Biology subjects

Dijkhuizen, R. M.

Publications and source records attributed to Dijkhuizen, R. M..

7 recordsLinked to original sources

bioRxiv2026

Loss of FMRP leads to translationally relevant functional connectivity differences in a rat model of Fragile X Syndrome

Fragile X syndrome (FXS), a leading monogenic cause of intellectual disability and autism-related features, results from loss of fragile X messenger ribonucleoprotein (FMRP). Although early synaptic and cellular abnormalities associated with the loss of FMRP are well described, it remains unclear how these changes shape the maturation of large-scale functional networks, or whether early pharmacological intervention can normalize circuit development. Our previous work demonstrated that cognitive deficits in Fmr1-/y rats emerge during development and can be prevented by brief early-life lovastatin treatment. Here, we asked whether large-scale functional connectivity (FC) shows a similarly dynamic developmental trajectory and whether early intervention alters its emergence. Using longitudinal resting-state functional magnetic resonance imaging (rsfMRI), we found that Fmr1-/y rats displayed an age-dependent FC phenotype, with increased connectivity within the retrosplenial cortex (RSC) at 4 weeks but reduced connectivity within the RSC and distributed brain networks by adulthood compared with wild-type controls. This suggests FC abnormalities emerge over development rather than representing a stable deficit. In contrast to its effects on cognitive measures, brief early-life lovastatin treatment rescues did not prevent the emergence of connectivity abnormalities. Reduced RSC FC was also observed in a small cohort of individuals with FXS (n = 5 per group), supporting further investigation of functional connectivity measures alongside behavioural and molecular endpoints in translational studies of FXS.

neuroscience↗

bioRxiv2024

Chronic hypertension and perfusion deficits conjointly affect disease outcome after tPA treatment in a rodent model of thromboembolic stroke

Futile recanalization hampers prognoses for ischemic stroke patients despite successful recanalization therapy. Allegedly, hypertension and reperfusion deficits contribute, but a better understanding is needed of how they interact and mediate disease outcome. We assessed data from spontaneously hypertensive and normotensive Wistar-Kyoto rats (male, n=6-7/group) that were subjected to two-hour embolic middle cerebral artery occlusion and thrombolysis in preclinical trials. Serial MRI allowed lesion monitoring and parcellation of regions-of-interest that represented infarcted (core) or recovered (perilesional) tissue. Imaging markers of hemodynamics and blood-brain barrier (BBB) status were related to tissue fate and neurological outcome. Despite comparable ischemic severity during occlusion between groups, hypertensive rats temporarily developed larger lesions after recanalization, with permanently aggravated vasogenic edema and BBB permeability. One day post-stroke, cerebral blood flow (CBF) was variably restored, but blood transit times were consistently prolonged in hypertensives. Compared to the core, perilesional CBF was normo-to- hyperperfused in both groups, yet this pattern reversed after seven days. Volumes of hypo- and hyperperfusion developed irrespective of strain, differentially associating with final infarct volume and behavioral outcome. Incomplete reperfusion and cerebral injury after thrombolysis were augmented in hypertensive rats. One day after thrombolysis, hypoperfusion associated with worsened outcomes, while regional hyperperfusion appeared beneficial or benign.

pathology↗

bioRxiv2023

A validation approach for computational models of TMSinduced brain currents using motor evoked potentials

The adoption of transcranial magnetic stimulation (TMS) has steadily increased in research as a tool capable to safely and non-invasively stimulate both the central and peripheral nervous systems. Initial clinical applications were limited to diagnostic use of TMS and readout signals such as electromyograms (EMG). Subsequently, repetitive TMS (rTMS) was appreciated for its therapeutics benefits as well. However, even after a decade of use of rTMS as an alternative treatment of major depression disorder in psychiatry, the mechanism of action is still not well understood. Computer models predicting the induced electric field distribution in the brain have been suggested before in the hope to resolve at least some of the uncertainty and resulting variable treatment response associated with the clinical use of TMS. We constructed a finite element model (FEM) of the head using individual volumetric tissue meshes obtained from an MRI scan and a detailed model of a TMS coil that together can predict the current induced in the head of a patient at any given location with any given coil position and orientation. We further designed several potential metrics of how a TMS induced current induced neuronal activation in the motor cortex, and added this to the model. We validated this model with motor evoked potentials (MEPs), EMG responses of the hand muscles after TMS on the motor cortex, in an experiment on 9 healthy subjects. We adopted a tailored MEP mapping protocol for model validation, which unlike traditional grid mappings, varies the TMS machine output intensity between stimulation locations. We further varied coil orientation on each point stimulated to allow exploration of the angular dependency of the model MEPs. Taken together, this approach covers a wide domain and scope of the modeled and measured responses, which are optimally suited for model validation. For each subject the motor hotspot was carefully identified using individual cortical anatomy and BOLD fMRI measurements. Modeled activation in the motor cortex did not show a good correlation to the observed magnitude of the observed MEPs, for none of the neuronal activation metrics adopted. For an activation metric that was asymmetric, taking into account induced current direction with respect to the motor cortex sulcal wall, was marginally better than other metrics. Generally all activation metrics based on induced currents performed better than a control metric agnostic of induced electric field magnitude. Our results suggest that one should take into account components of the injected currents and their relationship to the morphology of the underlying motor cortex, but the coarse metrics we used to model the relationship between induced current and neuronal activation probably did not do justice to the complex neuronal circuitry of the cortical sheet. Furthermore, it seemed MEP magnitudes in our experiment are too variable over subsequent stimulations, which could be mitigated by more repetitions per stimulation location and orientation. Further efforts to construct validated models predicting TMS effects in individual patients brains should incorporate microcircuits interactions in the cortical sheet, in addition to induced electrical field models, and take into account inherent trial to trial variability of MEPs.

neuroscience↗

bioRxiv2019

Distinct structure-function relationships across cortical regions and connectivity scales in the rat brain

An improved understanding of the structure-function relationship in the brain is necessary to know to what degree structural connectivity underpins abnormal functional connectivity seen in many disorders. We integrated high-field resting-state fMRI-based functional connectivity with high-resolution macro-scale diffusion-based and meso-scale neuronal tracer-based structural connectivity, to obtain an accurate depiction of the structure-function relationship in the rat brain. Our main goal was to identify to what extent structural and functional connectivity strengths are correlated, macro- and meso-scopically, across the cortex. Correlation analyses revealed a positive correspondence between functional connectivity and macro-scale diffusion-based structural connectivity, but no correspondence between functional connectivity and meso-scale neuronal tracer-based structural connectivity. Locally, strong functional connectivity was found in two well-known resting-state networks: the sensorimotor and default mode network. Strong functional connectivity within these networks coincided with strong short-range intrahemispheric structural connectivity, but with weak heterotopic interhemispheric and long-range intrahemispheric structural connectivity. Our study indicates the importance of combining measures of connectivity at distinct hierarchical levels to accurately determine connectivity across networks in the healthy and diseased brain. Distinct structure-function relationships across the brain can explain the organization of networks and may underlie variations in the impact of structural damage on functional networks and behavior.

neuroscience↗

bioRxiv2019

Skill acquisition increases myelination and strengthens functional connectivity in the sensorimotor circuit of the adult rat

The effects of skill acquisition on whole-brain structure and functional networks have been extensively investigated in humans but have yet to be explored in rodents. Forelimb reaching training in rodents results in well-established focal functional and structural reorganization within the motor cortex (M1) and cerebellum, indicating distributed alterations in both structure and function. However, it is unclear how local alterations in structure and function relate to distributed learning-related changes across motor networks. Here we trained adult rats in skilled reaching and used multimodal whole-brain in vivo MRI to assess both structural and functional plasticity over time.\n\nWe detected increases in a myelin-related MRI metric in white matter, cortical areas, and to a lesser extent in the cerebellum, paralleled by strengthened functional connectivity between M1 and cerebellum, possibly reflecting a decrease in cerebellum inhibition over M1. Skill learning therefore leads to myelin increases in pathways that connect sensorimotor regions, and in functional connectivity increases between areas involved in motor learning, all of which correlate with performance. These findings closely mirror previous reports of network-level changes following motor learning in humans and underlines the correspondence between human and rodent brain circuits for motor learning, despite important differences in the anatomy of physiology of movement circuits between species.

neuroscience↗

bioRxiv2018

Outcome of TMS-based motor mapping depends on TMS current direction

Navigated transcranial magnetic stimulation (TMS) in combination with electromyography (EMG) recordings can be used to map the brain regions in which TMS evokes motor-evoked potentials (MEPs) in certain muscles. Navigated TMS (nTMS) is used increasingly to identify the functional motor area of different muscles for clinical applications, including neurosurgical planning. However, the accuracy of TMS-based mapping of functional motor areas may depend on the TMS-induced current direction due to anisotropic cortical morphology, complicating association of the functional motor maps with neuroanatomical structures. Furthermore, it is not clear how well nTMS can distinguish nearby muscle representations on the cortical surface. We therefore investigated the functional motor maps obtained with posterior-to-anterior (PA) and lateral-to-medial (LM) TMS-induced currents within a spatially defined area by stimulating targets in a grid of locations over the left primary motor cortex in 8 healthy participants. Results were compared to functional MRI (fMRI) activation maps obtained using a voluntary opposing thumb movement task. We found that TMS applied with PA-induced currents identifies a motor area that is located significantly more anterior (8.7 - 10.4 mm depending on the muscle) with respect to an MEP motor area identified using LM-induced currents for the same muscle. Motor maps obtained with LM-induced currents show more overlap with the motor map identified using fMRI compared to PA-induced currents. In conclusion, the spatial representation of the MEP motor map identified by TMS is dependent on the direction of the induced current. These findings suggest that the application of nTMS using an LM-induced current direction corresponds best with the hand motor area as measured with fMRI.

neuroscience↗

bioRxiv2018

The power of language: functional brain network topology of deaf and hearing in relation to sign language experience

Prolonged auditory sensory deprivation leads to brain reorganization, indicated by functional enhancement in remaining sensory systems, a phenomenon known as cross-modal plasticity. In this study we investigated differences in functional brain network shifts from eyes-closed to eyes-open conditions between deaf and hearing people. Electroencephalography activity was recorded in deaf (N = 71) and hearing people (N = 122) living in rural Africa, which yielded a unique data-set of congenital, pre-lingual and post-lingual deaf people, with a divergent experience in American Sign Language. Functional networks were determined from the synchronization of electroencephalography signals between fourteen electrodes distributed over the scalp. We studied the synchronization between the auditory and visual cortex and performed whole-brain minimum spanning tree analysis based on the phase lag index of functional connectivity. This tree analysis accounts for variations in global network density and allows unbiased characterization of functional network backbones. We found increased functional connectivity between the auditory and visual cortex in deaf people during the eyes-closed condition in both the alpha and beta bands. Furthermore, we found functional network backbone shifts both in deaf and healthy people as they went from eyes-closed to eyes-open conditions. In both the alpha and beta band the deafs brain showed larger functional backbone-shifts in node strength compared to controls. In the alpha band this shift in network strength differed among deaf participants and depended on type of deafness: congenital, pre-lingual or post-lingual deafness. In addition, a correlation was found between functional backbone characteristics and experience of sign language. Our study revealed more insights in functional network reorganization specifically due to prolonged lack of auditory input, but might also be helpful for sensory deprivation and cross-modal plasticity in general. Global cortical network reorganization in deaf people supports the plastic capacities of the young brain. The differences between type of deafness stresses that etiology affects functional reorganization, whereas the association between network organization and acquired sign language experience reflects ongoing brain adaptation in people with hearing disabilities.

neuroscience↗