The brain-derived neurotrophic factor (
Ninety-five PD patients were enrolled. The Neuroticism, the Anxiety Sensitivity Inventory-Revised, Panic Disorder Severity Scale, and Beck Depression Inventory-II (BDI-II) were administered. Voxel-wise statistical analysis of diffusion tensor imaging data was performed within the CC regions using Tract-Based Spatial Statistics.
The GG genotype in
Our findings demonstrate that the
Panic disorder (PD)–encompassing psychological, neurological, and biological dimensions–is an anxiety disorder characterized by predictive anxiety, unexpected panic attacks, and physical symptoms. These symptoms include sensations of shortness of breath, palpitation, or fear of dying. Recently, research on neurobiological and genetic factors of PD has been emerged. Previously, several studies suggested that genetic factors might contribute to one’s susceptibility of developing PD. The relative risk in first-degree relatives of proband with PD between 2.6 to 20 times higher [
The brain-derived neurotrophic factor (BDNF) protein is encoded by a gene found in humans on chromosome 11 and is part of the neurotrophin family of nerve growth factor essential for neurodevelopment. In the brain, the
A previous study (of non-clinical samples) suggests that the GG (Val/Val) genotype of rs6265 in
So far, the amygdala, hippocampus, frontal cortex, and sensory cortex areas–as they relate to the fear network model of PD–has been studied extensively [
Further research investigating the association between the
The aim of our study is to determine 1) whether the
A total of 95 patients with PD participated in this study. Between January 2011 and May 2019, study participants were recruited from the pool of PD patients treated in the Department of Psychiatry at CHA Bundang Medical Center (Gyeonggi-do, Korea). All participants were between 17 and 64 years of age, right-handed, and of Korean descent. Individual and family histories of PD patients were collected through interviews.
Participants with PD–with or without agoraphobia–were diagnosed by practiced psychiatrists using the Structured Clinical Interview to evaluate DSM-VI-TR (as per the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) Axis I Disorder). Only patients with primary PD were included. Secondary lifetime diagnoses included major depressive disorders (17 patients) and generalized anxiety disorder (10 patients). Exclusion criteria included any history of schizophrenia, intellectual disabilities, alcohol and substance abuse or dependence, and current or past serious medical disorders–including neurological disorders, pregnancy, and contraindications to brain magnetic resonance imaging (MRI) scanning.
At the time of MRI acquisition, 78 PD patients were undergoing pharmacotherapy with selective serotonin reuptake inhibitors (SSRIs), including escitalopram, paroxetine, and sertraline [n=78; escitalopram equivalence dosage, mean (±SD) 9.33±7.48 mg/day], and benzodiazepines as anxiolytics, including lorazepam, alprazolam, clonazepam and diazepam [n=88; lorazepam equivalence dosage mean (±SD) 1.92±1.96 mg/day]. Brain MRIs were performed 11.55±24.11 days after the initiation of medication uptake. All patients with PD were undergoing pharmacotherapy with antidepressants and anxiolytics according to the Korean Mediation Algorithm for PD [
All study procedures conform to the Institutional Review Board regulations and the principles of Good Clinical Practice delineated by the CHA Bundang Medical Center. After a sufficient explanation of the study was given to the participants, written informed consent was obtained from each participant (2019-05-030, 2018-06-029, 2011-11-164).
The Neuroticism-Extraversion-Openness (NEO)-neuroticism Inventory [
The Panic Disorder Severity Scale (PDSS) [
Additionally, only supportive psychotherapy was allowed during the study period. The therapeutic response to pharmacology was measured twice: once at 8 weeks and again at 1 year. These measures are defined as 40% of the total PDSS score reduction compared to the baseline scores [
To analyze the
The genotype frequencies of
Magnetic resonance images were acquired using a 3 Tesla scanner (SignaHDxt, GE Healthcare, Milwaukee, WI, USA). Diffusion-weighted imaging (DWI) [
Voxelwise statistical analysis about fractional anisotropy (FA) data was performed using Tract-Based Spatial Statistics (TBSS) version 1.2, as implemented via the Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL version 4.1, Oxford, UK,
To compare DTI indices [FA, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD)], FSL FA images were used in order to achieve nonlinear registration and obtain stages of skeletonization, and to estimate the projection vectors from each individual subject onto the mean FA skeleton [
Mean FA skeletons were multiplied using the Johns Hopkins University DTI-based probabilistic tractography atlas, containing the CC [
We performed a voxel by voxel statistical analysis in order to detect regions of significant differences in the scores of the DTI indices (i.e., FA, MD, AD, and RD) among genotype groups [the
To confirm the voxel-wise analysis results, the DTI indices of the CC were extracted; the indices demonstrated significant differences in the FA, MD, and RD values between the two groups. These results were applied to further analysis. We conducted correlation analyses to investigate whether regional differences in the FA value could potentially be associated with the variance in clinical symptom ratings among in each genotype group.
We performed statistical analyses using SPSS version 26.0 (IBM Corporation, Armonk, NY, USA). Differences with p<0.05 were statistically significant.
We divided the participants with PD into either a GG genotype or a non-GG genotype (A-allele carrier) groups of the
The genotype distributions of all 95 patients with PD (GG: n=25, GA: n=53, AA: n=17) were in accordance with the Hardy-Weinberg equilibrium (χ2=1.46, df=1, p=0.23). Upon division of the participants with PD into the two aforementioned groups, they were not significantly different in terms of sex (p=0.11) or age (p=0.72) (
The GG genotype group showed significantly higher scores the NEO-neuroticism, and BDI-II scales. However, there was no significant difference via the ASI-R and its subscales (
Increased FA values in the posterior part of body and splenium of the CC were found in participants with the GG genotype compared to the non-GG genotype participants. However, the MD and RD values showed inverse results from the FA values (
Although the age and sex of PD patients did not show any significant correlation or association with the FA of the body and splenium of the CC, we decided to include age and sex so as to control for the potential confounding factors apparent in the regression model. Results of the linear regression of the FA values of the body and splenium of the CC on
Correlation analysis between the WM regions in the body and splenium of the CC–where the FA values significantly differed, according to genotype between the two groups’ trait vulnerability scores–reveals significant positive correlations between the FA values of the body of the CC regions, as well as the baseline ASI-R “fear of respiratory symptom” scores. In the GG genotype group, a positive and statistically significant correlation is shown, unlike in the non-GG genotype group (r=0.249, p=0.049) (
To our knowledge, this is the first study to demonstrate that in patients with PD 1) the GG genotype group has significantly higher FA values in regard to the posterior part of the body and splenium of the CC, and 2) that the GG genotype group exhibits higher degree of neuroticism–a vulnerability trait of PD–and depressive symptoms than patients in the non-GG genotype group. Furthermore, among the non-GG genotype group, PD patients with higher FA values in the body of the CC showed higher baseline ASI-R “fear of respiratory symptom” subscale scores. Our findings suggest that
In the present study, we observe that measures of neuroticism are higher among patients in the GG genotype group. Our results are similar to those of a the previous study of heterogeneous anxiety disorders, that included PD, post-traumatic stress disorder, obsessive-compulsive disorder, phobic disorder, and generalized anxiety disorder [
In this study, we further find that patients in the GG genotype group show higher FA values in the body and splenium areas of the CC, as well as lower MD and RD values when compared to those in the non-GG genotype group. These findings suggest the possibility of a relationship between axon and myelin microalterations in the body and splenium regions of the CC of PD patients, according to the
The reason why the
Literature regarding genetic-neuroimaging on
Our study also finds a positive association between the ASIR “fear of respiratory symptom” subscale score and the FA values in the body of the CC among patients in the non-GG genotype group. This result suggests that the WM connectivity of the body of the CC among PD patients in the non-GG genotype group might contribute to the trait vulnerability of anxiety sensitivity.
There were a number of limitations to our study. First, the sample size in each group was relatively small. Although significantly increased FA values in the CC regions were found among patients in the GG genotype group compared to the non-GG genotype group, further studies should include a larger sample for more accurate results. Secondly, only patients with PD were studied. To obtain the further understandings of the relationship between the
In conclusion, the current findings suggest that the BDNF Val66Met polymorphism is associated with WM connectivity of the body and splenium of the CC, and that it may also be related to neuroticism and depressive symptoms in individuals with PD. Furthermore, PD patients in the non-GG genotype group, those with higher FA values in the body of the CC show higher anxiety sensitivity. These results demonstrate that the CC microalterations (according to the
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea of funded by the Ministry of Education, Science and Technology (2011-0023359), by Ministry of Science and ICT (2018-R1D1A1B07046978) and (NRF-2019M3C7A1032262) to S.H. Lee. Thanks to Chaerim Song for the help of cluster analysis.
The authors have no potential conflicts of interest to disclose.
Conceptualization: Hyun-Ju Kim, Chun Il Park, Sang-Hyuk Lee. Data curation: Hyun-Ju Kim, Chun Il Park, Sang-Hyuk Lee. Formal analysis: Hyun-Ju Kim, Chun Il Park, Sang-Hyuk Lee. Funding acquisition: SangHyuk Lee. Investigation: Hyun-Ju Kim, Chun Il Park, Sang-Hyuk Lee. Methodology: Hyun-Ju Kim, Chun Il Park, Sang-Hyuk Lee. Project administration: Hyun-Ju Kim, Chun Il Park, Sang-Hyuk Lee. Resources: Hyun-Ju Kim, Chun Il Park, Sang-Hyuk Lee. Software: Sang-Hyuk Lee. Supervision: Chun Il Park, Sang-Hyuk Lee. Validation: all authors. Visualization: Hyun-Ju Kim, Sang-Hyuk Lee. Writing—original draft: Hyun-Ju Kim, Chun Il Park, Sang-Hyuk Lee. Writing—review & editing: Hyun-Ju Kim, Chun Il Park, Sang-Hyuk Lee.
Results of the Tract-Based Spatial Statistics analysis show significant increases in fractional anisotropy (FA) values in the posterior part of the body and splenium of the corpus callosum in panic disorder patients of the GG genotype group compared to non-GG genotype group patients. Voxels demonstrating significantly (corrected p<0.05) increased FA values for the GG genotype group (compared to the non-GG genotype group) in patients with PD are shown in red. However, the mean diffusivity (MD) and radial diffusivity (RD) values show inverse results from the FA values. FA, MD, RD, and axial diffusivity (AD) are superimposed on the Montreal Neurologic Institute (MNI) 1 mm template. For better visibility, the results were thickened using the “tbss-fill” command. Red, Blue, and Green (p<0.05; respectively; FEW corrected).
Significant positive correlations (corrected p<0.05) between the Anxiety Sensitivity Inventory-for Review only Revised (ASI-R) “fear of respiratory symptom” subscale score and fractional anisotropy (FA) values of the body of the corpus callosum in BDNF Val66Met polymorphism.
Comparison of the sociodemographic and clinical characteristics between BDNF genotype groups in panic disorder
GG (Val/Val) genotype group (N=25) | Non-GG (Met-carriers) genotype group (N=70) | t | df | p | |
---|---|---|---|---|---|
Sex, male/female (N) | 7/18 | 32/38 | 1.62 | 46 | 0.11 |
Age at scan (years, mean±SD) | 36.28±13.65 | 37.26±11.02 | -0.36 | 93 | 0.72 |
Education (years, mean±SD) | 12.88±2.97 | 13.61±2.99 | -1.04 | 91 | 0.30 |
Intracranial volume (mL, mean±SD) | 1502.406±104.84 | 1505.82±131.28 | -0.08 | 47 | 0.94 |
Agoraphobia, yes (%) | 13 (56.5) | 46 (71.9) | 1.28 | 35 | 0.21 |
Major depressive disorder, yes (%) | 5 (20.0) | 12 (17.1) | 0.32 | 93 | 0.75 |
Generalized anxiety disorder, yes (%) | 4 (16.0) | 6 (8.5) | 0.91 | 34 | 0.37 |
Duration of illness (months, mean±SD) | 62.28±48.99 | 50.89±35.73- | 1.24 | 93 | 0.22 |
Kinds of SSRI {escitalopram [N (%)]/praoxetine [N (%)]} | 9 (36.0)/10 (40.0) | 24 (34.3)/30 (42.9) | |||
SSRI equivalent dosage (mg, mean±SD)* | 11.08±10.27 | 7.96±7.98 | 1.55 | 96 | 0.13 |
Kinds of benzodiazepine {alprazolam [N (%)]/clonazepam [N (%)]} | 22 (88.0)/6 (24.0) | 55 (78.6)/15 (21.4) | |||
Benzodiazepine equivalent dosage (mg, mean±SD)† | 2.10±1.93 | 1.64±1.86 | 1.05 | 93 | 0.30 |
the approximate equivalent oral doses to 10 mg Escitalopram are given,
the approximate equivalent oral doses to 1 mg Lorazepam are given.
BDNF: brain-derived neurotrophic factor, SD: standard deviation, SSRI: selective serotonin re-uptake inhibitor
Comparison of trait vulnerability and symptom severity measures between BDNF genotype groups in panic disorder
GG (Val/Val) genotype group (N=25) | Non-GG (Met-carriers) genotype group (N=70) | t | df | p | |
---|---|---|---|---|---|
Neuroticism total score (mean±SD) | 8.58±3.23 | 6.80±3.74 | 2.07 | 88 | 0.04* |
ASI-R total score (mean±SD) | 54.23±35.92 | 48.71±22.96 | 0.67 | 27 | 0.51 |
ASI-R fear of respiratory symptom | 20.13±12.64 | 19.71±11.03 | 0.15 | 84 | 0.88 |
ASI-R fear of publicly observable anxiety reaction | 11.22±9.06 | 10.47±7.14 | 0.40 | 85 | 0.69 |
ASI-R fear of cardiovascular symptom | 13.83±10.62 | 12.38±7.80 | 0.69 | 84 | 0.49 |
ASI-R fear of cognitive dyscontrol | 8.50±8.32 | 6.02±5.78 | 1.35 | 31 | 0.19 |
Initial PDSS total score (mean±SD) | 13.00±6.70 | 12.77±6.34 | 0.15 | 87 | 0.88 |
PDSS decrease (%) at 8 weeks (mean±SD) | 2.11±45.21 | -2.73±172.00 | 0.30 | 78 | 0.76 |
PDSS decrease (%) at 1 year (mean±SD) | 6.57±73.21 | 19.81±121.61 | -0.19 | 68 | 0.85 |
BDI-II total score (mean±SD) | 21.17±13.04 | 15.74±8.04 | 2.37 | 88 | 0.02* |
BAI total score (mean±SD) | 28.29±16.52 | 25.63±12.52 | 0.81 | 86 | 0.42 |
p<0.05.
BDNF: brain-derived neurotrophic factor, SD: standard deviation, ASI-R: Anxiety Sensitivity Inventory-Revised, PDSS: Panic Disorder Severity Scale, BDI-II: Beck Depression Inventory-II, BAI: Beck Anxiety Inventory
Linear regression of the FA values of body and splenium of corpus callosum on BDNF Val66Met genotype in panic disorder
Dependent variable: FA values of splenium of corpus callosum (χ2=0.407, F=11.518, p<0.000) |
|||
---|---|---|---|
Variable | β | T | p |
Age | 0.23 | 2.52 | 0.01* |
Sex | 0.10 | 1.14 | 0.26 |
BDNF Val66Met genotype | -0.60 | -6.73 | <0.000† |
Neuroticism total score | 0.04 | 0.43 | 0.67 |
BDI-II total score | 0.05 | 0.55 | 0.59 |
Dependent variable: FA values of body of corpus callosum (χ2=0.210, F=4.460, p=0.001) |
|||
Variable | β | T | p |
Age | 0.08 | 0.82 | 0.42 |
Sex | -0.14 | -1.37 | 0.18 |
BDNF Val66Met genotype | -0.43 | -4.18 | <0.000† |
Neuroticism total score | -0.02 | -0.16 | 0.87 |
BDI-II total score | -0.09 | -0.79 | 0.43 |
p<0.05,
p<0.001.
BDNF: brain-derived neurotrophic factor, FA: fractional anisotropy, BDI-II: Beck Depression Inventory-II