- Email: [email protected]
Right temporal pole volume reduction in PTSD
Journal Pre-proof Right temporal pole volume reduction in PTSD
Savannah N. Gosnell, Hyuntaek Oh, Jake Schmidt, John Oldham, J. Christopher Fowler, Michelle Patriquin, David Ress, Ramiro Salas PII:
S0278-5846(19)30475-0
DOI:
https://doi.org/10.1016/j.pnpbp.2020.109890
Reference:
PNP 109890
To appear in:
Progress in Neuropsychopharmacology & Biological Psychiatry
Received date:
4 June 2019
Revised date:
24 January 2020
Accepted date:
16 February 2020
Please cite this article as: S.N. Gosnell, H. Oh, J. Schmidt, et al., Right temporal pole volume reduction in PTSD, Progress in Neuropsychopharmacology & Biological Psychiatry(2019), https://doi.org/10.1016/j.pnpbp.2020.109890
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
Journal Pre-proof Right temporal pole volume reduction in PTSD
Savannah N Gosnell1,2,3 #, Hyuntaek Oh1,4 #, Jake Schmidt5, John Oldham 1,4, J Christopher Fowler1, Michelle Patriquin1,4, David Ress 3, Ramiro Salas 1,2,3,4 * 1 Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston TX, USA
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2 Michael E DeBakey VA Medical Center, Houston TX, USA
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3 Department of Neuroscience, Baylor College of Medicine, Houston TX, USA
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4 The Menninger Clinic, Houston TX, USA
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5 EOG Resources INC – Data Science, Houston TX, USA
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#These two authors contributed equally to this work
*Corresponding Author: Ramiro Salas, PhD,
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Baylor College of Medicine, One Baylor Plaza – room A277 Houston, TX 77030, USA. Email: [email protected]; TE 713-798-3502; Fax 713-798-4488
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Journal Pre-proof Abstract Previous magnetic resonance imaging studies of post-traumatic stress disorder (PTSD) have reported cortical volume alterations in the parahippocampal, anterior cingulate cortex, and temporal pole. It is unclear, however, if these cortical regions are specifically associated with PTSD or associated with common comorbidities. Here, we present the result of cortical volume differences between PTSD and healthy and psychiatric controls. In this study, healthy controls
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(n=67) were matched for demographic characteristics (age, sex, race) and psychiatric controls (n=67) were matched for demographic characteristics plus all other psychiatric diagnoses (past
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and current) to a group of PTSD patients (N=67). We assessed group differences of 34 bilateral
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cortical structure volumes using statistically defined brain regions-of-interest from FreeSurfer
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between PTSD patients and healthy controls. We found 10 regions to be significantly different between PTSD and healthy controls and analyzed the group differences between PTSD and
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psychiatric controls within these regions. The right temporal pole volume in PTSD was found to
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be significantly smaller than both healthy and psychiatry controls. Our finding suggests only right temporal pole volume reduction is specifically associated with PTSD, and also highlights
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the need for using appropriate controls in psychiatry research.
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Highlights
PTSD is highly comorbid with other psychiatric disorders
PTSD patients should be compared to a group of psychiatric patient controls matched for demographic characteristics and comorbid psychiatric disorders, rather than healthy controls
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Lower right temporal pole volume distinguished PTSD patients from both healthy and
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psychiatric control groups, suggesting it may be a PTSD-specific biomarker
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Journal Pre-proof Keywords: Post-traumatic stress disorder (PTSD), Right temporal pole, Structural magnetic
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resonance imaging, Trauma
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Journal Pre-proof 1. Introduction Post-traumatic stress disorder (PTSD) is a psychiatric disorder resulting from various kinds of traumatic events such as military combat-related stress, accidents, childhood maltreatment, and/or sexual abuse. In the general population, the lifetime prevalence rate for PTSD is about 6.8%, whereas the rate for veterans is approximately 23% (Fulton et al., 2015; Kessler et al., 2005). PTSD is characterized by a series of symptoms including re-experience, avoidance,
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negative alterations in cognition and mood, arousal, and hypervigilance (American Psychiatric
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Association, 2013).
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Several MRI morphometry studies have explored volumetric alterations in both cortical and
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subcortical regions known to be associated with PTSD. In these studies, the hippocampus, amygdala, anterior cingulate cortex (ACC), and temporal pole have been analyzed because
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these areas are highly implicated in memory for episodic events (Gurvits et al., 1996; Patel et al.,
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2012) and emotion regulation (Etkin et al., 2011; Ochsner et al., 2002; Olson et al., 2007; Stevens et al., 2011). Previous meta-analyses have reported that hippocampal volumes are
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reduced in PTSD relative to the control group (Bromis et al., 2018; Karl et al., 2006; Kitayama et
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al., 2005; Kühn and Gallinat, 2013; Smith, 2005; Woon and Hedges, 2008; Woon et al., 2010). Meta-analysis of amygdala structural abnormalities has found an evidence for smaller volume of amygdala in PTSD (Karl et al., 2006), but the results are controversial (Kühn and Gallinat, 2013; Woon and Hedges, 2008, 2009). Recently, the Psychiatric Genomics Consortium (PGC)Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) demonstrated with large sample size (total n = 1868; 794 PTSD patients) that PTSD is associated with significantly lower hippocampal volume and possibly amygdala volume (Logue et al., 2018). In addition to subcortical brain structural abnormalities, meta-analyses of cortical volume reductions in PTSD have also been reported in regions such as the medial prefrontal cortex (mPFC), ACC, middle
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Journal Pre-proof temporal gyrus (MTG), temporal pole, parahippocampal and occipital cortex (Bromis et al., 2018; Karl et al., 2006; Kühn and Gallinat, 2013; Li et al., 2014; Meng et al., 2014).
PTSD is highly comorbid with other psychiatric disorders, such as major depression (Brown et al., 2001; Campbell et al., 2007; Kessler et al., 1995; Oquendo et al., 2005), substance abuse (Hien et al., 2004; Kilpatrick et al., 2003; Van Ameringen et al., 2008), and anxiety disorders
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(Hashemian et al., 2006; Sundquist et al., 2005). Having several concurrent psychiatric diagnoses is also common amongst PTSD patients (Brady and Clary, 2003; Gallagher and
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Brown, 2015). Because of this, previously reported findings of altered morphometry in PTSD
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could possibly be associated with other psychiatric disorders rather than the diagnosis of PTSD
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only. While previous brain structural abnormality studies and meta-analyses have compared PTSD patients to either healthy controls (HC) (Bremner et al., 1997; Pavliša et al., 2006;
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Villarreal et al., 2002) or traumatized healthy controls (Bremner et al., 2003; Lindauer et al.,
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2004; Lindauer et al., 2005), there have been limited efforts to use more appropriate controls (e.g. those with similar demographic characteristics and psychiatric comorbidities). In order to
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find PTSD-specific brain structural abnormalities, PTSD patients should be matched to non-
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PTSD patients using not only sex, age and race, but also comorbid psychiatric disorders.
Here, we investigate brain cortical differences between PTSD patients and HC and psychiatric controls (PC), using data from 134 psychiatric patients (culled from a total sample of 518 patients) and 67 healthy participants (culled from a sample of 141 healthy volunteers). A major advantage of this study in comparison with previous cortical abnormality studies and metaanalyses in PTSD is that we matched the PC group with both demographic characteristics and other psychiatric diagnoses. In addition, to promote comparison with previous studies and to limit the number of regions to study in the PTSD vs. PC comparison, we also included a HC group matched for demographic characteristics. We compared 34 bilateral, whole-brain cortical
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Journal Pre-proof ROIs between these groups. We hypothesized that the mPFC, ACC, MTG, temporal pole, parahippocampal and occipital cortex of PTSD patients may be smaller than HC, and that some of those volume reductions may be observed between PTSD and PC which would be associated with specific PTSD diagnosis.
2. Methods
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2.1. Participants 2.1.1. Healthy Controls
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HC were volunteers from the community (N = 141, of which 67 were used) with no diagnosis of
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mental illness (past or current). HC were excluded if they had a self-report history of
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neurological or psychiatric disorders, including substance abuse/dependence. Additional exclusion criteria were a previous history of traumatic brain injury (loss of consciousness of
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more than 10 minutes) or any contraindication to MRI. Fig. 1 shows demographic characteristics
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(age, sex, and race) of HC.
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2.1.2. Psychiatric Patients and Clinical Measures Psychiatric patients (PP; N = 518) were recruited from the Menninger Clinic in Houston, Texas
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as a part of the McNair Initiative for Neuroscience Discovery – Menninger/Baylor (MIND-MB) research study (Ambrosi et al., 2018; Gosnell et al., 2019a; Gosnell et al., 2019b; Wills et al., 2019). PP were considered for the study if deemed mentally stable enough to participate and had no contraindications for MRI. Procedures were approved by the Institutional Review Board and all participants gave signed, informed consent. PP from the clinic had a variety of psychiatric conditions including mood, anxiety, personality, and substance abuse disorders, with over 80% diagnosed with comorbid psychiatric disorders (Fig. 1). They remained at the clinic for several weeks (4-6 weeks) while receiving treatment, however, this was not relevant to this study as we assessed patients as close as possible to admission to the clinic. Demographic
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Journal Pre-proof data relevant to our study (age, gender, and race) and psychiatric diagnoses from the Structured Clinical Interview for DSM-IV disorders axis I and II were collected. We also conducted the Stressful Life Events Screening Questionnaire (SLESQ) for all patients in the
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study, to determine if they had ever experienced traumatic events (Goodman et al., 1998).
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Fig. 1. Demographic characteristics, the number of the experienced traumatic events and overview of comorbid disorders in psychiatric patients. A. demographics are shown for each group. The number of the experienced traumatic events (from the SLESQ) are shown for both PTSD and PC groups (p < 0.05). B. An overview of clinical diagnoses with PTSD and PC groups are shown. Note this is just for visualization, as the groups were matched based on all psychiatric diagnoses, individually, not just those shown. HC: healthy controls, PC: psychiatry controls, PTSD: post-traumatic stress disorder, SD: standard deviation, PD: personal disorders, BP: bipolar disorder, SUB/ALC: substance/alcohol use disorder, ED: eating disorders, ANX:
anxiety disorder not otherwise specified, MDD: major depressive disorder. 8
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2.1.3. Matching Control Groups to PTSD Group From the PP population we selected inpatients who met criteria with a primary DSM-IV diagnosis of PTSD (N = 67) for the study. A HC group and PC group of the same size were matched to the PTSD group in a one-to-one manner (Fig. 2). The HC group was matched for demographic characteristics (age, sex, race) and the PC group was matched for demographic
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characteristics plus all other psychiatric diagnoses (past and current). This was accomplished using a Euclidean distance-matching algorithm. The algorithm used each characteristic
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(normalized using z-scores) being matched for as a separate dimension to place each subject in
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multi-dimensional space. The algorithm minimized the sum of Euclidean distances between
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each pair (one PTSD and one control subject). All matching was coded in Python (version 3) and is available upon request. The accuracy of the matched groups was confirmed by
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assessing between group differences on all characteristics using t-tests for age and Chi-
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squared tests for all other variables to ensure the groups were not significantly different for any feature (p < 0.05, no multiple comparisons corrections). The result of this grouping was a HC
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group (N = 67) matched for age, gender, and race to the PTSD group and a PC group (N = 67)
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matched for demographics and psychiatric diagnoses to the PTSD group.
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Any current diagnosis of a psychiatric disorder (N = 518)
Demographics: age, sex and race
Match to PTSD patients
Select for current diagnosis of PTSD Demographics: age, sex and race and all past/current psychiatric diagnoses
Selection
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Match to PTSD patients
Healthy Controls
Psychiatric Controls
PTSD
(N = 67)
(N = 67)
(N = 67)
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Participants
Hypothesis generation
ROIs selection
p < 0.05. No Bonferroni correction
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Group Comparison
Psychiatric Patients
Hypothesis testing
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Group Selection
Recruiting
Healthy Volunteers No history or current diagnosis of a psychiatric disorder (N = 141)
ROIs comparison
p < 0.05. Bonferroni correction
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Fig. 2. Matching control groups (HC and PC) to PTSD group. A flowchart is shown to
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demonstrate the general procedure of selecting participants of interest (PTSD group) and matching participants in control groups (HC and PC). HC: healthy controls, PC: psychiatry
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controls, PTSD: post-traumatic stress disorders.
2.2. Neuroimaging Acquisition and Analysis Participants were scanned in a 3T Siemens Trio MR scanner in the Center for Advanced MR Imaging at Baylor College of Medicine in Houston, TX. For PP participants this occurred as close to their admission to the Menninger Clinic as possible. During the scan a ~4.5 min structural MPRAGE sequence (echo time (TE) = 2.66 ms, repetition time (TR) = 1200 ms, flip angle = 12°, 256 x 256 matrix, 160 one mm axial slices at 1 x 1 x 1 mm voxels) was collected. FreeSurfer
version 6.0 (http://surfer.nmr.mgh.harvard.edu)
was
used to perform
all
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Journal Pre-proof preprocessing and automated segmentation using the T1-weighted structural images. The segmentation of the cortical structures was performed using the FreeSurfer ‘recon-all’ pipeline. In brief, this technique automatically generates reliable volume and thickness segmentations of white matter, gray matter, and cortical volumes. This pipeline included removal of non-brain tissue, Talairach space transformations, segmentation of cortical white and deep gray matter, intensity normalization, and atlas registration. The segmentation of the cortical structures was
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based on the assignment of neuroanatomical labels to each voxel based on a-priori knowledge of spatial relationships estimated from a training set. It used differences in voxel intensity to
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locate and parcellate cortical structures and register to the Talairach space. The FreeSurfer
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processing approach have been described in detail previously (Desikan et al., 2006). After the
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‘recon-all’ function, all files were visually inspected for accuracy in all patients and controls. FreeSurfer segments regions of interest (ROIs) with probabilistic brain mapping based on the
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Desikan-Killiany cortical atlas (Desikan et al., 2006). This atlas was used to obtain volumes for all 34 bilateral cortical ROIs from the cortex as well as total intracranial volume (ICV). We
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controlled for ICV by dividing each patient’s individual ROI volume (in mm3) by his/her total ICV.
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In addition to explore brain volume differences between PTSD, HC, and PC, we performed
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cortical thickness and mean curvature analysis to examine group differences for all 34 bilateral ROIs. Note that these analyses were exploratory as the primary analysis was volume only, to limit number of multiple comparisons. We used gray matter thickness and mean curvature estimates obtained from FreeSurfer for a cortical thickness and vertex-wise analysis, respectively (Fischl, 2012).
2.3. Statistics T-tests (independent, 2-tailed) were used to determine between group differences for all 34 bilateral ROIs for PTSD vs HC (p < 0.05, no multiple comparisons corrections). Then t-tests were used to determine if the ROIs found to be significantly different between PTSD and HC
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Journal Pre-proof were also different when comparing PTSD to PC. Since we found 10 possibly differences in volume between HC and PTSD groups, we used a Bonferroni correction of 10 for the number of ROIs tested in PTSD vs PC (p < 0.005, multiple comparisons corrections). All statistical analyses were performed in SPSS (SPSS, INC., Chicago, Illinois).
Volume (mean ± std error)
Left Isthmus Cingulate Right Precuneus
PTSD vs HC
2.04 ± 0.038
1.98 ± 0.029
1.84 ± 0.032
1.88 ± 0.033
4.05 ± 0.046
3.98 ± 0.046
7.33 ± 0.091 1.39 ± 0.019 4.69 ± 0.073 1.81 ± 0.027 7.14 ± 0.081
Cohen’s d Effect Size
PTSD vs PC
PC vs HC
PTSD vs HC
PTSD vs PC
PC vs HC
0.0081**
0.77
0.014*
-3.832
-0.409
-3.554
0.0082**
0.015#
0.80
-3.828
-3.509
-0.358
0.0093**
0.26
0.23
-3.763
-1.628
-1.708
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2.10 ± 0.032
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Left Lingual
PTSD (N = 67) 8.96 ± 0.106 1.39 ± 0.026
1.73 ± 0.031
0.013*
0.00091***
0.37
-3.591
-4.835
1.285
3.89 ± 0.049
0.016*
0.20
0.24
-3.466
-1.844
-1.681
7.23 ± 0.110
7.00 ± 0.107
0.023*
0.15
0.48
-3.276
-2.050
-1.017
1.37 ± 0.020 4.61 ± 0.068 1.79 ± 0.027 6.98 ± 0.085
1.33 ± 0.018 4.45 ± 0.087 1.73 ± 0.024 6.91 ± 0.073
0.036*
0.15
0.54
-3.025
-2.087
-0.874
0.037*
0.14
0.46
-3.001
-2.139
-1.047
0.038*
0.10
0.68
-2.986
-2.376
-0.597
0.040*
0.55
0.18
-2.963
-0.847
-1.940
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Left Parahippocampal Right Parsorbitalis Right Temporal Pole Right Medial Orbitofrontal Right Supramarginal Right Parahippocampal
PC (N = 67) 9.00 ± 0.099 1.47 ± 0.024
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Right Precentral
p values
HC (N = 67) 9.36 ± 0.105 1.48 ± 0.025
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3. Results
Table 1. Group differences in cortical volumes. All regions significantly different between HC and PTSD (p < 0.05) are shown: several regions significantly different between PC vs PTSD and HC vs PC are not shown. Volumes are divided by intracranial volume to control for total brain volume. They are shown here multiplied by 1000. * p < 0.05; ** p < 0.01; *** p < 0.001. PC v PTSD that were significant after Bonferroni correction, or HC vs PC that were significant after Bonferroni correction; # signifies PC vs PTSD that did not survive Bonferroni correction, but
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Table 1 shows ten regions that have significantly smaller volumes in PTSD compared to HC (p < 0.05, no multiple comparisons corrections). These 10 ROIs were used in comparing the volumetric differences between PTSD and PC. Only one of these ROIs (right temporal pole)
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was significantly smaller in PTSD compared to PC (p < 0.005) when the Bonferroni correction for 10 comparisons was used. The right temporal pole volume for the three groups is shown in
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p = 0.37
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p = 0.013*
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R Temp Pole Vol (*1000/ICV)
Fig. 3.
HC (N = 67)
PC (N = 67)
p = 0.00091*** PTSD (N = 67)
Fig. 3. Right temporal pole volume for all groups. Boxplots show median value as horizontal line within boxes, the top line of the boxes is the upper quartile (75% of the data lies below this line), the bottom line of the boxes is the lower quartile (25% of the data lies below this line), whiskers represent the rest of the range of the data that is outside the interquartile. * p < 0.05; *** p < 0.001. R Temp Pole: right temporal pole, ICV: intracranial volume, HC: healthy controls, PC: psychiatry controls, PTSD: post-traumatic stress disorders.
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Journal Pre-proof Notably, 31 patients in the PC group who reported experiencing no past trauma according to the SLESQ had been matched to PTSD patients who reported past trauma. Therefore, in an exploratory analysis, we removed the 31 PC patients and their 31 PTSD matches to investigate if the difference between the right temporal pole remained when matching for presence of past trauma. Though this new comparison sample had fewer subjects (N=47 per group) and less power, the PTSD patients still had lower right temporal pole volumes (p = 0.048). In addition to
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the brain volume differences, we found 8 ROIs that were significantly thicker in PTSD compared to HC (left lateral occipital, left pericalcarine, left postcentral, left transverse temporal, right
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cuneus, right lateral occipital, right pericalcarine, and right rostral anterior cingulate), whereas 6
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ROIs that were significantly thicker in HC compared to PTSD (left lateral orbitofrontal, left
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paracentral, left superior frontal, right caudal middle frontal, right parahippocampal, and right superior frontal) (p < 0.05, no multiple comparisons corrections). These 14 ROIs were used in
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comparing the gray matter thickness between PTSD and PC, and no ROIs were survived when
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the Bonferroni correction for 14 comparisons was used (p < 0.00357). Finally, we examined the changes of curvature between PTSD and HC, and 4 ROIs revealed significantly varied
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curvature: in the left paracentral, and right insula, significantly increased mean curvature was
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observed in PTSD, but in the left banks of the superior temporal sulcus, and right cuneus, mean curvature increased dramatically in HC (p < 0.05, no multiple comparisons corrections). These 4 ROIs were used in comparing the mean curvature between PTSD and PC, and only one of these ROIs (right insula. p = 0.0094) was significantly increased in PTSD (0.1266 ± 0.009) compared to PC (0.1230 ± 0.006) when the Bonferroni correction for 4 comparisons was used (p < 0.0125).
4. Discussion In this study, we explored brain volume differences between PTSD patients and healthy and PC. We first demonstrated that when compared to healthy controls matched for demographic
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We found reduced volume in the right precentral, left parahippocampal, and right pars orbitalis of the inferior frontal gyrus in PTSD when we compared to HC. Our finding of lower cortical
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volume in the precentral gyrus in PTSD is consistent with an earlier study that reported reduced
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volume in PTSD compared to the healthy controls, although their finding did not survive family
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wise error correction (Kroes et al., 2011). Nonetheless, a previous fMRI study showed that a significant decrease activity in PTSD in the dorsal attention network, which includes the
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precentral gyrus (Mueller-Pfeiffer et al., 2013). Reduction in the left parahippocampal region
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volume is consistent with earlier studies that reported significantly smaller volume in PTSD compared to the trauma-exposed controls (Nardo et al., 2010; Woodward et al., 2009; Zhang et
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al., 2011), however, other studies have shown the larger parahippocampal volume in PTSD
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compared with healthy (Tupler and De Bellis, 2006) and trauma-exposed controls (Lindauer et al., 2005). Smaller cortical volume in pars orbitalis of the inferior frontal gyrus is consistent with a previous study (Woodward et al., 2009). However, when the PTSD group, matched by not only demographic characteristics but also the other psychiatric diagnoses (past and current), was compared to PC we did not find the cortical volume differences of the right precentral gyrus and right pars orbitalis. The left parahippocampal region in PTSD was only significantly smaller than HC and the result did not survive the Bonferroni correction for multiple comparisons with PC and should therefore be interpreted with caution. Our results suggest that cortical volume reductions in these regions may not be specific to PTSD, but be associated with common comorbidities.
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Our data shows that the right temporal pole volume in PTSD is significantly smaller than in both HC and PC. The reduced right temporal pole in PTSD is consistent with the results of a previous study comparing PTSD and trauma-exposed controls (Zhang et al., 2018). A meta-analysis reported volume reduction in the left temporal pole in PTSD, but not in the right temporal pole (Kühn and Gallinat, 2013). The temporal pole is a part of the paralimbic system along with the
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anterior cingulate cortex, orbitofrontal cortex, insula, and other emotion-related regions (Liberzon et al., 1999). Considered a node of the paralimbic cortex, the temporal pole is thought
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to play key roles in social and emotional processing and temporal pole damage due to trauma
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can lead to unstable mood states (Olson et al., 2007). Reduced temporal pole volume and
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functional activity in patients with bipolar disorder was reported in previous fMRI experiments of emotion recognition test (Maila de Castro et al., 2015). Combining previous evidence and our
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results, the temporal pole may be involved in emotion processing and temporal pole volume reduction may be associated with lack of mentalizing process which is the common
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psychological process of understanding other people’s mental states (e.g., desires, needs,
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feelings, reasons and emotions) (Frith and Frith, 2003; Kühn and Gallinat, 2013).
In an exploratory analysis, we found that the curvature of the right insula was significantly increased as compared to both HC and PC. Although the insula has been consistently implicated in PTSD (Kunimatsu et al., 2019), these results should be taken with caution as this was an exploratory analysis and we believe replication is necessary.
Our largely negative results emphasize the need for appropriate controls for pathology status when making comparisons in PTSD populations. Indeed, PTSD almost never occurs by itself, but, by its nature, is associated with a host of other disorders (Brown et al., 2001; Campbell et al., 2007; Hashemian et al., 2006; Van Ameringen et al., 2008). It therefore becomes unclear if
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Journal Pre-proof structural changes in the brain are caused primarily by PTSD itself, or by co-morbidities. Our results suggest that, in large part, PTSD does not directly cause much structural change, except for volume reduction at the temporal pole. Similar logic may be manifest for many other psychiatric populations where a primary diagnosis, e.g. depression, occurs amidst a welter of co-morbid disorders (Gosnell et al., 2020).
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Although reduced right temporal pole volume was observed in PTSD when compared to PC, several limitations of this study should be emphasized. First, because this study was designed
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to characterize mental illness in general, we did not collect scales and measures (e.g., Clinician-
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Administered PTSD Scale for DSM-5 (CAPS-5)), which are often used in PTSD research, and
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relied only on the SCID-I for PTSD diagnoses. Second, although we used a relatively large sample size, it is possible that our one size-difference result was a false positive. Finally, as
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expected, the number of the experienced traumatic events were significantly higher in PTSD
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than PC (Fig. 1). In addition, it is likely that the PTSD and PC groups experienced different kinds of events (e.g., life-threating accident, physical and sexual abuse, and/or witness to another
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person being killed or assaulted). Therefore, we suggest future work should further investigate
curvature.
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types of traumatic events possibly related to alterations in brain volume, thickness, and mean
5. Conclusion In summary, we characterized the brain cortical differences between PTSD patients, HC, and PC. Critically, the present study revealed that when populations are matched for both demographic characteristics and comorbid psychiatric disorders to compare between PTSD and PC, the right temporal pole volume in PTSD was significantly smaller than both HC and PC groups. Our finding provides evidence for a role for the temporal pole specifically in PTSD and may hold great promise for future research aimed at unraveling PTSD-specific pathophysiology
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Karl, A., Schaefer, M., Malta, L.S., Dörfel, D., Rohleder, N., Werner, A., 2006. A meta-analysis of structural brain abnormalities in PTSD. Neuroscience & Biobehavioral Reviews 30(7), 10041031. Kessler, R.C., Berglund, P., Demler, O., Jin, R., Merikangas, K.R., Walters, E.E., 2005. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of general psychiatry 62(6), 593-602. Kessler, R.C., Sonnega, A., Bromet, E., Hughes, M., Nelson, C.B., 1995. Posttraumatic stress disorder in the National Comorbidity Survey. Archives of general psychiatry 52(12), 1048-1060. Kilpatrick, D.G., Ruggiero, K.J., Acierno, R., Saunders, B.E., Resnick, H.S., Best, C.L., 2003. Violence and risk of PTSD, major depression, substance abuse/dependence, and comorbidity: results from the National Survey of Adolescents. Journal of consulting and clinical psychology 71(4), 692.
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Lindauer, R.J., Vlieger, E.-J., Jalink, M., Olff, M., Carlier, I.V., Majoie, C.B., Den Heeten, G.J., Gersons, B.P., 2005. Effects of psychotherapy on hippocampal volume in out-patients with posttraumatic stress disorder: a MRI investigation. Psychological medicine 35(10), 1421-1431. Logue, M.W., van Rooij, S.J., Dennis, E.L., Davis, S.L., Hayes, J.P., Stevens, J.S., Densmore, M., Haswell, C.C., Ipser, J., Koch, S.B., 2018. Smaller hippocampal volume in posttraumatic stress disorder: a multisite ENIGMA-PGC study: subcortical volumetry results from posttraumatic stress disorder consortia. Biological psychiatry 83(3), 244-253. Maila de Castro, L.N., Albuquerque, M.R., Malloy-Diniz, L., Nicolato, R., Neves, F.S., de SouzaDuran, F.L., Busatto, G., Corrêa, H., 2015. A voxel-based morphometry study of gray matter correlates of facial emotion recognition in bipolar disorder. Psychiatry Research: Neuroimaging 233(2), 158-164.
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Pavliša, G., Papa, J., Pavić, L., Pavliša, G., 2006. Bilateral MR volumetry of the amygdala in chronic PTSD patients. Collegium antropologicum 30(3), 565-568. Smith, M.E., 2005. Bilateral hippocampal volume reduction in adults with post‐traumatic stress disorder: A meta‐analysis of structural MRI studies. Hippocampus 15(6), 798-807. Stevens, F.L., Hurley, R.A., Taber, K.H., 2011. Anterior cingulate cortex: unique role in cognition and emotion. The Journal of neuropsychiatry and clinical neurosciences 23(2), 121-125. Sundquist, K., Johansson, L.-M., DeMarinis, V., Johansson, S.-E., Sundquist, J., 2005. Posttraumatic stress disorder and psychiatric co-morbidity: symptoms in a random sample of female Bosnian refugees. European Psychiatry 20(2), 158-164.
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Woon, F.L., Sood, S., Hedges, D.W., 2010. Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: a meta-analysis. Progress in Neuro-Psychopharmacology and Biological Psychiatry 34(7), 1181-1188. Zhang, J., Tan, Q., Yin, H., Zhang, X., Huan, Y., Tang, L., Wang, H., Xu, J., Li, L., 2011. Decreased gray matter volume in the left hippocampus and bilateral calcarine cortex in coal mine flood disaster survivors with recent onset PTSD. Psychiatry Research: Neuroimaging 192(2), 84-90. Zhang, X., Zhang, J., Wang, L., Zhang, W., 2018. Altered gray matter volume and its correlation with PTSD severity in Chinese earthquake survivors. Frontiers in psychiatry 9.
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Author statement Designed research: RS, JCF, JO, MP Analyzed data: SG, HO, RS Wrote software to match study groups: JS Interpret data, wrote paper: SG, HO, JO, JCF, MP, DR, RS
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Conflict of Interests The authors have no conflict of interest associated with this manuscript.
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Ethical statement The institution IRB committee approved the study. Written informed consent was obtained for all participants.
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Journal Pre-proof Highlights
PTSD is highly comorbid with other psychiatric disorders
PTSD patients should be compared to a group of psychiatric patient controls matched for demographic characteristics and comorbid psychiatric disorders, rather than healthy controls Lower right temporal pole volume distinguished PTSD patients from both healthy and
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psychiatric control groups, suggesting it may be a PTSD-specific biomarker
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Savannah N. Gosnell, Hyuntaek Oh, Jake Schmidt, John Oldham, J. Christopher Fowler, Michelle Patriquin, David Ress, Ramiro Salas PII:
S0278-5846(19)30475-0
DOI:
https://doi.org/10.1016/j.pnpbp.2020.109890
Reference:
PNP 109890
To appear in:
Progress in Neuropsychopharmacology & Biological Psychiatry
Received date:
4 June 2019
Revised date:
24 January 2020
Accepted date:
16 February 2020
Please cite this article as: S.N. Gosnell, H. Oh, J. Schmidt, et al., Right temporal pole volume reduction in PTSD, Progress in Neuropsychopharmacology & Biological Psychiatry(2019), https://doi.org/10.1016/j.pnpbp.2020.109890
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
Journal Pre-proof Right temporal pole volume reduction in PTSD
Savannah N Gosnell1,2,3 #, Hyuntaek Oh1,4 #, Jake Schmidt5, John Oldham 1,4, J Christopher Fowler1, Michelle Patriquin1,4, David Ress 3, Ramiro Salas 1,2,3,4 * 1 Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston TX, USA
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2 Michael E DeBakey VA Medical Center, Houston TX, USA
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3 Department of Neuroscience, Baylor College of Medicine, Houston TX, USA
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4 The Menninger Clinic, Houston TX, USA
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5 EOG Resources INC – Data Science, Houston TX, USA
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#These two authors contributed equally to this work
*Corresponding Author: Ramiro Salas, PhD,
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Baylor College of Medicine, One Baylor Plaza – room A277 Houston, TX 77030, USA. Email: [email protected]; TE 713-798-3502; Fax 713-798-4488
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Journal Pre-proof Abstract Previous magnetic resonance imaging studies of post-traumatic stress disorder (PTSD) have reported cortical volume alterations in the parahippocampal, anterior cingulate cortex, and temporal pole. It is unclear, however, if these cortical regions are specifically associated with PTSD or associated with common comorbidities. Here, we present the result of cortical volume differences between PTSD and healthy and psychiatric controls. In this study, healthy controls
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(n=67) were matched for demographic characteristics (age, sex, race) and psychiatric controls (n=67) were matched for demographic characteristics plus all other psychiatric diagnoses (past
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and current) to a group of PTSD patients (N=67). We assessed group differences of 34 bilateral
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cortical structure volumes using statistically defined brain regions-of-interest from FreeSurfer
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between PTSD patients and healthy controls. We found 10 regions to be significantly different between PTSD and healthy controls and analyzed the group differences between PTSD and
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psychiatric controls within these regions. The right temporal pole volume in PTSD was found to
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be significantly smaller than both healthy and psychiatry controls. Our finding suggests only right temporal pole volume reduction is specifically associated with PTSD, and also highlights
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the need for using appropriate controls in psychiatry research.
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Highlights
PTSD is highly comorbid with other psychiatric disorders
PTSD patients should be compared to a group of psychiatric patient controls matched for demographic characteristics and comorbid psychiatric disorders, rather than healthy controls
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Lower right temporal pole volume distinguished PTSD patients from both healthy and
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psychiatric control groups, suggesting it may be a PTSD-specific biomarker
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Journal Pre-proof Keywords: Post-traumatic stress disorder (PTSD), Right temporal pole, Structural magnetic
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resonance imaging, Trauma
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Journal Pre-proof 1. Introduction Post-traumatic stress disorder (PTSD) is a psychiatric disorder resulting from various kinds of traumatic events such as military combat-related stress, accidents, childhood maltreatment, and/or sexual abuse. In the general population, the lifetime prevalence rate for PTSD is about 6.8%, whereas the rate for veterans is approximately 23% (Fulton et al., 2015; Kessler et al., 2005). PTSD is characterized by a series of symptoms including re-experience, avoidance,
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negative alterations in cognition and mood, arousal, and hypervigilance (American Psychiatric
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Association, 2013).
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Several MRI morphometry studies have explored volumetric alterations in both cortical and
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subcortical regions known to be associated with PTSD. In these studies, the hippocampus, amygdala, anterior cingulate cortex (ACC), and temporal pole have been analyzed because
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these areas are highly implicated in memory for episodic events (Gurvits et al., 1996; Patel et al.,
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2012) and emotion regulation (Etkin et al., 2011; Ochsner et al., 2002; Olson et al., 2007; Stevens et al., 2011). Previous meta-analyses have reported that hippocampal volumes are
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reduced in PTSD relative to the control group (Bromis et al., 2018; Karl et al., 2006; Kitayama et
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al., 2005; Kühn and Gallinat, 2013; Smith, 2005; Woon and Hedges, 2008; Woon et al., 2010). Meta-analysis of amygdala structural abnormalities has found an evidence for smaller volume of amygdala in PTSD (Karl et al., 2006), but the results are controversial (Kühn and Gallinat, 2013; Woon and Hedges, 2008, 2009). Recently, the Psychiatric Genomics Consortium (PGC)Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) demonstrated with large sample size (total n = 1868; 794 PTSD patients) that PTSD is associated with significantly lower hippocampal volume and possibly amygdala volume (Logue et al., 2018). In addition to subcortical brain structural abnormalities, meta-analyses of cortical volume reductions in PTSD have also been reported in regions such as the medial prefrontal cortex (mPFC), ACC, middle
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Journal Pre-proof temporal gyrus (MTG), temporal pole, parahippocampal and occipital cortex (Bromis et al., 2018; Karl et al., 2006; Kühn and Gallinat, 2013; Li et al., 2014; Meng et al., 2014).
PTSD is highly comorbid with other psychiatric disorders, such as major depression (Brown et al., 2001; Campbell et al., 2007; Kessler et al., 1995; Oquendo et al., 2005), substance abuse (Hien et al., 2004; Kilpatrick et al., 2003; Van Ameringen et al., 2008), and anxiety disorders
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(Hashemian et al., 2006; Sundquist et al., 2005). Having several concurrent psychiatric diagnoses is also common amongst PTSD patients (Brady and Clary, 2003; Gallagher and
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Brown, 2015). Because of this, previously reported findings of altered morphometry in PTSD
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could possibly be associated with other psychiatric disorders rather than the diagnosis of PTSD
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only. While previous brain structural abnormality studies and meta-analyses have compared PTSD patients to either healthy controls (HC) (Bremner et al., 1997; Pavliša et al., 2006;
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Villarreal et al., 2002) or traumatized healthy controls (Bremner et al., 2003; Lindauer et al.,
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2004; Lindauer et al., 2005), there have been limited efforts to use more appropriate controls (e.g. those with similar demographic characteristics and psychiatric comorbidities). In order to
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find PTSD-specific brain structural abnormalities, PTSD patients should be matched to non-
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PTSD patients using not only sex, age and race, but also comorbid psychiatric disorders.
Here, we investigate brain cortical differences between PTSD patients and HC and psychiatric controls (PC), using data from 134 psychiatric patients (culled from a total sample of 518 patients) and 67 healthy participants (culled from a sample of 141 healthy volunteers). A major advantage of this study in comparison with previous cortical abnormality studies and metaanalyses in PTSD is that we matched the PC group with both demographic characteristics and other psychiatric diagnoses. In addition, to promote comparison with previous studies and to limit the number of regions to study in the PTSD vs. PC comparison, we also included a HC group matched for demographic characteristics. We compared 34 bilateral, whole-brain cortical
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Journal Pre-proof ROIs between these groups. We hypothesized that the mPFC, ACC, MTG, temporal pole, parahippocampal and occipital cortex of PTSD patients may be smaller than HC, and that some of those volume reductions may be observed between PTSD and PC which would be associated with specific PTSD diagnosis.
2. Methods
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2.1. Participants 2.1.1. Healthy Controls
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HC were volunteers from the community (N = 141, of which 67 were used) with no diagnosis of
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mental illness (past or current). HC were excluded if they had a self-report history of
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neurological or psychiatric disorders, including substance abuse/dependence. Additional exclusion criteria were a previous history of traumatic brain injury (loss of consciousness of
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more than 10 minutes) or any contraindication to MRI. Fig. 1 shows demographic characteristics
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(age, sex, and race) of HC.
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2.1.2. Psychiatric Patients and Clinical Measures Psychiatric patients (PP; N = 518) were recruited from the Menninger Clinic in Houston, Texas
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as a part of the McNair Initiative for Neuroscience Discovery – Menninger/Baylor (MIND-MB) research study (Ambrosi et al., 2018; Gosnell et al., 2019a; Gosnell et al., 2019b; Wills et al., 2019). PP were considered for the study if deemed mentally stable enough to participate and had no contraindications for MRI. Procedures were approved by the Institutional Review Board and all participants gave signed, informed consent. PP from the clinic had a variety of psychiatric conditions including mood, anxiety, personality, and substance abuse disorders, with over 80% diagnosed with comorbid psychiatric disorders (Fig. 1). They remained at the clinic for several weeks (4-6 weeks) while receiving treatment, however, this was not relevant to this study as we assessed patients as close as possible to admission to the clinic. Demographic
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Journal Pre-proof data relevant to our study (age, gender, and race) and psychiatric diagnoses from the Structured Clinical Interview for DSM-IV disorders axis I and II were collected. We also conducted the Stressful Life Events Screening Questionnaire (SLESQ) for all patients in the
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study, to determine if they had ever experienced traumatic events (Goodman et al., 1998).
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Fig. 1. Demographic characteristics, the number of the experienced traumatic events and overview of comorbid disorders in psychiatric patients. A. demographics are shown for each group. The number of the experienced traumatic events (from the SLESQ) are shown for both PTSD and PC groups (p < 0.05). B. An overview of clinical diagnoses with PTSD and PC groups are shown. Note this is just for visualization, as the groups were matched based on all psychiatric diagnoses, individually, not just those shown. HC: healthy controls, PC: psychiatry controls, PTSD: post-traumatic stress disorder, SD: standard deviation, PD: personal disorders, BP: bipolar disorder, SUB/ALC: substance/alcohol use disorder, ED: eating disorders, ANX:
anxiety disorder not otherwise specified, MDD: major depressive disorder. 8
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2.1.3. Matching Control Groups to PTSD Group From the PP population we selected inpatients who met criteria with a primary DSM-IV diagnosis of PTSD (N = 67) for the study. A HC group and PC group of the same size were matched to the PTSD group in a one-to-one manner (Fig. 2). The HC group was matched for demographic characteristics (age, sex, race) and the PC group was matched for demographic
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characteristics plus all other psychiatric diagnoses (past and current). This was accomplished using a Euclidean distance-matching algorithm. The algorithm used each characteristic
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(normalized using z-scores) being matched for as a separate dimension to place each subject in
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multi-dimensional space. The algorithm minimized the sum of Euclidean distances between
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each pair (one PTSD and one control subject). All matching was coded in Python (version 3) and is available upon request. The accuracy of the matched groups was confirmed by
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assessing between group differences on all characteristics using t-tests for age and Chi-
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squared tests for all other variables to ensure the groups were not significantly different for any feature (p < 0.05, no multiple comparisons corrections). The result of this grouping was a HC
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group (N = 67) matched for age, gender, and race to the PTSD group and a PC group (N = 67)
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matched for demographics and psychiatric diagnoses to the PTSD group.
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Any current diagnosis of a psychiatric disorder (N = 518)
Demographics: age, sex and race
Match to PTSD patients
Select for current diagnosis of PTSD Demographics: age, sex and race and all past/current psychiatric diagnoses
Selection
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Match to PTSD patients
Healthy Controls
Psychiatric Controls
PTSD
(N = 67)
(N = 67)
(N = 67)
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Participants
Hypothesis generation
ROIs selection
p < 0.05. No Bonferroni correction
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Group Comparison
Psychiatric Patients
Hypothesis testing
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Group Selection
Recruiting
Healthy Volunteers No history or current diagnosis of a psychiatric disorder (N = 141)
ROIs comparison
p < 0.05. Bonferroni correction
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Fig. 2. Matching control groups (HC and PC) to PTSD group. A flowchart is shown to
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demonstrate the general procedure of selecting participants of interest (PTSD group) and matching participants in control groups (HC and PC). HC: healthy controls, PC: psychiatry
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controls, PTSD: post-traumatic stress disorders.
2.2. Neuroimaging Acquisition and Analysis Participants were scanned in a 3T Siemens Trio MR scanner in the Center for Advanced MR Imaging at Baylor College of Medicine in Houston, TX. For PP participants this occurred as close to their admission to the Menninger Clinic as possible. During the scan a ~4.5 min structural MPRAGE sequence (echo time (TE) = 2.66 ms, repetition time (TR) = 1200 ms, flip angle = 12°, 256 x 256 matrix, 160 one mm axial slices at 1 x 1 x 1 mm voxels) was collected. FreeSurfer
version 6.0 (http://surfer.nmr.mgh.harvard.edu)
was
used to perform
all
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Journal Pre-proof preprocessing and automated segmentation using the T1-weighted structural images. The segmentation of the cortical structures was performed using the FreeSurfer ‘recon-all’ pipeline. In brief, this technique automatically generates reliable volume and thickness segmentations of white matter, gray matter, and cortical volumes. This pipeline included removal of non-brain tissue, Talairach space transformations, segmentation of cortical white and deep gray matter, intensity normalization, and atlas registration. The segmentation of the cortical structures was
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based on the assignment of neuroanatomical labels to each voxel based on a-priori knowledge of spatial relationships estimated from a training set. It used differences in voxel intensity to
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locate and parcellate cortical structures and register to the Talairach space. The FreeSurfer
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processing approach have been described in detail previously (Desikan et al., 2006). After the
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‘recon-all’ function, all files were visually inspected for accuracy in all patients and controls. FreeSurfer segments regions of interest (ROIs) with probabilistic brain mapping based on the
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Desikan-Killiany cortical atlas (Desikan et al., 2006). This atlas was used to obtain volumes for all 34 bilateral cortical ROIs from the cortex as well as total intracranial volume (ICV). We
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controlled for ICV by dividing each patient’s individual ROI volume (in mm3) by his/her total ICV.
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In addition to explore brain volume differences between PTSD, HC, and PC, we performed
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cortical thickness and mean curvature analysis to examine group differences for all 34 bilateral ROIs. Note that these analyses were exploratory as the primary analysis was volume only, to limit number of multiple comparisons. We used gray matter thickness and mean curvature estimates obtained from FreeSurfer for a cortical thickness and vertex-wise analysis, respectively (Fischl, 2012).
2.3. Statistics T-tests (independent, 2-tailed) were used to determine between group differences for all 34 bilateral ROIs for PTSD vs HC (p < 0.05, no multiple comparisons corrections). Then t-tests were used to determine if the ROIs found to be significantly different between PTSD and HC
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Journal Pre-proof were also different when comparing PTSD to PC. Since we found 10 possibly differences in volume between HC and PTSD groups, we used a Bonferroni correction of 10 for the number of ROIs tested in PTSD vs PC (p < 0.005, multiple comparisons corrections). All statistical analyses were performed in SPSS (SPSS, INC., Chicago, Illinois).
Volume (mean ± std error)
Left Isthmus Cingulate Right Precuneus
PTSD vs HC
2.04 ± 0.038
1.98 ± 0.029
1.84 ± 0.032
1.88 ± 0.033
4.05 ± 0.046
3.98 ± 0.046
7.33 ± 0.091 1.39 ± 0.019 4.69 ± 0.073 1.81 ± 0.027 7.14 ± 0.081
Cohen’s d Effect Size
PTSD vs PC
PC vs HC
PTSD vs HC
PTSD vs PC
PC vs HC
0.0081**
0.77
0.014*
-3.832
-0.409
-3.554
0.0082**
0.015#
0.80
-3.828
-3.509
-0.358
0.0093**
0.26
0.23
-3.763
-1.628
-1.708
re
-p
2.10 ± 0.032
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Left Lingual
PTSD (N = 67) 8.96 ± 0.106 1.39 ± 0.026
1.73 ± 0.031
0.013*
0.00091***
0.37
-3.591
-4.835
1.285
3.89 ± 0.049
0.016*
0.20
0.24
-3.466
-1.844
-1.681
7.23 ± 0.110
7.00 ± 0.107
0.023*
0.15
0.48
-3.276
-2.050
-1.017
1.37 ± 0.020 4.61 ± 0.068 1.79 ± 0.027 6.98 ± 0.085
1.33 ± 0.018 4.45 ± 0.087 1.73 ± 0.024 6.91 ± 0.073
0.036*
0.15
0.54
-3.025
-2.087
-0.874
0.037*
0.14
0.46
-3.001
-2.139
-1.047
0.038*
0.10
0.68
-2.986
-2.376
-0.597
0.040*
0.55
0.18
-2.963
-0.847
-1.940
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Left Parahippocampal Right Parsorbitalis Right Temporal Pole Right Medial Orbitofrontal Right Supramarginal Right Parahippocampal
PC (N = 67) 9.00 ± 0.099 1.47 ± 0.024
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Right Precentral
p values
HC (N = 67) 9.36 ± 0.105 1.48 ± 0.025
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Region
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3. Results
Table 1. Group differences in cortical volumes. All regions significantly different between HC and PTSD (p < 0.05) are shown: several regions significantly different between PC vs PTSD and HC vs PC are not shown. Volumes are divided by intracranial volume to control for total brain volume. They are shown here multiplied by 1000. * p < 0.05; ** p < 0.01; *** p < 0.001. PC v PTSD that were significant after Bonferroni correction, or HC vs PC that were significant after Bonferroni correction; # signifies PC vs PTSD that did not survive Bonferroni correction, but
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Journal Pre-proof were significant at p < 0.05. HC: healthy controls, PC: psychiatry controls, PTSD: post-traumatic stress disorders.
Table 1 shows ten regions that have significantly smaller volumes in PTSD compared to HC (p < 0.05, no multiple comparisons corrections). These 10 ROIs were used in comparing the volumetric differences between PTSD and PC. Only one of these ROIs (right temporal pole)
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was significantly smaller in PTSD compared to PC (p < 0.005) when the Bonferroni correction for 10 comparisons was used. The right temporal pole volume for the three groups is shown in
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p = 0.37
3
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p = 0.013*
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1
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R Temp Pole Vol (*1000/ICV)
Fig. 3.
HC (N = 67)
PC (N = 67)
p = 0.00091*** PTSD (N = 67)
Fig. 3. Right temporal pole volume for all groups. Boxplots show median value as horizontal line within boxes, the top line of the boxes is the upper quartile (75% of the data lies below this line), the bottom line of the boxes is the lower quartile (25% of the data lies below this line), whiskers represent the rest of the range of the data that is outside the interquartile. * p < 0.05; *** p < 0.001. R Temp Pole: right temporal pole, ICV: intracranial volume, HC: healthy controls, PC: psychiatry controls, PTSD: post-traumatic stress disorders.
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Journal Pre-proof Notably, 31 patients in the PC group who reported experiencing no past trauma according to the SLESQ had been matched to PTSD patients who reported past trauma. Therefore, in an exploratory analysis, we removed the 31 PC patients and their 31 PTSD matches to investigate if the difference between the right temporal pole remained when matching for presence of past trauma. Though this new comparison sample had fewer subjects (N=47 per group) and less power, the PTSD patients still had lower right temporal pole volumes (p = 0.048). In addition to
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the brain volume differences, we found 8 ROIs that were significantly thicker in PTSD compared to HC (left lateral occipital, left pericalcarine, left postcentral, left transverse temporal, right
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cuneus, right lateral occipital, right pericalcarine, and right rostral anterior cingulate), whereas 6
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ROIs that were significantly thicker in HC compared to PTSD (left lateral orbitofrontal, left
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paracentral, left superior frontal, right caudal middle frontal, right parahippocampal, and right superior frontal) (p < 0.05, no multiple comparisons corrections). These 14 ROIs were used in
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comparing the gray matter thickness between PTSD and PC, and no ROIs were survived when
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the Bonferroni correction for 14 comparisons was used (p < 0.00357). Finally, we examined the changes of curvature between PTSD and HC, and 4 ROIs revealed significantly varied
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curvature: in the left paracentral, and right insula, significantly increased mean curvature was
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observed in PTSD, but in the left banks of the superior temporal sulcus, and right cuneus, mean curvature increased dramatically in HC (p < 0.05, no multiple comparisons corrections). These 4 ROIs were used in comparing the mean curvature between PTSD and PC, and only one of these ROIs (right insula. p = 0.0094) was significantly increased in PTSD (0.1266 ± 0.009) compared to PC (0.1230 ± 0.006) when the Bonferroni correction for 4 comparisons was used (p < 0.0125).
4. Discussion In this study, we explored brain volume differences between PTSD patients and healthy and PC. We first demonstrated that when compared to healthy controls matched for demographic
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Journal Pre-proof characteristics (sex, age and race), we observed 10 ROIs including the right precentral, left parahippocampal and right pars orbitalis in PTSD were significantly smaller than HC group. We then compared to PC matched for both demographic characteristics and comorbid psychiatric disorders and found that only the right temporal pole in PTSD was significantly smaller than both HC and PC groups.
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We found reduced volume in the right precentral, left parahippocampal, and right pars orbitalis of the inferior frontal gyrus in PTSD when we compared to HC. Our finding of lower cortical
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volume in the precentral gyrus in PTSD is consistent with an earlier study that reported reduced
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volume in PTSD compared to the healthy controls, although their finding did not survive family
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wise error correction (Kroes et al., 2011). Nonetheless, a previous fMRI study showed that a significant decrease activity in PTSD in the dorsal attention network, which includes the
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precentral gyrus (Mueller-Pfeiffer et al., 2013). Reduction in the left parahippocampal region
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volume is consistent with earlier studies that reported significantly smaller volume in PTSD compared to the trauma-exposed controls (Nardo et al., 2010; Woodward et al., 2009; Zhang et
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al., 2011), however, other studies have shown the larger parahippocampal volume in PTSD
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compared with healthy (Tupler and De Bellis, 2006) and trauma-exposed controls (Lindauer et al., 2005). Smaller cortical volume in pars orbitalis of the inferior frontal gyrus is consistent with a previous study (Woodward et al., 2009). However, when the PTSD group, matched by not only demographic characteristics but also the other psychiatric diagnoses (past and current), was compared to PC we did not find the cortical volume differences of the right precentral gyrus and right pars orbitalis. The left parahippocampal region in PTSD was only significantly smaller than HC and the result did not survive the Bonferroni correction for multiple comparisons with PC and should therefore be interpreted with caution. Our results suggest that cortical volume reductions in these regions may not be specific to PTSD, but be associated with common comorbidities.
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Our data shows that the right temporal pole volume in PTSD is significantly smaller than in both HC and PC. The reduced right temporal pole in PTSD is consistent with the results of a previous study comparing PTSD and trauma-exposed controls (Zhang et al., 2018). A meta-analysis reported volume reduction in the left temporal pole in PTSD, but not in the right temporal pole (Kühn and Gallinat, 2013). The temporal pole is a part of the paralimbic system along with the
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anterior cingulate cortex, orbitofrontal cortex, insula, and other emotion-related regions (Liberzon et al., 1999). Considered a node of the paralimbic cortex, the temporal pole is thought
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to play key roles in social and emotional processing and temporal pole damage due to trauma
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can lead to unstable mood states (Olson et al., 2007). Reduced temporal pole volume and
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functional activity in patients with bipolar disorder was reported in previous fMRI experiments of emotion recognition test (Maila de Castro et al., 2015). Combining previous evidence and our
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results, the temporal pole may be involved in emotion processing and temporal pole volume reduction may be associated with lack of mentalizing process which is the common
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psychological process of understanding other people’s mental states (e.g., desires, needs,
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feelings, reasons and emotions) (Frith and Frith, 2003; Kühn and Gallinat, 2013).
In an exploratory analysis, we found that the curvature of the right insula was significantly increased as compared to both HC and PC. Although the insula has been consistently implicated in PTSD (Kunimatsu et al., 2019), these results should be taken with caution as this was an exploratory analysis and we believe replication is necessary.
Our largely negative results emphasize the need for appropriate controls for pathology status when making comparisons in PTSD populations. Indeed, PTSD almost never occurs by itself, but, by its nature, is associated with a host of other disorders (Brown et al., 2001; Campbell et al., 2007; Hashemian et al., 2006; Van Ameringen et al., 2008). It therefore becomes unclear if
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Journal Pre-proof structural changes in the brain are caused primarily by PTSD itself, or by co-morbidities. Our results suggest that, in large part, PTSD does not directly cause much structural change, except for volume reduction at the temporal pole. Similar logic may be manifest for many other psychiatric populations where a primary diagnosis, e.g. depression, occurs amidst a welter of co-morbid disorders (Gosnell et al., 2020).
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Although reduced right temporal pole volume was observed in PTSD when compared to PC, several limitations of this study should be emphasized. First, because this study was designed
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to characterize mental illness in general, we did not collect scales and measures (e.g., Clinician-
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Administered PTSD Scale for DSM-5 (CAPS-5)), which are often used in PTSD research, and
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relied only on the SCID-I for PTSD diagnoses. Second, although we used a relatively large sample size, it is possible that our one size-difference result was a false positive. Finally, as
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expected, the number of the experienced traumatic events were significantly higher in PTSD
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than PC (Fig. 1). In addition, it is likely that the PTSD and PC groups experienced different kinds of events (e.g., life-threating accident, physical and sexual abuse, and/or witness to another
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person being killed or assaulted). Therefore, we suggest future work should further investigate
curvature.
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types of traumatic events possibly related to alterations in brain volume, thickness, and mean
5. Conclusion In summary, we characterized the brain cortical differences between PTSD patients, HC, and PC. Critically, the present study revealed that when populations are matched for both demographic characteristics and comorbid psychiatric disorders to compare between PTSD and PC, the right temporal pole volume in PTSD was significantly smaller than both HC and PC groups. Our finding provides evidence for a role for the temporal pole specifically in PTSD and may hold great promise for future research aimed at unraveling PTSD-specific pathophysiology
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Author statement Designed research: RS, JCF, JO, MP Analyzed data: SG, HO, RS Wrote software to match study groups: JS Interpret data, wrote paper: SG, HO, JO, JCF, MP, DR, RS
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Conflict of Interests The authors have no conflict of interest associated with this manuscript.
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Ethical statement The institution IRB committee approved the study. Written informed consent was obtained for all participants.
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Journal Pre-proof Highlights
PTSD is highly comorbid with other psychiatric disorders
PTSD patients should be compared to a group of psychiatric patient controls matched for demographic characteristics and comorbid psychiatric disorders, rather than healthy controls Lower right temporal pole volume distinguished PTSD patients from both healthy and
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psychiatric control groups, suggesting it may be a PTSD-specific biomarker
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