S139. PROGRESSIVE DETERIORATION OF WHITE MATTER TRACTS IN SCHIZOPHRENIA: A DIFFUSION MRI STUDY ON A LARGE SINGLE COHORT USING NORMATIVE MODELS

Abstract Background Current diffusion MRI studies of schizophrenia are limited by methodology and sample size. With normative models and the largest single-site cohort, we aimed to delineate a comprehensive profile of tract alteration in unaffected siblings, first-episode schizophrenia (FES), and chronic schizophrenia. Methods A total of 277 patients with schizophrenia, 81 unaffected siblings, and 1023 healthy people underwent diffusion-weighted imaging on the same 3T scanner. Generalized fractional anisotropy (GFA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), were sampled along 45 major neural tracts. A normative model was built from the images of 1023 healthy people; Z scores represented the normalized deviation of the index value from that of the age- and sex-matched healthy population. Results Widespread involvement of neural tracts was found in patients with FES, and the tracts connecting the prefrontal lobe were the most severely affected. In patients with chronic schizophrenia, virtually all neural tracts were altered, with the tracts connecting the sensorimotor cortex the least affected. A significant negative correlation was observed between GFA alterations and the duration of illness. In unaffected siblings, scattered tracts were involved in GFA, but not in MD or RD. Discussion The study revealed widespread white matter involvement in the early stages of schizophrenia. The alteration continues to progress from the neural tracts connecting the prefrontal lobe to the entire brain. Compared to a large sample of normal controls, the attenuated peak and rapid decline of white matter GFA across the lifespan suggest that schizophrenia is associated with neurodevelopmental and neurodegenerative abnormalities of white matter.

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White-matter free-water diffusion MRI in schizophrenia: a systematic review and meta-analysis

Neuropsychopharmacology ◽

10.1038/s41386-022-01272-x ◽

2022 ◽

Author(s):

Inês Carreira Figueiredo ◽

Faith Borgan ◽

Ofer Pasternak ◽

Federico E. Turkheimer ◽

Oliver D. Howes

Keyword(s):

White Matter ◽

Healthy Volunteers ◽

Diffusion Mri ◽

Clinical Symptoms ◽

Free Water ◽

Brain Regions ◽

Water Levels ◽

First Episode ◽

Whole Brain ◽

Illness Duration

AbstractWhite-matter abnormalities, including increases in extracellular free-water, are implicated in the pathophysiology of schizophrenia. Recent advances in diffusion magnetic resonance imaging (MRI) enable free-water levels to be indexed. However, the brain levels in patients with schizophrenia have not yet been systematically investigated. We aimed to meta-analyse white-matter free-water levels in patients with schizophrenia compared to healthy volunteers. We performed a literature search in EMBASE, MEDLINE, and PsycINFO databases. Diffusion MRI studies reporting free-water in patients with schizophrenia compared to healthy controls were included. We investigated the effect of demographic variables, illness duration, chlorpromazine equivalents of antipsychotic medication, type of scanner, and clinical symptoms severity on free-water measures. Ten studies, including five of first episode of psychosis have investigated free-water levels in schizophrenia, with significantly higher levels reported in whole-brain and specific brain regions (including corona radiata, internal capsule, superior and inferior longitudinal fasciculus, cingulum bundle, and corpus callosum). Six studies, including a total of 614 participants met the inclusion criteria for quantitative analysis. Whole-brain free-water levels were significantly higher in patients relative to healthy volunteers (Hedge’s g = 0.38, 95% confidence interval (CI) 0.07–0.69, p = 0.02). Sex moderated this effect, such that smaller effects were seen in samples with more females (z = −2.54, p < 0.05), but antipsychotic dose, illness duration and symptom severity did not. Patients with schizophrenia have increased free-water compared to healthy volunteers. Future studies are necessary to determine the pathological sources of increased free-water, and its relationship with illness duration and severity.

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The extent of diffusion MRI markers of neuroinflammation and white matter deterioration in chronic schizophrenia

Schizophrenia Research ◽

10.1016/j.schres.2014.07.031 ◽

2015 ◽

Vol 161 (1) ◽

pp. 113-118 ◽

Cited By ~ 60

Author(s):

Ofer Pasternak ◽

Carl-Fredrik Westin ◽

Brian Dahlben ◽

Sylvain Bouix ◽

Marek Kubicki

Keyword(s):

White Matter ◽

Diffusion Mri ◽

Chronic Schizophrenia

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Perivascular space fluid contributes to diffusion tensor imaging changes in white matter

10.1101/395012 ◽

2018 ◽

Cited By ~ 3

Author(s):

Farshid Sepehrband ◽

Ryan P Cabeen ◽

Jeiran Choupan ◽

Giuseppe Barisano ◽

Meng Law ◽

...

Keyword(s):

Diffusion Tensor Imaging ◽

White Matter ◽

Fractional Anisotropy ◽

Diffusion Mri ◽

Diffusion Tensor ◽

Diffusion Imaging ◽

Mean Diffusivity ◽

Brain Parenchyma ◽

Perivascular Space ◽

List Type

AbstractDiffusion tensor imaging (DTI) has been extensively used to map changes in brain tissue related to neurological disorders. Among the most widespread DTI findings are increased mean diffusivity and decreased fractional anisotropy of white matter tissue in neurodegenerative diseases. Here we utilize multi-shell diffusion imaging to separate diffusion signal of the brain parenchyma from fluid within the white matter. We show that unincorporated anisotropic water in perivascular space (PVS) significantly, and systematically, biases DTI measures, casting new light on the biological validity of many previously reported findings. Despite the challenge this poses for interpreting these past findings, our results suggest that multi-shell diffusion MRI provides a new opportunity for incorporating the PVS contribution, ultimately strengthening the clinical and scientific value of diffusion MRI.HighlightsPerivascular space (PVS) fluid significantly contributes to diffusion tensor imaging metricsIncreased PVS fluid results in increased mean diffusivity and decreased fractional anisotropyPVS contribution to diffusion signal is overlooked and demands further investigation

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Diffusion MRI Captures White Matter Microstructure Alterations in PRKN Disease

Journal of Parkinson s Disease ◽

10.3233/jpd-202495 ◽

2021 ◽

pp. 1-15

Author(s):

Takahiro Koinuma ◽

Taku Hatano ◽

Koji Kamagata ◽

Christina Andica ◽

Akio Mori ◽

...

Keyword(s):

Oxidative Stress ◽

White Matter ◽

Diffusion Mri ◽

Disease Duration ◽

Diffusion Tensor ◽

Neuronal Degeneration ◽

Mean Diffusivity ◽

B Value ◽

Oxidative Stress Marker ◽

Systemic Oxidative Stress

Background: Although pathological studies usually indicate pure dopaminergic neuronal degeneration in patients with parkin (PRKN) mutations, there is no evidence to date regarding white matter (WM) pathology. A previous diffusion MRI study has revealed WM microstructural alterations caused by systemic oxidative stress in idiopathic Parkinson’s disease (PD), and we found that PRKN patients have systemic oxidative stress in serum biomarker studies. Thus, we hypothesized that PRKN mutations might lead to WM abnormalities. Objective: To investigate whether there are WM microstructural abnormalities in early-onset PD patients with PRKN mutations using diffusion tensor imaging (DTI). Methods: Nine PRKN patients and 19 age- and sex-matched healthy controls were recruited. DTI measures were acquired on a 3T MR scanner using a b value of 1,000 s/mm2 along 32 isotropic diffusion gradients. The DTI measures were compared between groups using tract-based spatial statistics (TBSS) analysis. Correlation analysis was also performed between the DTI parameters and several serum oxidative stress markers obtained in a previously conducted metabolomic analysis. Results: Although the WM volumes were not significantly different, the TBSS analysis revealed a corresponding decrease in fractional anisotropy and an increase in mean diffusivity and radial diffusivity in WM areas, such as the anterior and superior corona radiata and uncinate fasciculus, in PRKN patients compared with controls. Furthermore, 9-hydroxystearate, an oxidative stress marker, and disease duration were positively correlated with several parameters in PRKN patients. Conclusion: This pilot study suggests that WM microstructural impairments occur in PRKN patients and are associated with disease duration and oxidative stress.

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Structural and functional brain changes following four weeks of unimanual motor training: evidence from fMRI-guided diffusion MRI tractography

10.1101/088328 ◽

2016 ◽

Author(s):

Lee B Reid ◽

Martin V Sale ◽

Ross Cunnington ◽

Jason B Mattingley ◽

Stephen E Rose

Keyword(s):

White Matter ◽

Caudate Nucleus ◽

Fractional Anisotropy ◽

Diffusion Mri ◽

Mean Diffusivity ◽

Region Of Interest ◽

Motor Training ◽

Left Hand ◽

Dorsolateral Prefrontal ◽

The Right

AbstractWe have reported reliable changes in behaviour, brain structure and function in 24 healthy right-handed adults who practiced a finger-thumb opposition sequence task with their left hand for 10 mins daily, over four weeks. Here we extend these findings by employing diffusion MRI to investigate white-matter changes in the corticospinal tract, basal-ganglia, and connections of the dorsolateral prefrontal cortex. Twenty-three participant datasets were available with pre-training and post-training scans. Task performance improved in all participants (mean: 52.8%, SD: 20.0%; group p<0.01 FWE) and widespread microstructural changes were detected across the motor system of the ‘trained’ hemisphere. Specifically, region-of-interest based analyses of diffusion MRI (n=21) revealed significantly increased fractional anisotropy in the right caudate nucleus (4.9%; p<0.05 FWE), and decreased mean diffusivity in the left nucleus accumbens (-1.3%; p<0.05 FWE). Diffusion MRI tractography (n=22), seeded by sensorimotor cortex fMRI activation, also revealed increased fractional anisotropy in the right corticomotor tract (mean 3.28%; p<0.05 FWE) predominantly reflecting decreased radial diffusivity. These changes were consistent throughout the entire length of the tract. The left corticomotor tract did not show any changes. FA also increased in white matter connections between the right middle frontal gyrus and both right caudate nucleus (17/22 participants; p<0.05 FWE) and right supplementary motor area (18/22 participants; p<0.05 FWE). Equivalent changes in FA were not seen in the left (‘non-trained’) hemisphere. In combination with our functional and structural findings, this study provides detailed, multifocal evidence for widespread neuroplastic changes in the human brain resulting from motor training.

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Diffusion MRI Changes in the Healthy Aging Canine Brain

10.1101/2020.10.05.327205 ◽

2020 ◽

Author(s):

Erica F. Barry ◽

John P. Loftus ◽

Wen-Ming Luh ◽

Mony J. de Leon ◽

Sumit N. Niogi ◽

...

Keyword(s):

White Matter ◽

Diffusion Mri ◽

Healthy Aging ◽

Parietal Lobe ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

Human Aging ◽

Age Related ◽

Age Related Changes

AbstractWhite matter dysfunction and degeneration have been a topic of great interest in healthy and pathological aging. While ex vivo studies have investigated age-related changes in canines, little in vivo canine aging research exists. Quantitative diffusion MRI such as diffusion tensor imaging (DTI) has demonstrated aging and neurodegenerative white matter changes in humans. However, this method has not been applied and adapted in vivo to canine populations. This study aimed to test the hypothesis that white matter diffusion changes frequently reported in human aging are also found in aged canines. The study used Tract Based Spatial Statistics (TBSS) and a region of interest (ROI) approach to investigate age related changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AxD) and radial diffusivity (RD). The results show that, compared to younger animals, aged canines have significant decreases in FA in parietal and temporal regions as well as the corpus callosum and fornix. Additionally, AxD decreases were observed in parietal, frontal and midbrain regions. Similarly, an age-related increase in RD was observed in the right parietal lobe while MD decreases were found in the midbrain. These findings suggest that canine samples offer a model for healthy human aging as they exhibit similar white matter diffusion tensor changes with age.

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Loss and Reorganisation of Superficial White Matter in Alzheimer's disease: A Diffusion MRI study

10.1101/2021.05.07.21256728 ◽

2021 ◽

Author(s):

Thomas Veale ◽

Ian B Malone ◽

Teresa Poole ◽

Thomas D Parker ◽

Catherine F Slattery ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

White Matter ◽

Fractional Anisotropy ◽

Diffusion Mri ◽

Grey Matter ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

Young Onset ◽

Neurite Density

Pathological involvement of cerebral white matter in Alzheimer's disease has been shown using diffusion tensor imaging. Superficial white matter (SWM) changes have been relatively understudied despite their importance in cortico-cortical connections. Measuring SWM degeneration using diffusion tensor imaging is challenging due to its complex structure and proximity to the cortex. To overcome this we investigated diffusion MRI changes in young-onset Alzheimer's disease using standard diffusion tensor imaging and Neurite Orientation Dispersion and Density Imaging to distinguish between disease-related changes that are due to degeneration (e.g. loss of myelinated fibres) and those due to reorganisation (e.g. increased fibre dispersion). Twenty-nine young-onset Alzheimer's disease patients and 22 healthy controls had both single-shell and multi-shell diffusion MRI. We calculated fractional anisotropy, mean diffusivity, neurite density index, orientation dispersion index and tissue fraction (1-free water fraction). Diffusion metrics were sampled in 15 a priori regions of interest at four points along the cortical profile: cortical grey matter, the grey/white boundary, SWM (1mm below grey/white boundary) and SWM/deeper white matter (2mm below grey/white boundary). To estimate cross-sectional group differences, we used average marginal effects from linear mixed effect models of participants' diffusion metrics along the cortical profile. The SWM of young-onset Alzheimer's disease individuals had lower neurite density index compared to controls in five regions (superior and inferior parietal, precuneus, entorhinal and parahippocampus) (all P<0.05), and higher orientation dispersion index in three regions (fusiform, entorhinal and parahippocampus) (all P<0.05). Young-onset Alzheimer's disease individuals had lower fractional anisotropy in the SWM of two regions (entorhinal and parahippocampus) (both P<0.05) and higher fractional anisotropy within the postcentral region (P<0.05). Mean diffusivity in SWM was higher in the young-onset Alzheimer's disease group in the parahippocampal region (P<0.05) and lower in three regions (postcentral, precentral and superior temporal) (all P<0.05). In the overlying grey matter, disease-related changes were largely consistent with SWM findings when using neurite density index and fractional anisotropy, but appeared at odds with orientation dispersion and mean diffusivity SWM changes. Tissue fraction was significantly lower across all grey matter regions in young-onset Alzheimer's disease individuals (all P<0.001) but group differences reduced in magnitude and coverage when moving towards the SWM. These results show that microstructural changes occur within SWM and along the cortical profile in individuals with young-onset Alzheimer's disease. Lower neurite density and higher orientation dispersion suggests underlying SWM fibres undergo neurodegeneration and reorganisation, two effects previously indiscernible using standard diffusion tensor metrics in SWM.

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Neurobiological underpinnings of rapid white matter plasticity during intensive reading instruction

10.1101/2020.05.28.122499 ◽

2020 ◽

Author(s):

Elizabeth Huber ◽

Aviv Mezer ◽

Jason D. Yeatman

Keyword(s):

White Matter ◽

Reading Instruction ◽

Diffusion Mri ◽

Large Scale ◽

Mean Diffusivity ◽

Quantitative Mri ◽

Diffusion Kurtosis Imaging ◽

Control Group ◽

Intensive Reading ◽

Diffusion Kurtosis

AbstractHuman white matter is remarkably plastic. Yet it is challenging to infer the biological underpinnings of this plasticity using non-invasive measurements like diffusion MRI. Here we capitalize on metrics derived from diffusion kurtosis imaging (DKI) to interpret previously reported changes in mean diffusivity throughout the white matter during an 8-week, intensive reading intervention. We then use an independent quantitative MRI measurement of R1 (1/T1 relaxation time) in the same white matter regions; since R1 closely tracks variation in myelin content, it provides complementary information about white matter microstructure. Behavioral measures, multi-shell diffusion MRI data, and quantitative T1 data were collected at regular intervals during the intervention in a group of 33 children with reading difficulties (7-12 years old), and over the same period in an age-matched non-intervention control group. Changes in DKI parameters modeled over the intervention were consistent with increased hindrance in the extra-axonal space, rather than a large-scale change in axon density and/or myelination. Supporting this interpretation, analysis of R1 values did not suggest a change in myelin, although R1 estimates were correlated with individual differences in reading skill. Together, these results suggest that large-scale changes in diffusivity observed over a short timescale during an intensive educational experience are most likely to reflect changes occurring in the extra-axonal space, in line with recent work highlighting the role of glial cells in experience-dependent plasticity and learning.

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The role of the fornix in human navigational learning

10.1101/391888 ◽

2018 ◽

Author(s):

Carl J. Hodgetts ◽

Martina Stefani ◽

Angharad N. Williams ◽

Branden S. Kolarik ◽

Andrew P. Yonelinas ◽

...

Keyword(s):

White Matter ◽

Spatial Learning ◽

Diffusion Mri ◽

Animal Studies ◽

Mean Diffusivity ◽

Hippocampal Volume ◽

Learning Rate ◽

High Angular Resolution ◽

Thalamic Nuclei ◽

Navigational Learning

AbstractStudies in rodents have demonstrated that transecting the white matter pathway linking the hippocampus and anterior thalamic nuclei - the fornix - impairs flexible navigational learning in the Morris Water Maze (MWM), as well as similar spatial learning tasks. While diffusion MRI studies in humans have linked fornix microstructure to scene discrimination and memory, its role in human navigation is currently unknown. We used high-angular resolution diffusion MRI to ask whether inter-individual differences in fornix microstructure would be associated with spatial learning in a virtual MWM task. To increase sensitivity to individual learning across trials, we adopted a novel curve fitting approach to estimate a single index of learning rate. We found a significant correlation between learning rate and the microstructure (mean diffusivity) of the fornix, but not that of a control tract linking occipital and anterior temporal cortices (the inferior longitudinal fasciculus, ILF). Further, this correlation remained significant when controlling for hippocampal volume. These findings extend previous animal studies by demonstrating the functional relevance of the fornix for human navigational learning, and highlight the importance of a distributed neuroanatomical network, underpinned by key white matter pathways, such as the fornix, in complex spatial behaviour.

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Functional and diffusion MRI reveal the functional and structural basis of infants’ noxious-evoked brain activity

10.1101/2020.04.28.065730 ◽

2020 ◽

Author(s):

Luke Baxter ◽

Fiona Moultrie ◽

Sean Fitzgibbon ◽

Marianne Aspbury ◽

Roshni Mansfield ◽

...

Keyword(s):

White Matter ◽

Pain Management ◽

Resting State ◽

Diffusion Mri ◽

Brain Activity ◽

Mean Diffusivity ◽

Structural Basis ◽

Noxious Stimulation ◽

State Activity ◽

Human Connectome Project

AbstractUnderstanding the neurophysiology underlying pain perception in infants is central to improving early life pain management. In this multimodal MRI study, we use resting-state functional and white matter diffusion MRI to investigate individual variability in infants’ noxious-evoked brain activity. In an 18-infant nociception-paradigm dataset, we show it is possible to predict infants’ cerebral haemodynamic responses to experimental noxious stimulation using their resting-state activity across nine networks from a separate stimulus-free scan. In an independent 215-infant Developing Human Connectome Project dataset, we use this resting-state-based prediction model to generate noxious responses. We identify a significant correlation between these predicted noxious responses and infants’ white matter mean diffusivity, and this relationship is subsequently confirmed within our nociception-paradigm dataset. These findings reveal that a newborn infant’s pain-related brain activity is tightly coupled to both their spontaneous resting-state activity and underlying white matter microstructure. This work provides proof-of-concept that knowledge of an infant’s functional and structural brain architecture could be used to predict pain responses, informing infant pain management strategies and facilitating evidence-based personalisation of care.

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