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Background: Bilateral repetitive transcranial magnetic stimulation (BL-rTMS) over the dorsolateral prefrontal cortex is effective for treatment-resistant depression (TRD). Owing to a shorter treatment time, bilateral theta burst stimulation (BL-TBS) can be more efficient protocol. The non-inferiority of BL-TBS to BL-rTMS was established in late-life TRD; however, this has not been determined in adults of other age groups. Therefore, we investigated the non-inferiority in efficacy of BL-TBS versus BL-rTMS for TRD across a wide range of ages in a randomized, single-blind, multicenter trial. Methods: The study included 180 participants with major depressive disorder (moderate or greater severity) who were unresponsive to at least one antidepressant treatment between September 2018 and July 2022. Following venlafaxine treatment, patients were randomly assigned to BL-rTMS or BL-TBS (1:1 ratio). The primary outcome was baseline-adjusted Montgomery-Åsberg Depression Rating Scale scores at 6 weeks. The non-inferiority margin of −3.86 was compared against the baseline-adjusted difference. Secondary outcomes included other depression rating scales. Results: Seventy-seven patients were randomly assigned to BL-rTMS and 81 to BL-TBS, of whom 73 and 76 were assessed for the primary outcome, respectively. There was a −2.44 point difference, favoring BL-rTMS (one-tailed lower 95 % CI = −4.19, p = 0.091 for non-inferiority), and non-inferiority of BL-TBS was not established. However, non-inferiority was observed for secondary outcomes. The all-cause dropout rates and number of adverse effects were similar between them. Conclusion: Our study could not establish the non-inferiority of BL-TBS compared to BL-rTMS in terms of efficacy for patients with TRD across the adult lifespan.

Abstract Glutamatergic dysfunction is involved in the pathophysiology of treatment-resistant depression (TRD). However, few physiological studies have evaluated its pathophysiology in vivo in individuals with TRD. Transcranial magnetic stimulation-electroencephalography (TMS-EEG) techniques can assess intracortical facilitation (ICF), which reflects glutamatergic neurophysiological function in specific cortical regions. The objectives of this study were (1) to compare glutamatergic receptor-mediated function as indexed with ICF TMS-EEG in the dorsolateral prefrontal cortex (DLPFC) between participants with TRD and healthy controls (HCs) and (2) to explore the relationships between cell-specific gene expression levels and the group difference in glutamatergic neural propagation using virtual histology approach. Sixty participants with TRD and thirty HCs were examined with ICF TMS-EEG measure (80 single-pulse TMS and paired-pulse ICF) in the left DLPFC. Both sensor and source-level ICF measures were computed to compare them between the TRD and HC groups. Furthermore, we conducted spatial correlation analyses interregionally between ICF glutamatergic activity and cell-specific gene expression levels employing the Allen Human Brain Atlas dataset. DLPFC-ICF at the sensor level was not significantly different between the two groups, whereas DLPFC-ICF at the source level was reduced in the TRD group compared with the HC group (p = 0.026). Moreover, the reduced ICF signal propagation of TRD correlated with astrocyte-specific gene expression level (p

As novel biomarkers for gastroenteropancreatic neuroendocrine tumors (GEPNET) are in demand, we aimed to validate the clinical value of the NETest in Japanese patients. Between 2021 and 2023, blood and clinical data were collected from patients with GEPNET. Among 35 patients (median age: 59 [49–66] years), 27 cases originated from the pancreas and eight from the gastrointestinal tract. Of 69 samples sent to the laboratory, 56 (81.2%) underwent NETest. The diagnostic sensitivity was 97.1%. Among three patients who underwent R0 resection and four treated with peptide receptor radionuclide therapy, the changes in NETest scores closely correlated with disease progression. The NETest demonstrated high diagnostic efficacy and accurate therapeutic monitoring capabilities in a Japanese population.

Abstract Aim Bipolar disorder (BD) has a significant impact on global health, yet its neurophysiological basis remains poorly understood. Conventional treatments have limitations, highlighting the need for a better understanding of the neurophysiology of BD for early diagnosis and novel therapeutic strategies. Design Employing a systematic review approach of the PRISMA guidelines, this study assessed the usefulness and validity of transcranial magnetic stimulation (TMS) neurophysiology in patients with BD. Methods Databases searched included PubMed, MEDLINE, Embase, and PsycINFO, covering studies from January 1985 to January 2024. Results Out of 6597 articles screened, nine studies met the inclusion criteria, providing neurophysiological insights into the pathophysiological basis of BD using TMS–electromyography and TMS–electroencephalography methods. Findings revealed significant neurophysiological impairments in patients with BD compared to healthy controls, specifically in cortical inhibition and excitability. In particular, short‐interval cortical inhibition (SICI) was consistently diminished in BD across the studies, which suggests a fundamental impairment of cortical inhibitory function in BD. This systematic review corroborates the potential utility of TMS neurophysiology in elucidating the pathophysiological basis of BD. Specifically, the reduced cortical inhibition in the SICI paradigm observed in patients with BD suggests gamma‐aminobutyric acid (GABA)‐A receptor‐mediated dysfunction, but results from other TMS paradigms have been inconsistent. Thus, complex neurophysiological processes may be involved in the pathological basis underlying BD. This study demonstrated that BD has a neural basis involving impaired GABAergic function, and it is highly expected that further research on TMS neurophysiology will further elucidate the pathophysiological basis of BD.

Abstract Introduction Survival comparisons among patients with liver metastases from pancreatic and rectal neuroendocrine tumors (NETs) were limited, and the efficacy of observation rules in patients undergoing hepatectomy for neuroendocrine liver metastases (NELMs) was unknown. This study aims to distinguish these characteristics and clarify the effects of the observation rules on NELMs. Methods Clinical data were separately collected from patients with pancreatic and rectal NELMs at medical centers in both Japan and China. The Japanese cohort followed the observation rules for the resection of NELMs. A comparative analysis was conducted on clinical characteristics and prognosis features such as overall survival time (OS) and disease-free survival interval (DFS-I). Results Enrollment included 47 and 34 patients from Japan and China, respectively. Of these, 69 and 12 patients had tumors originating from the pancreas and rectum, respectively. The OS time in patients undergoing primary tumor resection was significantly longer; however, the OS time between the patients undergoing and not undergoing radical resection of liver metastasis was the same. In asynchronous NELMs, patients with rectal (R)-NELMs showed a significantly higher proportion of type III NELMs. Additionally, the median DFS-I of asynchronous R-NELMs was longer than the recommended follow-up time, with 71.4% of them classified as G2. In the Japanese cohort, patients who adhered to the observation rules exhibited a longer median DFS after hepatectomy for NELMs compared with their counterparts. Conclusion Although curative surgery is crucial for primary lesions, personalized approaches are required to manage NELMs. Extended overall follow-ups and shortened follow-up intervals are recommended for G2 stage rectal NETs. The observation rules for NELMs require further validation with a larger sample size.

Abstract Quantitative susceptibility mapping is a magnetic resonance imaging technique that measures brain tissues’ magnetic susceptibility, including iron deposition and myelination. This study examines the relationship between subcortical volume and magnetic susceptibility and determines specific differences in these measures among patients with major depressive disorder (MDD), patients with schizophrenia, and healthy controls (HCs). This was a cross-sectional study. Sex- and age- matched patients with MDD (n = 49), patients with schizophrenia (n = 24), and HCs (n = 50) were included. Magnetic resonance imaging was conducted using quantitative susceptibility mapping and T1-weighted imaging to measure subcortical susceptibility and volume. The acquired brain measurements were compared among groups using analyses of variance and post hoc comparisons. Finally, a general linear model examined the susceptibility–volume relationship. Significant group-level differences were found in the magnetic susceptibility of the nucleus accumbens and amygdala (p = 0.045). Post-hoc analyses indicated that the magnetic susceptibility of the nucleus accumbens and amygdala for the MDD group was significantly higher than that for the HC group (p = 0.0054, p = 0.0065, respectively). However, no significant differences in subcortical volume were found between the groups. The general linear model indicated a significant interaction between group and volume for the nucleus accumbens in MDD group but not schizophrenia or HC groups. This study showed susceptibility alterations in the nucleus accumbens and amygdala in MDD patients. A significant relationship was observed between subcortical susceptibility and volume in the MDD group’s nucleus accumbens, which indicated abnormalities in myelination and the dopaminergic system related to iron deposition.

Abstract Sleep disturbance is a common symptom of psychiatric and neurodevelopmental disorders and, especially in childhood, can be a precursor to various mental disorders. However, the genetic etiology of mental illness that contributes to sleep disturbance during childhood is poorly understood. We investigated whether the polygenic features of psychiatric and neurodevelopmental disorders are associated with sleep disturbance during childhood. We conducted polygenic risk score (PRS) analyses by utilizing large-scale genome-wide association studies (GWASs) (n = 46,350–500,199) of five major psychiatric and neurodevelopmental disorders (autism spectrum disorder, schizophrenia, attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and bipolar disorder) and, additionally, anxiety disorders as base datasets. We used the data of 9- to 10-year-olds from the Adolescent Brain Cognitive Development study (n = 9683) as a target dataset. Sleep disturbance was assessed based on the Sleep Disturbance Scale for Children (SDSC) scores. The effects of PRSs for these psychiatric and neurodevelopmental disorders on the total scores and six subscale scores of the SDSC were investigated. Of the PRSs for the five psychiatric and neurodevelopmental disorders, the PRSs for ADHD and MDD positively correlated with sleep disturbance in children (ADHD: R 2 = 0.0033, p = 6.19 × 10−5, MDD: R 2 = 0.0042, p = 5.69 × 10−6). Regarding the six subscale scores of the SDSC, the PRSs for ADHD positively correlated with both disorders of initiating and maintaining sleep (R 2 = 0.0028, p = 2.31 × 10−4) and excessive somnolence (R 2 = 0.0023, p = 8.44 × 10−4). Furthermore, the PRSs for MDD primarily positively correlated with disorders of initiating and maintaining sleep (R 2 = 0.0048, p = 1.26 × 10−6), followed by excessive somnolence (R 2 = 0.0023, p = 7.74 × 10−4) and sleep hyperhidrosis (R 2 = 0.0014, p = 9.55 × 10−3). Despite high genetic overlap between MDD and anxiety disorders, PRSs for anxiety disorders correlated with different types of sleep disturbances such as disorders of arousal or nightmares (R 2 = 0.0013, p = 0.011). These findings suggest that greater genetic susceptibility to specific psychiatric and neurodevelopmental disorders, as represented by ADHD, MDD, and anxiety disorders, may contribute to greater sleep problems among children.

ObjectiveAlthough anesthetics play an important role in electroconvulsive therapy (ECT), the clinical efficacy and seizure adequacy of sevoflurane in the course of ECT remain unclear. The purpose of this study was to examine the clinical efficacy and seizure adequacy of sevoflurane, compared with those of thiopental, in the course of ECT in patients with mood disorders.MethodsWe conducted a retrospective chart review. Patients who underwent a course of ECT and received sevoflurane (n = 26) or thiopental (n = 26) were included. Factors associated with ECT and treatment outcomes were compared between the two groups using propensity score (PS) matching. Between-group differences were examined using an independent t-test for continuous variables and a χ2-test for categorical variables.ResultsPatients who received sevoflurane needed more stimulations (sevoflurane: 13.2 ± 4 times, thiopental: 10.0 ± 2.5 times, df = 51, p = 0.001) and sessions (sevoflurane: 10.0 ± 2.1 times, thiopental: 8.4 ± 2.1 times, df = 51, p = 0.01) and had more inadequate seizures (sevoflurane: 5 ± 3.9 times, thiopental: 2.7 ± 2.7 times, df = 51, p = 0.015). Remission and response rates were similar in both groups.ConclusionThe present findings indicate that sevoflurane should be used with caution in ECT and only when the clinical rationale is clear.

Abstract Aim It is well accepted that early improvement with antipsychotics predicts subsequent response in patients with schizophrenia. However, no study has examined the contribution of individual symptoms rather than overall symptom severity as the predictors. Thus, we aimed to detect individual symptoms whose improvements could predict subsequent response in patients with schizophrenia during treatment with asenapine and examine whether a prediction model with individual symptoms would be superior to a model using overall symptom severity. Methods This study analyzed a dataset including 532 patients with schizophrenia enrolled in a 6‐week double‐blind, placebo‐controlled, randomized trial of asenapine. Response to asenapine was defined as a ≥30% decrease in Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 6. Stepwise logistic regression analyses were performed to investigate the associations among response and PANSS total/individual item score improvements at week 1 or week 2. Results Response was associated with early improvement in the following PANSS items: disturbance of volition, active social avoidance, poor impulse control at week 1; and active social avoidance, poor attention, lack of judgment and insight at week 2. Prediction accuracy was almost compatible between the model with individual symptoms and the model with PANSS total score both at weeks 1 and 2 (Nagelkerke R2: .51, .42 and .55, .54, respectively). Conclusion Early improvement in negative symptoms, poor attention and impulse control, and lack of insight, in particular predicted subsequent treatment response in patients with schizophrenia during treatment with asenapine as accurately as prediction based on overall symptom severity.

Identifying genuine cortical stimulation-elicited electroencephalography (EEG) is crucial for improving the validity and reliability of neurophysiology using transcranial magnetic stimulation (TMS) combined with EEG. In this study, we evaluated the spatiotemporal profiles of single-pulse TMS-elicited EEG response administered to the left dorsal prefrontal cortex (DLPFC) in 28 healthy participants, employing active and sham stimulation conditions. We hypothesized that the early component of TEP would be activated in active stimulation compared with sham stimulation. We specifically analyzed the (1) stimulus response, (2) frequency modulation, and (3) phase synchronization of TMS–EEG data at the sensor level and the source level. Compared with the sham condition, the active condition induced a significant increase in TMS-elicited EEG power in the 30–60 ms time interval in the stimulation area at the sensor level. Furthermore, in the source-based analysis, the active condition induced significant increases in TMS-elicited response in the 30–60 ms compared with the sham condition. Collectively, we found that the active condition could specifically activate the early component of TEP compared with the sham condition. Thus, the TMS–EEG method that was applied to the DLPFC could detect the genuine neurophysiological cortical responses by properly handling potential confounding factors such as indirect response noises.

Background: Treatment-resistant depression (TRD) is associated with gray matter volume reduction compared to healthy controls (HC). Since depression has increasingly been recognized as a disorder of dysregulated neural networks, it is important to evaluate these structural changes in terms of brain networks. Structural covariance is a measurement that gauges the association strength of structural measures between two regions, which is used to examine network-level alteration of brain structure. Although several studies reported abnormal structural covariance in depression, few studies have thus far investigated structural covariance alteration in relation to TRD. Aims and Objectives: In this study, we aimed to examine structural covariance alteration in TRD compared to HC. Methods: T1 images were obtained from 116 patients with TRD and 54 HC who were recruited at Keio University. Brain volume was calculated for each of 85 regions of the DK atlas using FreeSurfer 6.0. Group differences in brain volumes were examined by analysis of covariance controlling for age and sex. Structural covariances of brain volumes across 3570 pairs of brain regions were obtained by partial correlation analysis using age, sex, and total intracranial volume as covariates. Network-based statistics were used to extract networks with group differences in structural covariances. This study was conducted after obtaining approval from the respective ethics review committees. Results: There were no significant differences in brain volumes between the TRD and HC groups. The null hypothesis of equality in structural covariance between them was rejected using networkbased statistics. We found a single network comprising connections with elevated structural covariance in patients with TRD compared with HC. The left nucleus accumbens, bilateral pericalcarine, and supramarginal gyrus had high degree centrality in the structural covariance network. Discussion and Conclusion: Patients with TRD showed coordinated brain volume alterations in comparison with HC, even though there was no difference in brain volumes between them. Nucleus accumbens, an integral hub in the reward circuit, was one of the hubs of extracted network with elevated structural covariance in TRD, which is in line with a previous study that reported higher structural covariance of nucleus accumbens in depression. Further studies are warranted to examine structural covariance differences among TRD, non-TRD, and HC in order to confirm the link between structural alteration and pathophysiology of treatment resistance in depression. [ABSTRACT FROM AUTHOR]

Background: Delirium is a notable risk factor for cognitive dysfunction and poor prognosis. Despite its importance, there is currently no established blood marker that can predict postoperative delirium in the preoperative period. Aims & Objectives: We aimed to examine that water-soluble metabolites, lipids, and cytokines in peripheral blood could uniquely classify postoperative delirium. In addition, we investigated whether changes in neuroinflammation-related and water-soluble metabolites in the indoleamine 2,3-dioxygenase (IDO) pathway could predict postoperative delirium. Method: We designed a prospective cohort study of postoperative delirium and received approval from the Keio University School of Medicine Ethics Committee in December 2017. We used a comprehensive metabolomics and cytokine panel analysis involving 18 subjects in the delirium group and 24 subjects in the non-delirium group to determine whether preoperative blood metabolites, lipids, and cytokines could predict postoperative delirium. We also performed non-targeted metabolomics to investigate unanticipated small molecular weight metabolites in addition to IDO pathway metabolites and their correlations with cytokines indicative of an activated immune state. In addition, we conducted an in vitro experiment to test secretion with T-cell receptor stimulation on T cells. Results & Discussion: We found that preoperative levels of amino acid catabolites, especially tryptophan catabolites produced via the IDO pathway, were higher in the delirium group than in the non-delirium group. These catabolites were validated as reliable predictors of postoperative delirium. Interestingly, the delirium group had elevated levels of tryptophan catabolites even before surgery, but only a limited increase in these levels was observed postoperatively. This suggests that the tryptophan catabolic pathway may be activated preoperatively in patients at high risk for developing delirium. In addition, our non-targeted metabolomic analysis identified a set of preoperatively elevated gamma-glutamyl dipeptides as significant discriminators of postoperative delirium. In vitro experiments showed that T- cell receptor stimulation resulted in increased tryptophan metabolism and specific gamma-glutamyl dipeptide secretion, which may explain increased metabolic byproducts in postoperative delirium. Conclusion: Our study highlights the potential of blood concentrations of amino acid catabolites and dipeptides, including those secreted extracellularly upon T-cell activation, as reliable predictors of postoperative delirium. [ABSTRACT FROM AUTHOR]

Background: Behind the difficulty in diagnosing bipolar disorder (BD) is the reality that it takes several years after the initial consultation before the diagnosis is confirmed. In this context, it is essential to establish biomarkers that contribute to the diagnosis of BD. In recent years, electroencephalography (EEG) microstates (MS) have garnered great attention as a useful tool to elucidate whole-brain neural network activity due to their high reproducibility. Therefore, EEG-MS is expected to be an aid in the diagnosis of psychiatric disorders, including BD. Specifically, MS-E is associated with the processing of internal and emotional information as well as cognitive functions. Aims & Objectives: In this study, we aimed to identify EEG-MS biomarker of BD by comparison with that of healthy controls (HC). Method: We included 36 individuals with BD (age: 47.7±15.7, %female: 38.9%) and 72 HC (age: 47.5±15.4, %female: 38.9%). Using a 64-channel high-density EEG system, we recorded resting-state EEG for 5 minutes with participants eyes closed. EEG-MS were classified into five states from A to E using the k- means clustering method. Then, three temporal indices were calculated for each MS: duration, occurrence, and coverage. Two-way repeated-measures analysis of variance (ANOVA) was conducted for the three temporal indices of each MS. MS classes and three indices served as within-subject factors while participant groups were treated as a between-subject factor. For MS indices for which the interaction was significant, an independent t-test was performed as a post-hoc analysis to test for differences between the BD and HC groups. Results: The ANOVA showed significant interactions between the groups, MS classes, and temporal indices (F(1,8)=3.91, p<0.001). Subsequent ANOVAs indicated significant interactions across the two groups in duration (F(1,4)=2.412, p=0.049), occurrence (F(1,4)=3.861, p=0.004), and coverage (F(1,4)=2.924, p=0.021), as well as in MS-D (F(1,2)=3.304, p=0.039) and MS-E (F(1,2)=6.759, p=0.001). Finally, post-hoc independent t-tests for MS-D and MS-E revealed that in MS-D, the BD group showed longer values in duration (t(106)=3.967, p<0.001) and coverage (t(106)=2.904, p=0.004) compared to the HC group. In contrast, in MS-E, the BD group showed lower values in occurrence (t(106)=-2.600, p=0.011) and coverage (t(106)=-2.382, p=0.019) compared to the HC group. Discussion & Conclusion: This study demonstrated that the BD group exhibited a higher occurrence and longer duration for MS-D compared to the HC group. Conversely, regarding MS-E, the BD group showed a lower occurrence and decreased coverage than the HC group. Based on the physiological significance of MS-E, there may be a potential decline in cognitive function in the BD group compared to the HC group. [ABSTRACT FROM AUTHOR]

Background: Treatment-resistant depression (TRD) is a highly biologically heterogeneous disorder, which may be due to underlying neuroanatomical heterogeneity. However, neuroimaging studies to date have not yielded consistent results, possibly due in part to a lack of analytical approaches that account for clinicodemographic confounds. The heterogeneity through discriminative analysis (HYDRA) method (Varol et al. 2017) takes into account clinical confounding factors and enables biotyping based on neuroanatomical heterogeneity. Previous studies have reported neuroanatomical biotypes in psychiatric disorders such as schizophrenia (Chand et al. 2020; Lalousis et al. 2022). However, no study has explored neuroanatomical heterogeneity in TRD using HYDRA. Aims & Objectives: This study aimed to classify the biotypes of TRD by examining the neuroanatomical signatures of the subtypes and exploring their clinicodemographic characteristics. Methods: This study was approved by the ethical committee at Keio University School of Medicine and the Keio Certified Review Board. Fifty-five healthy controls (37.1±15.2 years old, 55 females [48%]) and 117 patients with TRD (44.9±12.8 years old, 50 females [43%]) provided written informed consent. They underwent structural MRI for T1- and T2-weighted images. Structural preprocessing was performed using FreeSurfer 6 for parcellation with 160 ROIs (68 bilateral cortical volumes, 68 white matter (WM) volumes, and 24 other subcortical volumes) for HYDRA clustering. Fifty healthy controls (HC) and 103 TRD patients were successfully preprocessed, and three covariates (age, sex, and total intracranial volume) were included in HYDRA for their data, identifying biotypes based on volumetric ROI metrics. Cortical volume differences in biotypes between TRD and HCs were examined using Permutation Analysis of Linear Models (FMRIB Software Library, version 6.0.5) with vertex-wise analysis (corrected p-value <0.05). WM and other subcortical volumes were compared to HCs in the ROI under false discovery rate (FDR) correction. Results: HYDRA identified two optimal clusters and named them TRD1 and TRD2, respectively. Volumetric vertex- wise analysis revealed that TRD1 exhibited smaller volume than HCs in the left precentral, left medial orbitofrontal, right lateral orbitofrontal, right postcentral, and right middle temporal cortex (p <0.05). Conversely, TRD2 showed a larger volume than HCs in the left precuneus, left postcentral, right pericalcarine, and right supramarginal cortex (p <0.05). Comparing TRD1 to HC regarding WM and other subcortical volumes, only the left accumbens showed a significant volume decrease in TRD1. The comparisons of clinical data (age, sex, socioeconomic status, psychosis onset, duration of illness, and Montgomery Å sberg Depression Rating Scale scores) between TRD1 and TRD2 did not show significant differences. Discussion & Conclusion: The present study revealed two distinct TRD biotypes: one with increased brain volume and the other with decreased brain volume. HYDRA's ability to biotype based on key depression-related regions, such as the precuneus cortex, orbitofrontal cortex, and nucleus accumbens, aligns with prior studies and offers insight into biologically clustered illness. [ABSTRACT FROM AUTHOR]

Background: Progressive abnormalities in brain structures have consistently been reported in depression. However, the distinct trajectories of progressive structural abnormalities in TRD remain unknown. Moreover, treatment-resistant depression (TRD) is suggested to have a heterogeneous pathophysiology. The Subtype and Stage Inference (SuStaIn) algorithm, an unsupervised machine learning technique, has shown premise in distinguishing disease biotypes with different progression trajectories. Aims & Objectives: This study aimed to identify patterns of structural abnormalities in TRD with SuStaIn and associate each of them with clinical characteristics. Method: The study received approval from the ethical committee at Keio University School of Medicine. All participants gave written informed consent. We included 129 adult patients with TRD (45.0±12.5 years old, 59 females [46%]) and 93 healthy controls (HC) (46.2±17.7 years old, 37 females [40%]). Participants underwent magnetic resonance imaging (MRI) scans with a Siemens Prisma 3T MRI scanner. Cortical thickness and gray matter volume from 13 cortical regions and bilateral hippocampus reported by mega-analysis studies (Schmaal et al., 2017; Schmaal et al., 2016) were calculated using FreeSurfer 6.0 and then z-scored using HC data. We applied the SuStaIn algorithm with 10-fold cross-validation using pySuStaIn. The optimal number of subtypes was determined through cross validation information criterion and test set log likelihood across folds. Furthermore, we explored the relationship between SuStaIn output (subtype and stage) and clinico-demographic variables. Results: The SuStaIn algorithm identified two subtypes with distinct progression patterns. Subtype 1 (medial frontal cortex (mFC) type) (n=65) exhibited mild cortical thinning in the bilateral medial orbitofrontal cortex (mOFC) followed by the rostral anterior cingulate cortex (rACC). Subtype 2 (hippocampus and posterior cingulate cortex (Hip &PCC) type) (n=21) showed a marked reduction in the bilateral hippocampal volume followed by mild cortical thinning in the left PCC. Hip &PCC type had an earlier stage than mFC type (p<0.001). No significant group difference in scores of the Montgomery-Å sberg Depression Rating Scale (p=0.73), onset age (p=0.33), or duration of untreated depression (p=0.79) was observed. There was no correlation between stage and these clinical variables in the whole group. In Hip &PCC type, stage correlated with visuospatial constructional ability assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (r=-0.57, p=0.007). Discussion & Conclusion: Previous studies suggest that abnormalities in the mOFC and Hip are the starting points for progressive structural changes in depression. Our results indicate that they may separately emerge in the two distinct subtypes. Additionally, both subtypes revealed progressive structural abnormalities in the regions in the hippocampal-medial prefrontal cortex network, a brain network crucial for depression. Hip &PCC type had an earlier stage than mFC type, suggesting less severe and more localized neurodegeneration in Hip &PCC type than mFC type. Only in Hip &PCC type, stage progression was linked to visuospatial dysfunction. Given the association between reduced Hip volume and cognitive impairment in MDD, the trajectories of structural changes might provide insights into the heterogeneity of cognitive impairment in TRD. [ABSTRACT FROM AUTHOR]