Simon Dubeau

Cerebrovascular hemodynamic correlates of aging in the Lou/c rat: a model of healthy aging.

The LOU/c rat is an inbred strain considered a model of healthy aging. It exhibits a longer free disease lifespan and a low adiposity throughout life. While this animal model has been shown to maintain eating behavior and neuroendocrine, metabolic and cognitive functions with age, no study has yet investigated vascular correlates in this model of healthy aging. In the present work, multispectral optical imaging was used to investigate the hemodynamic response in the somatosensory cortex of LOU/c rats following forepaw stimulation in three age groups, 4, 24 and 40months. Results indicate reduced hemodynamic responses in the contralateral somatosensory cortex between young (4months) and older groups following stimulation. This decrease was associated with an increase in the spatial extent of activation. The ipsilateral response did not change with aging leading to decreased laterality. Estimations of the relative change in the local cerebral metabolic rate of oxygen during stimulation based on multimodal data showed no significant change with age. The exponent describing the relation between blood volume and blood flow changes, Grubbs parameter, did display a significant change with age which may suggest vessel compliance modifications. This work finds its relevance in recent findings underlying the importance of vascular changes with aging and its impact on neurodegenerative disease.

Characterization of the hemodynamic response in the rat lumbar spinal cord using intrinsic optical imaging and laser speckle

Quantifying spinal cord functions is crucial for understanding neurophysiological mechanisms governing the intact and the injured spinal cord. Intrinsic optical imaging (IOI) and laser speckle provides measures of deoxyhemoglobin (HbR) and oxyhemoglobin (HbO(2)) concentrations, blood volume (BV) and blood flow (BF) at high spatial and temporal resolution. In this study we used IOI and laser speckle to characterize the hemodynamic response to neuronal activation in the lumbar spinal cord of anaesthetized rats (N=9). We report consistent temporal variations of HbR, HbO(2), BV and BF located ipsilaterally at L3-L5. Responses were significantly higher when stimulation intensity was increased. Vascular changes extended several millimetres from the epicenter, supporting the venous drainage observed in functional magnetic resonance imaging studies.

Functional electrical stimulation post-spinal cord injury improves locomotion and increases afferent input into the central nervous system in rats.

Abstract Background Functional electrical stimulation (FES) has been found to be effective in restoring voluntary functions after spinal cord injury (SCI) and stroke. However, the central nervous system (CNS) changes that occur in as a result of this therapy are largely unknown. Objective To examine the effects of FES on the restoration of voluntary locomotor function of the CNS in a SCI rat model. Methods SCI rats were instrumented with chronic FES electrodes in the hindlimb muscles and were divided into two groups: (a) FES therapy and (b) sedentary. At day 7 post-SCI, the animals were assessed for locomotion performance by using a Basso, Beattie and Bresnahan (BBB) scale. They were then anesthetized for a terminal in vivo experiment. The lumbar spinal cord and somatosensory cortex were exposed and the instrumented muscles were stimulated electrically. Associated neurovascular responses in the CNS were recorded with an intrinsic optical imaging system. Results FES greatly improved locomotion recovery by day 7 post-SCI, as measured by BBB scores (P < 0.05): (a) FES 10 ± 2 and (b) controls 3 ± 1. Furthermore, the FES group showed a significant increase (P < 0.05) of neurovascular activation in the spinal cord and somatosensory cortex when the muscles were stimulated between 1 and 3 motor threshold (MT). Conclusion Hind limb rehabilitation with FES is an effective strategy to improve locomotion during the acute phase post-SCI. The results of this study indicate that after FES, the CNS preserves/acquires the capacity to respond to peripheral electrical stimulation.

Optical imaging of vascular and metabolic responses in the lumbar spinal cord after T10 transection in rats

Neuronal and vascular reorganization after spinal cord injury (SCI) is scarcely known although its characterization has major implications in understanding the functioning of the altered spinal cord. Several electrophysiological and anatomical lines of evidence support plasticity caudal to the lesion site, but do not provide sufficient clues about neuronal and vascular reorganization after SCI. The aim of the present study was to compare neuronal activation in the lumbar spinal cord between uninjured and SCI rats with novel optical imaging technology. The results showed significant haemodynamic response differences after sciatic nerve stimulation in uninjured controls, in comparison to SCI rats. Both timing and shape of the response were modified. In uninjured rats, blood flow presented an initial dip but was rapidly drained from the activation site through the venous system. In comparison, the blood transfer rate in SCI rats was much slower. Damaged blood vessels at the lesion site after thoracic SCI impacted the vascular response upon neuronal activation in the lumbar spinal cord. This observation is important in the study of spinal cord function after SCI by imaging techniques based on haemodynamics (blood oxygenation level-dependent using functional magnetic resonance imaging (BOLD fMRI) and optical imaging). In conclusion, our results indicate that new avenues quantifying the influence of vascular plumbing will have to be developed to explore the efficacy of rehabilitation and pharmacological therapies by haemodynamic imaging.

Biophysical model estimation of neurovascular parameters in a rat model of healthy aging

Neuronal, vascular and metabolic factors result in a deterioration of the cerebral hemodynamic response with age. The interpretation of neuroimaging studies in the context of aging is rendered difficult due to the challenge in untangling the composite effect of these modifications. In this work we integrate multimodal optical imaging in biophysical models to investigate vascular and metabolic changes occurring in aging. Multispectral intrinsic optical imaging of an animal model of healthy aging, the LOU/c rat, is used in combination with somatosensory stimulation to study the modifications of the hemodynamic response with increasing age. Results are fitted with three macroscopic biophysical models to extract parameters, providing a phenomenological description of vascular and metabolic changes. Our results show that 1) biophysical parameters are estimable from multimodal data and 2) parameter estimates in this population change with aging.

Multimodal study of the hemodynamic response to hypercapnia in anesthetized aged rats

With aging, the brain undergoes changes in metabolism and perfusion, both of which influence the widely used blood-oxygenation-level-dependent (BOLD) MRI signal. To isolate the vascular effects associated with age, this study measured the response to a hypercapnic challenge using different imaging modalities in 19 young (3 months-old) and 13 old (24 months-old) Long-Evans rats. Intrinsic optical imaging was used to measure oxy (HbO), deoxy (HbR) and total (HbT) hemoglobin concentration changes, laser speckle for cerebral blood flow (CBF) changes, and MRI for the BOLD signal. Older rats had smaller HbO (41% smaller), HbT (50%) and CBF (34%) responses, but the temporal dynamics did not exhibit significant age differences. The ratio of CBV to CBF responses was also smaller in older adults, potentially indicating a change in the compliance of vessels.

Neurovascular deconvolution of optical signals as a proxy for the true neuronal inputs

UNLABELLED Since the Kalman filter and Monte Carlo techniques, much theoretical work has been put into the development of signal deconvolution tools. Among recent developments taking place in neuroscience are Dynamic Expectation Maximization, Generalized Filtering and the Cubature Kalman Filter. While there are exciting prospects to use these tools for Dynamic Causal Modeling and other analyses of networks, there has been comparatively little work to validate the algorithms on controlled experimental data. In this work, the latest evolution of these tools, the square-root cubature Kalman smoother (SCKS), is tested for its effectiveness on multimodal neurovascular data. Multispectral intrinsic optical imaging and electrophysiological measurements of Wistar rats are used in combination with somatosensory stimulation. The Buxton-Friston (B-F) balloon model is then deconvolved with the SCKS algorithm to obtain the estimated neuronal inputs u(t) from the hemodynamic measurements (flow, oxy- and deoxygenated hemoglobin). RESULTS The estimated neuronal inputs are compared to the stimulation protocol and a sensitivity and specificity analysis is carried out. SCKS succeeds in recovering most of the stimulations. Next, the estimated inputs are compared to actual measures of neuronal activity: local field potentials (LFPs) and multiunit activity (MUA). Good sensitivity of the technique is obtained with both LFPs and MUA over the whole recordings, with the area of the ROC curves favoring LFPs. A weak correlation between SCKS estimated inputs and LFPs is found outside stimulation periods, significant at one standard deviation. Finally, the accuracy of state reconstructions is studied and SCKS reconstructed states are highly concordant with measured states.

Tight neurovascular coupling in a rat model of quasi-periodic interictal spiking using multispectral optical imaging

The hemodynamic responses to 4-aminopyridine (4-AP) induced focal epileptic spikes and electrical stimulations are compared in a rat model. Nonlinearities are quantified with biophysical models. Supranormal oxygen consumption from epileptic spikes is inferred. In one recording, interictal spikes followed an almost periodic pattern. Such rhythmic spiking is a well-documented phenomenon in electrophysiological studies, but the hemodynamics correlates have been less studied. Spikes occurred every 12.5 ± 1.0 s. Peaks in total hemoglobin (HbT), a proxy for regional cerebral blood volume, followed spikes by 2.6 ± 0.3 s. Troughs in HbT preceded spikes by 1.68 ± 1.2 s. The narrowness of this distribution is surprising. From it, one may derive a significant but paradoxical fall in HbT several seconds before the spikes, but which this decrease in HbT is better interpreted as being due to the interictal spike that occurred before.

Microscopic Dynamics of Cerebral Capillary Blood Flow in Aged Anesthetized Rats

Using two-photon laser scanning fluorescence microscopy in cerebral capillaries of anesthetized rats, we measured higher red blood cell speed and capillary diameter in old animals, but lower capillary hematocrit and density.

Biophysical Model Estimation from Multispectral Intrinsic Optical Imaging in a Rat Model of Epilepsy

The hemodynamic responses to 4-AP induced focal epileptic spikes and electrical stimulations are compared in a rat model. Nonlinearities are quantified with biophysical models. Supranormal oxygen consumption from epileptic spikes is inferred.