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Open research questions in Functional Brain Connectivity Studies

148 unresolved questions extracted from the limitations and future-work sections of 855 Functional Brain Connectivity Studies papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Background Long-term exposure to a high-altitude (HA) hypoxic environment induces cognitive impairments, but the underlying mechanisms remain unclear.

    Alterations in static and dynamic topological properties of brain functional network after chronic high altitude exposure: a panel study · 2026 · DOI

  • In ADHD, however, it remains unclear whether neuroimaging-derived markers can not only predict inter-individual differences in cognition but also track longitudinal cognitive development and capture cognition-psychopathology relationships.

    Multimodal MRI-based neuromarkers trace longitudinal changes in cognitive functioning in ADHD · 2026 · DOI

  • Progress will require greater theoretical intentionality in selecting area-level measures, transparent justification of geographic resolution, treatment of dataset and measure non-independence, and investment in understudied developmental periods and non-US contexts.

    Area-level context and functional brain organization across the lifespan · 2026 · DOI

  • Previous research has used various MRI sequences to profile FCD lesions, but multi-site studies using personalized features derived from sequences routinely used in the clinic are sparse.

    Multiscale alterations and cortex-wide organizational trends in focal cortical dysplasia · 2026 · DOI

  • However, the regional distribution of EEG relative power (RP) across finer frequency bands, particularly in adolescent schizophrenia, remains poorly characterized.

    Region-Specific Delta and Alpha2 Relative Power Alterations in Male Adolescent Schizophrenia: Occipital Predominance in Resting-State EEG · 2026 · DOI

  • While the effects of varied implementations of ME-ICA on signal and noise characteristics have been tested thoroughly in breath-hold data, the effects of similar modeling decisions have not been studied in motor-task data, which present with a more localized neural response.

    Impact of multi-echo ICA modeling decisions on motor-task fMRI analysis · 2026 · DOI

  • ABSTRACT Transcutaneous auricular vagus nerve stimulation (taVNS) has shown promise in enhancing cognitive and emotional functions, yet its neural mechanisms remain unclear largely because existing analytical methods cannot characterize multiscale functional connectivity nor reliably infer causal interactions between brain regions in the presence of hemodynamic delays in fMRI signals.

    A Multiscale Spatiotemporal Causal Mapping Algorithm for Revealing Neural Network Mechanisms of Transcutaneous Auricular Vagus Nerve Stimulation · 2026 · DOI

  • Alterations in functional connectivity (FC) have been associated with ASD, yet it remains unclear whether and how divergent brain network properties may account for individual differences across ASD‐related symptomatology and behaviors.

    Cortical Network Overconnectivity Relates to Sensory, Cognitive, and Social Dimensions in Young Children With Autism Spectrum Disorder · 2026 · DOI

  • Identifying generalizable brain-based biotypes across independent cohorts is critical for parsing heterogeneity in Major Depressive Disorder (MDD), yet robust subtypes spanning micro- and macroscales remain poorly defined.

    Mapping generalizable brain-based depression subtypes across clinical, cognitive, and neurotransmitter dimensions · 2026 · DOI

  • AbstractThe locus coeruleus (LC) regulates attention, arousal, and adaptive behavior via widespread noradrenergic projections to cortex, yet its large-scale cortical organization and age-related vulnerability remain poorly understood.

    Age-related reorganization of locus coeruleus-cortical functional connectivity gradients · 2026 · DOI

  • AbstractThe hippocampus and amygdala are neighboring medial temporal lobe structures linked to memory and affect, yet how their subregions are jointly embedded within distributed isocortical systems remains unclear.

    Selective convergence and graded divergence of hippocampal and amygdala subregions using functional connectivity · 2026 · DOI

  • Third, while we have included confounder-specific baseline analyses and sex-stratified analyses, additional sensitivity analyses— such as regression analysis with confounders removed and systematic assessment of correlations between model predictions and potential confounders—remain to be conducted. Fourth, the CSA strategy is used in this study as an overall framework comprising multiple components, and the specific contribution of each component should be further examined in future studies.

    Cross-attention-guided subject-adaptive graph learning for multimodal autism classification: integrating structural and functional MRI data · 2026 · DOI

  • -- -- -- -- -- -- -- taking 292 293 17 bioRxiv preprint The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is https://doi.org/10.64898/2026.06.29.735242 this version posted July 3, 2026. doi: ; made available under a CC-BY-NC-ND 4.0 International license . 294 295 Figure 4. Prediction of cognitive flexibility from IFGpt connectivity properties. Top: The connectivity 296 strength of the IFGpt predicted cognitive flexibility performance (Blue dots – Young adults; Violet 297 dots – Older adults). Middle and Bottom: The clustering in the IFGpt predicted the cognitive flexibility 298 299 performance in young adults (middle) but not in older adults (bottom). FS-full sample; YA-young adults; OA-older adults. 18 bioRxiv preprint The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is https://doi.org/10.64898/2026.06.29.735242 this version posted July 3, 2026. doi: ; made available under a CC-BY-NC-ND 4.0 International license . 300 301 302 Figure 5. Prediction of cognitive flexibility associated traits from local connectivity properties. A) 303 The connectivity strength in the IPL negatively predicted dogmatism (Dogmatism I) in the full sample. 304 B) The clustering in the IFGpt negatively predicted dogmatism (DOG) in the full sample. Blue dots – 305 Young adults; Violet dots – Older adults. 306 3.5 Prediction of cognitive flexibility and associated traits from the IPL-putamen and IPL-precuneus 307 connectivity strength. 19 bioRxiv preprint The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is https://doi.org/10.64898/2026.06.29.735242 this version posted July 3, 2026. doi: ; made available under a CC-BY-NC-ND 4.0 International license . 308 The connectivity strength between the left IPL and the left putamen in interaction with age 309 negatively predicted dogmatism (DOG; Table 5). Posthoc analyses indicated that a stronger left IPL- 310 left putamen connectivity was related to lower dogmatism (DOG) in older adults, but no relationship 311 was observed in young adults (young: r=.18, p=.27 ; old: r=-.33 , p = .05; Figure 6). 312 313 Table 6. Regression models predicting cognitive flexibility and associated traits from structural 314 connectivity of the left IPL with the bilateral putamen and the right precuneus.

    A better connected brain relates to lower dogmatism in young and older adults · 2026 · DOI

  • -- -- -- -- -- -- -- taking 272 *Age in years 273 15 bioRxiv preprint The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is https://doi.org/10.64898/2026.06.29.735242 this version posted July 3, 2026. doi: ; made available under a CC-BY-NC-ND 4.0 International license . 274 275 Figure 3. Prediction of cognitive flexibility associated traits from global connectivity properties. 276 Top: Clustering negatively predicted dogmatism (Dogmatism I). Bottom: Connection Strength 277 negatively predicted dogmatism (DOG). Blue dots – Young adults; Violet dots – Older adults. 278 3.4 Prediction of cognitive flexibility and associated traits from structural connectivity properties of 279 the IFGpt and IPL. 280 The connectivity strength in the full sample and the clustering from the same region in interaction 281 with age significantly predicted the performance in the Rule Switching task. Posthoc analyses 16 bioRxiv preprint The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is https://doi.org/10.64898/2026.06.29.735242 this version posted July 3, 2026. doi: ; made available under a CC-BY-NC-ND 4.0 International license . 282 indicated that a higher clustering in IFGpt was related to a better cognitive flexibility performance in 283 young adults but no significant relationship was observed in older adults (young: r=.52, p=.003; old: 284 r=.36, p=.006; Figure 4; Table 4). The connectivity strength from IPL significantly and negatively 285 predicted dogmatism (Dogmatism I; a higher connectivity strength was associated to lower 286 dogmatism) in the full sample (Figure 5A, Table 4). Finally, the clustering of the IFGpt negatively 287 predicted dogmatism (DOG; a higher clustering related to a lower dogmatism) in the full sample 288 (Figure 5B; Table 4). 289 290 Table 4. Regression models predicting cognitive flexibility and associated traits from structural 291 connectivity properties of the IFGpt and IPL.

    A better connected brain relates to lower dogmatism in young and older adults · 2026 · DOI

  • Taking (.57) -- .03 .31s .05 -- 259 Note. The correlations of dependence on routines in YA are done with the Spearman method, as this 260 variable was non-normal in this group [(p) – Pearson correlations, (s) – Spearman correlations]. 261 Ciphers in bold indicate values that survived multiple comparisons correction. 262 263 3.3 Prediction of cognitive flexibility and associated traits from global structural connectivity 264 properties. 265 Regression (stepwise) models revealed that clustering negatively predicted dogmatism (Dogmatism I) 266 267 in the full sample (i.e. a higher clustering was related to lower levels of dogmatism). In addition, strength negatively predicted dogmatism (DOG) in the full sample (Figure 3; Table 3): higher 268 connection strength was related to lower dogmatism levels. 269 270 Table 3. Regression models predicting cognitive flexibility and associated traits from global brain 271 connectivity properties.

    A better connected brain relates to lower dogmatism in young and older adults · 2026 · DOI

  • Despite its advantages, studies have primarily focused on understanding individual-specific cortical activation, preventing a holistic view of a systems-level functional response, and to date, best approaches for the statistical analysis of controlled task-based, densely sampled, whole-brain data have not yet been fully established.

    Evaluating Approaches for Inference Testing of Whole-Brain Densely Sampled Single-Subject Task fMRI Data · 2026 · DOI

  • It remains unknown whether brain network reorganization in NREM sleep stages N2 and N3 can uniquely be mapped onto individual differences in cognitive performance after a recovery nap following sleep deprivation.

    NREM sleep brain networks modulate cognitive recovery from sleep deprivation · 2026 · DOI

  • Existing machine learning approaches struggle to effectively integrate the temporal dynamics of DFC with inter-subject differences in functional connectivity patterns and are further limited by the poor generalizability and opaque decision-making processes inherent to the small sample sizes typical of neuroimaging data.

    A multi-view graph neural network framework for Parkinson’s disease identification based on dynamic functional connectivity · 2026 · DOI

  • sample The present study has limitations. First, though the study demonstrated the generalizability of the problematic- gaming-severity network across multiple brain states, an external replication sample was not used. Future studies should incorporate a second independent to further examine the replicability and generalizability of the predictive model. Second, the functional significance of the identified networks in relation to other forms of psychopa- thology associated with problematic gaming in adolescents remains to be tested, as similarly described by Yip et al. (2019) and Ibrahim et al. (2022). The present study did not entirely rule out the potential influence of other clinical variables (e.g., the concurrent use of substances) on con- nectivity, but notably remained robust when multiple covariates were included. Third, the CPM analyses used scores on the VGAQ, which is a relatively infrequently used measure. That being said, no single assessment tool has been found to be superior in measuring GD or the spectrum of problematic-gaming behaviors (King et al., 2020; Park, King, Wilkinson-Meyers, & Rodda, 2023). When a gold standard for assessing problematic gaming is established, it could be used to validate and extend the current study findings.

    Connectome-based predictive modelling of problematic gaming in youth from the ABCD study · 2026 · DOI

  • Small sample sizes are widely assumed to contribute to this variability, yet their impact on the reliability of EEG group comparisons has not been systematically quantified at scale.

    Sample size critically shapes the reliability of EEG case-control findings in psychiatry · 2026 · DOI

  • Moreover, a fused rest-task group-level atlas improves the accuracy, reliability, and individual specificity of inferred parcellations, particularly when individual-level data are limited.

    Precision Functional Parcellation of the Human Cortex via Rest-Task fMRI Fusion · 2026 · DOI

  • Functional connectivity (FC) approaches from resting-state fMRI (rs-fMRI) are amply spread to investigate the cortical organization, yet the brainstem remains relatively underexplored despite its pivotal roles in both physiological and pathological conditions.

    Physiologically Informed PCA-Partial Correlation for highly Collinear Brainstem fMRI Networks · 2026 · DOI

  • Background: Investigation of the neural substrates of post-traumatic stress disorder (PTSD) in military personnel using whole-brain approaches remains scarce, hindering the development of circuit-based neuromodulatory interventions.

    Clinical Correlates of Resting-State Functional Magnetic Resonance Imaging in Military Personnel with Adulthood—Onset War—Related Post—Traumatic Stress Disorder · 2026 · DOI

  • The fusiform gyrus (FFG), central to face and social perception, shows differences in functional connectivity in autism, yet is rarely examined dynamically or as a spatially heterogeneous structure.

    Attenuation of typical sex differences in the time-resolved functional connectivity of the fusiform gyrus in autism · 2026 · DOI

  • We demonstrate that, across 80 MRI phenotypes, a class of machine-learning approaches collectively known as supervised domain adaptation can substantially reduce cross-ethnicity disparities in neuroimaging-based cognitive prediction, even when only limited data from underrepresented groups are available.

    Supervised Domain Adaptation Mitigates Cross-Ethnicity Prediction Error in Neuroimaging Based Cognitive Prediction · 2026 · DOI

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148 open questions have been extracted from the limitations and future-work passages of 855 Functional Brain Connectivity Studies papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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