Open research questions in Advanced Neuroimaging Techniques and Applications

What the literature leaves open

• Investigating the causal relationship between age-related changes in white matter and decline in bimanual performance, - Examining the effects of age-related changes in white matter on other motor and cognitive functions, - Using larger and more diverse samples, - Exploring the potential of interventions to improve white matter structure and function in older adults

  Age-group differences in diffusion MRI characteristics of cortico-cerebellar tracts and their association with bimanual performance · 2026 · DOI

• The organization of white matter morphometric similarity networks and their disruption remain insufficiently understood. There is a lack of large-scale studies characterizing WM-MSNs in MDD at the individual level. The integration of these network alterations with spatial transcriptomic architecture is a novel contribution.

  Cell-type and spatiotemporal transcriptional signatures of white matter morphometric similarity network alterations in major depressive disorder · 2026 · DOI

• Investigating the relationship between brain development and neurological conditions, - Examining the effects of different factors on brain maturation, - Developing more accurate machine-learning models for predicting chronological age, - Expanding the study to include a larger and more diverse population

  Age- and sex-divergent neurodevelopmental patterns revealed through structural magnetic resonance imaging features · 2026 · DOI

• Limited understanding of age-related morphometric patterns and sex differences in brain structure. Lack of a robust machine learning framework to predict chronological age from MRI features.

  Age- and sex-divergent neurodevelopmental patterns revealed through structural magnetic resonance imaging features · 2026 · DOI

• limited number of studies on ANX and PTSD, - imbalance in the number of studies available for MDD compared to ANX and PTSD, - potential influence on statistical power and ability to detect consistent WM alterations, - use of a more lenient threshold to explore abnormalities

  Structural brain correlates in major depressive disorder, anxiety disorders, and post-traumatic stress disorder: a diffusion tensor imaging meta-analysis · 2025 · DOI

• further studies are needed to investigate the neurobiological mechanisms underlying WM alterations, - more research is required to fully understand the clinical characteristics of MDD, ANX, and PTSD, - future studies should aim to include more participants and studies on ANX and PTSD

  Structural brain correlates in major depressive disorder, anxiety disorders, and post-traumatic stress disorder: a diffusion tensor imaging meta-analysis · 2025 · DOI

• small sample size, - limited number of studies investigating WM microstructural differences in LLD, - exclusion criteria for LLD group include primary referral for assessment of cognitive impairment and comorbid major psychiatric illness

  Gray and white matter differences in the medial temporal lobe in late-life depression: a multimodal PET-MRI investigation · 2025 · DOI

• investigate the relationship between cerebrovascular burden and brain tissue differences in LLD, - examine the effects of tau accumulation on GM/WM differences in LLD, - study the association between the duration of the current depressive episode and GM/WM differences

  Gray and white matter differences in the medial temporal lobe in late-life depression: a multimodal PET-MRI investigation · 2025 · DOI

• Prior studies have shown inconsistent findings on the impact of childhood trauma on fractional anisotropy in schizophrenia. There is a need to investigate the impact of childhood trauma on specific cellular or extracellular compartments of fractional anisotropy. The current study aims to address this gap by examining the impact of childhood trauma on free water-corrected fractional anisotropy and extracellular free water.

  Cellular and extracellular white matter alterations after childhood trauma experience in individuals with schizophrenia · 2024 · DOI

• Age-related differences in cortico-cerebellar pathways remain insufficiently understood. The relationship between age-related changes in white matter structure and decline in bimanual performance is not well understood.

  Age-group differences in diffusion MRI characteristics of cortico-cerebellar tracts and their association with bimanual performance · 2026 · DOI

• However, the temporal sequence and molecular changes linking these cocaine-induced phenotypes remain unclear.

  Acute head shaking precedes chronic corpus callosum deficits during repeated cocaine exposure in common marmosets · 2026 · DOI

• White matter tracts (WMTs), which mediate information transmission in the brain, are closely associated with the pathogenesis of psychiatric disorders, yet the causality of their associations remain unclear.

  Unveiling causal relationship between white matter tracts and psychiatric disorders · 2025 · DOI

• BACKGROUND AND OBJECTIVES: It remains unclear whether longitudinal changes in brain microstructural integrity, measured by diffusion MRI, relate to cognition and vascular risks.

  Longitudinal Changes in Brain Diffusion Characteristics Associated With Cognition and Vascular Risk Factors · 2025 · DOI

• Superficial white matter (SWM), containing short-range association connections beneath the cortex, has been affected in mild cognitive impairment and AD, with gaps in understanding the disease's early stages.

  Association of Superficial White Matter Microstructure With Cortical Pathology Deposition Across Early Stages of the AD Continuum · 2025 · DOI

• Therefore, both functional and diffusion signals, as well as their relationship with global patterns of connectivity reorganization, are poorly understood.

  Functional and structural reorganization in brain tumors: a machine learning approach using desynchronized functional oscillations · 2024 · DOI

• However, specific local and network-level neural substrates of thalamic aphasia remain incompletely understood.

  Fronto-thalamic networks and the left ventral thalamic nuclei play a key role in aphasia after thalamic stroke · 2024 · DOI

• Different patterns of WM atrophy, WM hyperintensities (WMHs), and microstructural integrity could reflect distinct pathologies and disease risks, but large-scale imaging studies investigating WM signatures are lacking.

  Cluster-Based White Matter Signatures and the Risk of Dementia, Stroke, and Mortality in Community-Dwelling Adults · 2024 · DOI

• Despite the unique disease trajectory in MDD patients with CT, the underlying neurobiological mechanisms remain unclear.

  Alterations in the white matter structure of major depressive disorder patients and their link to childhood trauma · 2024 · DOI

• Therefore, future studies are needed to reduce confounding effects of antidepressant medications and to adopt longitudinal and multimodal approaches in order to better characterize the differences in WM integrity between responders and non-responders.

  White matter integrity and medication response to antidepressants in major depressive disorder: a review of the literature · 2024 · DOI

• This study has at least seven limitations. First, because the subjects were Japanese, caution is required when applying to people in other countries. Japanese workers tend to remain in the same workplace for long periods despite reporting low levels of job satisfaction and work engagement, largely due to the low fluidity of the labor market. As a result, they are often exposed to high-stress environments characterized by heavy workloads, burnout, and even frequent cases of karoshi (death from overwork) (Matsui 2024). This particu- lar socio-cultural context may have influenced the results to some extent. Second, our methodological approach has certain limita- tions. We characterized the white matter integrity of each tract using a single mean FA-BHQ value. While this pro- vides a useful and easily interpretable summary metric, it may mask regional variability along the length of the fiber tract. For instance, workload-related effects might be con- centrated in a specific segment of the SLF, a nuance that a single mean value cannot capture. Future research using fiber tracking or profile analysis along the tracts could provide more localized insights. In addition, fractional anisotropy is a non-specific index influenced by multiple microstruc- tural properties, including myelination, axonal density, and fiber coherence, and therefore the present findings cannot be attributed to any single biological mechanism. Furthermore, although the observed associations were statistically robust, their effect sizes were small, which is typical for individual- differences neuroimaging research; accordingly, the results should be interpreted as subtle population-level associa- tions rather than markers with immediate individual-level or practical applicability. Third, we employed a widely-used atlas-based approach (the JHU atlas) to define white matter tracts rather than performing subject-specific tractography. While individual tractography may yield more precise anatomical localiza- tion, it can be challenging to standardize across a large group of participants and is sensitive to user-defined param- eters. Our approach, which combines a validated atlas with high-precision non-linear spatial normalization (FNIRT), ensures that we are comparing anatomically homologous regions across all participants, which is a robust method for group-level analysis. The JHU atlas has been extensively validated in healthy adult populations, making it a suitable choice for this study. Fourth, although the sample size was relatively large compared to previous studies, the small sample size reduces the generalizability of the results. Fifth, because this study employed cross-sectional analysis, the causal relationship of the variables is unclear. It is important to take these issues seriously and not exaggerate the results. Sixth, one of the Brain Structure and Function (2026) 231:61 1 3 three measures of burnout, professional efficacy, did not fol- low a normal distribution, suggesting that different results may occur if professional efficacy were to be measured using a normally distributed sample. Finally, because this study only used FA as an index of brain structure, future studies may consider incorporating other indices, such as intrinsic brain activity and connectiv- ity (Ma et al. 2024) and structural-functional connectivity (Suo et al. 2025), to gain a more comprehensive under- standing of the neurobiological mechanisms associated with burnout. Therefore, future research should verify the pres- ent findings in larger cross-sectional and longitudinal sam- ples that include participants from more diverse national and cultural backgrounds.

  White matter fibers mediate the relationship between workload, resource use, and burnout: a new attempt to apply the conservation of resources theory to neuroscience · 2026 · DOI

• The comparative accuracy of DTI-based deterministic and probabilistic tractography algorithms remains a critical area of investigation. There is a need for more accurate tractography algorithms for preoperative planning and surgical management of brain tumors.

  Accuracy of corticospinal tract reconstruction: DTI-based deterministic versus probabilistic tractography with intraoperative validation · 2026 · DOI

• However, it remains unclear whether an MRI signature of pTau exists, and whether such a signature could enable accurate voxelwise detection of tau concentration.

  Multidimensional MRI Maps Histology-Defined Phosphorylated Tau Burden in Alzheimer’s Disease · 2026

• The origins of white matter microstructure abnormalities in people with bipolar disorder or schizophrenia are unknown. Case-control studies cannot inform us about the origins of these deviations in white matter structure.

  White matter microstructure in relatives of people with schizophrenia or bipolar disorder: an ENIGMA meta-analysis · 2026 · DOI

• Our study design provides a unique opportunity to compare patient vs. control differences to FDR-BD/SZ vs. control differ- ences, since the patients came from the same samples, their data was analyzed the same way, and they were compared to the same controls. In addition, we applied a transdiagnostic approach, and achieved higher power than most previous work by combining 11 datasets. The largely standardized and robust processing and analysis pipeline ensured high quality data from all datasets, which is often not guaranteed with traditional meta-analysis. Yet, the findings have to be considered in light of several limitations. First, studies varied in their age range. However, we adjusted for age and age-squared within each sample. We also corrected for sex within each sample, and all samples contained both males and females. We did not examine interactions between sex and group as we did not expect sex differences based on the literature [1, 6, 27]. Second, only a subset of studies had information on working memory or childhood trauma, so the meta-analyses of these effects were performed on a more limited sample size. Particularly for childhood trauma, it will be useful to repeat these analyses when more datasets with this information are available. Third, the total sample contains a mix of different types of first-degree relatives: siblings, twins, offspring, and parents. These have the same genetic risk, but vary in the relation to the patient and therefore in environmental risk factors. We did not have the power to compare the types of relatives, and the type of relative is confounded with other factors, e.g. offspring are younger, making direct comparison difficult. Fourth, the datasets in this meta-analysis all came from western countries (Europe, Australia and north-America). We recommend confirming findings in samples from other continents before generalizing across all ethnicities/cultures. Fifth, despite the protocol being largely standardized (i.e. same TBSS pipeline, ROI definitions, extraction process, statistical thresholding), some variation was allowed in the preprocessing. This is because preprocessing options depend on acquisition parameters, which are in turn a balancing act of data quality and scan time. All included studies had whole-brain coverage, b-values < 2000 (which is best for tensor fitting), and at least 30 directions. Variation arose for example in the reverse phase-encoding data that was collected and, as a result, in the susceptibility distortion correction. Since all datasets were of good enough quality and all contained relatives and control groups, we don’t expect this variation to have biased our results. Yet, it could have increased noise compared to a situation where all datasets had been obtained with the most high-quality (and thus lengthy) acquisition. Finally, we focused on mean FA across major tracts. This approach does not consider microstructure of the peripheral white matter or local disruptions along specific points in a tract [28], which would be valuable to examine in future research.

  White matter microstructure in relatives of people with schizophrenia or bipolar disorder: an ENIGMA meta-analysis · 2026 · DOI

• The application of diffusion MRI to gray matter remains less explored. There is a need for novel biomarkers for cognitive disorders.

  General microstructure factor analysis of diffusion MRI in gray-matter predicts cognitive scores · 2026 · DOI

Most-cited papers in Advanced Neuroimaging Techniques and Applications

• Structural Magnetic Resonance Imaging of the Adolescent Brain · Annals of the New York Academy of Sciences · 2004 · 1,188 citations
• Lower Hippocampal Volume in Patients Suffering From Depression: A Meta-Analysis · American Journal of Psychiatry · 2004 · 937 citations
• Aging of cerebral white matter: a review of MRI findings · International Journal of Geriatric Psychiatry · 2008 · 476 citations
• Brain Gray and White Matter Volume Loss Accelerates with Aging in Chronic Alcoholics: A Quantitative MRI Study · Alcoholism Clinical and Experimental Research · 1992 · 454 citations
• Pathways That Make Voices · Archives of General Psychiatry · 2004 · 415 citations
• Abnormal Brain Connectivity in Children After Early Severe Socioemotional Deprivation: A Diffusion Tensor Imaging Study · PEDIATRICS · 2006 · 388 citations
• Neuroanatomy of Down’s Syndrome: A High-Resolution MRI Study · American Journal of Psychiatry · 2001 · 380 citations
• Compromised White Matter Tract Integrity in Schizophrenia Inferred From Diffusion Tensor Imaging · Archives of General Psychiatry · 1999 · 365 citations
• Uncinate Fasciculus Findings in Schizophrenia: A Magnetic Resonance Diffusion Tensor Imaging Study · American Journal of Psychiatry · 2002 · 359 citations
• Neuroanatomical substrates of age-related cognitive decline. · Psychological Bulletin · 2011 · 344 citations

Most recent work

• Decoding gray matter, large-scale analysis of brain cell morphometry to inform microstructural modeling of diffusion MR signals · Communications Biology · 2026
• Joint and Distinct Cognitive-Motor Associations with Multivariate White Matter Microstructure and Connectivity · bioRxiv · 2026
• MRI Diffusion Tensor Image Analysis Along the Perivascular Space: Effects of Mean Tract Orientation Divergence · Journal of Magnetic Resonance Imaging · 2026
• Comparison of Automated White Matter Lesion Segmentation Approaches for Use in Large, Multi-Site Data Analyses in Parkinson's Disease · bioRxiv · 2026
• The Role of Dendritic Spines in Water Exchange Measurements With Diffusion MRI: Double Diffusion Encoding and Free‐Waveform MRI · NMR in Biomedicine · 2026
• Dependence of the Extra‐Cellular Diffusion Coefficient on the Fractions of Neurites and Cell Bodies in Gray Matter · Magnetic Resonance in Medicine · 2026
• Learning sculpts microstructure in real time: evidence from dense temporal sampling of diffusion MRI · bioRxiv · 2026
• Impact of clinical risk factors on white matter microstructure in preterm-born infants: Investigation with diffusion MRI and tractography at term-equivalent age · medRxiv · 2026
• Teaching NeuroImages: Longitudinal Motor Pathway Reorganization After Hemorrhagic Stroke on Diffusion Tensor Tractography · Neurology · 2026
• Modeling of Fiber Orientation‐Dependent R1 Relaxation in Human White Matter In Vivo Within The Framework of The Transient Hydrogen Bond Model · Magnetic Resonance in Medicine · 2026

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