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Mapping Neurophysiological Subtypes of Major Depressive Disorder Using Normative Models of the Functional Connectome
Open accessPublished version of a preprint
Abstract
Background Major depressive disorder (MDD) is a highly heterogeneous disorder that typically emerges in adolescence and can occur throughout adulthood. Studies aimed at quantitatively uncovering the heterogeneity of individual functional connectome abnormalities in MDD and identifying reproducibly distinct neurophysiological MDD subtypes across the lifespan, which could provide promising insights for precise diagnosis and treatment prediction, are still lacking.Methods Leveraging resting-state functional magnetic resonance imaging data from 1148 patients with MDD and 1079 healthy control participants (ages 11-93), we conducted the largest multisite analysis to date for neurophysiological MDD subtyping. First, we characterized typical lifespan trajectories of functional connectivity strength based on the normative model and quantitatively mapped the heterogeneous individual deviations among patients with MDD. Then, we identified neurobiological MDD subtypes using an unsupervised clustering algorithm and evaluated intersite reproducibility. Finally, we validated the subtype differences in baseline clinical variables and longitudinal treatment predictive capacity.Results Our findings indicated great intersubject heterogeneity in the spatial distribution and severity of functional connectome deviations among patients with MDD, which inspired the identification of 2 reproducible neurophysiological subtypes. Subtype 1 showed severe deviations, with positive deviations in the default mode, limbic, and subcortical areas and negative deviations in the sensorimotor and attention areas. Subtype 2 showed a moderate but converse deviation pattern. More importantly, subtype differences were observed in depressive item scores and the predictive ability of baseline deviations for antidepressant treatment outcomes.Conclusions These findings shed light on our understanding of different neurobiological mechanisms underlying the clinical heterogeneity of MDD and are essential for developing personalized treatments for this disorder.
Overview
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Written from the paper’s full text.
TL;DR
Using multisite resting-state fMRI from 1,148 MDD patients and 1,079 healthy controls, this study built normative models of functional connectivity strength and mapped individual deviations to identify neurophysiological MDD subtypes. Two subtypes emerged: a severe-deviation subtype with positive deviations in default mode, limbic, and subcortical areas and a moderate, largely converse subtype, with clinical differences and treatment-response prediction in the severe subtype.
Key findings
- MDD patients showed larger individual FCS deviation indexes than HCs: number of extremely deviated regions (t=4.22), sum of positive extreme deviations (t=4.11), and sum of negative extreme deviations (t=-2.77; p<0.05, FDR corrected). 72.82% (N=836) of patients had an extreme FCS deviation in at least one region; extreme positive deviations in 25.78% (N=296) and extreme negative deviations in 66.38% (N=762). For any single brain region, extreme deviations were low: ≤2.35% positive (N=27) and ≤3.14% negative (N=36).
- Two MDD subtypes were identified. Subtype 1 (37%, N=425) showed severe deviations with positive deviations in DMN, LIM, and SUB areas and negative deviations in SMN, DAN, and VAN areas. Subtype 2 (63%, N=723) showed moderate but converse deviations: negative in DMN, LIM, and SUB and positive in SMN, DAN, and VAN. Subtype 1 had significantly higher deviation indexes than HCs and subtype 2; subtype 2 had lower number of extremely deviated regions and sum of negative extreme deviations than HCs.
- The severe-deviation subtype was older (t=2.64, p=0.008), had higher medicated proportion (χ²=6.11, p=0.013), and higher Suicide item score (t=2.02, p=0.044). The moderate-deviation subtype had higher Work and Activities (t=3.11, p=0.002) and Depressed Mood (t=2.42, p=0.016) item scores. HDRS-17 score correlated negatively with onset age in the severe subtype (r=-0.24, p=0.004) but not the moderate subtype (r=-0.00, p=0.966; subtype difference F=4.41, p=0.037).
- In a 43-patient treatment subsample (16 severe, 27 moderate), baseline deviation maps predicted 6-month HDRS changes in the severe subtype (r=0.47, p=0.019, one-tailed permutation test) but not the moderate subtype (r=-0.14, p=0.785). Most positively contributive features were in DMN (24.1%), FPN (16.1%), and VAN (15.6%); most negatively contributive were in VIS (40.5%).
Methods
- Multisite resting-state fMRI data from the DIDA-MDD working group: initially 2,414 participants (1,276 MDD, 1,138 HCs); final sample after quality control was 1,148 MDD patients (aged 11–93) and 1,079 HCs (aged 13–81). A subsample of 43 patients received 6-month paroxetine treatment.
- Functional connectivity strength (FCS) was computed for 220 cerebral regions using a predefined parcellation; Pearson correlations were thresholded at r=0.2, Fisher r-to-z transformed, summed per region, z-normalized, and ComBat-harmonized for site effects. Normative models of FCS as a function of age and gender were estimated in HCs using Gaussian process regression with 10-fold cross-validation; individual deviations were expressed as Z values, with extreme deviations thresholded at Z=±2.6 (p<0.005).
- K-means clustering was applied to individual deviation maps, with cluster number 2–10 assessed by 22 effective indexes via NbClust. Subtype differences in deviation patterns and demographic/clinical variables were tested; support vector regression with embedded 5-fold cross-validation and permutation tests examined prediction of treatment response. Validation included leave-one-site-out and alternative thresholds.
Limitations
- Stated by the authors: the analysis is cross-sectional, so age-related trajectories are population-level rather than individual trajectories; longitudinal samples are needed. Clinical characterization used HDRS-17 item scores, and cognitive impairments were not collected. Treatment prediction included only paroxetine responders, so nonresponders are needed to model treatment-resistant depression. Subtypes were based on FCS alteration patterns, and future work should incorporate genetic and environmental information.
- Evident from the text: the treatment-response prediction subsample was very small (43 patients; 16 severe, 27 moderate), limiting generalizability. The normative models and subtype solutions depend on analytic choices such as correlation threshold and extreme-deviation threshold, although the authors report validation across several alternatives.
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32 Own result · 17 Not checked yet · 16 Own interpretation · 10 Own method · 5 No basis given
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“while those with decreased FCS were mainly in the precuneus, posterior cingulate cortex, medial prefrontal cortex, angular gyrus, insula, and medial temporal areas”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“The 10-fold cross-validation in the HCs revealed a high generalizability of the fitting performance of normative models for FCS, as indicated by overall standardized mean squared error close to 1 (0.996 ± 0.013) and mean squared log-loss close to 0 (-0.001 ± 0.007) (Supplementary Fig. 2).”
hedged- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A total of 72.82% (N=836) of the patients with MDD showed extreme FCS deviations from the normative model in at least one brain region”
plainn = 836- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Specifically, regions with increased age-related FCS values were located mostly in the lateral frontoparietal cortices, dorsal anterior cingulate cortex, medial occipital cortices, sensorimotor areas, and subcortical areas”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we found that the brain regions can be clustered (Supplement) into two categories according to their age-related FCS change trajectories in both female (Fig. 2a) and male groups (Supplementary Fig. 3).”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The extreme positive deviations in patients with MDD were mostly located in the prefrontal cortex, precuneus, angular gyrus, and subcortical areas”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“From the perspective of brain regions, 99.55% (N=219) of the nodes showed an extreme FCS deviation in at least one patient”
plainn = 836- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The k-means clustering approach identified two MDD subtypes based on individual FCS deviations.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The baseline individual deviation map could significantly predict HDRS score changes after treatment for patients with the severe-deviation subtype ( r =0.47, p =0.019, one-tailed permutation test”
hedgedcorrelationaln = 16 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
- Rests on an assumption: The 43-patient subsample receiving 6-month paroxetine treatment is representative of MDD patients' antidepressant treatment response.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This optimal subcluster number was consistently selected by 11 of 22 effective quality indexes”
plain- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 34
- Probably not a substantial claim. 14
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Compared to the HCs, patients with MDD exhibited significantly larger individual FCS deviation indexes, including the number of extremely deviated regions ( t =4.22) and the sum of positive ( t =4.11) and negative ( t =-2.77) extreme deviations”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Regionally, the patient group had significantly larger FCS deviations than the HC group, with positive deviations mainly in the bilateral lateral frontal cortex, precuneus, angular gyrus, and subcortical areas and negative deviations in the left parahippocampal gyrus, right Rolandic operculum, and middle cingulum gyrus”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the extreme negative deviations were widespread over the whole brain, especially in the medial sensorimotor cortex and the temporal lobe”
plainn = 36- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“including extreme positive deviations in 25.78% (N=296) of patients and extreme negative deviations in 66.38% (N=762) of patients”
plainn = 836- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The HDRS-17 score was negatively correlated with onset age in patients with the severe-deviation subtype ( r =-0.24, p =0.004) but not in patients with the moderate-deviation subtype ( r =-0.00, p =0.966)”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“while patients with the moderate-deviation subtype exhibited more severe symptoms in the Work and Activities ( t =3.11, p =0.002) and Depressed Mood items ( t =2.42, p =0.016)”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“patients with the severe-deviation subtype were significantly older ( t =2.64, p =0.008) and had a higher medicated proportion ( χ 2 =6.11, p =0.013) than patients with the moderate-deviation subtype”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The most positively contributive features were located in the DMN (24.1%), FPN (16.1%), and VAN (15.6%), and the most negatively contributive features were in the VIS (40.5%)”
plainn = 16- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
- Rests on an assumption: The 43-patient subsample receiving 6-month paroxetine treatment is representative of MDD patients' antidepressant treatment response.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among the patients who had follow-up treatment outcomes, 16 patients were clustered into the severe-deviation subtype and the other 27 patients were clustered into the moderate-deviation subtype.”
plainn = 16- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
- Rests on an assumption: The 43-patient subsample receiving 6-month paroxetine treatment is representative of MDD patients' antidepressant treatment response.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Statistical comparisons showed that the number of extremely deviated regions, the sum of positive extreme deviations, and the sum of negative extreme deviations observed in subtype 1 patients were significantly higher than those observed in HCs and subtype 2 patients”
plaincorrelationaln = 425- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, the deviations observed in patients with subtype 2 (63%, N=723) were moderate, and the deviation patterns were significantly different, with negative deviations in the DMN, LIM, and SUB areas and positive deviations in the SMN, DAN, and V AN areas”
plaincorrelationaln = 723- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“while the number of extremely deviated regions and the sum of negative extreme deviations observed in subtype 2 patients were significantly lower than those observed in HCs”
plainn = 723- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found positive FCS deviations mainly in the DMN and SUB areas and negative deviations mainly in the sensorimotor and lateral temporal cortices.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The FCS deviations in the DMN, LIM, SUB, SMN, DAN, and VAN exhibited significant differences and opposite alterations between the two subtypes, and the DMN showed the most.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“More importantly, we found the predictive power of FCS deviation patterns for treatment effects in the severe-deviation subtype but not found in the other subtype.”
- Also stated in: § Figure legends · plain
“The prediction ability of deviation values for treatment response in patients of the severe-deviation subtype.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § Figure legends · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this study, we uncovered the neurophysiological heterogeneity and subtypes of patients with MDD through mapping deviations from the normative models of functional connectome, by leveraging the currently largest R-fMRI dataset in MDD.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
- Rests on an assumption: The DIDA-MDD sample of 1,148 MDD patients and 1,079 HCs is representative of the broader MDD and healthy populations, so findings generalize.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Compared to the traditional general linear model, the novel framework normative model does not require assumptions about the change trajectories and provides a useful tool to characterize any nonlinear changes in features.”
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“our results highlight not only differences in the spatial distribution of functional connectome abnormalities but also significant disparities in demographic and clinical characteristics between the two identified neurobiological subtypes of MDD.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
- Rests on an assumption: The DIDA-MDD sample of 1,148 MDD patients and 1,079 HCs is representative of the broader MDD and healthy populations, so findings generalize.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Under different thresholds in FCS calculation (r=0.15, 0.25), the normative models and patient deviations were similar to our main results, the overlap rates of the resulting subtype indexes with the clustered indexes in the main results were >96%, and the subtype differences largely remained”
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“When different threshold was used to define extreme deviations (FDR p <0.05), the spatial overlap maps were slightly sparser, but the specific brain regions affected by MDD still varied markedly among individual patients”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Similar to our findings, several previous studies found linear-age-related FCS decreases in the medial prefrontal cortex, precuneus, insula, and calcarine and linear FCS increases in sensorimotor areas based on the general linear model [36-38].”
What the sources say
- Not checked yetcites [36] Filley, 1994, Attention and vigilance functions in normal aging, Appl Neuropsychol source
- Not checked yetcites [37] Sambataro, 2010, Age-related alterations in default mode network: Impact on working memory performance, Neurobiol Aging source
- Not checked yetcites [38] Feczko, 2019, The heterogeneity problem: Approaches to identify psychiatric subtypes, Trends Cogn Sci source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The overlap rates of the resulting clustered indexes in the leave-one-site-out validation with the clustered indexes in the main results were all >92%, and the subtype differences were largely unchanged”
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Conversely, the sensorimotor areas are the least affected by aging [36].”
What the sources say
- Not checked yetcites [36] Filley, 1994, Attention and vigilance functions in normal aging, Appl Neuropsychol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, in our study, although brain regions had overall increased or decreased change trajectories, the changes did not always follow a linear or quadratic change, which demonstrates the high value of the normative model in characterizing the natural FCS change trajectories more accurately.”
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Importantly, the model can recognize all sources of variance and reduce overly optimistic inferences and thus obtain more accurate and patient-specific individual deviations for patients.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The FCS alterations in these regions have been proven to be related to the regulation of widespread cognitive, emotional, and executive control functions in patients with MDD [6, 42-50].”
What the sources say
- Not checked yetcites [6] Harald, 2012, Meta-review of depressive subtyping models, J Affect Disord source
- Not checked yetcites [42] Wang, 2014, Overlapping and segregated resting-state functional connectivity in patients with major depressive disorder with and without childhood neglect, Hum Brain Mapp source
- Not checked yetcites [43] Wang, 2015, The effects of antidepressant treatment on resting-state functional brain networks in patients with major depressive disorder, Hum Brain Mapp source
- Not checked yetcites [44] Shi, 2020, Abnormal functional connectivity strength in first-episode, drug-naive adult patients with major depressive disorder, Prog Neuropsychopharmacol Biol Psychiatry source
- Not checked yetcites [45] Zhang, 2021, Identification of psychiatric disorder subtypes from functional connectivity patterns in resting-state electroencephalography, Nat Biomed Eng source
- Not checked yetcites [46] Price, 2017, Data-driven subgroups in depression derived from directed functional connectivity paths at rest, Neuropsychopharmacology source
- Not checked yetcites [47] Chang, 2021, Identifying and validating subtypes within major psychiatric disorders based on frontal-posterior functional imbalance via deep learning, Mol Psychiatry source
- Not checked yetcites [48] Greene, 2022, Brain-phenotype models fail for individuals who defy sample stereotypes, Nature source
- Not checked yetcites [49] Dhamala, 2023, One size does not fit all: Methodological considerations for brain-based predictive modeling in psychiatry, Biol Psychiatry source
- Not checked yetcites [50] Auerbach, 2021, Neural correlates associated with suicide and nonsuicidal self-injury in youth, Biol Psychiatry source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The areas of FCS decrease are the prominent hubs of global and local functional connectivity, and the age-related decrease could underlie the performance decline in working memory and visual sustained attention, which are the most affected cognitive functions that occur with aging [39-41].”
What the sources say
- Not checked yetcites [39] Feczko, 2020, Methods and challenges for assessing heterogeneity, Biol Psychiatry source
- Not checked yetcites [40] Yang, 2020, Brain structural and functional alterations specific to low sleep efficiency in major depressive disorder, Front Neurosci source
- Not checked yetcites [41] Zhang, 2011, Disrupted brain connectivity networks in drug-naive, first-episode major depressive disorder, Biol Psychiatry source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our results suggest that FCS alteration is an important neuropathological feature of MDD, while the alteration patterns among patients are largely different and there might be multiple forms of MDD.”
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
- Rests on an assumption: The DIDA-MDD sample of 1,148 MDD patients and 1,079 HCs is representative of the broader MDD and healthy populations, so findings generalize.
In the paper
“When individuals are involved in regurgitating negative emotions about themselves, suicidal thoughts and behaviors occur in response to the individual's desire to escape from both self-awareness and the associated unpleasant feelings [59].”
What the sources say
- Not checked yetcites [59] Felger, 2016, Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression, Mol Psychiatry source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Studies have shown that the increased functional connectomes and activities of the DMN and LIM areas are related to suicide, including the orbitofrontal cortex, medial prefrontal cortex, cingulate cortex, and striatum [56-59].”
What the sources say
- Not checked yetcites [56] First, 1997
- Not checked yetcites [57] Höflich, 2019, Circuit mechanisms of reward, anhedonia, and depression, Int J Neuropsychopharmacol source
- Not checked yetcites [58] Su, 2022, Progress and challenges in research of the mechanisms of anhedonia in major depressive disorder, Gen Psychiatr
- Not checked yetcites [59] Felger, 2016, Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression, Mol Psychiatry source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“Increasing evidence suggests that alterations in self-referential thinking may be associated with suicidal behavior [61].”
What the sources say
- Not checked yetcites [61] Geller, 2021, Specificity of anhedonic alterations in resting-state network connectivity and structure: A transdiagnostic approach, Psychiatry Res Neuroimaging source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Combined with these findings, our results indicate that the functional connectome and activity of DMN areas are important biomarkers for the neurophysiological subtyping of MDD.”
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
In the paper
“The orbitofrontal cortex is involved in learning, prediction, and decision-making for emotional and reward-related behaviors and is important in the regulation of behavioral impulsivity and response inhibition [60].”
What the sources say
- Not checked yetcites [60] Gabbay, 2013, Striatum-based circuitry of adolescent depression and anhedonia, J Am Acad Child Adolesc Psychiatry source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Also, these findings reflect the useful application of normative model of functional connectome for identifying individual abnormities and parsing heterogeneity of MDD.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
In the paper
“Moreover, evidence has shown that brain resilience increases during development and early adulthood and then decreases during aging [70].”
What the sources say
- Not checked yetcites [70] Dichter, 2015, A systematic review of relations between resting-state functional-MRI and treatment response in major depressive disorder, J Affect Disord source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Similar to the alteration patterns in our results, studies of late-life depression showed increased FCS in the inferior parietal lobule and parahippocampal gyrus and decreased FCS in the somatosensory and motor cortices compared to HCs [69].”
What the sources say
- Not checked yetcites [69] Chin Fatt, 2020, Effect of intrinsic patterns of functional brain connectivity in moderating antidepressant treatment response in major depression, Am J Psychiatry source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Several studies have explored the association between the onset age and HDRS-17 score in patient with MDD, but the results were inconsistent [71-74].”
What the sources say
- Not checked yetcites [71] Flint, 2014, The genetics of major depression, Neuron source
- Not checked yetcites [72] Nguyen, 2022, Genetic heterogeneity and subtypes of major depression, Mol Psychiatry source
- Not checked yetcites [73] Tokuda, 2018, Identification of depression subtypes and relevant brain regions using a data-driven approach, Sci Rep source
- Not checked yetcites [74]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the ability of the brain to withstand disease may decrease and thus experience more severe alterations in older patients.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The alterations in these areas might be related to the increased negative self-focused thought, impaired visuospatial and episodic memory, poor sleep quality, and deficits in physical health and functions in late-life patients.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The age-related change trajectories shown here do not represent the trajectories of each participant, and they reveal age-specific population-level means and individual variabilities.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The patients with MDD also had varied cognitive impairments, which were not collected in the current retrospective study.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The age-related change trajectories shown here do not represent the trajectories of each participant, and they reveal age-specific population-level means and individual variabilities.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“First, our analysis was performed based on a cross-sectional sample.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Ten-fold cross-validation were performed to assess the generalizability of the models.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The normative model of FCS built from healthy controls provides a valid reference for estimating disease-related deviations in MDD patients.
“For each patient with MDD, the FCS of the brain regions were positioned on the normative percentile charts from HCs to estimate individual deviation (Fig. 1b).”
The paper relies on this without support.
The DIDA-MDD sample of 1,148 MDD patients and 1,079 HCs is representative of the broader MDD and healthy populations, so findings generalize.
“we conducted a comprehensive investigation into the neurobiological heterogeneity and subtypes of MDD using a large multisite r-fMRI dataset of 1,148 patients with MDD and 1,079 matched healthy controls (HCs).”
The paper relies on this without support.
The 43-patient subsample receiving 6-month paroxetine treatment is representative of MDD patients' antidepressant treatment response.
“Additionally, a subsample of 43 patients (Supplementary Table 1) received a 6-month treatment with paroxetine (an antidepressant of selective serotonin reuptake inhibitor, SSRI), and the treatment outcomes were recorded (Supplement).”
The paper relies on this without support.
The areas of the DMN are related to self-referential processing.
“The areas of the DMN are related to self-referential processing.”
The paper relies on this without support.
Previous studies have found different alteration patterns between patients in different age stages.
“Previous studies have found different alteration patterns between patients in different age stages.”
The paper relies on this without support.
Patients with MDD have varied cognitive impairments.
“The patients with MDD also had varied cognitive impairments, which were not collected in the current retrospective study.”
Citations
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Neural correlates of distance-related functional reorganization in obsessive compulsive disorder
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Metabolic-Brain Functional Coupling Mechanism Underlying iTBS Treatment for Adolescent Depression
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Metadata
- Authors
- Sun, X., Sun, J., Lu, X., Dong, Q., Zhang, L., Wang, W., Liu, J., Ma, Q., Wang, X., Wei, D., Chen, Y., Liu, B., Huang, C.-C., Zheng, Y., Wu, Y., Chen, T., Cheng, Y., Xu, X., Gong, Q., Si, T., Qiu, S., Lin, C.-P., Cheng, J., Tang, Y., Wang, F., Qiu, J., Xie, P., Li, L., He, Y., He, Y., Li, L., Cheng, J., Gong, Q., Lin, C.-P., Qiu, J., Qiu, S., Si, T., Tang, Y., Wang, F., Xie, P., Xu, X., Xia, M., & Xia, M.
- Affiliations
- Beijing Normal University (CN)
- Central South University (CN)
- Shanghai Medical College of Fudan University (CN)
- Southwest University (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- East China Normal University (CN)
- First Affiliated Hospital of Guangzhou University of Chinese Medicine (CN)
- Peking University (CN)
- Sichuan University (CN)
- First Affiliated Hospital of Kunming Medical University (CN)
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2023-12
- Volume
- 94
- Issue
- 12
- Pages
- 936-947
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W4379741254
- Cited by
- 129
- References
- 88
- Citations by year
- 2026: 54 · 2025: 53 · 2024: 20 · 2023: 2
- FWCI
- 19.27
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Biological Psychiatry (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Science and Technology Planning Project of Fuzhou (2018-1002-SF-0442)
- National Natural Science Foundation of China (81471251, 81771344, 81920108019, 82021004, 82071998, 91649117)
- Beijing Nova Program (Z191100001119023)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Mental Health Research Topics
- Keywords
- major depressive disorder, functional connectome, resting-state functional connectivity, normative model, lifespan trajectories, default mode network, limbic system, antidepressant response, treatment prediction, personalized treatment, clinical heterogeneity
- MeSH terms
- Adolescent, Adult, Brain, Brain Mapping, Major Depressive Disorder, Humans, Magnetic Resonance Imaging, Reproducibility of Results, Connectome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-08, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-08 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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