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Fahmeed Hyder

Publications and source records attributed to Fahmeed Hyder.

At least 19 recordsLinked to original sources

A BOLD search for baseline.

While we occasionally observe negative BOLD signals, its physiological basis has remained uncertain. This is in part due to the qualitative use of fMRI where the baseline is conveniently differenced away to reveal focal area(s) of interest. Recently, however, there has been a noticeable trend towards quantitative neuroimaging where changes in oxidative energetics (CMR(O2)) are quantified by calibrated fMRI. Pasley et al. [Pasley, B.N., Inglis, B.A., Freeman, R.D., 2007. Analysis of oxygen metabolism implies a neural origin for the negative BOLD response in human visual cortex. NeuroImage] used calibrated fMRI in conjunction with a novel stimulus paradigm to investigate the neural basis of the negative BOLD signal in awake humans. They hypothesized - based on prior results - that if the baseline was lowered then DeltaCMR(O2) would have to be larger. While their main findings point to an energetic basis for the negative BOLD signal, their results have far reaching implications for the present definition of baseline as well as for future research investigating the neural and/or energetic basis of baseline.

Adult↗

Dynamics of changes in blood flow, volume, and oxygenation: implications for dynamic functional magnetic resonance imaging calibration.

Changes in cerebral blood flow (CBF), volume (CBV), and oxygenation (blood-oxygenation level dependent (BOLD)) during functional activation are important for calculating changes in cerebral metabolic rate of oxygen consumption (CMRo2) from calibrated functional MRI (fMRI). An important part of this process is the CBF/CBV relationship, which is signified by a power-law parameter: gamma=ln (1+DeltaCBV/CBV)/ln (1+DeltaCBF/CBF). Because of difficulty in measuring CBF and CBV with MRI, the value of gamma is therefore assumed to be approximately 0.4 from a prior primate study under hypercapnia. For dynamic fMRI calibration, it is important to know if the value of gamma varies after stimulation onset. We measured transient relationships between DeltaCBF, DeltaCBV, and DeltaBOLD by multimodal MRI with temporal resolution of 500 ms (at 7.0 T) from the rat somatosensory cortex during forepaw stimulation, where the stimulus duration ranged from 4 to 32 secs. Changes in CBF and BOLD were measured before the administration of the contrast agent for CBV measurements in the same subjects. We observed that the relationship between DeltaCBF and DeltaCBV varied dynamically from stimulation onset for all stimulus durations. Typically after stimulation onset and at the peak or plateau of the DeltaCBF, the value of gamma ranged between 0.1 and 0.2. However, after stimulation offset, the value of gamma increased to 0.4 primarily because of rapid and slow decays in DeltaCBF and DeltaCBV, respectively. These results suggest caution in using dynamic measurements of DeltaCBF and DeltaBOLD required for calculating DeltaCMRo2 for functional stimulation, when either DeltaCBV has not been accurately measured or a fixed value of gamma during hypercapnia perturbation is used.

Animals↗

Reproducibility of odor maps by fMRI in rodents.

The interactions of volatile odorants with the approximately 1000 types of olfactory receptor neurons in the olfactory mucosa are represented in the olfactory bulb by glomerular spatial activity maps. If these spatial maps underlie the perceptual identification of odorants then, for a given organism, they must be both specific and reproducible. However, this intra-organism reproducibility need not be present between organisms because genetic and developmental studies of olfactory bulb wiring suggest that there is substantial variation between the glomerular arrangements of closely related organisms and even between the two bulbs in a given animal. The ability of functional MRI (fMRI) to record responses of the entire rodent olfactory bulb repeatedly within the same subject has made it possible to assess the reproducibility of odor-induced spatial activity maps both within and between subjects exposed to equivalent stimuli. For a range of odorants, representing multiple chemical classes, a level of fMRI reproducibility (at 7.0 T and 9.4 T) comparable or superior to other cortical regions was demonstrated. While the responses of different bulbs to the same odorant could be localized within the same broad regions of the glomerular sheet, the precise magnitude and topology of the response within those regions were both often highly variable. These results demonstrate the robustness of high-field fMRI as a tool for assaying olfactory bulb function and provide evidence that equivalent perceptual outcomes may arise from divergent neural substrates.

Animals↗

Neuronal-glial glucose oxidation and glutamatergic-GABAergic function.

Prior 13C magnetic resonance spectroscopy (MRS) experiments, which simultaneously measured in vivo rates of total glutamate-glutamine cycling (V(cyc(tot))) and neuronal glucose oxidation (CMR(glc(ox), N)), revealed a linear relationship between these fluxes above isoelectricity, with a slope of approximately 1. In vitro glial culture studies examining glutamate uptake indicated that glutamate, which is cotransported with Na+, stimulated glial uptake of glucose and release of lactate. These in vivo and in vitro results were consolidated into a model: recycling of one molecule of neurotransmitter between glia and neurons was associated with oxidation of one glucose molecule in neurons; however, the glucose was taken up only by glia and all the lactate (pyruvate) generated by glial glycolysis was transferred to neurons for oxidation. The model was consistent with the 1:1 relationship between DeltaCMR(glc(ox), N) and DeltaV(cyc(tot)) measured by 13C MRS. However, the model could not specify the energetics of glia and gamma-amino butyric acid (GABA) neurons because quantitative values for these pathways were not available. Here, we review recent 13C and 14C tracer studies that enable us to include these fluxes in a more comprehensive model. The revised model shows that glia produce at least 8% of total oxidative ATP and GABAergic neurons generate approximately 18% of total oxidative ATP in neurons. Neurons produce at least 88% of total oxidative ATP, and take up approximately 26% of the total glucose oxidized. Glial lactate (pyruvate) still makes the major contribution to neuronal oxidation, but approximately 30% less than predicted by the prior model. The relationship observed between DeltaCMR(glc(ox), N) and DeltaV(cyc(tot)) is determined by glial glycolytic ATP as before. Quantitative aspects of the model, which can be tested by experimentation, are discussed.

Animals↗

Regional temperature changes in the brain during somatosensory stimulation.

Time-dependent variations in the brain temperature (Tt) are likely to be caused by fluctuations of cerebral blood flow (CBF) and cerebral metabolic rate of oxidative consumption (CMRO2) both of which are seemingly coupled to alterations in neuronal activity. We combined magnetic resonance, optical imaging, temperature sensing, and electrophysiologic methods in alpha-chloralose anesthetized rats to obtain multimodal measurements during forepaw stimulation. Localized changes in neuronal activity were colocalized with regional increases in Tt (by approximately 0.2%), CBF (by approximately 95%), and CMRO2 (by approximately 73%). The time-to-peak for Tt (42+/-11 secs) was significantly longer than those for CBF and CMRO2 (5+/-2 and 18+/-4 secs, respectively) with a 2-min stimulation. Net heat in the region of interest (ROI) was modeled as being dependent on the sum of heats attributed to changes in CMRO2 (Qm) and CBF (Qf) as well as conductive heat loss from the ROI to neighboring regions (Qc) and to the environment (Qe). Although tissue cooling because of Qf and Qc can occur and are enhanced during activation, the net increase in Tt corresponded to a large rise in Qm, whereas effects of Qe can be ignored. The results show that Tt increases slowly (by approximately 0.1 degrees C) during physiologic stimulation in alpha-chloralose anesthetized rats. Because the potential cooling effect of CBF depends on the temperature of blood entering the brain, Tt is mainly affected by CMRO2 during functional challenges. Implications of these findings for functional studies in awake humans and temperature regulation are discussed.

Animals↗

A multiparametric assessment of oxygen efflux from the brain.

A quantitative understanding of unidirectional versus net extraction of oxygen in the brain is required because an important factor in calculating oxidative metabolism by calibrated functional magnetic resonance imaging (fMRI) as well as oxygen inhalation methods of positron emission tomography (15O2-PET) and nuclear magnetic resonance (17O2-NMR)) is the degree of oxygen efflux from the brain back into the blood. Because mechanisms of oxygen transport from blood to brain are dependent on cerebral metabolic rate of oxygen consumption (CMRO2), cerebral blood flow (CBF), and oxygen partial pressure (pO2) values in intravascular (Piv) and extravascular (Pev) compartments, we implemented multimodal measurements of these parameters into a compartmental model of oxygen transport and metabolism (i.e., hemoglobin-bound oxygen, oxygen dissolved in plasma and tissue spaces, oxygen metabolized in the mitochondria). In the alpha-chloralose anesthetized rat brain, we used magnetic resonance (7.0 T) and fluorescence quenching methods to measure CMRO2 (2.5+/-1.0 micromol/g min), CBF (0.7+/-0.2 mL/g min), Piv (74+/-10 mm Hg), and Pev (16+/-5 mm Hg) to estimate the degree of oxygen efflux from the brain. In the axially distributed compartmental model, oxygen molecules in blood had two possible fates: enter the tissue space or remain in the same compartment; while in tissue there were three possible fates: enter the blood or the mitochondrial space, or remain in the same compartment. The multiparametric results indicate that the probability of unmetabolized (i.e., dissolved) oxygen molecules reentering the blood from the tissue is negligible and thus its inclusion may unnecessarily complicate calculations of CMRO2 for 15O-PET, 17O-NMR, and calibrated fMRI methods.

Animals↗

Brain homocarnosine and seizure control of patients taking gabapentin or topiramate.

PURPOSE: To assess the relation between seizure control and brain homocarnosine and gamma-aminobutyric acid (GABA) levels of patients with complex partial seizures taking gabapentin (GBP) or topiramate (TPM) as adjunctive therapy. METHODS: In vivo measurements of GABA and homocarnosine were made of a 14-cc volume in the occipital cortex by using (1)H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Poor seizure control was defined as more recent seizures than the median for the two groups of patients studied. RESULTS: Homocarnosine levels were higher in patients with better seizure control than in those with poor control. No differences were found in the intracellular GABA levels between the patients who responded to GBP or TPM compared with those who did not. CONCLUSIONS: In the visual neocortex, which is remote from the presumed seizure-onset zone, higher homocarnosine levels were associated with better seizure control in the patients taking GBP or TPM as adjunctive therapy; elevated intracellular GABA levels appeared to offer no additional protection.

Adult↗

Physiology of functional magnetic resonance imaging: energetics and function.

Quantitative magnetic resonance spectroscopy (MRS) and imaging (MRI) measurements of energy metabolism (i.e., cerebral metabolic rate of oxygen consumption, CMRo2), blood circulation (i.e., cerebral blood flow, CBF; and cerebral blood volume, CBV), and functional MRI (fMRI) were used to interpret the physiological basis of blood oxygenation level-dependent (BOLD) image contrast at 7 T in rat brain. Multimodal signals over a wide range of activity, for primarily glutamatergic neurons, were measured. Because each parameter that can influence the BOLD image contrast was measured quantitatively and separately, multimodal measurements of changes in CMRo2, CBF, CBV, and BOLD signal allowed calibration as well as validation of fMRI. Good agreement between changes in CMRo2 calculated from BOLD theory and measured by 13C MRS reveal that BOLD signal changes at 7 T are closely linked with alterations in neuronal glucose oxidation of glutamatergic neurons, both for activation and deactivation paradigms. Additional neurochemical and neurophysiological studies with fMRI suggest that the BOLD response from the cerebral cortex is closely linked to neurotransmitter release and energetic demand of glutamatergic neurons. Thus, calibrated fMRI may be used to reflect energetic changes of ensembles of glutamatergic neurons in the cerebral cortex.

Animals↗

Simultaneous activation of mouse main and accessory olfactory bulbs by odors or pheromones.

It is generally believed that the main olfactory system processes common odors and the accessory olfactory system is specifically for pheromones. The potential for these two systems to respond simultaneously to the same stimuli has not been fully explored due to methodological limitations. Here we examine this phenomenon using high-resolution functional magnetic resonance imaging (fMRI) to reveal simultaneously the responses in the main (MOB) and accessory olfactory bulbs (AOB) to odors and pheromones. Common odorants elicited strong signals in the MOB and weak signals in the AOB. 2-Heptanone, a known mouse pheromone, elicited strong signals in both the MOB and AOB. Urine odor, a complicated mixture of pheromones and odorants, elicited significant signals in limited regions of the MOB and large regions of the AOB. The fMRI results demonstrate that both the main and the accessory olfactory systems may respond to volatile compounds but with different selectivity, suggesting a greater integration of the two olfactory pathways than traditionally believed.

Animals↗

Lamotrigine suppresses neurophysiological responses to somatosensory stimulation in the rodent.

Neurotransmitter release and voltage-gated ion channel activity in excitatory neurons are critical for understanding and interpreting neuroimaging signals. Couplings between changes in neural activity and energetic/vascular responses are assumed for interpretation of neuroimaging signals. To investigate involvement of neural events to neuroenergetic/neurovascular responses, we conducted multi-modal magnetic resonance imaging (MRI) measurements (at 7.0 T) and electrophysiological recordings (with high impedance microelectrodes) for local field potential (LFP) and spiking frequency (nu) in alpha-chloralose-anesthetized rats. The rats underwent forepaw stimulation before and after treatment of lamotrigine, a neuronal voltage-gated ion channel blocker and glutamate release inhibitor. Multi-modal MRI measurements of cerebral blood flow (CBF) and blood oxygenation level-dependent (BOLD) signal were combined to estimate changes in cerebral metabolic rate of oxygen consumption (CMRo2). Lamotrigine did not appreciably affect values of nu, CBF, and CMRo2 in the resting state. After lamotrigine treatment, evoked changes in LFP and nu were attenuated, which were consistent with commensurate declines in deltaCBF and deltaCMRo2. While number of evoked BOLD-activated voxels was considerably reduced with lamotrigine, intensities of voxels in middle cortical layers were affected to a lesser degree by lamotrigine. The results suggest that lamotrigine suppresses evoked neurophysiological (i.e., neural/energetic/vascular) responses, both in terms of volume of tissue activated and degree of activation in the foci. Since lamotrigine affects evoked responses but not the basal signals, it can be suggested that glutamate release and activity of voltage-gated ion channels are essential for initiating evoked energetic/vascular responses, and thereby important for interpretation of incremental changes in neuroimaging signal.

Algorithms↗

Adaptation in the rodent olfactory bulb measured by fMRI.

Effective evaluation of the odor environment necessitates the ability to attenuate responses to potent background odors in favor of novel and less robust stimuli. Olfactory receptor neuron studies suggest that some of this adaptation takes place in the primary sensory neurons, but the more extensive adaptation seen in higher cortical areas implies the involvement of additional neural mechanisms. At 7.0 T, high-resolution fMRI was used to assess the response of the rodent olfactory bulb, the most peripheral cortical structure involved in olfactory processing, to a variety of odor stimuli. The results suggest that there are additional regulatory mechanisms in the olfactory bulb that result in greater adaptation in deeper areas than that seen in sensory receptors alone and that the resultant adaptation is positively affected by increasing stimulus duration and concentration and decreasing recovery time. The implications of these findings for the integration of peripheral input with perception are discussed.

Adaptation, Physiological↗

Neuroimaging with calibrated FMRI.

The conventional functional MRI (fMRI) map offers information indirectly about localized changes in neuronal activity because it reflects changes in blood oxygenation, not actual neuronal activity. To provide a neurophysiological basis of fMRI, researchers have used electrophysiology to show correlations of fMRI and electric signals. However, quantitative interpretation of the degree to which neuronal activity has changed still cannot be made from conventional fMRI data. The fMRI signal has 2 parts: one describes the correlation between oxidative metabolism (cerebral metabolic rate of oxygen [CMRO2]) and cerebral blood flow (CBF), which supports the bioelectric work to sustain neuronal excitability; the other is the requisite dilation of blood vessels (cerebral blood volume [CBV]), which is the mechanical response involved in removal of waste while providing nutrients. Since changes in energy metabolism are related to bioelectric work, we tested whether spiking frequency of a neuronal ensemble (nu) is reflected by local energy metabolism (CMRO2) in rat brain. We used extracellular recordings to measure Deltanu/nu and calibrated fMRI (ie, using fMRI signal, CBF, and CBV maps) to measure DeltaCMRO2/CMRO2 during sensory stimulation. We found that DeltaCMRO2/CMRO2 is approximately Deltanu/nu, which suggests efficient energy use during brain work. Thus, calibrated fMRI provides data on where and by how much the neuronal activity has changed. Possibilities of utilizing calibrated fMRI as a neuroimaging method are discussed.

Animals↗

A novel approach for selective brain cooling: implications for hypercapnia and seizure activity.

OBJECTIVE: During selective brain cooling (SBC) the brain temperature (TB) is reduced while the core temperature (TC) remains unchanged. This animal study investigated changes in brain temperature induced by a novel approach of cooling the brain from the pharynx (pSBC) and whether these temperature changes are related to commonly encountered clinical situations (i.e., seizure activity and hypercapnia). DESIGN: Experimental animal study. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: pSBC was achieved by a heat exchanger placed in the pharynx; hypercapnia and seizure activity were induced by adding CO2 to the respiratory gases and by intravenous injection of bicuculline, respectively. MEASUREMENTS AND RESULTS: TB, TC, and pharynx (TP) were measured continuously with thermocouples. During pSBC TB declined significantly from 36.9+/-0.67 degrees C to 33.1+/-1.23 degrees C. There was a trend towards lower TC during pSBC (from 36.9+/-0.70 to 36.4+/-1.2 degrees C). TP during pSBC was 29.1+/-2.19 degrees C. From the lowest achieved pSBC temperature TB rose during CO2 challenge by 1.22+/-0.67 degrees C (vs. 0.85+/-0.34 degrees C in non-SBC controls). From the lowest pSBC temperature during seizure activity TB rose by 2.08+/-0.35 degrees C (vs. 1.15+/-0.55 degrees C in non-SBC controls). CONCLUSIONS: Significant cooling of the cortex can be achieved by pSBC in a rat rodent model. Marked increases in TB with hypercapnia and with seizure activity were observed. These results may have implications for cooling methods in clinical settings. For example, pSBC may offer distinct advantages over alternative methods such as whole-body cooling and externally implemented SBC.

Animals↗

Energetic basis of brain activity: implications for neuroimaging.

The complex activities of the brain need not distract us from the certainty that it uses energy and performs work very efficiently. The human brain, which claims approximately 2% of our body mass, is responsible for approximately 20% of our body oxygen consumption. In vivo magnetic resonance spectroscopy (MRS) follows the metabolic pathways of energy production (as glucose oxidation) and work (as monitored by the cycling of glutamate and GABA neurotransmitters). In the resting awake state, approximately 80% of energy used by the brain supports events associated with neuronal firing and cycling of GABA and glutamate neurotransmitters. Small differences in neuronal activity between stimulation and control conditions can be measured and localized using functional magnetic resonance imaging (fMRI). MRS and fMRI experiments show that the majority of cerebral activity, which is often disregarded in imaging experiments, is ongoing even when the brain appears to be doing nothing.

Animals↗

Dynamic fMRI and EEG recordings during spike-wave seizures and generalized tonic-clonic seizures in WAG/Rij rats.

Generalized epileptic seizures produce widespread physiological changes in the brain. Recent studies suggest that "generalized" seizures may not involve the whole brain homogeneously. For example, electrophysiological recordings in WAG/Rij rats, an established model of human absence seizures, have shown that spike-and-wave discharges are most intense in the perioral somatosensory cortex and thalamus, but spare the occipital cortex. Is this heterogeneous increased neuronal activity matched by changes in local cerebral blood flow sufficient to meet or exceed cerebral oxygen consumption? To investigate this, we performed blood oxygen level-dependent functional magnetic resonance imaging (fMRI) measurements at 7T with simultaneous electroencephalogram recordings. During spontaneous spike-wave seizures in WAG/Rij rats under fentanylhaloperidol anesthesia, we found increased fMRI signals in focal regions including the perioral somatosensory cortex, known to be intensely involved during seizures, whereas the occipital cortex was spared. For comparison, we also studied bicuculline-induced generalized tonic-clonic seizures under the same conditions, and found fMRI increases to be larger and more widespread than during spike-and-wave seizures. These findings suggest that even in regions with intense neuronal activity during epileptic seizures, oxygen delivery exceeds metabolic needs, enabling fMRI to be used for investigation of dynamic cortical and subcortical network involvement in this disorder.

Animals↗

Relative changes in cerebral blood flow and neuronal activity in local microdomains during generalized seizures.

There is broad agreement that generalized tonic-clonic seizures (GTCS) and normal somatosensory stimulation are associated with increases in regional CBF. However, the data regarding CBF changes during absence seizures are controversial. Electrophysiologic studies in WAG/Rij rats, an established animal model of absence seizures, have shown spike-wave discharges (SWD) that are largest in the perioral somatosensory cortex while sparing the visual cortex. Recent functional magnetic resonance imaging (fMRI) studies in the same model have also shown localized increases in fMRI signals in the perioral somatosensory cortex during SWD. Because fMRI signals are only indirectly related to neuronal activity, the authors directly measured CBF and neuronal activity from specific microdomains of the WAG/Rij cortex using a specially designed probe combining laser-Doppler flowmetry and extra-cellular microelectrode recordings under fentanyl/haloperidol anesthesia. Using this approach, parallel increases in neuronal activity and CBF were observed during SWD in the whisker somatosensory (barrel) cortex, whereas the visual cortex showed no significant changes. For comparison, these measurements were repeated during somatosensory (whisker) stimulation, and bicuculline-induced GTCS in the same animals. Interestingly, whisker stimulation increased neuronal activity and CBF in the barrel cortex more than during SWD. During GTCS, much larger increases that included both the somatosensory and visual cortex were observed. Thus, SWD in this model produce parallel localized increases in neuronal activity and CBF with similar distribution to somatosensory stimulation, whereas GTCS produce larger and more widespread changes. The normal response to somatosensory stimulation appears to be poised between two abnormal responses produced by two physiologically different types of seizures.

Animals↗

Dynamic imaging of perfusion and oxygenation by functional magnetic resonance imaging.

Cerebral blood flow can be measured with magnetic resonance imaging (MRI) by arterial spin labeling techniques, where magnetic labeling of flowing spins in arterial blood water functions as the endogenous tracer upon mixing with the unlabeled stationary spins of tissue water. The consequence is that the apparent longitudinal relaxation time (T1) of tissue water is attenuated. A modified functional MRI scheme for dynamic CBF measurement is proposed that depends on extraction of T1 weighting from the blood oxygenation level-dependent (BOLD) image contrast, because the functional MRI signal also has an intrinsic T1 weighting that can be altered by variations of the excitation flip angle. In the alpha-chloralose-anesthetized rat model at 7T, the authors show that the stimulation-induced BOLD signal change measured with two different flip angles can be combined to obtain a T1-weighted MRI signal, reflecting the magnitude of the CBF change, which can be deconvolved to obtain dynamic changes in CBF. The deconvolution of the T1-weighted MRI signal, which is a necessary step for accurate reflection of the dynamic changes in CBF, was made possible by a transfer function obtained from parallel laser-Doppler flowmetry experiments. For all stimulus durations (ranging from 4 to 32 seconds), the peak CBF response measured by MRI after the deconvolution was reached at 4.5 +/- 1.0 seconds, which is in good agreement with (present and prior) laser-Doppler measurements. Because the low flip angle data can also provide dynamic changes of the conventional BOLD image contrast, this method can be used for simultaneous imaging of CBF and BOLD dynamics.

Animals↗

Informatics approaches to functional MRI odor mapping of the rodent olfactory bulb: OdorMapBuilder and OdorMapDB.

The present study applies informatics tools to aid and extend fMRI analysis of the coding mechanism of neural signals in the rodent olfactory system. Odor stimulation evokes unique spatial patterns of activity in the glomerular layer of the mammalian olfactory bulb (OB). An open-source software program, OdorMap-Builder, has been developed to process the high resolution anatomical and functional MRI images of the OB and to generate single two-dimensional flat maps, called odor maps, that describe the spatial activity patterns in the entire glomerular layer. Odor maps help identify the spatial activity patterns from the tremendous amount of fMRI data and they serve as ideal representation of space coding for the olfactory signals in the OB in response to a given odor stimulation. Based on the fMRI technology, OdorMapBuilder provides comparable odor maps on the intra-subject basis, a significant step towards the detailed analyses of the effects of odor types and/or concentrations. In addition, a new database, OdorMapDB, is developed to provide a repository for the generated odor maps. Web interfaces to the database are provided for the data entry, modification and retrieval. OdorMapDB is based on the EAV/CR (entity-attribute-value with classes and relationships) architecture and it is integrated with two other SenseLab olfactory databases: the olfactory receptor and odor databases. Both OdorMapBuilder and OdorMapDB should serve as useful tools and resources for the field and help facilitate experimental research in understanding the olfactory system and the mechanism for smell perception.

Animals↗