled to the range (t-value) more than the cut-off threshold (p < 0.05, FWE-corrected).(a) The patients showed significantly increased activities in the STG during the trauma-related distractor trial.(b) The STG was commonly activated during WM maintenance and trauma-related distractor trials.(b) Intersection set of distractor trial (trauma-related > neutral distractors) and WM maintenance trial which highlights the overlapping areas with different colors, i.e. green, distractor trial (trauma-related > neutral distractors); red, WM maintenance trial; yellow, the intersection of the two sets, red and green.

Table 1
Demographic and clinical characteristics of the PTSD patients and healthy controls.

Table 2
Brain activities in PTSD patient and healthy control (HC) groups during WM maintenance trial (a) and distractor trial (b).