Longitudinal evolution of diffusion metrics after left hemisphere ischaemic stroke.

White matter is often severely affected after human ischaemic stroke. While animal studies have suggested that various factors may contribute to white matter structural damage after ischaemic stroke, the characterization of damaging processes to the affected hemisphere after human stroke remains poorly understood. Thus, the present study aims to thoroughly describe the longitudinal pattern of evolution of diffusion magnetic resonance imaging metrics in different parts of the ipsilesional white matter after stroke. We acquired diffusion and anatomical images in 17 patients who had suffered from a single left hemisphere ischaemic stroke, at 24-72 h, 8-14 days and 6 months post-stroke. For each patient, we created three regions of interest: (i) the white matter lesion; (ii) the perilesional white matter; and (iii) the remaining white matter of the left hemisphere. We extracted diffusion metrics (fractional anisotropy, mean, axial and radial diffusivities) for each region and conducted two-way repeated measures ANOVAs with stage post-stroke (acute, subacute and chronic) × regions of interest (white matter lesion, perilesional white matter and remaining white matter). Fractional anisotropy values stayed consistent across time-points, with significantly lower values in the white matter lesion compared to the perilesional white matter and remaining white matter tissue. Fractional anisotropy values of the perilesional white matter were also significantly lower than that of the remaining white matter. Mean, axial and radial diffusivities in the white matter lesion were all decreased in the acute stage compared to perilesional white matter and remaining white matter, but significantly increased in both the subacute and chronic stages. Significant increases in mean and radial diffusivities in the perilesional white matter were seen in the later stages of stroke. Our findings suggest that various physiological processes are at play in the acute, subacute and chronic stages following ischaemic stroke, with the infarct territory and perilesional white matter affected by ischaemia at different rates and to different extents throughout the stroke recovery stages. The examination of multiple diffusivity metrics may inform us about the mechanisms occurring at different time-points, i.e. focal swelling, axonal damage or myelin loss.

Treatment-induced neuroplasticity after anomia therapy in post-stroke aphasia: A systematic review of neuroimaging studies.

We systematically reviewed the literature on neural changes following anomia treatment post-stroke. We conducted electronic searches of CINAHL, Cochrane Trials, Embase, Ovid MEDLINE, MEDLINE-in-Process and PsycINFO databases; two independent raters assessed all abstracts and full texts. Accepted studies reported original data on adults with post-stroke aphasia, who received behavioural treatment for anomia, and magnetic resonance brain imaging (MRI) pre- and post-treatment. Search results yielded 2481 citations; 33 studies were accepted. Most studies employed functional MRI and the quality of reporting neuroimaging methodology was variable, particularly for pre-processing steps and statistical analyses. The most methodologically robust data were synthesized, focusing on pre- versus post-treatment contrasts. Studies more commonly reported increases (versus decreases) in activation following naming therapy, primarily in the left supramarginal gyrus, and left/bilateral precunei. Our findings highlight the methodological heterogeneity across MRI studies, and the paucity of robust evidence demonstrating direct links between brain and behaviour in anomia rehabilitation.

Functional network and structural connections involved in picture naming.

We mapped the left hemisphere cortical regions and fiber bundles involved in picture naming in adults by integrating task-based fMRI with dMRI tractography. We showed that a ventral pathway that "maps image and sound to meaning" involves the middle occipital, inferior temporal, superior temporal, inferior frontal gyri, and the temporal pole where a signal exchange is made possible by the inferior fronto-occipital, inferior longitudinal, middle longitudinal, uncinate fasciculi, and the extreme capsule. A dorsal pathway that "maps sound to speech" implicates the inferior temporal, superior temporal, inferior frontal, precentral gyri, and the supplementary motor area where the arcuate fasciculus and the frontal aslant ensure intercommunication. This study provides a neurocognitive model of picture naming and supports the hypothesis that the ventral indirect route passes through the temporal pole. This further supports the idea that the inferior and superior temporal gyri may play pivotal roles within the dual-stream framework of language.

A methodological scoping review of the integration of fMRI to guide dMRI tractography. What has been done and what can be improved: A 20-year perspective.

Combining MRI modalities is a growing trend in neurosciences. It provides opportunities to investigate the brain architecture supporting cognitive functions. Integrating fMRI activation to guide dMRI tractography offers potential advantages over standard tractography methods. A quick glimpse of the literature on this topic reveals that this technique is challenging, and no consensus or "best practices" currently exist, at least not within a single document. We present the first attempt to systematically analyze and summarize the literature of 80 studies that integrated task-based fMRI results to guide tractography, over the last two decades. We report 19 findings that cover challenges related to sample size, microstructure modelling, seeding methods, multimodal space registration, false negatives/positives, specificity/validity, gray/white matter interface and more. These findings will help the scientific community (1) understand the strengths and limitations of the approaches, (2) design studies using this integrative framework, and (3) motivate researchers to fill the gaps identified. We provide references toward best practices, in order to improve the overall result's replicability, sensitivity, specificity, and validity.

Connected speech markers of amyloid burden in primary progressive aphasia.

INTRODUCTION: Positron emission tomography (PET) amyloid imaging has become an important part of the diagnostic workup for patients with primary progressive aphasia (PPA) and uncertain underlying pathology. Here, we employ a semi-automated analysis of connected speech (CS) with a twofold objective. First, to determine if quantitative CS features can help select primary progressive aphasia (PPA) patients with a higher probability of a positive PET amyloid imaging result. Second, to examine the relevant group differences from a clinical perspective. METHODS: 117 CS samples from a well-characterised cohort of PPA patients who underwent PET amyloid imaging were collected. Expert consensus established PET amyloid status for each patient, and 40% of the sample was amyloid positive. RESULTS: Leave-one-out cross-validation yields 77% classification accuracy (sensitivity: 74%, specificity: 79%). DISCUSSION: Our results confirm the potential of CS analysis as a screening tool. Discriminant CS features from lexical, syntactic, pragmatic, and semantic domains are discussed.

Sleep spindles are resilient to extensive white matter deterioration.

Sleep spindles are an essential part of non-rapid eye movement sleep, notably involved in sleep consolidation, cognition, learning and memory. These oscillatory waves depend on an interaction loop between the thalamus and the cortex, which relies on a structural backbone of thalamo-cortical white matter tracts. It is still largely unknown if the brain can properly produce sleep spindles when it underwent extensive white matter deterioration in these tracts, and we hypothesized that it would affect sleep spindle generation and morphology. We tested this hypothesis with chronic moderate to severe traumatic brain injury (n = 23; 30.5 ± 11.1 years old; 17 m/6f), a unique human model of extensive white matter deterioration, and a healthy control group (n = 27; 30.3 ± 13.4 years old; 21m/6f). Sleep spindles were analysed on a full night of polysomnography over the frontal, central and parietal brain regions, and we measured their density, morphology and sigma-band power. White matter deterioration was quantified using diffusion-weighted MRI, with which we performed both whole-brain voxel-wise analysis (Tract-Based Spatial Statistics) and probabilistic tractography (with High Angular Resolution Diffusion Imaging) to target the thalamo-cortical tracts. Group differences were assessed for all variables and correlations were performed separately in each group, corrected for age and multiple comparisons. Surprisingly, although extensive white matter damage across the brain including all thalamo-cortical tracts was evident in the brain-injured group, sleep spindles remained completely undisrupted when compared to a healthy control group. In addition, almost all sleep spindle characteristics were not associated with the degree of white matter deterioration in the brain-injured group, except that more white matter deterioration correlated with lower spindle frequency over the frontal regions. This study highlights the resilience of sleep spindles to the deterioration of all white matter tracts critical to their existence, as they conserve normal density during non-rapid eye movement sleep with mostly unaltered morphology. We show that even with such a severe traumatic event, the brain has the ability to adapt or to withstand alterations in order to conserve normal sleep spindles.

Association of education with Aß burden in preclinical familial and sporadic Alzheimer disease.

OBJECTIVE: To determine whether years of education and the ε4 risk allele at APOE influence ß-amyloid (Aß) pathology similarly in asymptomatic individuals with a family history of sporadic Alzheimer disease (AD) and presymptomatic autosomal dominant AD mutation carriers. METHODS: We analyzed cross-sectional data from 106 asymptomatic individuals with a parental history of sporadic AD (PREVENT-AD cohort; age 67.28 ± 4.72 years) and 117 presymptomatic autosomal dominant AD mutation carriers (DIAN cohort; age 35.04 ± 9.43 years). All participants underwent structural MRI and Aß-PET imaging. In each cohort we investigated the influence of years of education, APOE ε4 status, and their interaction on Aß-PET. RESULTS: Asymptomatic individuals with a parental history of sporadic AD showed increased Aß burden associated with APOE ε4 carriage and lower level of education, but no interaction between these. Presymptomatic mutation carriers of autosomal dominant AD showed no relation between APOE ε4 and Aß burden, but increasing level of education was associated with reduced Aß burden. The association between educational attainment and Aß burden was similar in the 2 cohorts. CONCLUSIONS: While the APOE ε4 allele confers increased tendency toward Aß accumulation in sporadic AD only, protective environmental factors, like increased education, may promote brain resistance against Aß pathology in both sporadic and autosomal dominant AD.

Deformation-based shape analysis of the hippocampus in the semantic variant of primary progressive aphasia and Alzheimer's disease.

BACKGROUND: Increasing evidence shows that the semantic variant of primary progressive aphasia (svPPA) is characterized by hippocampal atrophy. However, less is known about disease-related morphological hippocampal changes. The goal of the present study is to conduct a detailed characterization of the impact of svPPA on global hippocampus volume and morphology compared with control subjects and patients with Alzheimer's disease (AD). METHODS: We measured hippocampal volume and deformation-based shape differences in 22 patients with svPPA compared with 99 patients with AD and 92 controls. Multiple Automatically Generated Templates Brain Segmentation Algorithm (MAGeT-Brain) was used on MRI images obtained at the diagnostic visit. RESULTS: Comparable left and right hippocampal atrophy were observed in svPPA and AD. Deformation-based shape analysis showed a common pattern of morphological deformation in svPPA and AD compared with controls. More specifically, both svPPA and AD showed inward deformations in the dorsal surface of the hippocampus, from head to tail on the left side, and more limited to the anterior portion of the body in the right hemisphere. These results also pointed out that both diseases are characterized by a lateral displacement of the central part (body) of the hippocampus. DISCUSSION: Our study provides critical new evidence of hippocampal morphological changes in svPPA, similar to those found in AD. These findings highlight the importance of considering morphological hippocampal changes as part of the anatomical profile of patients with svPPA.

Cerebral white matter diffusion properties and free-water with obstructive sleep apnea severity in older adults.

Characterizing the effects of obstructive sleep apnea (OSA) on the aging brain could be key in our understanding of neurodegeneration in this population. Our objective was to assess white matter properties in newly diagnosed and untreated adults with mild to severe OSA. Sixty-five adults aged 55 to 85 were recruited and divided into three groups: control (apnea-hypopnea index ≤5/hr; n = 18; 65.2 ± 7.2 years old), mild (>5 to ≤15 hr; n = 27; 64.2 ± 5.3 years old) and moderate to severe OSA (>15/hr; n = 20; 65.2 ± 5.5 years old). Diffusion tensor imaging metrics (fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity, and mean diffusivity) were compared between groups with Tract-Based Spatial Statistics within the white matter skeleton created by the technique. Groups were also compared for white matter hyperintensities volume and the free-water (FW) fraction. Compared with controls, mild OSA participants showed widespread areas of lower diffusivity (p < .05 corrected) and lower FW fraction (p < .05). Participants with moderate to severe OSA showed lower AD in the corpus callosum compared with controls (p < .05 corrected). No between-group differences were observed for FA or white matter hyperintensities. Lower white matter diffusivity metrics is especially marked in mild OSA, suggesting that even the milder form may lead to detrimental outcomes. In moderate to severe OSA, competing pathological responses might have led to partial normalization of diffusion metrics.

Predicting Early Post-stroke Aphasia Outcome From Initial Aphasia Severity.

Background: The greatest degree of language recovery in post-stroke aphasia takes place within the first weeks. Aphasia severity and lesion measures have been shown to be good predictors of long-term outcomes. However, little is known about their implications in early spontaneous recovery. The present study sought to determine which factors better predict early language outcomes in individuals with post-stroke aphasia. Methods: Twenty individuals with post-stroke aphasia were assessed <72 h (acute) and 10-14 days (subacute) after stroke onset. We developed a composite score (CS) consisting of several linguistic sub-tests: repetition, oral comprehension and naming. Lesion volume, lesion load and diffusion measures [fractional anisotropy (FA) and axial diffusivity (AD)] from both arcuate fasciculi (AF) were also extracted using MRI scans performed at the same time points. A series of regression analyses were performed to predict the CS at the second assessment. Results: Among the diffusion measures, only FA from right AF was found to be a significant predictor of early subacute aphasia outcome. However, when combined in two hierarchical models with FA, age and either lesion load or lesion size, the initial aphasia severity was found to account for most of the variance (R 2 = 0.678), similarly to the complete models (R 2 = 0.703 and R 2 = 0.73, respectively). Conclusions: Initial aphasia severity was the best predictor of early post-stroke aphasia outcome, whereas lesion measures, though highly correlated, show less influence on the prediction model. We suggest that factors predicting early recovery may differ from those involved in long-term recovery.

Intermediate flortaucipir uptake is associated with Aß-PET and CSF tau in asymptomatic adults.

OBJECTIVE: To investigate relationships between flortaucipir (FTP) uptake, age, and established Alzheimer disease (AD) markers in asymptomatic adults at increased risk of AD. METHODS: One-hundred nineteen individuals with a family history of AD (Presymptomatic Evaluation of Experimental or Novel Treatments of Alzheimer's Disease [PREVENT-AD] cohort, mean age 67 ± 5 years) underwent tau-PET ([18F]FTP), ß-amyloid (Aß)-PET ([18F]NAV4694 [NAV]), and cognitive assessment. Seventy-four participants also had CSF phosphorylated tau and total tau data available. We investigated the association between age and FTP in this relatively young cohort of older adults. We also investigated regional FTP standardized uptake value ratio (SUVR) differences between Aß-positive and Aß-negative individuals and regional correlations between FTP and NAV retention. In cortical regions showing consistent associations across analyses, we assessed whether FTP was in addition related to CSF tau and cognitive performance. Lastly, we identified the lowest FTP value at which associations with Aß-PET, CSF, and cognition were detectable. RESULTS: Increased age was associated only with amygdala and transverse temporal lobe FTP retention. Aß-positive individuals had higher FTP SUVR values in several brain regions, further showing correlation with NAV load through the cortex. Increased FTP SUVRs in medial temporal regions were associated with increased CSF tau values and worse cognition. The SUVRs at which associations between entorhinal FTP SUVR and other AD markers were first detected differed by modality, with a detection point of 1.12 for CSF values, 1.2 for Aß-PET, and 1.4 for cognition. CONCLUSIONS: Relatively low FTP-PET SUVRs are associated with pathologic markers of AD in the preclinical phase of the disease. Adjustment in the tau threshold should be considered, depending on the purpose of the tau classification.

Author Correction: The challenge of mapping the human connectome based on diffusion tractography.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The role of the hippocampus in the semantic variant of primary progressive aphasia: A resting-state fcMRI study.

The goal of the study was to determine whether the semantic variant of primary progressive aphasia (svPPA) affects the intrinsic connectivity network anchored to left and right anterior hippocampus, but spares the posterior hippocampus. A resting-state functional connectivity MRI (rs-fcMRI) study was conducted in a group of patients with svPPA and in controls, using a seed-to-voxel approach. In comparison to controls, massively reduced connectivity was found in the anterior hippocampus, mainly the left one, for svPPA patients but not in the left or right posterior hippocampus. In svPPA, the anterior hippocampus showed reduced functional connectivity with regions implicated in the semantic memory network. Significant correlation was also found between the functional connectivity strength of the left anterior hippocampus and the ventromedial cortex, and performance in semantic tasks. These findings indicate that the functional disconnection of the anterior hippocampus may be a promising in vivo biomarker of svPPA and illustrate the role of this hippocampal subregion in the semantic memory system.

Visual and auditory perceptual strength norms for 3,596 French nouns and their relationship with other psycholinguistic variables.

Perceptual experience plays a critical role in the conceptual representation of words. Higher levels of semantic variables such as imageability, concreteness, and sensory experience are generally associated with faster and more accurate word processing. Nevertheless, these variables tend to be assessed mostly on the basis of visual experience. This underestimates the potential contributions of other perceptual modalities. Accordingly, recent evidence has stressed the importance of providing modality-specific perceptual strength norms. In the present study, we developed French Canadian norms of visual and auditory perceptual strength (i.e., the modalities that have major impact on word processing) for 3,596 nouns. We then explored the relationship between these newly developed variables and other lexical, orthographic, and semantic variables. Finally, we demonstrated the contributions of visual and auditory perceptual strength ratings to visual word processing beyond those of other semantic variables related to perceptual experience (e.g., concreteness, imageability, and sensory experience ratings). The ratings developed in this study are a meaningful contribution toward the implementation of new studies that will shed further light on the interaction between linguistic, semantic, and perceptual systems.

Brain white matter damage and its association with neuronal synchrony during sleep.

The restorative function of sleep partly relies on its ability to deeply synchronize cerebral networks to create large slow oscillations observable with EEG. However, whether a brain can properly synchronize and produce a restorative sleep when it undergoes massive and widespread white matter damage is unknown. Here, we answer this question by testing 23 patients with various levels of white matter damage secondary to moderate to severe traumatic brain injuries (ages 18-56; 17 males, six females, 11-39 months post-injury) and compared them to 27 healthy subjects of similar age and sex. We used MRI and diffusion tensor imaging metrics (e.g. fractional anisotropy as well as mean, axial and radial diffusivities) to characterize voxel-wise white matter damage. We measured the following slow wave characteristics for all slow waves detected in N2 and N3 sleep stages: peak-to-peak amplitude, negative-to-positive slope, negative and positive phase durations, oscillation frequency, and slow wave density. Correlation analyses were performed in traumatic brain injury and control participants separately, with age as a covariate. Contrary to our hypotheses, we found that greater white matter damage mainly over the frontal and temporal brain regions was strongly correlated with a pattern of higher neuronal synchrony characterized by slow waves of larger amplitudes and steeper negative-to-positive slopes during non-rapid eye movement sleep. The same pattern of associations with white matter damage was also observed with markers of high homeostatic sleep pressure. More specifically, higher white matter damage was associated with higher slow-wave activity power, as well as with more severe complaints of cognitive fatigue. These associations between white matter damage and sleep were found only in our traumatic brain injured participants, with no such correlation in controls. Our results suggest that, contrary to previous observations in healthy controls, white matter damage does not prevent the expected high cerebral synchrony during sleep. Moreover, our observations challenge the current line of hypotheses that white matter microstructure deterioration reduces cerebral synchrony during sleep. Our results showed that the relationship between white matter and the brain's ability to synchronize during sleep is neither linear nor simple.

Norms of conceptual familiarity for 3,596 French nouns and their contribution in lexical decision.

In the last decade, research has shown that word processing is influenced by the lexical and semantic features of words. However, norms for a crucial semantic variable-that is, conceptual familiarity-have not been available for a sizeable French database. We thus developed French Canadian conceptual familiarity norms for 3,596 nouns. This enriches Desrochers and Thompson's (2009) database, in which subjective frequency and imageability values are already available for the same words. We collected online data from 313 Canadian French speakers. The full database of conceptual familiarity ratings is freely available at http://lingualab.ca/fr/projets/normes-de-familiarite-conceptuelle . We then demonstrated the utility of these new conceptual familiarity norms by assessing their contribution to lexical decision times. We conducted a stepwise regression model with conceptual familiarity in the last step. This allowed us to assess the independent contribution of conceptual familiarity beyond the contributions of other well-known psycholinguistic variables, such as frequency, imageability, and age of acquisition. The results showed that conceptual familiarity facilitated lexical decision latencies. In sum, these ratings will help researchers select French stimuli for experiments in which conceptual familiarity must be taken into account.

Abnormal Gray Matter Shape, Thickness, and Volume in the Motor Cortico-Subcortical Loop in Idiopathic Rapid Eye Movement Sleep Behavior Disorder: Association with Clinical and Motor Features.

Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a major risk factor for Parkinson's disease and dementia with Lewy bodies. Anatomical gray matter abnormalities in the motor cortico-subcortical loop areas remain under studied in iRBD patients. We acquired T1-weighted images and administrated quantitative motor tasks in 41 patients with polysomnography-confirmed iRBD and 41 healthy subjects. Cortical thickness and voxel-based morphometry (VBM) analyses were performed to investigate local cortical thickness and gray matter volume changes, vertex-based shape analysis to investigate shape of subcortical structures, and structure-based volumetric analyses to investigate volumes of subcortical and brainstem structures. Cortical thickness analysis revealed thinning in iRBD patients in bilateral medial superior frontal, orbitofrontal, anterior cingulate cortices, and the right dorsolateral primary motor cortex. VBM results showed lower gray matter volume in iRBD patients in the frontal lobes, anterior cingulate gyri, and caudate nucleus. Shape analysis revealed extensive surface contraction in the external and internal segments of the left pallidum. Clinical and motor impaired features in iRBD were associated with anomalies of the motor cortico-subcortical loop. In summary, iRBD patients showed numerous gray matter structural abnormalities in the motor cortico-subcortical loop, which are associated with lower motor performance and clinical manifestations of iRBD.

Test-Retest Reliability of Diffusion Measures Extracted Along White Matter Language Fiber Bundles Using HARDI-Based Tractography.

High angular resolution diffusion imaging (HARDI)-based tractography has been increasingly used in longitudinal studies on white matter macro- and micro-structural changes in the language network during language acquisition and in language impairments. However, test-retest reliability measurements are essential to ascertain that the longitudinal variations observed are not related to data processing. The aims of this study were to determine the reproducibility of the reconstruction of major white matter fiber bundles of the language network using anatomically constrained probabilistic tractography with constrained spherical deconvolution based on HARDI data, as well as to assess the test-retest reliability of diffusion measures extracted along them. Eighteen right-handed participants were scanned twice, one week apart. The arcuate, inferior longitudinal, inferior fronto-occipital, and uncinate fasciculi were reconstructed in the left and right hemispheres and the following diffusion measures were extracted along each tract: fractional anisotropy, mean, axial, and radial diffusivity, number of fiber orientations, mean length of streamlines, and volume. All fiber bundles showed good morphological overlap between the two scanning timepoints and the test-retest reliability of all diffusion measures in most fiber bundles was good to excellent. We thus propose a fairly simple, but robust, HARDI-based tractography pipeline reliable for the longitudinal study of white matter language fiber bundles, which increases its potential applicability to research on the neurobiological mechanisms supporting language.

The challenge of mapping the human connectome based on diffusion tractography.

Tractography based on non-invasive diffusion imaging is central to the study of human brain connectivity. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain data set with ground truth tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. Here, we report the encouraging finding that most state-of-the-art algorithms produce tractograms containing 90% of the ground truth bundles (to at least some extent). However, the same tractograms contain many more invalid than valid bundles, and half of these invalid bundles occur systematically across research groups. Taken together, our results demonstrate and confirm fundamental ambiguities inherent in tract reconstruction based on orientation information alone, which need to be considered when interpreting tractography and connectivity results. Our approach provides a novel framework for estimating reliability of tractography and encourages innovation to address its current limitations.