Fatima A. Nasrallah

Imaging brain deoxyglucose uptake and metabolism by glucoCEST MRI

2-Deoxy-D-glucose (2DG) is a known surrogate molecule that is useful for inferring glucose uptake and metabolism. Although 13C-labeled 2DG can be detected by nuclear magnetic resonance (NMR), its low sensitivity for detection prohibits imaging to be performed. Using chemical exchange saturation transfer (CEST) as a signal-amplification mechanism, 2DG and the phosphorylated 2DG-6-phosphate (2DG6P) can be indirectly detected in 1H magnetic resonance imaging (MRI). We showed that the CEST signal changed with 2DG concentration, and was reduced by suppressing cerebral metabolism with increased general anesthetic. The signal changes were not affected by cerebral or plasma pH, and were not correlated with altered cerebral blood flow as demonstrated by hypercapnia; neither were they related to the extracellular glucose amounts as compared with injection of D- and L-glucose. In vivo 31P NMR revealed similar changes in 2DG6P concentration, suggesting that the CEST signal reflected the rate of glucose assimilation. This method provides a new way to use widely available MRI techniques to image deoxyglucose/glucose uptake and metabolism in vivo without the need for isotopic labeling of the molecules.

Detection of functional connectivity in the resting mouse brain.

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.

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

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.

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

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 α(2)-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 α(2)-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.

Modulation of Brain Metabolism by Very Low Concentrations of the Commonly Used Drug Delivery Vehicle Dimethyl Sulfoxide (DMSO)

Dimethyl sulfoxide (DMSO) has long been used in studies as a vehicle to enhance the solubility and transport of ligands in biological systems. The effects of this drug on the outcomes of such studies are still unclear, with concentrations of DMSO reported as “safe” varying considerably. In the present work, we investigated the effects of very low concentrations of DMSO on the brain metabolism of [3‐13C]pyruvate and D‐[1‐13C]glucose using 1H/13C NMR spectroscopy and a guinea pig cortical brain slice model. Our results show that DMSO is accumulated by brain slices. DMSO at all concentrations [0.000025%–0.25% (v/v)] increased the metabolic rate when [3‐13C]pyruvate was used as a substrate and also in the presence of D‐[1‐13C]glucose (0.00025%–0.1% DMSO). These results are consistent with DMSO stimulating respiration, which it may do through altering the kinetics of ATP‐requiring reactions. Our results also emphasize that there is no practical concentration of DMSO that can be used in metabolic experiments without effect. Therefore, care should be taken when evaluating the actions of drugs administered in combination with DMSO.

Alanine metabolism, transport, and cycling in the brain.

Brain glutamate/glutamine cycling is incomplete without return of ammonia to glial cells. Previous studies suggest that alanine is an important carrier for ammonia transfer. In this study, we investigated alanine transport and metabolism in Guinea pig brain cortical tissue slices and prisms, in primary cultures of neurons and astrocytes, and in synaptosomes. Alanine uptake into astrocytes was largely mediated by system L isoform LAT2, whereas alanine uptake into neurons was mediated by Na+‐dependent transporters with properties similar to system B0 isoform B0AT2. To investigate the role of alanine transport in metabolism, its uptake was inhibited in cortical tissue slices under depolarizing conditions using the system L transport inhibitors 2‐aminobicyclo[2.2.1]heptane‐2‐carboxylic acid and cycloleucine (1‐aminocyclopentanecarboxylic acid; cLeu). The results indicated that alanine cycling occurs subsequent to glutamate/glutamine cycling and that a significant proportion of cycling occurs via amino acid transport system L. Our results show that system L isoform LAT2 is critical for alanine uptake into astrocytes. However, alanine does not provide any significant carbon for energy or neurotransmitter metabolism under the conditions studied.

γ-Hydroxybutyrate and the GABAergic footprint: a metabolomic approach to unpicking the actions of GHB

J. Neurochem. (2010) 115, 58–67.

Neural correlate of resting-state functional connectivity under α2 adrenergic receptor agonist, medetomidine

Correlative fluctuations in functional MRI (fMRI) signals across the brain at rest have been taken as a measure of functional connectivity, but the neural basis of this resting-state MRI (rsMRI) signal is not clear. Previously, we found that the α2 adrenergic agonist, medetomidine, suppressed the rsMRI correlation dose-dependently but not the stimulus evoked activation. To understand the underlying electrophysiology and neurovascular coupling, which might be altered due to the vasoconstrictive nature of medetomidine, somatosensory evoked potential (SEP) and resting electroencephalography (EEG) were measured and correlated with corresponding BOLD signals in rat brains under three dosages of medetomidine. The SEP elicited by electrical stimulation to both forepaws was unchanged regardless of medetomidine dosage, which was consistent with the BOLD activation. Identical relationship between the SEP and BOLD signal under different medetomidine dosages indicates that the neurovascular coupling was not affected. Under resting state, EEG power was the same but a depression of inter-hemispheric EEG coherence in the gamma band was observed at higher medetomidine dosage. Different from medetomidine, both resting EEG power and BOLD power and coherence were significantly suppressed with increased isoflurane level. Such reduction was likely due to suppressed neural activity as shown by diminished SEP and BOLD activation under isoflurane, suggesting different mechanisms of losing synchrony at resting-state. Even though, similarity between electrophysiology and BOLD under stimulation and resting-state implicates a tight neurovascular coupling in both medetomidine and isoflurane. Our results confirm that medetomidine does not suppress neural activity but dissociates connectivity in the somatosensory cortex. The differential effect of medetomidine and its receptor specific action supports the neuronal origin of functional connectivity and implicates the mechanism of its sedative effect.

Understanding your inhibitions. Modulation of brain cortical metabolism by GABAB receptors

Although the impact of neuronal excitation on the functional activity of brain is well understood, the nature of functional responses to inhibitory modulation is far from clear. In this work, we investigated the effects of modulation of the metabotropic GABAB receptor on brain metabolism using a targeted neuropharmacological, 1H/13C nuclear magnetic resonance spectroscopy, and metabolomic approach. While agonists at GABAB receptors (Baclofen and SKF 97541) generally decreased metabolic activity, mild agonist action could also stimulate metabolism. Less potent antagonists (CGP 35348, Phaclofen) significantly decreased metabolic activity, while more potent antagonists (CGP 52432 and SCH 50911) had opposite, stimulatory, effects. Examination of the data by principal components analysis showed clear divisions of the effects into excitatory and inhibitory components. GABAergic modulation can, therefore, have stimulatory, inhibitory, or even neutral net effects on metabolic activity in brain tissue. This is consistent with GABAergic activity being context dependent, and this conclusion should be taken into account when evaluating functional imaging data involving modulation of neuronal inhibition.

A Magnetic Resonance Compatible Soft Wearable Robotic Glove for Hand Rehabilitation and Brain Imaging

In this paper, we present the design, fabrication and evaluation of a soft wearable robotic glove, which can be used with functional Magnetic Resonance imaging (fMRI) during the hand rehabilitation and task specific training. The soft wearable robotic glove, called MR-Glove, consists of two major components: a) a set of soft pneumatic actuators and b) a glove. The soft pneumatic actuators, which are made of silicone elastomers, generate bending motion and actuate finger joints upon pressurization. The device is MR-compatible as it contains no ferromagnetic materials and operates pneumatically. Our results show that the device did not cause artifacts to fMRI images during hand rehabilitation and task-specific exercises. This study demonstrated the possibility of using fMRI and MR-compatible soft wearable robotic device to study brain activities and motor performances during hand rehabilitation, and to unravel the functional effects of rehabilitation robotics on brain stimulation.