Biology subjects

Ivanov, D.

Publications and source records attributed to Ivanov, D..

25 records · Page 2Linked to original sources

bioRxiv2021

Neurodegenerative and functional signatures of the cerebellar cortex in m.3243A>G patients

Mutations of the mitochondrial DNA are an important cause of inherited diseases that can severely affect the tissues homeostasis and integrity. The m.3243A>G mutation is the most commonly observed across mitochondrial disorders and is linked to multisystemic complications, including cognitive deficits. In line with in vitro experiments demonstrating the m.3243A>Gs negative impact on neuronal energy production and integrity, m.3243A>G patients show cerebral gray matter tissue changes. However, its impact on the most neuron-dense, and therefore energy-consuming brain structure - the cerebellum - remains elusive. In this work, we used high resolution structural and functional data acquired using 7 Tesla MRI to characterize the neurodegenerative and functional signatures of the cerebellar cortex in m.3243A>G patients. Our results reveal altered tissue integrity within distinct clusters across the cerebellar cortex, apparent by their significantly reduced volume and longitudinal relaxation rate compared to healthy controls, indicating macroscopic atrophy and microstructural pathology. Spatial characterization reveals that these changes occur especially in regions related to the frontoparietal brain network that is involved in information processing and selective attention. In addition, based on resting-state fMRI data, these clusters exhibit reduced functional connectivity to frontal and parietal cortical regions, especially in patients characterized by (i) a severe disease phenotype and (ii) reduced information processing speed and attention control. Combined with our previous work, these results provide insight into the neuropathological changes and a solid base to guide longitudinal studies aimed to track disease progression.

neuroscience↗

bioRxiv2020

Guiding functional near-infrared spectroscopy optode-layout design using individual (f)MRI data: Effects on signal quality and sensitivity

Designing optode layouts is an essential step for functional near-infrared spectroscopy (fNIRS) experiments as the quality of the measured signal and the sensitivity to cortical regions-of-interest depend on how optodes are arranged on the scalp. This becomes particularly relevant for fNIRS-based brain-computer interfaces (BCIs), where developing robust systems with few optodes is crucial for clinical applications. Available resources often dictate the approach researchers use for optode-layout design. Here we compared four approaches that incrementally incorporated subject-specific magnetic resonance imaging (MRI) information while participants performed mental-calculation, mental-rotation and inner-speech tasks. The literature-based approach (LIT) used a literature review to guide the optode layout design. The probabilistic approach (PROB), employed individual anatomical data and probabilistic maps of functional MRI (fMRI)-activation from an independent dataset. The individual fMRI (iFMRI) approach used individual anatomical and fMRI data, and the fourth approach used individual anatomical, functional and vascular information of the same subject (fVASC). The four approaches resulted in different optode layouts and the more informed approaches outperformed the minimally informed approach (LIT) in terms of signal quality and sensitivity. Further, PROB, iFMRI and fVASC approaches resulted in a similar outcome. We conclude that additional individual MRI data leads to a better outcome, but that not all the modalities tested here are required to achieve a robust setup. Finally, we give preliminary advice to efficiently using resources for developing robust optode layouts for BCI and neurofeedback applications.

neuroscience↗

bioRxiv2020

Sub-millimetre resolution laminar fMRI using Arterial Spin Labelling in humans at 7T

Laminar fMRI at ultra-high magnetic field strength is typically carried out using the Blood Oxygenation Level-Dependent (BOLD) contrast. Despite its unrivalled sensitivity to detecting activation, the BOLD contrast is limited in its spatial specificity due to signals stemming from intra-cortical ascending and pial veins. Alternatively, regional changes in perfusion (i.e., cerebral blood flow through tissue) are colocalised to neuronal activation, which can be non-invasively measured using arterial spin labelling (ASL) MRI. In addition, ASL provides a quantitative marker of neuronal activation in terms of perfusion signal, which is simultaneously acquired along with the BOLD signal. However, ASL for laminar imaging is challenging due to the lower SNR of the perfusion signal and higher RF power deposition i.e., specific absorption rate (SAR) of ASL sequences. In the present study, we present for the first time in humans, isotropic sub-millimetre spatial resolution functional perfusion images using Flow-sensitive Alternating Inversion Recovery (FAIR) ASL with a 3D-EPI readout at 7T. We show that robust statistical activation maps can be obtained with perfusion-weighting in a single session. We observed the characteristic BOLD amplitude increase towards the superficial laminae, and, in apparent discrepancy, the relative perfusion profile shows a decrease of the amplitude and the absolute perfusion profile a much smaller increase towards the cortical surface. Considering the draining vein effect on the BOLD signal using model-based spatial convolution, we show that the empirically measured perfusion and BOLD profiles are, in fact, consistent with each other. This study demonstrates that laminar perfusion fMRI in humans is feasible at 7T and that caution must be exercised when interpreting BOLD signal laminar profiles as direct representation of the cortical distribution of neuronal activity.

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↗

bioRxiv2019

Depth-resolved ultra-high field fMRI reveals feedback contributions to surface motion perception

Human visual surface perception has neural correlates in early visual cortex, but the extent to which feedback contributes to this activity is not well known. Feedback projections preferentially enter superficial and deep anatomical layers, while avoiding the middle layer, which provides a hypothesis for the cortical depth distribution of fMRI activity related to feedback in early visual cortex. Here, we presented human participants uniform surfaces on a dark, textured background. The grey surface in the left hemifield was either perceived as static or moving based on a manipulation in the right hemifield. Physically, the surface was identical in the left visual hemifield, so any difference in percept likely was related to feedback. Using ultra-high field fMRI, we report the first evidence for a depth distribution of activation in line with feedback during the (illusory) perception of surface motion. Our results fit with a signal re-entering in superficial depths of V1, followed by a feedforward sweep of the re-entered information through V2 and V3, as suggested by activity centred in the middle-depth levels of the latter areas. This positive modulation of the BOLD signal due to illusory surface motion was on top of a strong negative BOLD response in the cortical representation of the surface stimuli, which depended on the presence of texture in the background. Hence, the magnitude and sign of the BOLD response to the surface strongly depended on background properties, and was additionally modulated by the presence or absence of illusory motion perception in a manner compatible with feedback. In summary, the present study demonstrates the potential of depth resolved fMRI in tackling biomechanical questions on perception that so far were only within reach of invasive animal experimentation.

neuroscience↗

bioRxiv2018

Sub-millimeter fMRI reveals multiple topographical digit representations that form action maps in human motor cortex

The human brain coordinates a wide variety of motor activities. On a large scale, the cortical motor system is topographically organized such that neighboring body parts are represented by neighboring brain areas. This homunculus-like somatotopic organization along the central sulcus has been observed using neuroimaging for large body parts such as the face, hands and feet. However, on a finer scale, invasive electrical stimulation studies show deviations from this somatotopic organization that suggest an organizing principle based on motor actions rather than body part moved. It has not been clear how the action-map organization principle of the motor cortex in the mesoscopic (sub-millimeter) regime integrates into a body map organization principle on a macroscopic scale (cm). Here we developed and applied advanced mesoscopic (sub-millimeter) fMRI and analysis methodology to non-invasively investigate the functional organization topography across columnar and laminar structures in humans. We find that individual fingers have multiple mirrored representations in the primary motor cortex depending on the movements they are involved in. We find that individual digits have cortical representations up to 3 mm apart from each other arranged in a column-like fashion. These representations are differentially engaged depending on whether the digits muscles are used for different motor actions such as flexion movements like grasping a ball or retraction movements like releasing a ball. This research provides a starting point for noninvasive investigation of mesoscale topography across layers and columns of the human cortex and bridges the gap between invasive electrophysiological investigations and large coverage non-invasive neuroimaging.

neuroscience↗

bioRxiv2018

Gene-Based Analysis in HRC Imputed Genome Wide Association Data Identifies Three Novel Genes For Alzheimer’s Disease

A novel POLARIS gene-based analysis approach was employed to compute gene-based polygenic risk score (PRS) for all individuals in the latest HRC imputed GERAD (N cases=3,332 and N controls=9,832) data using the International Genomics of Alzheimers Project summary statistics (N cases=13,676 and N controls=27,322, excluding GERAD subjects) to identify the SNPs and weight their risk alleles for the PRS score. SNPs were assigned to known, protein coding genes using GENCODE (v19). SNPs are assigned using both 1) no window around the gene and 2) a window of 35kb upstream and 10kb downstream to include transcriptional regulatory elements. The overall association of a gene is determined using a logistic regression model, adjusting for population covariates.\n\nThree novel gene-wide significant genes were determined from the POLARIS gene-based analysis using a gene window; PPARGC1A, RORA and ZNF423. The ZNF423 gene resides in an Alzheimers disease (AD)-specific protein network which also includes other AD-related genes. The PPARGC1A gene has been linked to energy metabolism and the generation of amyloid beta plaques and the RORA has strong links with genes which are differentially expressed in the hippocampus. We also demonstrate no enrichment for genes in either loss of function intolerant or conserved noncoding sequence regions.

genetics↗