Open research questions in Advanced Neuroimaging Techniques and Applications

What the literature leaves open

• People differ widely in their sensitivity to pain, and this variability is clinically relevant, yet the underlying structural brain mechanisms remain poorly understood.

  Structural Brain Pathways Linking White Matter Hyperintensities to Pain Sensitivity · 2026 · DOI

• White matter hyperintensities (WMH), a common imaging marker of cerebral small vessel disease, are associated with microstructural abnormalities in white matter tracts and have also been linked to pain-related outcomes; however, the mechanisms linking WMH to altered pain perception remain unclear.

  Structural Brain Pathways Linking White Matter Hyperintensities to Pain Sensitivity · 2026 · DOI

• Several limitations must be acknowledged. First, the primary inclusion criterion was the diagnosis of SSD, which predominantly included schizophrenia but also other psychotic disorders so we cannot specify the results for each disorder. Second, given the limited effect sizes reported here, larger cohorts may be needed to validate subtler associations or subgroup effects. Third, the cross- sectional design limits our ability to draw conclusions about developmental trajectories. Longitudinal studies are required to characterize the progression of microstructural changes over time and evaluate their potential utility as prognostic markers. Fourth, given the low SANS scores observed in our patient sample, the statistical power to detect associations with negative symptoms was lower than for the other symptom dimensions explored in this study. Fifth, although hospitalization and its duration may reasonably correlate with first- episode severity, they are also influenced by patient-specific factors, clinical features, and institutional practices. Consequently, hospitalization should not be interpreted as a direct measure of severity. CONCLUSIONS In summary, our findings provide converging evidence that early-stage psychosis is characterized by a distinct pattern of structural alterations involving cortical, subcortical, and WM alterations. Raw cMD showed the highest sensitivity to positive symptoms and was associated with key clinical features at the first episode, including hospitalization and overall illness severity. While reductions in CT, ventricular enlargement, and increased cortical diffusivity were prominent, weaker effect sizes were found in DWM. The differential correlations between symptom dimensions and structural features support the presence of medRxiv preprint doi: https://doi.org/10.64898/2026.01.09.26343760 ; this version posted June 26, 2026. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . distinct neurobiological mechanisms underlying positive, negative, and global psychopathology. These results emphasize the need for multidimensional clinical assessment and suggest that early deviations from normative brain structure, together with alterations in raw cMD measures, may reflect microstructural and macrostructural abnormalities associated with SSD.

  Early deviations from normative brain morphology and cortical microstructure in schizophrenia spectrum disorders · 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

• This study had several limitations. The primary limitation was the small sample size. Histological validation was per- formed in three myocardial layers, which may introduce sampling bias. In addition, there was an interval of approxi- mately four hours between heart excision and ex-vivo MRI evaluation, during which the heart was stored in an ice bath to prevent decomposition. However, the low temperature may also have an impact on diffusion tensor parameters [26].

  Impact of formalin fixation on biventricular parameters in cardiac diffusion tensor imaging: A pilot study in a miniature swine model · 2026 · DOI

• While our framework demonstrates promising robustness across datasets and acquisition protocols, several limitations remain. First, the model is trained on the HCP dataset, which primarily consists of young, healthy adults. Although the subgroup-wise CNP analysis suggests consistent behavior across healthy controls, schizophrenia, bipolar disorder, and ADHD, this evaluation is necessarily indirect because CNP does not provide reliable voxel-wise DK reference labels in diffusion space. As a result, supervised metrics such as Dice and HD95 cannot be computed on CNP, and the analysis in these populations is restricted to homogeneity-based evaluation rather than direct supervised segmentation accuracy. Thus, the CNP results provide label-free evidence of external robustness, but they do not constitute full supervised cross-dataset validation. Although RSD provides Scientific Reports | (2026) 16:17182 | https://doi.org/10.1038/s41598-026-54446-8 12 Fig. 4. Parcellation comparison between our framework and the co-registered T1-weighted parcellation projected onto the dMRI space (T1w-reg) in the CNP dataset. a common homogeneity criterion across HCP and CNP, it does not directly measure voxel-wise anatomical agreement. On HCP, RSD is complementary because the models are trained to reproduce the projected DK reference labels and therefore tend to preserve the homogeneity profile of the supervisory parcellation. On CNP, RSD is useful as a label-free criterion, but it cannot replace supervised validation. Future work should evaluate the framework on external datasets with reliable diffusion-space DK labels or expert-validated annotations, ideally with harmonized preprocessing and controlled resolution or protocol analyses. Second, susceptibility-induced EPI distortion correction could not be applied to the CNP dataset because the required auxiliary acquisitions were unavailable. This may affect the absolute RSD values for both T1w-reg and the proposed models. For T1w-reg, residual distortion can influence anatomical-to-diffusion registration. For the proposed models, it can alter the diffusion-derived input maps and increase the preprocessing-domain difference relative to the distortion-corrected HCP training data. Future validation on datasets with the auxiliary data required for EPI correction is needed to directly assess the effect of EPI correction on RSD, anatomical alignment, and model generalization. Third, although the hierarchical design improves parcellation accuracy, inference time could be further optimized for clinical workflows. Fourth, the present study is restricted to DTI-derived inputs from the b = 1000 s/mm2 shell to remain compatible with legacy single-shell datasets such as CNP. Future work should examine robustness to higher b-value shells and multi-shell diffusion modeling, as well as richer microstructural representations such as NODDI or DKI.

  Deep learning-based Desikan-Killiany parcellation of the brain using diffusion MRI · 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

• 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

• Recent studies have presented evidence that ε4 affects microstructural properties of brain white matter (WM) in non-demented carriers of the ε4 allele, but conflicting evidence has been presented as well.

  The <scp>APOE </scp><b>ε</b>4 allele in relation to brain white‐matter microstructure in adulthood and aging · 2014 · DOI

• Despite the importance of white matter connections for proper brain function, little is known about how these connections, and the deep gray matter structures that act as relay stations, are affected in children with FASD.

  Brain Diffusion Abnormalities in Children With Fetal Alcohol Spectrum Disorder · 2008 · DOI

• Exposure to adverse childhood experiences (ACEs) can have physiological effects that may alter how the brain responds to injury, yet the effects of ACEs on white matter injury and recovery processes remain unclear.

  Longitudinal White Matter Changes in Concussed Adolescents with Adverse Childhood Experiences · 2026 · DOI

• Non-motor symptoms in Parkinson's disease impair quality of life, yet their neural basis is unclear, the link between amygdala subregion fiber properties and these symptoms remains unexplored.

  Association between amygdala subregions and non-motor symptoms in Parkinson’s disease: a fixel-based analysis · 2026 · DOI

• Birds evolved large, cognitively capable forebrains independently of mammals, yet comparative analyses of avian brain organization have been constrained by the lack of standardized resources capable of resolving internal parcellation and long-range connectivity across species.

  Mosaic evolution of avian brain compartments revealed by comparative MRI · 2026 · DOI

• Despite this prominence, and growing attention in the diffusion MRI field, the connectional organization of the SWM remains poorly defined.

  Connectional neuroanatomy of U-fibers in the rhesus monkey brain · 2026 · DOI

• Individuals with alcohol use disorders show white matter abnormality relative to normal samples, but differences in white matter profiles have not yet been investigated as a function of abstinence.

  Diffusion tensor imaging of white matter networks in individuals with current and remitted alcohol use disorders and comorbid conditions. · 2012 · DOI

• The details of the relationships between anatomical changes and behavioral changes, and the forces that influence brain development, have not been well established and remain a prominent goal of ongoing investigations.

  Structural Magnetic Resonance Imaging of the Adolescent Brain · 2004 · DOI

• Slice thickness or other scan parameters did not account for a substantive amount of the variance in results, whereas clinical variables of the populations studied, such as duration of illness or presence of abuse, may account for much of the discrepancy between findings.

  Lower Hippocampal Volume in Patients Suffering From Depression: A Meta-Analysis · 2004 · DOI

• CONCLUSIONS: Although the effect of major depressive disorder on amygdala volume remains to be conclusively established, inclusion of the amygdala with the hippocampus appears to have decreased the likelihood of detecting volumetric differences in either structure.

  Lower Hippocampal Volume in Patients Suffering From Depression: A Meta-Analysis · 2004 · 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
• Diffusion Tensor Imaging: A Review for Pediatric Researchers and Clinicians · Journal of Developmental & Behavioral Pediatrics · 2010 · 327 citations
• Tract‐specific analyses of diffusion tensor imaging show widespread white matter compromise in autism spectrum disorder · Journal of Child Psychology and Psychiatry · 2010 · 193 citations
• Brain Diffusion Abnormalities in Children With Fetal Alcohol Spectrum Disorder · Alcoholism Clinical and Experimental Research · 2008 · 178 citations
• Voxel-based meta-analysis of regional white-matter volume differences in autism spectrum disorder<i>versus</i>healthy controls · Psychological Medicine · 2010 · 139 citations
• Brain Microstructure Is Related to Math Ability in Children With Fetal Alcohol Spectrum Disorder · Alcoholism Clinical and Experimental Research · 2009 · 88 citations
• Disrupted White Matter Integrity in Heroin Dependence: A Controlled Study Utilizing Diffusion Tensor Imaging · The American Journal of Drug and Alcohol Abuse · 2008 · 83 citations
• Decreasing myelin density reflected increasing white matter pathology in Alzheimer's disease—a neuropathological study · International Journal of Geriatric Psychiatry · 2005 · 80 citations
• White matter integrity, substance use, and risk taking in adolescence. · Psychology of Addictive Behaviors · 2012 · 77 citations

Most recent work

• <scp>MRI</scp> 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
• 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
• White Matter Structural Biomarkers Derived from Diffusion Tensor Imaging to Estimate Upper-Extremity Motor Function in Stroke Using Machine Learning · Brain Topography · 2026
• End-to-end susceptibility-induced distortion correction for diffusion MRI with unsupervised deep learning · Pattern Recognition · 2026
• White matter fibers mediate the relationship between workload, resource use, and burnout: a new attempt to apply the conservation of resources theory to neuroscience · Brain Structure and Function · 2026
• Structural Brain Alterations Following Speed-Reading Training in Sinhala-Speaking Adults: A Voxel-Based Morphometry and Tract-Based Spatial Statistics Study · Brain and Language · 2026
• Accuracy of corticospinal tract reconstruction: DTI-based deterministic versus probabilistic tractography with intraoperative validation · Frontiers in Oncology · 2026
• 471. White Matter Microstructural Correlates of Neuroticism in Major Depression: A Longitudinal Diffusion Tensor Imaging Study · Biological Psychiatry · 2026

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