Structural Elucidation of Ubiquitin via Gas-Phase Ion/Ion Cross-Linking Reactions Using Sodium-Cationized Reagents Coupled with Infrared Multiphoton Dissociation.

Accurate structural determination of proteins is critical to understanding their biological functions and the impact of structural disruption on disease progression. Gas-phase cross-linking mass spectrometry (XL-MS) via ion/ion reactions between multiply charged protein cations and singly charged cross-linker anions has previously been developed to obtain low-resolution structural information on proteins. This method significantly shortens experimental time relative to conventional solution-phase XL-MS but has several technical limitations: (1) the singly deprotonated N-hydroxysulfosuccinimide (sulfo-NHS)-based cross-linker anions are restricted to attachment at neutral amine groups of basic amino acid residues and (2) analyzing terminal cross-linked fragment ions is insufficient to unambiguously localize sites of linker attachment. Herein, we demonstrate enhanced structural information for alcohol-denatured A-state ubiquitin obtained from an alternative gas-phase XL-MS approach. Briefly, singly sodiated ethylene glycol bis(sulfosuccinimidyl succinate) (sulfo-EGS) cross-linker anions enable covalent cross-linking at both ammonium and amine groups. Additionally, covalently modified internal fragment ions, along with terminal b-/y-type counterparts, improve the determination of linker attachment sites. Molecular dynamics simulations validate experimentally obtained gas-phase conformations of denatured ubiquitin. This method has identified four cross-linking sites across 8+ ubiquitin, including two new sites in the N-terminal region of the protein that were originally inaccessible in prior gas-phase XL approaches. The two N-terminal cross-linking sites suggest that the N-terminal half of ubiquitin is more compact in gas-phase conformations. By comparison, the two C-terminal linker sites indicate the signature transformation of this region of the protein from a native to a denatured conformation. Overall, the results suggest that the solution-phase secondary structures of the A-state ubiquitin are conserved in the gas phase. This method also provides sufficient sensitivity to differentiate between two gas-phase conformers of the same charge state with subtle structural variations.

Relative Quantification of Lipid Isomers in Imaging Mass Spectrometry Using Gas-Phase Charge Inversion Ion/Ion Reactions and Infrared Multiphoton Dissociation.

Accurate structural identification of lipids in imaging mass spectrometry is critical to properly contextualizing spatial distributions with tissue biochemistry. Gas-phase charge inversion ion/ion reactions alter the ion type prior to dissociation to allow for more structurally informative fragmentation and improve lipid identification at the isomeric level. In this work, infrared multiphoton dissociation (IRMPD) was interfaced with a commercial hybrid Qh-FT-ICR mass spectrometer to enable the rapid fragmentation of gas-phase charge inversion ion/ion reaction products at every pixel in imaging mass spectrometry experiments. An ion/ion reaction between phosphatidylcholine (PC) monocations generated from rat brain tissue via matrix-assisted laser desorption/ionization (MALDI) and 1,4-phenylenediproprionic acid reagent dianions generated via electrospray ionization (ESI) followed by IRMPD of the resulting product ion complex produces selective fatty acyl chain cleavages indicative of fatty acyl carbon compositions in the lipid. Ion/ion reaction images using this workflow allow for mapping of the relative spatial distribution of multiple PC isomers under a single sum composition lipid identification. Lipid isomers display significantly different relative spatial distributions within rat brain tissue, highlighting the importance of resolving isomers in imaging mass spectrometry experiments.

Decreased cortical gyrification in major depressive disorder.

BACKGROUND: Early neurodevelopmental deviations, such as abnormal cortical folding patterns, are candidate biomarkers of major depressive disorder (MDD). We aimed to investigate the association of MDD with the local gyrification index (LGI) in each cortical region at the whole-brain level, and the association of the LGI with clinical characteristics of MDD. METHODS: We obtained T1-weighted images from 234 patients with MDD and 215 healthy controls (HCs). The LGI values from 66 cortical regions in the bilateral hemispheres were automatically calculated according to the Desikan-Killiany atlas. We compared the LGI values between the MDD and HC groups using analysis of covariance, including age, sex, and years of education as covariates. The association between the clinical characteristics and LGI values was investigated in the MDD group. RESULTS: Compared with HCs, patients with MDD showed significantly decreased LGI values in the cortical regions, including the bilateral ventrolateral and dorsolateral prefrontal cortices, medial and lateral orbitofrontal cortices, insula, right rostral anterior cingulate cortex, and several temporal and parietal regions, with the largest effect size in the left pars triangularis (Cohen's f2 = 0.361; p = 1.78 × 10-13). Regarding the association of clinical characteristics with LGIs within the MDD group, recurrence and longer illness duration were associated with increased gyrification in several occipital and temporal regions, which showed no significant difference in LGIs between the MDD and HC groups. CONCLUSIONS: These findings suggest that the LGI may be a relatively stable neuroimaging marker associated with MDD predisposition.

Gray and white matter abnormalities in major depressive disorder patients and its associations with childhood adversity.

OBJECTIVE: Early life stress of childhood adversity (CA) may result in major depressive disorder (MDD) by sensitizing individuals to proximal stressors in life events. The neurobiological changes that underlie adult depression may result from the absence of proper care and supervision of caregivers. We aimed to find both gray and white matter abnormalities in MDD patients, who reported the experiences of CA. METHODS: The present study examined cortical alterations in 54 patients with MDD and 167 healthy controls (HCs) using voxel-based morphology and fractional anisotropy (FA) tract-based spatial statistics (TBSS). Both patients and HCs were administered the self-questionnaire clinical scale (the Korean translation of the Childhood Trauma Questionnaire CTQK). Pearson's correlation analysis was performed to find the associations between FA and CTQK. RESULTS: The MDD group showed a significant decrease in gray matter (GM) in the left rectus at both the cluster and peak levels after family-wise error correction. The TBSS results showed significantly reduced FA in widespread regions, including the corpus callosum (CC), superior corona radiata, cingulate gyrus, and superior longitudinal fasciculus. The CA was negatively correlated with the FA in CC and crossing pontine tract. CONCLUSION: Our findings demonstrated GM atrophy and white matter (WM) connectivity changes in patients with MDD. The major findings of the widespread FA reduction in WM provided the evidence of brain alterations in MDD. We further propose that the WM would be vulnerable to emotional, physical, and sexual abuse in early childhood during the brain development.

Childhood Sexual Abuse and Cortical Thinning in Adults With Major Depressive Disorder.

OBJECTIVE: A growing body of evidence reports on the effect of different types of childhood abuse on the structural and functional architecture of the brain. In the present study, we aimed to investigate the differences in cortical thickness according to specific types of childhood abuse between patients with major depressive disorder (MDD) and healthy controls (HCs). METHODS: A total of 61 patients with MDD and 98 HCs were included in this study. All participants underwent T1-weighted magnetic resonance imaging, and the occurrence of childhood abuse was assessed using the Childhood Trauma Questionnaire. We investigated the association between whole-brain cortical thickness and exposure to any type of childhood abuse and specific type of childhood abuse in the total sample using the FreeSurfer software. RESULTS: No significant difference was reported in the cortical thickness between the MDD and HC groups nor between the "any abuse" and "no abuse" groups. Compared to no exposure to childhood sexual abuse (CSA), exposure to CSA was significantly associated with cortical thinning in the left rostral middle frontal gyrus (p=0.00020), left (p=0.00240), right fusiform gyri (p=0.00599), and right supramarginal gyrus (p=0.00679). CONCLUSION: Exposure to CSA may lead to cortical thinning of the dorsolateral prefrontal cortex, which is deeply involved in emotion regulation, to a greater extent than other types of childhood abuse.

The Association of White Matter Tracts with Alexithymia among Individuals with Major Depressive Disorder.

Alexithymia is characterized by impairments in the processing of emotions. Although the disruptions in the white matter (WM) integrity in Major depressive disorder (MDD) has frequently been reported, the underlying relationship with alexithymia remains unclear. In the present study, we investigated WM tracts with Tracts Constrained by UnderLying Anatomy approach to discover potential associations between alexithymia and WM integrity to identify the neural basis of impaired emotional self-awareness in MDD. 101 patients with MDD and 99 healthy sex- and age-matched individuals underwent diffusion-weighted imaging. All participants were assessed with the 20-item Toronto Alexithymia Scale (TAS). TAS scores were significantly higher in MDD patients than in controls. Patients with MDD exhibited significantly lower FA values in the left inferior longitudinal fasciculus and it also showed negative associations with TAS. These results contribute to the neurobiological evidence on the association between MDD and alexithymia. Additionally, they suggest that reduced white matter integrity in the regions constitutes a principal pathophysiology underlying impaired emotional recognition and description in MDD.

Extraskeletal Osteochondroma in the Posterior Neck of a Middle-Aged Female: A Case Report.

Extraskeletal osteochondroma, a variant of chondroma, typically arises in the para-articular location of hands and feet. It is a rare disease and is particularly uncommon when joint components are not involved or localized away from joints. Herein, we report a case of extraskeletal osteochondroma in the posterior neck of a 66-year-old female. The characteristic radiologic finding of our case is presented, along with the typical findings of the disease and review of related literature reports.

Shape analysis of the subcortical structures in North Korean refugees with post-traumatic stress disorder and major depressive disorder.

BACKGROUND: Despite the growing number of refugees and their mental health issues, neurobiological mechanisms to explain clinical symptoms resulting from traumatic events, such as post-traumatic stress disorder (PTSD) or major depressive disorder (MDD), have not been extensively investigated. Research on the mental health of North Korean refugees (NKRs) who defected to South Korea for resettlement is still at an early stage but commonly reports structural and functional abnormalities in brain regions related to reward and motivational processing. The nucleus accumbens (NAc) and ventral pallidum (VP) are the major sites in subcortical structures that play key roles in reward and motivation. METHODS: The present study examined subcortical structural abnormalities of 28 NKRs and age-, sex- matched South Korean Controls (SKCs) using shape analysis at the vertex level. RESULTS: Among the 28 NKRs, 18 had psychiatric disorders, including PTSD and MDD. The NKRs showed significantly reduced volumes in the right NAc and bilateral VP compared to the SKRs. The volume of the right VP showed a significant negative correlation with current PTSD severity in the NKR group. CONCLUSIONS: Our findings demonstrated that structural alterations of the NAc and VP may explain PTSD and MDD observed in the refugees and further suggest that the aftereffect of trauma, manifested as anhedonia and anxiety, may show chronically.

Association of DNA Methylation of the NLRP3 Gene with Changes in Cortical Thickness in Major Depressive Disorder.

The Nod-like receptor pyrin containing 3 (NLRP3) inflammasome has been reported to be a convergent point linking the peripheral immune response induced by psychological stress and neuroinflammatory processes in the brain. We aimed to identify differences in the methylation profiles of the NLRP3 gene between major depressive disorder (MDD) patients and healthy controls (HCs). We also investigated the correlation of the methylation score of loci in NLRP3 with cortical thickness in the MDD group using magnetic resonance imaging (MRI) data. A total of 220 patients with MDD and 82 HCs were included in the study, and genome-wide DNA methylation profiling of the NLRP3 gene was performed. Among the total sample, 88 patients with MDD and 74 HCs underwent T1-weighted structural MRI and were included in the neuroimaging-methylation analysis. We identified five significant differentially methylated positions (DMPs) in NLRP3. In the MDD group, the methylation scores of cg18793688 and cg09418290 showed significant positive or negative correlations with cortical thickness in the occipital, parietal, temporal, and frontal regions, which showed significant differences in cortical thickness between the MDD and HC groups. Our findings suggest that NLRP3 DNA methylation may predispose to depression-related brain structural changes by increasing NLRP3 inflammasome-related neuroinflammatory processes in MDD.

External validation of deep learning-based bone-age software: a preliminary study with real world data.

Artificial intelligence (AI) is increasingly being used in bone-age (BA) assessment due to its complicated and lengthy nature. We aimed to evaluate the clinical performance of a commercially available deep learning (DL)-based software for BA assessment using a real-world data. From Nov. 2018 to Feb. 2019, 474 children (35 boys, 439 girls, age 4-17 years) were enrolled. We compared the BA estimated by DL software (DL-BA) with that independently estimated by 3 reviewers (R1: Musculoskeletal radiologist, R2: Radiology resident, R3: Pediatric endocrinologist) using the traditional Greulich-Pyle atlas, then to his/her chronological age (CA). A paired t-test, Pearson's correlation coefficient, Bland-Altman plot, mean absolute error (MAE) and root mean square error (RMSE) were used for the statistical analysis. The intraclass correlation coefficient (ICC) was used for inter-rater variation. There were significant differences between DL-BA and each reviewer's BA (P < 0.025), but the correlation was good with one another (r = 0.983, P < 0.025). RMSE (MAE) values were 10.09 (7.21), 10.76 (7.88) and 13.06 (10.06) months between DL-BA and R1, R2, R3 BA. Compared with the CA, RMSE (MAE) values were 13.54 (11.06), 15.18 (12.11), 16.19 (12.78) and 19.53 (17.71) months for DL-BA, R1, R2, R3 BA, respectively. Bland-Altman plots revealed the software and reviewers' tendency to overestimate the BA in general. ICC values between 3 reviewers were 0.97, 0.85 and 0.86, and the overall ICC value was 0.93. The BA estimated by DL-based software showed statistically similar, or even better performance than that of reviewers' compared to the chronological age in the real world clinic.

Decreased cortical gyrification in patients with bipolar disorder.

BACKGROUND: An aberrant neural connectivity has been known to be associated with bipolar disorder (BD). Local gyrification may reflect the early neural development of cortical connectivity and has been studied as a possible endophenotype of psychiatric disorders. This study aimed to investigate differences in the local gyrification index (LGI) in each cortical region between patients with BD and healthy controls (HCs). METHODS: LGI values, as measured using FreeSurfer software, were compared between 61 patients with BD and 183 HCs. The values were also compared between patients with BD type I and type II as a sub-group analysis. Furthermore, we evaluated whether there was a correlation between LGI values and illness duration or depressive symptom severity in patients with BD. RESULTS: Patients with BD showed significant hypogyria in various cortical regions, including the left inferior frontal gyrus (pars opercularis), precentral gyrus, postcentral gyrus, superior temporal cortex, insula, right entorhinal cortex, and both transverse temporal cortices, compared to HCs after the Bonferroni correction (p < 0.05/66, 0.000758). LGI was not associated with clinical factors such as illness duration, depressive symptom severity, and lithium treatment. No significant differences in cortical gyrification according to the BD subtype were found. CONCLUSIONS: BD appears to be characterized by a significant regionally localized hypogyria, in various cortical areas. This abnormality may be a structural and developmental endophenotype marking the risk for BD, and it might help to clarify the etiology of BD.

Alterations in the Occipital Cortex of Drug-Naïve Adults With Major Depressive Disorder: A Surface-Based Analysis of Surface Area and Cortical Thickness.

OBJECTIVE: Advances in surface-based morphometric methods have allowed researchers to separate cortical volume into cortical thickness (CTh) and surface area (SA). Although CTh alterations in major depressive disorder (MDD) have been observed in numerous studies, few studies have described significant SA alterations. Our study aimed to measure patients' SAs and to compare it with their CTh to examine whether SA exhibits alteration patterns that differ from those of CTh in drug-naïve patients with MDD. METHODS: A total of 71 drug-naïve MDD patients and 111 healthy controls underwent structural magnetic resonance imaging, and SA and CTh were analyzed between the groups. RESULTS: We found a smaller SA in the left superior occipital gyrus (L-SOG) in drug-naïve patients with MDD. In the CTh analysis, the bilateral fusiform gyrus, left middle occipital gyrus, left temporal superior gyrus, and right posterior cingulate showed thinner cortices in patients with MDD, while the CTh of the bilateral SOG, right straight gyrus, right posterior cingulate, and left lingual gyrus were increased. CONCLUSION: Compared with the bilateral occipito-temporal changes in CTh, SA alterations in patients with MDD were confined to the L-SOG. These findings may improve our understanding of the neurobiological mechanisms of SA alteration in relation to MDD.

Cortical Thickness and Surface Area Abnormalities in Bipolar I and II Disorders.

OBJECTIVE: Although bipolar II disorder (BD II) is not simply a mitigated form of bipolar I disorder (BD I), their neurobiological differences have not been elucidated. The present study aimed to explore cortical thickness (CT) and surface area (SA) in patients with BD I and BD II and healthy controls (HCs) to investigate the shared and unique neurobiological mechanisms of BD subtypes. METHODS: We enrolled 30 and 44 patients with BD I and BD II, respectively, and 100 HCs. We evaluated CT and SA using FreeSurfer and estimated differences in CT and SA among the three groups (BD I vs. BD II vs. HC). We adjusted for age, sex, educational level, and intracranial volume as confounding factors. RESULTS: We found widespread cortical thinning in the bilateral frontal, temporal, and occipital regions; cingulate gyrus; and insula in patients with BD. Alterations in SA, including increased SA of the pars triangularis and decreased SA of the insula, were noted in patients with BD. Overall, we found BD II patients demonstrated decreased SA in the right long insula compared to BD I patients. CONCLUSION: Our results suggest that decreased SA in the right long insula is crucial for differentiating BD subtypes.

Volumetric alterations in subregions of the amygdala in adults with major depressive disorder.

BACKGROUND: Although major depressive disorder (MDD) has been associated with volumetric abnormalities in the amygdala, studies investigating the association between structural alterations of the amygdala and depression have yielded varying results. Since the amygdala comprises several subregions, it is difficult to detect subtle regional changes by measuring the total amygdala volume. This study aimed to examine the volume in each amygdala subregion in adults with and without a diagnosis of MDD. METHODS: A total of 147 participants with a current history of major depression and 144 healthy participants ranging in age from 19 to 64 years underwent 3T magnetic resonance imaging scanning. Automatic segmentation of the nine nuclei of the amygdala was performed using FreeSurfer. One-way analysis of covariance, with individual volumes as dependent variables, and age, sex, and total intracranial volume as covariates, was performed to analyze volume differences. RESULTS: Patients with MDD had significantly lower volumes of the entire amygdala and subregions, including the lateral nucleus and anterior amygdaloid area, than healthy volunteers (HCs). There were no significant associations between subregion volumes and antidepressant use, illness duration, or depression severity. LIMITATIONS: Our cross-sectional design cannot provide a causal relationship between the volume change in the amygdala subregion and the risk of MDD. CONCLUSION: Our findings suggest that specific amygdala subregions are more susceptible to volumetric alterations in patients with MDD than in HCs. These findings may advance our understanding of the neuroanatomic basis on MDD.

Association of Prefrontal Cortex Thinning with High Impulsivity in Healthy Adults.

OBJECTIVE: Studies have been conducted to identify brain structural alterations related to high impulsivity in psychiatric populations. However, research on healthy subjects is relatively less extensive. Therefore, we aimed to investigate the correlation between the cortical thickness of whole brain regions and the impulsivity level in a healthy population. METHODS: We included 100 healthy participants aged 19-65 years. Their T1-weighted magnetic resonance images and the 23-item Barratt Impulsiveness Scale (BIS) score were obtained. The patients were divided into high and low impulsivity groups according to the 75th percentile score of the BIS in the sample. The thickness of each cortical region was calculated using the FreeSurfer, and the difference in cortical thickness of the whole brain between the high and low impulsivity groups was analyzed using one-way analysis of covariance including age, sex, education level, and total intracranial cavity volume as covariates. RESULTS: The high impulsivity group showed significant cortical thinning in the left pars opercularis. The cortical thickness of the left pars opercularis significantly correlated negatively with the total, attention, and motor scores of the BIS scale. CONCLUSION: Our findings suggest that prefrontal cortex thinning may play an important role in the development of high impulsivity in healthy adults.

Hopping and Flipping of RNA Polymerase on DNA during Recycling for Reinitiation after Intrinsic Termination in Bacterial Transcription.

Two different molecular mechanisms, sliding and hopping, are employed by DNA-binding proteins for their one-dimensional facilitated diffusion on nonspecific DNA regions until reaching their specific target sequences. While it has been controversial whether RNA polymerases (RNAPs) use one-dimensional diffusion in targeting their promoters for transcription initiation, two recent single-molecule studies discovered that post-terminational RNAPs use one-dimensional diffusion for their reinitiation on the same DNA molecules. Escherichia coli RNAP, after synthesizing and releasing product RNA at intrinsic termination, mostly remains bound on DNA and diffuses in both forward and backward directions for recycling, which facilitates reinitiation on nearby promoters. However, it has remained unsolved which mechanism of one-dimensional diffusion is employed by recycling RNAP between termination and reinitiation. Single-molecule fluorescence measurements in this study reveal that post-terminational RNAPs undergo hopping diffusion during recycling on DNA, as their one-dimensional diffusion coefficients increase with rising salt concentrations. We additionally find that reinitiation can occur on promoters positioned in sense and antisense orientations with comparable efficiencies, so reinitiation efficiency depends primarily on distance rather than direction of recycling diffusion. This additional finding confirms that orientation change or flipping of RNAP with respect to DNA efficiently occurs as expected from hopping diffusion.

Local shape volume alterations in subcortical structures of suicide attempters with major depressive disorder.

Suicide is among the most important global health concerns; accordingly, an increasing number of studies have shown the risks for suicide attempt(s) in terms of brain morphometric features and their clinical correlates. However, brain studies addressing suicidal vulnerability have been more focused on demonstrating impairments in cortical structures than in the subcortical structures. Using local shape volumes (LSV) analysis, we investigated subcortical structures with their clinical correlates in depressed patients who attempted suicide. Then we compared them with depressed patients without a suicidal history and age- and sex-matched healthy controls (HCs; i.e., 47 suicide attempters with depression, 47 non-suicide attempters with depression, and 109 HCs). Significant volumetric differences were found between suicidal and nonsuicidal depressed patients in several vertices: 16 in the left amygdala; 201 in the left hippocampus; 1,057 in the left putamen; and 140 in the left pallidum; 1 in the right pallidum; and 6 in the bilateral thalamus. These findings indicated subcortical alterations in LSV in components of the limbic-cortical-striatal-pallidal-thalamic circuits. Moreover, our results demonstrated that the basal ganglia was correlated with perceived stress levels, and the thalamus was correlated with suicidal ideation. We suggest that suicidality in major depressive disorder may involve subcortical volume alterations.

Identifying resting-state effective connectivity abnormalities in drug-naïve major depressive disorder diagnosis via graph convolutional networks.

Major depressive disorder (MDD) is a leading cause of disability; its symptoms interfere with social, occupational, interpersonal, and academic functioning. However, the diagnosis of MDD is still made by phenomenological approach. The advent of neuroimaging techniques allowed numerous studies to use resting-state functional magnetic resonance imaging (rs-fMRI) and estimate functional connectivity for brain-disease identification. Recently, attempts have been made to investigate effective connectivity (EC) that represents causal relations among regions of interest. In the meantime, to identify meaningful phenotypes for clinical diagnosis, graph-based approaches such as graph convolutional networks (GCNs) have been leveraged recently to explore complex pairwise similarities in imaging/nonimaging features among subjects. In this study, we validate the use of EC for MDD identification by estimating its measures via a group sparse representation along with a structured equation modeling approach in a whole-brain data-driven manner from rs-fMRI. To distinguish drug-naïve MDD patients from healthy controls, we utilize spectral GCNs based on a population graph to successfully integrate EC and nonimaging phenotypic information. Furthermore, we devise a novel sensitivity analysis method to investigate the discriminant connections for MDD identification in our trained GCNs. Our experimental results validated the effectiveness of our method in various scenarios, and we identified altered connectivities associated with the diagnosis of MDD.

Changes in cortical thickness and volume of cerebellar subregions in patients with bipolar disorders.

BACKGROUND: Numerous studies have suggested that structural changes in the cerebellum are implicated in the pathophysiology of bipolar disorder (BD). We aimed to investigate differences in the volume and cortical thickness of the cerebellar subregions between patients with BD and healthy controls (HCs). METHODS: Ninety patients with BD and one hundred sixty-six HCs participated in this study and underwent T1-weighted structural magnetic resonance imaging. We analyzed the volume and cortical thickness of each cerebellar hemisphere divided into 12 subregions using T1-weighted images of participants. One-way analysis of covariance was used to evaluate differences between the groups, with age, sex, medication, and total intracranial cavity volume used as covariates. RESULTS: The BD group had significantly increased cortical thickness of the cerebellum in all cerebellar subregions compared to the HC group. The cortical thicknesses of the whole cerebellum and each hemisphere were also significantly thicker in the BD group than in the HC group. The volume of the left lobule IX was significantly lower in patients with BD than in HCs, whereas no significant differences in the volumes were observed in the other subregions. LIMITATIONS: Our cross-sectional design cannot provide a causal relationship between the increased cortical thickness of the cerebellum and the risk of BD. CONCLUSIONS: We observed widespread and significant cortical thickening in all the cerebellar subregions. Our results provide evidence for the involvement of the cerebellum in BD. Further studies are required to integrate neurobiological evidence and structural brain imaging to elucidate the pathophysiology of BD.