Biology subjects

Khan, A. R.

Publications and source records attributed to Khan, A. R..

48 records · Page 3Linked to original sources

bioRxiv2020

Microstructural characterization and validation of a 3D printed phantom for diffusion MRI

PurposeTo introduce and characterize inexpensive and easily produced 3D-printed axon-mimetic (3AM) diffusion MRI (dMRI) phantoms in terms of pore geometry and diffusion kurtosis imaging (DKI) metrics. MethodsPhantoms were 3D-printed with a composite printing material that, after dissolution of the PVA, exhibits microscopic fibrous pores. Confocal microscopy and synchrotron phase contrast micro-CT imaging were performed to visualize and assess the pore sizes. dMRI scans of four identical phantoms and phantoms with varying print parameters in water were performed at 9.4T. DKI was fit to both datasets and used to assess the reproducibility between phantoms and effects of print parameters on DKI metrics. Identical scans were performed 25 and 76 days later to test their stability. ResultsSegmentation of pores in three microscopy images yielded a mean, median, and standard deviation of equivalent pore diameters of 7.57 m, 3.51 m, and 12.13 m, respectively. Phantoms with identical parameters showed a low coefficient of variation ([~]10%) in DKI metrics (D=1.38 x10-3 mm2/s and K=0.52, T1= 3960 ms and T2=119 ms). Printing temperature and speed had a small effect on DKI metrics (<16%) while infill density had a larger and more variable effect (>16%). The stability analysis showed small changes over 2.5 months (<7%). Conclusion3AM phantoms can mimic the fibrous structure of axon bundles on a microscopic scale, serving as complex, anisotropic dMRI phantoms.

neuroscience↗

bioRxiv2020

DIFFUSION MRI OF THE UNFOLDED HIPPOCAMPUS

The hippocampus is implicated in numerous neurological disorders and the ability to detect subtle or focal hippocampal abnormalities earlier in disease progression could significantly improve the treatment of patients. Ex vivo studies with ultra-high field have revealed that diffusion MRI (dMRI) can reveal microstructural variations within the hippocampal subfields and lamina, and may also be sensitive to intra-hippocampal pathways. However, translation to lower resolution in vivo dMRI studies of the hippocampus is challenging due to its complicated geometry. One novel way to overcome some of these obstacles is by transforming the usual Cartesian coordinates in an MRI image to coordinates that are crafted to curve themselves according to the complicated geometry of the hippocampus. This procedure allows us to virtually unfold the hippocampus into a thin sheet. In this work, we introduce an algorithm to map diffusion MRI data to this sheet, allowing us to overcome the difficulties associated with the hippocampus complicated geometry. We demonstrate how our method can be readily integrated into existing implementations of traditional tractography methods and how it leads to enhancements in the resulting tracts. Further, our results on high quality in vivo dMRI acquisitions show that unfolding the hippocampus leads to a more anatomically plausible modelling of the connectivity of the hippocampus as probed by probabilistic tractography, revealing key elements of the polysynaptic pathway and anterior-posterior connectivity gradients.

neuroscience↗

bioRxiv2020

Direct visualization and characterization of the human zona incerta and surrounding structures

The zona incerta (ZI) is a small gray matter region of the deep brain first identified in the 19th century, yet direct in vivo visualization and characterization has remained elusive. Noninvasive detection of the ZI and surrounding region could be critical to further our understanding of this widely connected but poorly understood deep brain region and could contribute to the development and optimization of neuromodulatory therapies. We demonstrate that high resolution (submillimetric) longitudinal (T1) relaxometry measurements at high magnetic field strength (7 Tesla) can be used to delineate the ZI from surrounding white matter structures, specifically the fasciculus cerebellothalamicus, fields of Forel (fasciculus lenticularis, fasciculus thalamicus, field H), and medial lemniscus. Using this approach, we successfully derived in vivo estimates of the size, shape, location, and tissue characteristics of substructures in the ZI region, confirming observations only previously possible through histological evaluation that this region is not just a space between structures but contains distinct morphological entities that should be considered separately. Our findings pave the way for increasingly detailed in vivo study and provide a structural foundation for precise functional and neuromodulatory investigation.

neuroscience↗

bioRxiv2020

Effects of MP2RAGE B1+ sensitivity on inter-site T1 reproducibility and morphometry at 7T

Most neuroanatomical studies are based on MR images, whose intensity profiles are not solely determined by the tissues longitudinal relaxation times (T1) but also affected by varying non-T1 contributions, hampering data reproducibility. In contrast, quantitative imaging using the MP2RAGE sequence, for example, allows direct characterization of the brain based on the tissue property of interest. Combined with 7 Tesla (7T) MRI, this offers unique opportunities to obtain robust high-resolution brain data characterized by a high reproducibility, sensitivity and specificity. However, specific MP2RAGE parameters choices - e.g., to emphasize intracortical myelin-dependent contrast variations - can substantially impact image quality and cortical analyses through remnants of B1+-related intensity variations, as illustrated in our previous work. To follow up on this: we (1) validate this protocol effect using a dataset acquired with a particularly B1+ insensitive set of MP2RAGE parameters combined with parallel transmission excitation; and (2) extend our analyses to evaluate the effects on hippocampal and subcortical morphometry. The latter remained unexplored initially but will provide important insights related to generalizability and reproducibility of neurodegenerative research using 7T MRI. We confirm that B1+ inhomogeneities have a considerably variable effect on cortical T1 and thickness estimates, as well as on hippocampal and subcortical morphometry depending on MP2RAGE setup. While T1 differed substantially across datasets initially, we show inter-site T1 comparability improves after correcting for the spatially varying B1+ field using a separately acquired Sa2RAGE B1+ map. Finally, as for cortical thickness, removal of B1+ residuals affects hippocampal and subcortical volumetry and boundary definitions, particularly near structures characterized by strong intensity changes (e.g. cerebral spinal fluid and arteries). Taken together, we show that the choice of MP2RAGE parameters can impact T1 comparability across sites and present evidence that hippocampal and subcortical segmentation results are modulated by B1+ inhomogeneities. This calls for careful (1) consideration of sequence parameters when setting acquisition protocols; as well as (2) interpretation of results focused on neuroanatomical changes due to disease. HighlightsO_LIPreviously observed effects of B1+ inhomogeneities on cortical T1 and thickness depend strongly on MP2RAGE parameters C_LIO_LIInter-site comparability of cortical T1 and thickness greatly improves after removal of B1+ residuals C_LIO_LIPost-hoc MP2RAGE B1+ correction affects hippocampal (and subcortical) size and shape analyses C_LIO_LINeuroradiological research would benefit from careful examination of imaging protocols and their impact on results, especially when B1+ maps are not acquired C_LI

neuroscience↗

bioRxiv2020

Understanding the Effect of Left Prefrontal Stimulation on Positive Symptoms of Schizophrenia: A Dynamic Causal Modeling Study of Ultra-high field (7-Tesla) Resting-state fMRI

Repetitive transcranial magnetic stimulation (rTMS), when applied to left dorsolateral prefrontal cortex (LDLPFC), reduces negative symptoms of schizophrenia, but has no effect on positive symptoms. In a small number of cases, it appears to worsen the severity of positive symptoms. It has been hypothesized that high frequency rTMS of the LDLPFC might increase the dopaminergic neurotransmission by driving the activity of the left striatum in the basal ganglia (LSTR)--increasing striatal dopaminergic activity. This hypothesis relies on the assumption that either the frontal-striatal connection or the intrinsic frontal and/or striatal connections covary with the severity of positive symptoms. The current work aimed to evaluate this assumption by studying the association between positive and negative symptoms severity and the effective connectivity within the frontal and striatal network using dynamic causal modeling (DCM) of ultra-high field (7 Tesla) resting state fMRI in a sample of 19 first episode psychosis (FEP) subjects. We found that of all core symptoms of schizophrenia, only delusions are strongly associated with the fronto striatal circuitry. Stronger intrinsic inhibitory tone of LDLPFC and LSTR, as well as a pronounced backward inhibition of the LDLPFC on the LSTR related to the severity of delusions. We interpret that an increase in striatal dopaminergic tone that underlies delusional symptoms, is likely associated with increased prefrontal inhibitory tone, strengthening the frontostriatal brake. Furthermore, based on our model, we propose that lessening of positive symptoms could be achieved by means of continuous theta-burst or low frequency (1Hz) rTMS of the prefrontal area.

neuroscience↗

bioRxiv2019

Ultra-high field imaging of hippocampal neuroanatomy in first episode psychosis demonstrates receptor-specific morphometric patterning

ObjectiveThe hippocampus is considered a putative marker in schizophrenia with early volume deficits of select subfields. Certain subregions are thought to be more vulnerable due to a glutamate-driven mechanism of excitotoxicity, hypermetabolism, and then degeneration. Here, we explored whether hippocampal anomalies in first-episode psychosis (FEP) correlate with glutamate receptor density via a serotonin receptor proxy by leveraging structural neuroimaging, spectroscopy (MRS), and gene expression.\n\nMethodsHigh field 7T brain MR images were collected from 27 control, 41 FEP participants, along with 1H-MRS measures of glutamate. Automated methods were used to delineate the hippocampus and atlases of the serotonin receptor system were used to map receptor density across the hippocampus and subfields. We used gene expression data from the Allen Human Brain Atlas to test for correlations between serotonin and glutamate receptor genes.\n\nResultsWe found reduced hippocampal volumes in FEP, replicating previous findings. Amongst the subfields, CA4-dentate gyrus showed greatest reductions. Gene expression analysis indicated 5-HTR1A and 5-HTR4 receptor subtypes as predictors of AMPA and NMDA receptor expression, respectively. Volumetric differences in the subfields correlated most strongly with 5-HT1A (R=0.64, p=4.09E-03) and 5-HT4 (R=0.54, p=0.02) densities as expected, and replicated using previously published data from two FEP studies. Measures of individual structure-receptor alignment were derived through normative modeling of hippocampal shape and correlations to receptor distributions, termed Receptor-Specific Morphometric Signatures (RSMS). Right-sided 5-HT4 RSMS was correlated with glutamate (R=0.357, p=0.048).\n\nConclusionsWe demonstrate glutamate-driven hippocampal remodeling in FEP through a receptor-density gated mechanism, thus providing a mechanistic explanation of how redox dysregulation affects brain structure and symptomatic heterogeneity in schizophrenia.

neuroscience↗

bioRxiv2019

Structural basis for Rab8a GTPase recruitment of RILPL2 via LRRK2 phosphorylation of switch 2

Rab8a GTPase is associated with the dynamic regulation of membrane protrusions in polarized cells. Rab8a is one of several Rab-family GTPases that are substrates of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine kinase that is linked to inherited Parkinsons disease. Rab8a is phosphorylated at T72 (pT72) in its switch 2 helix and the post-translational modification facilitates phospho-Rab8a (pRab8a) interactions with RILPL2, which subsequently regulates ciliogenesis. Here we report the crystal structure of pRab8a in complex with the phospho-Rab binding domain of RILPL2. The complex is a heterotetramer with RILPL2 forming a central -helical dimer that bridges two pRab8a molecules. The N-termini of the -helices cross over to form an X-shaped cap (X-cap) that enables electrostatic interactions between Arg residues from RILPL2 and the phosphate moiety from pT72. RILPL2 residues in the X-cap that are critical for pRab8a binding are conserved in the RILP family of effector proteins. We find that JIP3 and JIP4 also interact specifically with LRRK2-phosphorylated Rab10, suggesting a general mode of recognition for phosphorylated Rab GTPases by phospho-specific effectors.

biochemistry↗

bioRxiv2019

Longitudinal, Multiparametric MRI Assessment of repetitive mild TBI in rats

Repetitive mild traumatic brain injury (mTBI) has long term health effects and may result in the development of neurodegenerative or neuropsychiatric disorders. Histology shows axonal and dendritic beading, synaptic atrophy, vasodilation and gliosis occuring within hours/days post-mTBI. However, current neuroimaging techniques are unable to detect the early effects of repetitive mTBI. Consequently, mTBI brain scans are normal appearing and inconclusive. Hence, neuroimaging markers capable of detecting subtle microstructural and functional alterations are needed. We present results from longitudinal, multiparametric magnetic resonance imaging (MRI) assessment of repetitive mTBI in rats. We employ advanced in-vivo diffusion MRI (dMRI) to probe brain microstructural alterations, perfusion MRI to assess cerebral blood flow (CBF), close to the injury site, and proton MR spectroscopy to assess metabolic alterations in the ipsilateral cerebral cortex. High resolution anatomical scans were also acquired. In agreement with clinical observations, anatomical scans of rats were normal appearing even after repeated mTBI. Throughout, significance is regarded as p<0.05 post false discovery rate correction. dMRI revealed significant microstructural remodelling in ipsilateral hippocampus (reduced radial kurtosis), may be due to axonal/dendritic beading, demyelination, synaptic atrophy and edema. Consistent with prior reports of reduced cell/fiber density in mTBI, we find significantly increased mean diffusivity in ipsilateral corpus callosum. We also find significantly decreased glutathione (GSH) and increased total Choline (tCho) following second and third mTBI (vs baseline), also reported in clinical mTBI cohorts. Reduced GSH suggests oxidative stress and increase in tCho indicate cell damage/repair. CBF did not change significantly, however, high variability in CBF following the second and third mTBI suggest increased variability in CBF likely due to tissue hypoxia and oxidative stress. Oxidative stress may affect capillary blood flow by disturbing pericyte capillary contraction. Around 40% of pericytes retract after mTBI causing pericyte depletion and white matter dysfunction as suggested by dMRI findings. Multiparametric MRI detects meaningful mTBI-induced alterations otherwise undetectable with conventional MRI. Similar strategies may provide useful information to aid diagnosis of human mTBI.

neuroscience↗

bioRxiv2019

Bridging micro and macro: accurate registration of the BigBrain dataset with the MNI PD25 and ICBM152 atlases

Brain atlases that encompass detailed anatomical or physiological features are instrumental in the research and surgical planning of various neurological conditions. Magnetic resonance imaging (MRI) has played important roles in neuro-image analysis while histological data remain crucial as a gold standard to guide and validate such analyses. With cellular-scale resolution, the BigBrain atlas offers 3D histology of a complete human brain, and is highly valuable to the research and clinical community. To bridge the insights at macro- and micro-levels, accurate mapping of BigBrain and established MRI brain atlases is necessary, but the existing registration is unsatisfactory. The described dataset includes co-registration of the BigBrain atlas to the MNI PD25 atlas and the ICBM152 2009b atlases (symmetric and asymmetric versions) in addition to manual segmentation of the basal ganglia, red nucleus, and hippocampus for all mentioned atlases. The dataset intends to provide the bridge between insights from histological data and MRI studies in research and neurosurgical planning. The registered atlases, anatomical segmentations, and deformation matrices are available at: nist.mni.mcgill.ca/?p=1209.

bioengineering↗

bioRxiv2018

A framework for evaluating correspondence between brain images using anatomical fiducials

Accurate spatial correspondence between template and subject images is a crucial step in neuroimaging studies and clinical applications like stereotactic neurosurgery. In the absence of a robust quantitative approach, we sought to propose and validate a set of point landmarks, anatomical fiducials (AFIDs), that could be quickly, accurately, and reliably placed on magnetic resonance images of the human brain. Using several publicly available brain templates and individual participant datasets, novice users could be trained to place a set of 32 AFIDs with millimetric accuracy. Furthermore, the utility of the AFIDs protocol is demonstrated for evaluating subject-to-template and template-to-template registration. Specifically, we found that commonly used voxel overlap metrics were relatively insensitive to focal misregistrations compared to AFID point-based measures. Our entire protocol and study framework leverages open resources and tools, and has been developed with full transparency in mind so that others may freely use, adopt, and modify. This protocol holds value for a broad number of applications including alignment of brain images and teaching neuroanatomy.

neuroscience↗

bioRxiv2017

Unfolding the hippocampus: An intrinsic coordinate system for subfield segmentations and quantitative mapping

The hippocampus, like the neocortex, has a morphological structure that is complex and variable in its folding pattern, especially in the hippocampal head. The current study presents a computational method to unfold hippocampal grey matter, with a particular focus on the hippocampal head where complexity is highest due to medial curving of the structure and the variable presence of digitations. This unfolding was performed on segmentations from high-resolution, T2-weighted 7T MRI data from 12 healthy participants and one surgical patient with epilepsy whose resected hippocampal tissue was used for histological validation. We traced a critical hippocampal component, the hippocampal sulcus and stratum radiatum, lacunosum moleculaire, (SRLM) in these images, then employed user-guided semi-automated techniques to detect and subsequently unfold the surrounding hippocampal grey matter. This unfolding was performed by solving Laplaces equation in three dimensions of interest (long-axis, proximal-distal, and laminar). The resulting unfolded coordinate space provides an intuitive way of mapping the hippocampal subfields in 2D space (long-axis and proximal-distal), such that similar borders can be applied in the head, body, and tail of the hippocampus independently of variability in folding. This unfolded coordinate space was employed to map intracortical myelin and thickness in relation to subfield borders, which revealed intracortical myelin differences that closely follow the subfield borders used here. Examination of a histological sample from a patient with epilepsy reveals that our unfolded coordinate system shows biological validity, and that subfield segmentations applied in this space are able to capture features not seen in manual tracing protocols.\n\nResearch highlightsO_LISRLM in hippocampal head consistently detected with 7T, T2 isotropic MRI\nC_LIO_LIHippocampal grey matter unfolded using Laplaces equation in 3D\nC_LIO_LIIntracortical myelin and thickness mapped in unfolded coordinate space\nC_LIO_LIUnfolded subfields capture critical structural regularities and agree with histology\nC_LI

neuroscience↗

bioRxiv2016

Tractography-based connectomes are dominated by false-positive connections

Fiber tractography based on non-invasive diffusion imaging is at the heart of connectivity studies of the human brain. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain dataset with ground truth white matter tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. While most state-of-the-art algorithms reconstructed 90% of ground truth bundles to at least some extent, on average they produced four times more invalid than valid bundles. About half of the invalid bundles occurred systematically in the majority of submissions. Our results demonstrate fundamental ambiguities inherent to tract reconstruction methods based on diffusion orientation information, with critical consequences for the approach of diffusion tractography in particular and human connectivity studies in general.

neuroscience↗