Evaluation of cerebral cortex viscoelastic property estimation with nonlinear inversion magnetic resonance elastography

Objective. Magnetic resonance elastography (MRE) of the brain has shown promise as a sensitive neuroimaging biomarker for neurodegenerative disorders; however, the accuracy of performing MRE of the cerebral cortex warrants investigation due to the unique challenges of studying thinner and more complex geometries. Approach. A series of realistic, whole-brain simulation experiments are performed to examine the accuracy of MRE to measure the viscoelasticity (shear stiffness, μ, and damping ratio, ξ) of cortical structures predominantly effected in aging and neurodegeneration. Variations to MRE spatial resolution and the regularization of a nonlinear inversion (NLI) approach are examined. Main results. Higher-resolution MRE displacement data (1.25 mm isotropic resolution) and NLI with a low soft prior regularization weighting provided minimal measurement error compared to other studied protocols. With the optimized protocol, an average error in μ and ξ was 3% and 11%, respectively, when compared with the known ground truth. Mid-line structures, as opposed to those on the cortical surface, generally display greater error. Varying model boundary conditions and reducing the thickness of the cortex by up to 0.67 mm (which is a realistic portrayal of neurodegenerative pathology) results in no loss in reconstruction accuracy. Significance. These experiments establish quantitative guidelines for the accuracy expected of in vivo MRE of the cortex, with the proposed method providing valid MRE measures for future investigations into cortical viscoelasticity and relationships with health, cognition, and behavior

Standard‐space atlas of the viscoelastic properties of the human brain

Standard anatomical atlases are common in neuroimaging because they facilitate data analyses and comparisons across subjects and studies. The purpose of this study was to develop a standardized human brain atlas based on the physical mechanical properties (i.e., tissue viscoelasticity) of brain tissue using magnetic resonance elastography (MRE). MRE is a phase contrast-based MRI method that quantifies tissue viscoelasticity noninvasively and in vivo thus providing a macroscopic representation of the microstructural constituents of soft biological tissue. The development of standardized brain MRE atlases are therefore beneficial for comparing neural tissue integrity across populations. Data from a large number of healthy, young adults from multiple studies collected using common MRE acquisition and analysis protocols were assembled (N = 134; 78F/ 56 M; 18–35 years). Nonlinear image registration methods were applied to normalize viscoelastic property maps (shear stiffness, μ, and damping ratio, ξ) to the MNI152 standard structural template within the spatial coordinates of the ICBM-152. We find that average MRE brain templates contain emerging and symmetrized anatomical detail. Leveraging the substantial amount of data assembled, we illustrate that subcortical gray matter structures, white matter tracts, and regions of the cerebral cortex exhibit differing mechanical characteristics. Moreover, we report sex differences in viscoelasticity for specific neuroanatomical structures, which has implications for understanding patterns of individual differences in health and disease. These atlases provide reference values for clinical investigations as well as novel biophysical signatures of neuroanatomy. The templates are made openly available (github.com/mechneurolab/mre134) to foster collaboration across research institutions and to support robust cross-center comparisons

Aging brain mechanics: Progress and promise of magnetic resonance elastography

Neuroimaging techniques that can sensitivity characterize healthy brain aging and detect subtle neuropathologies have enormous potential to assist in the early detection of neurodegenerative conditions such as Alzheimer's disease. Magnetic resonance elastography (MRE) has recently emerged as a reliable, high-resolution, and especially sensitive technique that can noninvasively characterize tissue biomechanical properties (i.e., viscoelasticity) in vivo in the living human brain. Brain tissue viscoelasticity provides a unique biophysical signature of neuroanatomy that are representative of the composition and organization of the complex tissue microstructure. In this article, we detail how progress in brain MRE technology has provided unique insights into healthy brain aging, neurodegeneration, and structure-function relationships. We further discuss additional promising technical innovations that will enhance the specificity and sensitivity for brain MRE to reveal considerably more about brain aging as well as its potentially valuable role as an imaging biomarker of neurodegeneration. MRE sensitivity may be particularly useful for assessing the efficacy of rehabilitation strategies, assisting in differentiating between dementia subtypes, and in understanding the causal mechanisms of disease which may lead to eventual pharmacotherapeutic development

Lateralized hippocampal oscillations underlie distinct aspects of human spatial memory and navigation

The hippocampus plays a vital role in various aspects of cognition including both memory and spatial navigation. To understand electrophysiologically how the hippocampus supports these processes, we recorded intracranial electroencephalographic activity from 46 neurosurgical patients as they performed a spatial memory task. We measure signals from multiple brain regions, including both left and right hippocampi, and we use spectral analysis to identify oscillatory patterns related to memory encoding and navigation. We show that in the left but not right hippocampus, the amplitude of oscillations in the 1–3-Hz “low theta” band increases when viewing subsequently remembered object–location pairs. In contrast, in the right but not left hippocampus, low-theta activity increases during periods of navigation. The frequencies of these hippocampal signals are slower than task-related signals in the neocortex. These results suggest that the human brain includes multiple lateralized oscillatory networks that support different aspects of cognition

Early characterisation of neurodegeneration with high-resolution magnetic resonance elastography

This thesis contributes to recent interest within medical imaging regarding the development and clinical application of magnetic resonance elastography (MRE) to the human brain. MRE is a non-invasive phase-contrast MRI technique for measurement of brain mechanical properties in vivo, shown to reflect the composition and organisation of the complex tissue microstructure. MRE is a promising imaging biomarker for the early characterisation of neurodegeneration due to its exquisite sensitivity to variation among healthy and pathological tissue. Neurodegenerative diseases are debilitating conditions of the human nervous system for which there is currently no cure. Novel biomarkers are required to improve early detection, differential diagnosis and monitoring of disease progression, and could also ultimately improve our understanding of the pathophysiological mechanisms underlying degenerative processes. This thesis begins with a theoretical background of brain MRE and a description of the experimental considerations. A systematic review of the literature is then performed to summarise brain MRE quantitative measurements in healthy participants and to determine the success of MRE to characterise neurological disorders. This review further identified the most promising acquisition and analysis methods within the field. As such, subsequent visits to three brain MRE research centres, within the USA and Germany, enabled the acquisition of exemplar phantom and brain data to assist in discussions to refine an experimental protocol for installation at the Edinburgh Imaging Facility, QMRI (EIF-QMRI). Through collaborations with world-leading brain MRE centres, two high-resolution - yet fundamentally different - MRE pipelines were installed at the EIF-QMRI. Several optimisations were implemented to improve MRE image quality, while the clinical utility of MRE was enhanced by the novel development of a Graphical User Interface (GUI) for the optimised and automatic MRE-toanatomical coregistration and generation of MRE derived output measures. The first experimental study was performed in 6 young and 6 older healthy adults to compare the results from the two MRE pipelines to investigate test-retest agreement of the whole brain and a brain structure of interest: the hippocampal formation. The MRE protocol shown to possess superior reproducibility was subsequently applied in a second experimental study of 12 young and 12 older cognitively healthy adults. Results include finding that the MRE imaging procedure is very well tolerated across the recruited population. Novel findings include significantly softer brains in older adults both across the global cerebrum and in the majority of subcortical grey matter structures including the pallidum, putamen, caudate, and thalamus. Changes in tissue stiffness likely reflect an alteration to the strength in the composition of the tissue network. All MRE effects persist after correcting for brain structure volume suggesting changes in volume alone were not reflective of the detected MRE age differences. Interestingly, no age-related differences to tissue stiffness were found for the amygdala or hippocampus. As for brain viscosity, no group differences were detected for either the brain globally or subcortical structures, suggesting a preservation of the organisation of the tissue network in older age. The third experiment performed in this thesis finds a direct structure-function relationship in older adults between hippocampal viscosity and episodic memory as measured with verbal-paired recall. The source of this association was located to the left hippocampus, thus complementing previous literature suggesting unilateral hippocampal specialisation. Additionally, a more significant relationship was found between left hippocampal viscosity and memory after a new procedure was developed to remove voxels containing cerebrospinal fluid from the MRE analysis. Collectively, these results support the transition of brain MRE into a clinically useful neuroimaging modality that could, in particular, be used in the early characterisation of memory specific disorders such as amnestic Mild Cognitive Impairment and Alzheimer’s disease

Hippocampus at 25

The journal Hippocampus has passed the milestone of 25 years of publications on the topic of a highly studied brain structure, and its closely associated brain areas. In a recent celebration of this event, a Boston memory group invited 16 speakers to address the question of progress in understanding the hippocampus that has been achieved. Here we present a summary of these talks organized as progress on four main themes: (1) Understanding the hippocampus in terms of its interactions with multiple cortical areas within the medial temporal lobe memory system, (2) understanding the relationship between memory and spatial information processing functions of the hippocampal region, (3) understanding the role of temporal organization in spatial and memory processing by the hippocampus, and (4) understanding how the hippocampus integrates related events into networks of memories

Structural and Diffusion Parameters Related to Pattern Separation in Multiple Sclerosis

Multiple sclerosis (MS) is a progressive, neurodegenerative disease of the central nervous system characterized by widespread lesions and plaques that disrupt neural transmission. In addition to physical disability, cognitive impairment is experienced in about half of the MS population, which profoundly impacts vocational ability and quality of life. Amongst people with MS experiencing cognitive deficits, memory impairment is one of the most common symptoms. Assessing memory impairment in MS, a critical step in treatment, has been a difficult process. Traditional clinical batteries assessing memory impairment in MS may not adequately capture the multiple subprocesses of memory. Pattern separation, the ability to discriminate between similar yet distinct memories, is one aspect of memory that remains unexplored in the MS population. Previous research in animals and other memory-impaired populations links the underlying neuronal computational processes of pattern separation to the subsections of the hippocampus. Moreover, hippocampal atrophy is common in MS. Therefore, this study uses the Mnemonic Similarities Task, a behavioral measure of pattern separation, to investigate pattern separation performance in a sample of MS participants as well as its relationship to structural brain parameter of hippocampal atrophy and white matter microstructural integrity. Results revealed strong positive correlations whereby lower pattern separation performance was related to smaller hippocampal volumes. Microstructural analysis of white matter tracts revealed no differences between high and low MS pattern separation performers, although this may be due to sample size. Results have implications for clinical assessment and suggest a need for future research into how pattern separation ability is affected in MS patients

Organization of spatiotemporal information and relational memory in the hippocampus

This work examines the role of the hippocampus and relational memory in organizing episodic memory during navigation and reconstruction. Navigation is a critical component in most organisms’ survival. Reconstruction, on the other hand, provides an incredibly rich method of evaluating the precise information remembered by an individual after attempting to learn and remember that information. Through validating the computational framework in this work on amnesic patients with hippocampal damage, an understanding of some of the specific types of relations which rely on the hippocampus can be established. Then, this framework can be applied to a much more complex, spatiotemporal navigation and reconstruction task in healthy individuals to gain a wider perspective on the organization of episodic memory, which is known to critically rely on the hippocampus. The first experiment and associated analysis framework presented in this document (Chapter 2) uses spatial reconstruction to establish that not all types of spatial relations are impaired in hippocampal damaged patients. In particular, the arbitrary, identity-location relations (i.e. those relationships where the element being bound could have just as easily been anything) are critically impaired in hippocampal damaged patients while location information, disregarding identity, is not. The use of reconstruction in this context allows for the establishment of a set of critical computational metrics which relate to hippocampal function in reconstruction which can then be applied to other reconstruction tasks in healthy individuals to learn more about the wider structure and organization of memory. In the second experiment (Chapters 3 and 4), the methodologies which were applied to hippocampal damaged patients in the first experiment are applied to a novel Spatiotemporal Navigation Task in healthy young adults. In this task, participants are not just asked to study and reconstruct items in space, but instead, participants are asked to, in Virtual Reality, navigate space and time (via normal movement and simulated Time Travel) and study, then reconstruct the locations of events in spacetime. The computational framework established in the previous chapter is then applied to show that relational memory errors in time are far more common in this task than in space, suggesting differences in representations between these two domains even when the navigation and exploration of the domains are put on a more equal footing. Additionally, in time, these relational memory errors are far more likely to occur within a shared contextual region than should occur by chance. In fact, this error (temporal relational memory error within a context) gets worse across the first 3 trials, suggesting a systematic bias due to context. Finally, a more traditional bias, the context boundary effect (i.e. a “squishing” of within context temporal locations and “stretching” of across context temporal locations) is observed even though participants are allowed to reexplore the contexts arbitrarily, multiple times. This suggests that the context boundaries are having a profound impact on both the distance judgements and relational memory structure associated with events in spacetime. Finally, in the fourth chapter, the navigation component of the previous Spatiotemporal Navigation Task is examined to determine if changes in study time navigation and exploration relate to changes in the various test metrics discussed in the previous chapter. More rapid improvements in spatial and temporal navigation are shown to relate to more rapid improvements in memory in those domains, separably, suggesting that spatial and temporal representations may in some way be separable in this task in both the relational representations and the navigation strategies supporting those representations. Relational memory improvements are shown to be uniquely tied to changes in navigation complexity and systematicity, pointing to an interplay between in-the-moment, memory-guided decision making and subsequent relational memory efficacy. Context boundaries are suggested to act as more of a discriminatory feature (at least in this task) than one used to strengthen within-context relational memory organization accuracy as there is a significant relationship between changes in context boundary crossing and both the context boundary effect and across-context temporal relational memory errors. Finally, a preference towards exploring an otherwise temporally-flexible environment in the implied, forward order with increasing contiguity is suggested to be a critical element in improving temporal, relational, and contextual memory organization. Taken together, this work shows the richness of spatiotemporal navigation and reconstruction in observing the complex interplay between navigation in space, navigation in time and how these ultimately may relate to navigation in memory. Through embracing principled approaches to analysis of behavioral data, and the inclusion of complex behavioral mechanics (such as simulated time travel), this work extends our understanding of the role of hippocampal relational memory and overall memory organization

Acute effects of high-intensity exercise on brain mechanical properties and cognitive function

Previous studies have shown that engagement in even a single session of exercise can improve cognitive performance in the short term. However, the underlying physiological mechanisms contributing to this effect are still being studied. Recently, with improvements to advanced quantitative neuroimaging techniques, brain tissue mechanical properties can be sensitively and noninvasively measured with magnetic resonance elastography (MRE) and regional brain mechanical properties have been shown to reflect individual cognitive performance. Here we assess brain mechanical properties before and immediately after engagement in a high-intensity interval training (HIIT) regimen, as well as one-hour post-exercise. We find that immediately after exercise, subjects in the HIIT group had an average global brain stiffness decrease of 4.2% (p < 0.001), and an average brain damping ratio increase of 3.1% (p = 0.002). In contrast, control participants who did not engage in exercise showed no significant change over time in either stiffness or damping ratio. Changes in brain mechanical properties with exercise appeared to be regionally dependent, with the hippocampus decreasing in stiffness by 10.4%. We also found that one-hour after exercise, brain mechanical properties returned to initial baseline values. The magnitude of changes to brain mechanical properties also correlated with improvements in reaction time on executive control tasks (Eriksen Flanker and Stroop) with exercise. Understanding the neural changes that arise in response to exercise may inform potential mechanisms behind improvements to cognitive performance with acute exercise

Viscoelastic Property of the Brain Assessed With Magnetic Resonance Elastography and Its Association With Glymphatic System in Neurologically Normal Individuals

Objective: To investigate the feasibility of assessing the viscoelastic properties of the brain using magnetic resonance elastography (MRE) and a novel MRE transducer to determine the relationship between the viscoelastic properties and glymphatic function in neurologically normal individuals. Materials and Methods: This prospective study included 47 neurologically normal individuals aged 23–74 years (male-tofemale ratio, 21:26). The MRE was acquired using a gravitational transducer based on a rotational eccentric mass as the driving system. The magnitude of the complex shear modulusG*and the phase angle φ were measured in the centrum semiovale area. To evaluate glymphatic function, the Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS) method was utilized and the ALPS index was calculated. Univariable and multivariable (variables with P < 0.2 from the univariable analysis) linear regression analyses were performed forG*and φ and included sex, age, normalized white matter hyperintensity (WMH) volume, brain parenchymal volume, and ALPS index as covariates. Results: In the univariable analysis forG*, age (P = 0.005), brain parenchymal volume (P = 0.152), normalized WMH volume (P = 0.011), and ALPS index (P = 0.005) were identified as candidates with P < 0.2. In the multivariable analysis, only the ALPS index was independently associated withG*, showing a positive relationship (β = 0.300, P = 0.029). For φ, normalized WMH volume (P = 0.128) and ALPS index (P = 0.015) were identified as candidates for multivariable analysis, and only the ALPS index was independently associated with φ (β = 0.057, P = 0.039). Conclusion: Brain MRE using a gravitational transducer is feasible in neurologically normal individuals over a wide age range. The significant correlation between the viscoelastic properties of the brain and glymphatic function suggests that a more organized or preserved microenvironment of the brain parenchyma is associated with a more unimpeded glymphatic fluid flow.ope