Person: Alpert, Nathaniel
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Alpert
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Nathaniel
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Alpert, Nathaniel
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Publication In Vivo Quantification of Mitochondrial Membrane Potential(Springer Science and Business Media LLC, 2020-07-08) Alpert, Nathaniel; Pelletier-Galarneau, Matthieu; Petibon, Yoann; Normandin, Marc; El Fakhri, GeorgesMomcilovic et al1 report mitochondrial metabolism differences amongst various mouse lung cancer subtypes, as measured by positron emission tomography (PET) and a voltage-sensitive tracer. They describe their experiments as measurements of mitochondrial membrane potential, ΔΨm, and suggest that they might be used as a non-invasive biomarker to guide the delivery of complex I inhibitors in cancer. Contrary to their claims, Momcilovic et al did not measure membrane potential in an absolute sense, instead relying on an empirical endpoint, namely the percent dose per gram of the tracer in tumor to that in heart, which only partially depends on ΔΨm. Despite the biomedical significance of their findings, their work represents critical methodological misunderstandings and omissions about the underlying basis for application of voltage sensing tracers which could ultimately hinder the successful clinical translation of the technique.Publication Quantitative in vivo mapping of myocardial mitochondrial membrane potential(Public Library of Science, 2018) Alpert, Nathaniel; Guehl, Nicolas; Ptaszek, Leon; Pelletier-Galarneau, Matthieu; Ruskin, Jeremy; Mansour, Moussa; Wooten, Dustin; Ma, Chao; Takahashi, Kazue; Zhou, Yun; Shoup, Timothy; Normandin, Marc; El Fakhri, GeorgesBackground: Mitochondrial membrane potential (ΔΨm) arises from normal function of the electron transport chain. Maintenance of ΔΨm within a narrow range is essential for mitochondrial function. Methods for in vivo measurement of ΔΨm do not exist. We use 18F-labeled tetraphenylphosphonium (18F-TPP+) to measure and map the total membrane potential, ΔΨT, as the sum of ΔΨm and cellular (ΔΨc) electrical potentials. Methods: Eight pigs, five controls and three with a scar-like injury, were studied. Pigs were studied with a dynamic PET scanning protocol to measure 18F-TPP+ volume of distribution, VT. Fractional extracellular space (fECS) was measured in 3 pigs. We derived equations expressing ΔΨT as a function of VT and the volume-fractions of mitochondria and fECS. Seventeen segment polar maps and parametric images of ΔΨT were calculated in millivolts (mV). Results: In controls, mean segmental ΔΨT = -129.4±1.4 mV (SEM). In pigs with segmental tissue injury, ΔΨT was clearly separated from control segments but variable, in the range -100 to 0 mV. The quality of ΔΨT maps was excellent, with low noise and good resolution. Measurements of ΔΨT in the left ventricle of pigs agree with previous in in-vitro measurements. Conclusions: We have analyzed the factors affecting the uptake of voltage sensing tracers and developed a minimally invasive method for mapping ΔΨT in left ventricular myocardium of pigs. ΔΨT is computed in absolute units, allowing for visual and statistical comparison of individual values with normative data. These studies demonstrate the first in vivo application of quantitative mapping of total tissue membrane potential, ΔΨT.Publication Neurovascular coupling to D2/D3 dopamine receptor occupancy using simultaneous PET/functional MRI(Proceedings of the National Academy of Sciences, 2013) Sander, C. Y.; Hooker, Jacob; Catana, Ciprian; Normandin, Marc; Alpert, Nathaniel; Knudsen, G. M.; Vanduffel, Wim; Rosen, Bruce; Mandeville, JosephThis study employed simultaneous neuroimaging with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to demonstrate the relationship between changes in receptor occupancy measured by PET and changes in brain activity inferred by fMRI. By administering the D2/D3 dopamine receptor antagonist [11C]raclopride at varying specific activities to anesthetized nonhuman primates, we mapped associations between changes in receptor occupancy and hemodynamics [cerebral blood volume (CBV)] in the domains of space, time, and dose. Mass doses of raclopride above tracer levels caused increases in CBV and reductions in binding potential that were localized to the dopamine-rich striatum. Moreover, similar temporal profiles were observed for specific binding estimates and changes in CBV. Injection of graded raclopride mass doses revealed a monotonic coupling between neurovascular responses and receptor occupancies. The distinct CBV magnitudes between putamen and caudate at matched occupancies approximately matched literature differences in basal dopamine levels, suggesting that the relative fMRI measurements reflect basal D2/D3 dopamine receptor occupancy. These results can provide a basis for models that relate dopaminergic occupancies to hemodynamic changes in the basal ganglia. Overall, these data demonstrate the utility of simultaneous PET/fMRI for investigations of neurovascular coupling that correlate neurochemistry with hemodynamic changes in vivo for any receptor system with an available PET tracer.Publication A Receptor-Based Model for Dopamine-Induced fMRI Signal(Elsevier BV, 2013) Mandeville, Joseph; Sander, Christin Y.M.; Jenkins, Bruce; Hooker, Jacob; Catana, Ciprian; Vanduffel, Wim; Alpert, Nathaniel; Rosen, Bruce; Normandin, MarcThis report describes a multi-receptor physiological model of the fMRI temporal response and signal magnitude evoked by drugs that elevate synaptic dopamine in basal ganglia. The model is formulated as a summation of dopamine's effects at D1-like and D2-like receptor families, which produce functional excitation and inhibition, respectively, as measured by molecular indicators like adenylate cyclase or neuroimaging techniques like fMRI. Functional effects within the model are described in terms of relative changes in receptor occupancies scaled by receptor densities and neuro-vascular coupling constants. Using literature parameters, the model reconciles many discrepant observations and interpretations of pre-clinical data. Additionally, we present data showing that amphetamine stimulation produces fMRI inhibition at low doses and a biphasic response at higher doses in the basal ganglia of non-human primates (NHP), in agreement with model predictions based upon the respective levels of evoked dopamine. Because information about dopamine release is required to inform the fMRI model, we simultaneously acquired PET 11C-raclopride data in several studies to evaluate the relationship between raclopride displacement and assumptions about dopamine release. At high levels of dopamine release, results suggest that refinements of the model will be required to consistently describe the PET and fMRI data. Overall, the remarkable success of the model in describing a wide range of preclinical fMRI data indicate that this approach will be useful for guiding the design and analysis of basic science and clinical investigations and for interpreting the functional consequences of dopaminergic stimulation in normal subjects and in populations with dopaminergic neuroadaptations.Publication Auditory Priming within and across Modalities: Evidence from Positron Emission Tomography(Massachusetts Institute of Technology Press, 1999) Badgaiyan, Rajendra D; Schacter, Daniel; Alpert, NathanielPrevious neuroimaging studies of perceptual priming have reported priming-related decreases in the extrastriate cortex. However, because these experiments have used visual stimuli, it is unclear whether the observed decreases are associated specifically with some aspect of visual perceptual processing or with more general aspects of priming. We studied within-and cross-modality priming using an auditory word stem completion paradigm. Positron emission tomography (PET) images were obtained during stem completion and a fixation task. Within-modality auditory priming was associated with blood flow decreases in the extrastriate cortex (bilateral), medial/ right anterior prefrontal cortex, right angular gyrus, and precuneus. In cross-modality priming, the study list was presented visually, and subjects completed auditory word stems. Cross-modality priming was associated with trends for blood flow decreases in the left angular gyrus and increases in the medial/right anterior prefrontal cortex. Results thus indicate that reduced activity in the extrastriate cortex accompanies within-modality priming in both visual and auditory modalities.Publication Individual Differences in Cerebral Blood Flow in Area 17 Predict the Time to Evaluate Visualized Letters(Massachusetts Institute of Technology Press, 1996) Kosslyn, Stephen; Thompson, William; Kim, Irene J.; Rauch, Scott; Alpert, NathanielSixteen subjects closed their eyes and visualized uppercase letters of the alphabet at two sizes, as small as possible or as large as possible while remaining “visible.” Subjects evaluated a shape characteristic of each letter (e.g., whether it has any curved lines), and responded as quickly as possible. Cerebral blood flow was normalized to the same value for each subject, and relative blood flow was computed for a set of regions of interest. The mean response time for each subject in the task was regressed onto the blood flow values. Blood flow in area 17 was negatively correlated with response time (r = -0.65), as was blood flow in area 19 (r = -0.66), whereas blood flow in the inferior parietal lobe was positively correlated with response time (r = 0.54). The first two effects persisted even when variance due to the other correlations was removed. These findings suggest that individual differences in the activation of specific brain loci are directly related to performance of tasks that rely on processing in those loci.Publication Visual Mental Imagery Activates Topographically Organized Visual Cortex: PET Investigations(Massachusetts Institute of Technology Press, 1993) Kosslyn, Stephen; Alpert, Nathaniel; Thompson, William; Maljkovic, Vera; Weise, Steven B.; Chabris, Christopher; Hamilton, Sania E.; Rauch, Scott; Buonanno, FerdinandoCerebral blood flow was measured using positron emission tomography (PET) in three experiments while subjects performed mental imagery or analogous perceptual tasks. In Experiment 1, the subjects either visualized letters in grids and decided whether an X mark would have fallen on each letter if it were actually in the grid, or they saw letters in grids and decided whether an X mark fell on each letter. A region identified as part of area 17 by the Talairach and Tournoux (1988) atlas, in addition to other areas involved in vision, was activated more in the mental imagery task than in the perception task. In Experiment 2, the identical stimuli were presented in imagery and baseline conditions, but subjects were asked to form images only in the imagery condition; the portion of area 17 that was more active in the imagery condition of Experiment 1 was also more activated in imagery than in the baseline condition, as was part of area 18. Subjects also were tested with degraded perceptual stimuli, which caused visual cortex to be activated to the same degree in imagery and perception. In both Experiments 1 and 2, however, imagery selectively activated the extreme anterior part of what was identified as area 17, which is inconsistent with the relatively small size of the imaged stimuli. These results, then, suggest that imagery may have activated another region just anterior to area 17. In Experiment 3, subjects were instructed to close their eyes and evaluate visual mental images of upper case letters that were formed at a small size or large size. The small mental images engendered more activation in the posterior portion of visual cortex, and the large mental images engendered more activation in anterior portions of visual cortex. This finding is strong evidence that imagery activates topographically mapped cortex. The activated regions were also consistent with their being localized in area 17. Finally, additional results were consistent with the existence of two types of imagery, one that rests on allocating attention to form a pattern and one that rests on activating stored visual memories.