Brabec J, Friedjungová M, Vašata D, Englund E, Bengzon J, Knutsson L, Szczepankiewicz F, van Westen D, Sundgren PC, Nilsson M. Meningioma Microstructure Assessed by Diffusion MRI: An Investigation of the Source of Mean Diffusivity and Fractional Anisotropy by Quantitative Histology. NeuroImage Clin. 2023;37:103365.

BACKGROUND: Mean diffusivity (MD) and fractional anisotropy (FA) from diffusion MRI (dMRI) have been associated with cell density and tissue anisotropy across tumors, but it is unknown whether these associations persist at the microscopic level.

PURPOSE: To quantify the degree to which cell density and anisotropy, as determined from histology, account for the intra-tumor variability of MD and FA in meningioma tumors. Furthermore, to clarify whether other histological features account for additional intra-tumor variability of dMRI parameters.

MATERIALS AND METHODS: We performed ex-vivo dMRI at 200 μm isotropic resolution and histological imaging of 16 excised meningioma tumor samples. Diffusion tensor imaging (DTI) was used to map MD and FA, as well as the in-plane FA (FAIP). Histology images were analyzed in terms of cell nuclei density (CD) and structure anisotropy (SA; obtained from structure tensor analysis) and were used separately in a regression analysis to predict MD and FAIP, respectively. A convolutional neural network (CNN) was also trained to predict the dMRI parameters from histology patches. The association between MRI and histology was analyzed in terms of out-of-sample (R2OS) on the intra-tumor level and within-sample R2 across tumors. Regions where the dMRI parameters were poorly predicted from histology were analyzed to identify features apart from CD and SA that could influence MD and FAIP, respectively.

RESULTS: Cell density assessed by histology poorly explained intra-tumor variability of MD at the mesoscopic level (200 μm), as median R2OS = 0.04 (interquartile range 0.01-0.26). Structure anisotropy explained more of the variation in FAIP (median R2OS = 0.31, 0.20-0.42). Samples with low R2OS for FAIP exhibited low variations throughout the samples and thus low explainable variability, however, this was not the case for MD. Across tumors, CD and SA were clearly associated with MD (R2 = 0.60) and FAIP (R2 = 0.81), respectively. In 37% of the samples (6 out of 16), cell density did not explain intra-tumor variability of MD when compared to the degree explained by the CNN. Tumor vascularization, psammoma bodies, microcysts, and tissue cohesivity were associated with bias in MD prediction based solely on CD. Our results support that FAIP is high in the presence of elongated and aligned cell structures, but low otherwise.

CONCLUSION: Cell density and structure anisotropy account for variability in MD and FAIP across tumors but cell density does not explain MD variations within the tumor, which means that low or high values of MD locally may not always reflect high or low tumor cell density. Features beyond cell density need to be considered when interpreting MD.

Tregidgo HFJ, Soskic S, Althonayan J, Maffei C, Van Leemput K, Golland P, Insausti R, Lerma-Usabiaga G, Caballero-Gaudes C, Paz-Alonso PM, Yendiki A, Alexander DC, Bocchetta M, Rohrer JD, Iglesias JE, Initiative A's DN. Accurate Bayesian segmentation of thalamic nuclei using diffusion MRI and an improved histological atlas. NeuroImage 2023;274:120129.

The human thalamus is a highly connected brain structure, which is key for the control of numerous functions and is involved in several neurological disorders. Recently, neuroimaging studies have increasingly focused on the volume and connectivity of the specific nuclei comprising this structure, rather than looking at the thalamus as a whole. However, accurate identification of cytoarchitectonically designed histological nuclei on standard in vivo structural MRI is hampered by the lack of image contrast that can be used to distinguish nuclei from each other and from surrounding white matter tracts. While diffusion MRI may offer such contrast, it has lower resolution and lacks some boundaries visible in structural imaging. In this work, we present a Bayesian segmentation algorithm for the thalamus. This algorithm combines prior information from a probabilistic atlas with likelihood models for both structural and diffusion MRI, allowing segmentation of 25 thalamic labels per hemisphere informed by both modalities. We present an improved probabilistic atlas, incorporating thalamic nuclei identified from histology and 45 white matter tracts surrounding the thalamus identified in ultra-high gradient strength diffusion imaging. We present a family of likelihood models for diffusion tensor imaging, ensuring compatibility with the vast majority of neuroimaging datasets that include diffusion MRI data. The use of these diffusion likelihood models greatly improves identification of nuclear groups versus segmentation based solely on structural MRI. Dice comparison of 5 manually identifiable groups of nuclei to ground truth segmentations show improvements of up to 10 percentage points. Additionally, our chosen model shows a high degree of reliability, with median test-retest Dice scores above 0.85 for four out of five nuclei groups, whilst also offering improved detection of differential thalamic involvement in Alzheimer's disease (AUROC 81.98%). The probabilistic atlas and segmentation tool will be made publicly available as part of the neuroimaging package FreeSurfer (


Xu J, Moyer D, Grant E, Golland P, Iglesias JE, Adalsteinsson E. SVoRT: Iterative Transformer for Slice-to-Volume Registration in Fetal Brain MRI. Medical image computing and computer-assisted intervention : MICCAI .. International Conference on Medical Image Computing and Computer-Assisted Intervention 2022;13436:3-13.

Volumetric reconstruction of fetal brains from multiple stacks of MR slices, acquired in the presence of almost unpredictable and often severe subject motion, is a challenging task that is highly sensitive to the initialization of slice-to-volume transformations. We propose a novel slice-to-volume registration method using Transformers trained on synthetically transformed data, which model multiple stacks of MR slices as a sequence. With the attention mechanism, our model automatically detects the relevance between slices and predicts the transformation of one slice using information from other slices. We also estimate the underlying 3D volume to assist slice-to-volume registration and update the volume and transformations alternately to improve accuracy. Results on synthetic data show that our method achieves lower registration error and better reconstruction quality compared with existing state-of-the-art methods. Experiments with real-world MRI data are also performed to demonstrate the ability of the proposed model to improve the quality of 3D reconstruction under severe fetal motion.

Zekelman LR, Zhang F, Makris N, He J, Chen Y, Xue T, Liera D, Drane DL, Rathi Y, Golby AJ, Donnell LJO. White Matter Association Tracts Underlying Language and Theory of Mind: An Investigation of 809 Brains from the Human Connectome Project. Neuroimage 2022;246:118739.

Language and theory of mind (ToM) are the cognitive capacities that allow for the successful interpretation and expression of meaning. While functional MRI investigations are able to consistently localize language and ToM to specific cortical regions, diffusion MRI investigations point to an inconsistent and sometimes overlapping set of white matter tracts associated with these two cognitive domains. To further examine the white matter tracts that may underlie these domains, we use a two-tensor tractography method to investigate the white matter microstructure of 809 participants from the Human Connectome Project. 20 association white matter tracts (10 in each hemisphere) are uniquely identified by leveraging a neuroanatomist-curated automated white matter tract atlas. The mean fractional anisotropy (FA), mean diffusivity (MD), and number of streamlines (NoS) are measured for each white matter tract. Performance on neuropsychological assessments of semantic memory (NIH Toolbox Picture Vocabulary Test, TPVT) and emotion perception (Penn Emotion Recognition Test, PERT) are used to measure critical subcomponents of the language and ToM networks, respectively. Regression models are constructed to examine how structural measurements of left and right white matter tracts influence performance across these two assessments. We find that semantic memory performance is influenced by the number of streamlines of the left superior longitudinal fasciculus III (SLF-III), and emotion perception performance is influenced by the number of streamlines of the right SLF-III. Additionally, we find that performance on both semantic memory & emotion perception is influenced by the FA of the left arcuate fasciculus (AF). The results point to multiple, overlapping white matter tracts that underlie the cognitive domains of language and ToM. Results are discussed in terms of hemispheric dominance and concordance with prior investigations.

Robles DJ, Dharani A, Rostowsky KA, Chaudhari NN, Ngo V, Zhang F, Donnell LJO, Green L, Sheikh-Bahaei N, Chui HC, Irimia A. Older Age, Male Sex, and Cerebral Microbleeds Predict White Matter Loss After Traumatic Brain Injury. Geroscience 2022;44(1):83-102.

Little is known on how mild traumatic brain injury affects white matter based on age at injury, sex, cerebral microbleeds, and time since injury. Here, we study the fractional anisotropy of white matter to study these effects in 109 participants aged 18-77 (46 females, age μ ± σ = 40 ± 17 years) imaged within [Formula: see text] 1 week and [Formula: see text] 6 months post-injury. Age is found to be linearly associated with white matter degradation, likely due not only to injury but also to cumulative effects of other pathologies and to their interactions with injury. Age is associated with mean anisotropy decreases in the corpus callosum, middle longitudinal fasciculi, inferior longitudinal and occipitofrontal fasciculi, and superficial frontal and temporal fasciculi. Over [Formula: see text] 6 months, the mean anisotropies of the corpus callosum, left superficial frontal fasciculi, and left corticospinal tract decrease significantly. Independently of other predictors, age and cerebral microbleeds contribute to anisotropy decrease in the callosal genu. Chronically, the white matter of commissural tracts, left superficial frontal fasciculi, and left corticospinal tract degrade appreciably, independently of other predictors. Our findings suggest that large commissural and intra-hemispheric structures are at high risk for post-traumatic degradation. This study identifies detailed neuroanatomic substrates consistent with brain injury patients’ age-dependent deficits in information processing speed, interhemispheric communication, motor coordination, visual acuity, sensory integration, reading speed/comprehension, executive function, personality, and memory. We also identify neuroanatomic features underlying white matter degradation whose severity is associated with the male sex. Future studies should compare our findings to functional measures and other neurodegenerative processes.

Gagoski B, Xu J, Wighton P, Tisdall D, Frost R, Lo W-C, Golland P, van der Kouwe A, Adalsteinsson E, Grant E. Automated Detection and Reacquisition of Motion-degraded Images in Fetal HASTE Imaging at 3T. Magn Reson Med 2022;87(4):1914-22.

PURPOSE: Fetal brain Magnetic Resonance Imaging suffers from unpredictable and unconstrained fetal motion that causes severe image artifacts even with half-Fourier single-shot fast spin echo (HASTE) readouts. This work presents the implementation of a closed-loop pipeline that automatically detects and reacquires HASTE images that were degraded by fetal motion without any human interaction. METHODS: A convolutional neural network that performs automatic image quality assessment (IQA) was run on an external GPU-equipped computer that was connected to the internal network of the MRI scanner. The modified HASTE pulse sequence sent each image to the external computer, where the IQA convolutional neural network evaluated it, and then the IQA score was sent back to the sequence. At the end of the HASTE stack, the IQA scores from all the slices were sorted, and only slices with the lowest scores (corresponding to the slices with worst image quality) were reacquired. RESULTS: The closed-loop HASTE acquisition framework was tested on 10 pregnant mothers, for a total of 73 acquisitions of our modified HASTE sequence. The IQA convolutional neural network, which was successfully employed by our modified sequence in real time, achieved an accuracy of 85.2% and area under the receiver operator characteristic of 0.899. CONCLUSION: The proposed acquisition/reconstruction pipeline was shown to successfully identify and automatically reacquire only the motion degraded fetal brain HASTE slices in the prescribed stack. This minimizes the overall time spent on HASTE acquisitions by avoiding the need to repeat the entire stack if only few slices in the stack are motion-degraded.

Brabec J, Szczepankiewicz F, Lennartsson F, Englund E, Pebdani H, Bengzon J, Knutsson L, Westin C-F, Sundgren PC, Nilsson M. Histogram Analysis of Tensor-Valued Diffusion MRI in Meningiomas: Relation to Consistency, Histological Grade and Type. Neuroimage Clin 2022;33:102912.

BACKGROUND: Preoperative radiological assessment of meningioma characteristics is of value for pre- and post-operative patient management, counselling, and surgical approach. PURPOSE: To investigate whether tensor-valued diffusion MRI can add to the preoperative prediction of meningioma consistency, grade and type. MATERIALS AND METHODS: 30 patients with intracranial meningiomas (22 WHO grade I, 8 WHO grade II) underwent MRI prior to surgery. Diffusion MRI was performed with linear and spherical b-tensors with b-values up to 2000 s/mm2. The data were used to estimate mean diffusivity (MD), fractional anisotropy (FA), mean kurtosis (MK) and its components-the anisotropic and isotropic kurtoses (MKA and MKI). Meningioma consistency was estimated for 16 patients during resection based on ultrasonic aspiration intensity, ease of resection with instrumentation or suction. Grade and type were determined by histopathological analysis. The relation between consistency, grade and type and dMRI parameters was analyzed inside the tumor ("whole-tumor") and within brain tissue in the immediate periphery outside the tumor ("rim") by histogram analysis. RESULTS: Lower 10th percentiles of MK and MKA in the whole-tumor were associated with firm consistency compared with pooled soft and variable consistency (n = 7 vs 9; U test, p = 0.02 for MKA 10 and p = 0.04 for MK10) and lower 10th percentile of MD with variable against soft and firm (n = 5 vs 11; U test, p = 0.02). Higher standard deviation of MKI in the rim was associated with lower grade (n = 22 vs 8; U test, p = 0.04) and in the MKI maps we observed elevated rim-like structure that could be associated with grade. Higher median MKA and lower median MKI distinguished psammomatous type from other pooled meningioma types (n = 5 vs 25; U test; p = 0.03 for MKA 50 and p = 0.03 and p = 0.04 for MKI 50). CONCLUSION: Parameters from tensor-valued dMRI can facilitate prediction of consistency, grade and type.

Ji Y, Hoge S, Gagoski B, Westin C-F, Rathi Y, Ning L. Accelerating Joint Relaxation-Diffusion MRI by Integrating Time Division Multiplexing and Simultaneous Multi-Slice (TDM-SMS) Strategies. Magn Reson Med 2022;87(6):2697-709.

PURPOSE: To accelerate the acquisition of relaxation-diffusion imaging by integrating time-division multiplexing (TDM) with simultaneous multi-slice (SMS) for EPI and evaluate imaging quality and diffusion measures. METHODS: The time-division multiplexing (TDM) technique and SMS method were integrated to achieve a high slice-acceleration (e.g., 6×) factor for acquiring relaxation-diffusion MRI. Two variants of the sequence, referred to as TDM3e-SMS and TDM2s-SMS, were developed to simultaneously acquire slice groups with three distinct TEs and two slice groups with the same TE, respectively. Both sequences were evaluated on a 3T scanner with in vivo human brains and compared with standard single-band (SB) -EPI and SMS-EPI using diffusion measures and tractography results. RESULTS: Experimental results showed that the TDM3e-SMS sequence with total slice acceleration of 6 (multiplexing factor (MP) = 3 × multi-band factor (MB) = 2) provided similar image intensity and microstructure measures compared to standard SMS-EPI with MB = 2, and yielded less bias in intensity compared to standard SMS-EPI with MB = 4. The three sequences showed a similar positive correlation between TE and mean kurtosis (MK) and a negative correlation between TE and mean diffusivity (MD) in white matter. Multi-fiber tractography also shows consistency of results in TE-dependent measures between different sequences. The TDM2s-SMS sequence (MP = 2, MB = 2) also provided imaging measures similar to standard SMS-EPI sequences (MB = 2) for single-TE diffusion imaging. CONCLUSIONS: The TDM-SMS sequence can provide additional 2x to 3x acceleration to SMS without degrading imaging quality. With the significant reduction in scan time, TDM-SMS makes joint relaxation-diffusion MRI a feasible technique in neuroimaging research to investigate new markers of brain disorders.

Zhang F, Daducci A, He Y, Schiavi S, Seguin C, Smith RE, Yeh C-H, Zhao T, Donnell LJO. Quantitative Mapping of the Brain’s Structural Connectivity Using Diffusion MRI Tractography: A Review. Neuroimage 2022;249:118870.

Diffusion magnetic resonance imaging (dMRI) tractography is an advanced imaging technique that enables in vivo reconstruction of the brain’s white matter connections at macro scale. It provides an important tool for quantitative mapping of the brain’s structural connectivity using measures of connectivity or tissue microstructure. Over the last two decades, the study of brain connectivity using dMRI tractography has played a prominent role in the neuroimaging research landscape. In this paper, we provide a high-level overview of how tractography is used to enable quantitative analysis of the brain’s structural connectivity in health and disease. We focus on two types of quantitative analyses of tractography, including: 1) tract-specific analysis that refers to research that is typically hypothesis-driven and studies particular anatomical fiber tracts, and 2) connectome-based analysis that refers to research that is more data-driven and generally studies the structural connectivity of the entire brain. We first provide a review of methodology involved in three main processing steps that are common across most approaches for quantitative analysis of tractography, including methods for tractography correction, segmentation and quantification. For each step, we aim to describe methodological choices, their popularity, and potential pros and cons. We then review studies that have used quantitative tractography approaches to study the brain’s white matter, focusing on applications in neurodevelopment, aging, neurological disorders, mental disorders, and neurosurgery. We conclude that, while there have been considerable advancements in methodological technologies and breadth of applications, there nevertheless remains no consensus about the "best" methodology in quantitative analysis of tractography, and researchers should remain cautious when interpreting results in research and clinical applications.