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Fatima A. Nasrallah

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12 papers

2 author rows

YNICL Journal 2020 Journal Article

Evaluating spatiotemporal microstructural alterations following diffuse traumatic brain injury

Abdalla Z Mohamed
Frances Corrigan
Lyndsey E. Collins-Praino
Stephanie L. Plummer
Neha Soni
Fatima A. Nasrallah

BACKGROUND: Diffuse traumatic brain injury (TBI) is known to lead to microstructural changes within both white and grey matter detected in vivo with diffusion tensor imaging (DTI). Numerous studies have shown alterations in fractional anisotropy (FA) and mean diffusivity (MD) within prominent white matter tracts, but few have linked these to changes within the grey matter with confirmation via histological assessment. This is especially important as alterations in the grey matter may be predictive of long-term functional deficits. METHODS: A total of 33 male Sprague Dawley rats underwent severe closed-head TBI. Eight animals underwent tensor-based morphometry (TBM) and DTI at baseline (pre-TBI), 24 hours (24 h), 7, 14, and 30 days post-TBI. Immunohistochemical analysis for the detection of ionised calcium-binding adaptor molecule 1 (IBA1) to assess microglia number and percentage of activated cells, β-amyloid precursor protein (APP) as a marker of axonal injury, and myelin basic protein (MBP) to investigate myelination was performed at each time-point. RESULTS: DTI showed significant alterations in FA and RD in numerous white matter tracts including the corpus callosum, internal and external capsule, and optic tract and in the grey-matter in the cortex, thalamus, and hippocampus, with the most significant effects observed at 14 D post-TBI. TBM confirmed volumetric changes within the hippocampus and thalamus. Changes in DTI were in line with significant axonal injury noted at 24 h post-injury via immunohistochemical analysis of APP, with widespread microglial activation seen within prominent white matter tracts and the grey matter, which persisted to 30 D within the hippocampus and thalamus. Microstructural alterations in MBP+ve fibres were also noted within the hippocampus and thalamus, as well as the cortex. CONCLUSION: This study confirms the widespread effects of diffuse TBI on white matter tracts which could be detected via DTI and extends these findings to key grey matter regions, with a comprehensive investigation of the whole brain. In particular, the hippocampus and thalamus appear to be vulnerable to ongoing pathology post-TBI, with DTI able to detect these alterations supporting the clinical utility in evaluating these regions post-TBI.

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YNIMG Journal 2019 Journal Article

Evaluation of nuisance removal for functional MRI of rodent brain

Kai-Hsiang Chuang
Hsu-Lei Lee
Zengmin Li
Wei-Tang Chang
Fatima A. Nasrallah
Ling Yun Yeow
Kavita Kaur D./O.Ranjit Singh

Functional MRI (fMRI) has become an important translational tool for studying brain activity and connectivity in animal models and humans. For accurate and reliable measurement of functional connectivity, nuisance removal strategies developed for human brain, such as regressing motion parameters, cerebrospinal fluid (CSF)/white matter-derived signals and the global signal, have been applied to rodent. However, due to the very different anatomy, with the majority of the rodent brain being gray matter, and experimental conditions, in which animals are anesthetized and head-fixed, these methods may not be suitable for rodent fMRI. In this study, we assessed various nuisance regression methods and the effects of motion correction on a large dataset of both task and resting fMRI of anesthetized rat brain. Sensitivity and specificity were assessed in the somatosensory pathway under forepaw stimulation and resting state. Reproducibility at various sample sizes was simulated by randomly subsampling the dataset. To overcome the difficulty in extracting nuisance from the brain, a method using principal components estimated from tissues outside the brain was evaluated. Our results showed that neither detrend, motion correction, motion regression nor CSF signal regression could improve specificity despite increasing temporal signal-to-noise ratios. Although global signal regression increased the specificity of task activation and functional connectivity, the sensitivity and connectivity strength was drastically reduced, likely due to its strong correlation with the cortical signal. Motion parameters also correlated with task activation and the global signal, indicating that motion correction detected intensity variations in the brain. The nuisance estimated from tissues outside the brain produced a moderate improvement in specificity. In conclusion, nuisance removal suitable for human fMRI may not be optimal for rodents. While further development is needed, estimating nuisance from tissues outside the brain may be an alternative.

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YNIMG Journal 2019 Journal Article

Functional connectivity of brain associated with passive range of motion exercise: Proprioceptive input promoting motor activation?

Fatima A. Nasrallah
Abdalla Z. Mohamed
Megan EJ. Campbell
Hong Kai Yap
Chen-Hua Yeow
Jeong Hoon Lim

Soft robotics have come to the forefront of devices available for rehabilitation following stroke; however, objective evaluation of the specific brain changes following rehabilitation with these devices is lacking. In this study, we utilized functional Magnetic Resonance Imaging (fMRI) and dynamic causal modeling (DCM) to characterize the activation of brain areas with a MRI compatible glove actuator compared to the conventional manual therapy. Thirteen healthy volunteers engaged in a motor-visual fMRI task under four different conditions namely active movement, manual passive movement, passive movement using a glove actuator, and crude tactile stimulation. Brain activity following each task clearly identified the somatosensory motor area (SMA) as a major hub orchestrating activity between the primary motor (M1) and sensory (S1) cortex. During the glove-induced passive movement, activity in the motor-somatosensory areas was reduced, but there were significant increases in motor cortical activity compared to manual passive movement. We estimated the modulatory signaling from within a defined sensorimotor network (SMA, M1, and S1), through DCM and highlighted a dual-gating of sensorimotor inputs to the SMA. Proprioceptive signaling from S1 to the SMA reflected positive coupling for the manually assisted condition, while M1 activity was positively coupled to the SMA during the glove condition. Importantly, both the S1 and M1 were shown to influence each other’s connections with the SMA, with inhibitory nonlinear modulation by the M1 on the S1-SMA connection, and similarly S1 gated the M1-SMA connection. The work is one of the first to have applied effective connectivity to examine sensorimotor activity ensued by manual or robotic passive range of motion exercise, crude tactile stimulation, and voluntary movements to provide a basis for the mechanism by which soft actuators can alter brain activity.

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YNICL Journal 2019 Journal Article

Response to the letter concerning the publication: Amyloid pathology fingerprint differentiates post-traumatic stress disorder and traumatic brain injury. Mohamed AZ, et al. NeuroImage Clinical 2018 June 5;19:716–726

Abdalla Z. Mohamed
Paul Cumming
Fatima A. Nasrallah

In August 2018, Weiner and colleagues raised a red flag concerning certain errors in the tables and figures of our article, "Amyloid pathology fingerprint differentiates post-traumatic stress disorder and traumatic brain injury. NeuroImage Clinical 2018 Jun 5;19:716-726". We have addressed this in detail in our published "Corrigendum to 'Amyloid pathology fingerprint differentiates post-traumatic stress disorder and traumatic brain injury' NeuroImage: Clinical. 19 (2018) 716-726". However, recently Prof. Weiner and colleagues have raised a new issue in indicating that they could not 'replicate our results, despite accurately emulating our methods. We have prepared this letter in response to their recent letter.

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YNIMG Journal 2017 Journal Article

Functional networks and network perturbations in rodents

Kai-Hsiang Chuang
Fatima A. Nasrallah

Synchronous low-frequency oscillation in the resting human brain has been found to form networks of functionally associated areas and hence has been widely used to map the functional connectivity of the brain using techniques such as resting-state functional MRI (rsfMRI). Interestingly, similar resting-state networks can also be detected in the anesthetized rodent brain, including the default mode-like network. This opens up opportunities for understanding the neurophysiological basis of the rsfMRI signal, the behavioral relevance of the network characteristics, connectomic deficits in diseases and treatment effects on brain connectivity using rodents, particularly transgenic mouse models. In this review, we will provide an overview on the resting-state networks in the rat and mouse brains, the effects of pharmacological agents, brain stimulation, structural connectivity, genetics on these networks, neuroplasticity after behavioral training and applications in models of neurological disease and psychiatric disorders. The influence of anesthesia, strain difference, and physiological variation on the rsfMRI-based connectivity measure will be discussed.

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YNIMG Journal 2017 Journal Article

GABAergic effect on resting-state functional connectivity: Dynamics under pharmacological antagonism

Fatima A. Nasrallah
Kavita Kaur D./O.Ranjit Singh
Ling Yun Yeow
Kai-Hsiang Chuang

Resting state functional connectivity MRI measures synchronous activity among brain regions although the mechanisms governing the temporally coherent BOLD signals remain unclear. Recent studies suggest that γ-amino butyric acid (GABA) levels are correlated with functional connectivity. To understand whether changes in GABA transmission alter functional connectivity, we modulated the GABAergic activity by a GABAA receptor antagonist, bicuculline. Resting and evoked electrophysiology and BOLD signals were measured in isoflurane-anesthetized rats under infusion of low-dose bicuculline or vehicle individually. Both somatosensory BOLD activations and evoked potentials induced by forepaw stimulation were increased significantly under bicuculline compared to vehicle, indicating increased excitability. Gradually elevated resting BOLD correlation within and between the somatosensory and visual cortices, as well as between somatosensory and caudate putamen but not within subcortical areas were found with the infusion of bicuculline. Increased cerebral blood flow was observed throughout the cortical and subcortical areas where the receptor density is high, but it didn’t correlate with BOLD connectivity except in the primary somatosensory cortex. Furthermore, resting EEG coherence in the alpha and beta bands exhibited consistent change with the BOLD correlation. The increased cortico-cortical and cortico-striatal connectivity without dependence on the receptor distribution indicate that the functional connectivity may be mediated by long-range projection via the cortical and striatal GABAergic inter-neurons. Our results indicate an important role of the GABAergic system on neural and hemodynamic oscillations, which further supports the neuronal basis of functional connectivity MRI and its correlation with neurotransmission.

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YNIMG Journal 2016 Journal Article

Functional connectivity MRI tracks memory networks after maze learning in rodents

Fatima A. Nasrallah
Xuan Vinh To
Der-Yow Chen
Aryeh Routtenberg
Kai-Hsiang Chuang

Learning and memory employs a series of cognitive processes which require the coordination of multiple areas across the brain. However in vivo imaging of cognitive function has been challenging in rodents. Since these processes involve synchronous firing among different brain loci we explored functional connectivity imaging with resting-state fMRI. After 5-day training on a hidden platform watermaze task, notable signal correlations were seen between the hippocampal CA3 and other structures, including thalamus, septum and cingulate cortex, compared to swim control or naïve animals. The connectivity sustained 7days after training and was reorganized toward the cortex, consistent with views of memory trace distribution leading to memory consolidation. These data demonstrates that, after a cognitive task, altered functional connectivity can be detected in the subsequently sedated rodent using in vivo imaging. This approach paves the way to understand dynamics of area-dependent distribution processes in animal models of cognition.

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ICRA Conference 2015 Conference Paper

A soft exoskeleton for hand assistive and rehabilitation application using pneumatic actuators with variable stiffness

Hong Kai Yap
Jeong Hoon Lim
Fatima A. Nasrallah
James C. H. Goh
Raye C. H. Yeow

In this paper, we present the design of a soft wearable exoskeleton that comprises of a glove embedded with pneumatic actuators of variable stiffness for hand assistive and rehabilitation application. The device is lightweight and easily wearable due to the usage of soft pneumatic actuators. A key feature of the device is the variable stiffness of the actuators at different localities that not only conform to the finger profile during actuation, but also provides customizability for different hand dimensions. The actuators can achieve different bending profiles with variable stiffness implemented at different localities. Therefore, the device is able to perform different hand therapy exercises such as full fist, straight fist, hook fist and table top. The device was characterized in terms of its range of motion and maximum force output. Experiments were conducted to examine the differences between active and passive actuation. The results showed that the device could achieve hand grasping and pinching with acceptable range of motion and force.

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YNIMG Journal 2015 Journal Article

Dependence of BOLD signal fluctuation on arterial blood CO2 and O2: Implication for resting-state functional connectivity

Fatima A. Nasrallah
Ling Yun Yeow
Bharat Biswal
Kai-Hsiang Chuang

Blood oxygenation level dependent (BOLD) functional MRI signal is known to be modulated by the CO2 level. Typically only end-tidal CO2, rather than the arterial partial pressure of CO2 (paCO2), was measured while the arterial partial pressure of O2 (paO2) level was not controlled due to free breathing, making their contribution not separable. Especially, the influences of paO2 and paCO2 on resting-state functional connectivity are not well studied. In this study, we investigated the relationship between paCO2 and resting as well as stimulus-evoked BOLD signals under hyperoxic and hypercapnic manipulation with tight control of arterial paO2. Rats under isoflurane anesthesia were subjected to six inspired gas conditions: 47% O2 in air (Normal), adding 1%, 2% or 5% CO2, carbogen (95% O2/5% CO2), and 100% O2. Somatosensory BOLD activation was significantly increased under 100% O2, while reduced with increased paCO2 levels. However, while resting BOLD connectivity pattern expanded and bilateral correlation increased under 100% O2, the correlation coefficient between the left and right somatosensory cortex was generally not dependent on paCO2 or paO2. Interestingly, the correlation in 0. 04–0. 07Hz range significantly increased with CO2 levels. Intracortical electrophysiological recordings showed a similar trend as the BOLD but the neurovascular coupling varied. The results suggest that paO2 and paCO2 together rather than paCO2 alone alter the BOLD signal. The response is not purely vascular in nature but has strong neuronal origins. This should be taken into consideration when designing calibrated BOLD experiment and interpreting functional connectivity data especially in aging, under drug, or neurological disorders.

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YNIMG Journal 2014 Journal Article

Detection of functional connectivity in the resting mouse brain

Fatima A. Nasrallah
Hui-Chien Tay
Kai-Hsiang Chuang

Resting-state functional connectivity, manifested as spontaneous synchronous activity in the brain, has been detected by functional MRI (fMRI) across species such as humans, monkeys, and rats. Yet, most networks, especially the classical bilateral connectivity between hemispheres, have not been reliably found in the mouse brain. This could be due to anesthetic effects on neural activity and difficulty in maintaining proper physiology and neurovascular coupling in anesthetized mouse. For example, α2 adrenoceptor agonist, medetomidine, is a sedative for longitudinal mouse fMRI. However, the higher dosage needed compared to rats may suppress the functional synchrony and lead to unilateral connectivity. In this study, we investigated the influence of medetomidine dosage on neural activation and resting-state networks in mouse brain. We show that mouse can be stabilized with dosage as low as 0. 1mg/kg/h. The stimulation-induced somatosensory activation was unchanged when medetomidine was increased from 0. 1 to 6 and 10 folds. Especially, robust bilateral connectivity can be observed in the primary, secondary somatosensory and visual cortices, as well as the hippocampus, caudate putamen, and thalamus at low dose of medetomidine. Significant suppression of inter-hemispheric correlation was seen in the thalamus, where the receptor density is high, under 0. 6mg/kg/h, and in all regions except the caudate, where the receptor density is low, under 1. 0mg/kg/h. Furthermore, in mice whose activation was weaker or took longer time to detect, the bilateral connectivity was lower. This demonstrates that, with proper sedation and conservation of neurovascular coupling, similar bilateral networks like other species can be detected in the mouse brain.

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YNIMG Journal 2014 Journal Article

Pharmacological insight into neurotransmission origins of resting-state functional connectivity: α2-adrenergic agonist vs antagonist

Fatima A. Nasrallah
Si-Min Amanda Low
Si Kang Lew
Kaina Chen
Kai-Hsiang Chuang

Resting-state functional connectivity MRI has emerged as a powerful tool for mapping large-scale neural networks based on synchronous BOLD signal; however, the neurobiological mechanisms are still unknown. To understand its neural substrates, especially the underlying neurotransmission, we applied pharmacological modulation with a receptor specific agonist and antagonist. Resting and evoked electrophysiology and BOLD signals in rat brains were measured under infusion of α2-adrenergic receptor agonist, medetomidine, the antagonist, atipamezole, and the vehicle individually. Both somatosensory BOLD activation and evoked potential were increased significantly under medetomidine compared to the vehicle while atipamezole slightly decreased both. The interhemispheric correlation at the resting state, in contrast, was suppressed by medetomidine but increased by atipamezole in regions with high receptor densities including the somatosensory cortex and thalamus. No change was seen in the caudate putamen, where receptor occupancy is low. The regional difference in connectivity was not related to cerebral blood flow, indicating that BOLD signal correlation is unlikely due to the vascular effects of the drugs. Resting intracortical recording exhibited agonist/antagonist dependent changes in beta and gamma bands that correlated with the BOLD functional connectivity measure. Our results confirm an important role of the adrenergic system on functional connectivity and suggest a neurotransmission basis of the phenomenon.

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YNIMG Journal 2012 Journal Article

Pharmacological modulation of functional connectivity: α2-adrenergic receptor agonist alters synchrony but not neural activation

Fatima A. Nasrallah
Jolena Tan
Kai-Hsiang Chuang

Correlative low frequency fluctuations in functional MRI (fMRI) signals across brain regions at rest have been taken as a measure of functional connectivity to map large-scale neural networks; however, the neural origin is still not clear. Receptor-targeted pharmacological manipulation could elucidate the role of neuroreceptor systems in resting-state functional connectivity to provide another perspective on the mechanism. In this study, the dose-dependent effects of an α2-adrenergic receptor agonist, medetomidine, on brain activation and functional connectivity were investigated. Forepaw stimulation-induced activation and resting-state fluctuation in the rat somatosensory cortices and caudate putamen were measured using the blood oxygenation level dependent (BOLD) fMRI. The results showed significant dose-dependent suppression of inter-hemispheric correlation but not the amplitude in the somatosensory areas, while the stimulation-induced activation in the same areas remained unchanged. To clarify the potential change in the hemodynamic response caused by the vasoconstrictive effect of medetomidine, the resting perfusion fluctuation was studied by arterial spin labeling and showed similar results as the BOLD. This suggests that the oxygen metabolic rate and hence the neural activity may not be affected by medetomidine but only the synchrony between brain regions was suppressed. Furthermore, no change in functional connectivity with medetomidine dosages was seen in the caudate putamen, a region with much lower α2-receptor density. These results indicate that resting-state signal correlation may reflect underlying neuroreceptor activity and a potential role of the adrenergic system in the functional connectivity.

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