Research Interests: Genetics, Neuroscience, Computer Science, Chemistry, Neurology, and 15 moreCognitive Neuroscience, Neural Network, Medicine, Manganese, Mice, Animals, Smell, Neuroimage, Odors, Image Enhancement, Nasal cavity, Olfactory Bulb, Olfactory Pathways, Psychology and Cognitive Sciences, and Medical and Health Sciences
Research Interests: Neuroscience, Computer Science, Neurology, Magnetic Resonance Imaging, Biology, and 15 moreCognitive Neuroscience, Medicine, Neuroimmunology, Cerebral Cortex, Animals, Neuroimage, Male, Animal Model, Image Enhancement, Layer, Neural pathways, Manganese Compounds, Contrast Media, Chlorides, and Medical and Health Sciences
Research Interests: Chemistry, Biomedical Engineering, Flow Cytometry, Biology, Cell Migration, and 15 moreApoptosis, Humans, Iron Oxide, Clinical Sciences, Image Enhancement, Lymphocytes, Contrast Media, Cytotoxic T cells, Cell Labeling, Chlorides, Magnetic resonance image, Annexin, Lymphocyte, human lymphocyte, and B cell
Remyelination is crucial to recover from inflammatory demyelination in multiple sclerosis (MS). Investigating remyelination in vivo using magnetic resonance imaging (MRI) is difficult in MS, where collecting serial short-interval scans is... more
Remyelination is crucial to recover from inflammatory demyelination in multiple sclerosis (MS). Investigating remyelination in vivo using magnetic resonance imaging (MRI) is difficult in MS, where collecting serial short-interval scans is challenging. Using experimental autoimmune encephalomyelitis (EAE) in common marmosets, a model of MS that recapitulates focal cerebral inflammatory demyelinating lesions, we investigated whether MRI is sensitive to, and can characterize, remyelination. In six animals followed with multisequence 7 T MRI, 31 focal lesions, predicted to be demyelinated or remyelinated based on signal intensity on proton density-weighted images, were subsequently assessed with histopathology. Remyelination occurred in four of six marmosets and 45% of lesions. Radiological-pathological comparison showed that MRI had high statistical sensitivity (100%) and specificity (90%) for detecting remyelination. This study demonstrates the prevalence of spontaneous remyelination ...
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Developmental malformations (dysgenesis) of the corpus callosum lead to neurological conditions with a broad range of clinical presentations. Investigating the altered brain connectivity patterns is crucial to understanding both adaptive... more
Developmental malformations (dysgenesis) of the corpus callosum lead to neurological conditions with a broad range of clinical presentations. Investigating the altered brain connectivity patterns is crucial to understanding both adaptive and maladaptive neuroplasticity in corpus callosum dysgenesis patients. Here, we acquired structural diffusion-weighted and resting-state functional MRI data from a cohort of 11 corpus callosum dysgenesis patients (five with agenesis and six with hypoplasia) and compared their structural and functional connectivity patterns to healthy subjects selected from the Human Connectome Project. We found that these patients have fewer structural inter- and intra-hemispheric brain connections relative to healthy controls. Interestingly, the patients with callosal agenesis have a scant number of inter-hemispheric connections but manage to maintain the full integrity of functional connectivity between the same cortical regions as the healthy subjects. On the ot...
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Cortical lesions are a primary driver of disability in multiple sclerosis (MS). However, noninvasive detection of cortical lesions with in vivo magnetic resonance imaging (MRI) remains challenging. Experimental autoimmune... more
Cortical lesions are a primary driver of disability in multiple sclerosis (MS). However, noninvasive detection of cortical lesions with in vivo magnetic resonance imaging (MRI) remains challenging. Experimental autoimmune encephalomyelitis (EAE) in the common marmoset is a relevant animal model of MS for investigating the pathophysiological mechanisms leading to brain damage. This study aimed to characterize cortical lesions in marmosets with EAE using ultrahigh-field (7 T) MRI and histological analysis. Tissue preparation was optimized to enable the acquisition of high-spatial resolution (50-μm isotropic) T2*-weighted images. A total of 14 animals were scanned in this study, and 70% of the diseased animals presented at least one cortical lesion on postmortem imaging. Cortical lesions identified on MRI were verified with myelin proteolipid protein immunostaining. An optimized T2*-weighted sequence was developed for in vivo imaging and shown to capture 65% of cortical lesions detecte...
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MAGL (monoacylglycerol lipase) is an enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol and regulates the production of arachidonic acid and prostaglandins-substances that mediate tissue inflammatory response. Here, we have... more
MAGL (monoacylglycerol lipase) is an enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol and regulates the production of arachidonic acid and prostaglandins-substances that mediate tissue inflammatory response. Here, we have studied the effects of the selective MAGL inhibitors JZL184 and MJN110 and their underlying molecular mechanisms on 3 different experimental models of focal cerebral ischemia. SHR (spontaneously hypertensive rats) and normotensive WKY (Wistar Kyoto) rats were subject to an intracortical injection of the potent vasoconstrictor endothelin-1, permanent occlusion of a distal segment of the middle cerebral artery via craniectomy, or transient occlusion of the middle cerebral artery by the intraluminal suture method. JZL184 or MJN110 was administered 60 minutes after focal cerebral ischemia. Infarct volumes, hemispheric swelling, and functional outcomes were assessed between days 1 to 28 by magnetic resonance imaging, histology, and behavioral tests. Pha...
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Curiosity is a fundamental nature of animals for adapting to changing environments, but its underlying brain circuits and mechanisms remain poorly understood. One main barrier is that existing studies use rewards to train animals and... more
Curiosity is a fundamental nature of animals for adapting to changing environments, but its underlying brain circuits and mechanisms remain poorly understood. One main barrier is that existing studies use rewards to train animals and motivate their engagement in behavioral tasks. As such, the rewards become significant confounders in interpreting curiosity. Here, we overcame this problem by studying research-naïve and naturally curious marmosets that can proactively and persistently participate in a visual choice task without external rewards. When performing the task, the marmosets manifested a strong innate preference towards acquiring new information, associated with faster behavioral responses. Longitudinally functional magnetic resonance imaging revealed behavior-relevant brain states that reflected choice preferences and engaged several brain regions, including the cerebellum, the hippocampus, and cortical areas 19DI, 25, and 46D, with the cerebellum being the most prominent. ...
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Manganese overexposure in non-human primates and humans causes a neurodegenerative disorder called manganism thought to be related to an accumulation of the metal in the basal ganglia. Here, we assess changes in the concentration of... more
Manganese overexposure in non-human primates and humans causes a neurodegenerative disorder called manganism thought to be related to an accumulation of the metal in the basal ganglia. Here, we assess changes in the concentration of manganese in regions of the brain of a non-human primate (the common marmoset, Callithrix jacchus) following four systemic injections of 30 mg/kg MnCl2·H20 in the tail vein using T1-weighted magnetic resonance imaging (MRI) and compare these to changes in the rat following the same exposure route and dose. The doses were spaced 48 hours apart and we imaged the animals 48 hours after the final dose. We find that marmosets have significantly larger T1-weighted image enhancements in regions of the brain compared to rats, notably in the basal ganglia and the visual cortex. To confirm this difference across species reflects actual differences in manganese concentrations and not variations in the MRI properties of manganese, we measured the longitudinal relaxivity of manganese (χ1) in the in vivo brain and found no significant species’ difference. The high manganese uptake in the marmoset basal ganglia and visual cortex can be explained by CSF-brain transport from the large lateral ventricles and we confirm this route of uptake with time-course MRI during a tail-vein infusion of manganese. There is also high uptake in the substructures of the hippocampus that are adjacent to the ventricles. The large manganese accumulation in these structures on overexposure may be common to all primates, including humans.
Research Interests: Cognitive Science, Magnetic Resonance Imaging, Manganese, Rodentia, Brain Mapping, and 15 moreCerebrospinal Fluid, Brain, Female, Animals, Male, Image Enhancement, Rats, Rat, Basal ganglia, Callithrix, Brain Chemistry, Nuclear Magnetic Resonance Imaging, Neurosciences, Magnetic resonance image, and Neurodegenerative disorder
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Research Interests: Materials Science, Biomedical Engineering, Carbon Dioxide, Medicine, Brain Mapping, and 15 moreBrain, Hemodynamics, Animals, Male, Magnetic Resonance, Mathematical Computing, Animal Model, Constant Time Delay, Image Enhancement, Blood Flow, Magnetization, Cerebral Blood Flow, Nuclear Magnetic Resonance Imaging, Blood Flow Velocity, and Cerebral Blood Volume
Research Interests: Chemistry, Biomedical Engineering, Magnetic Resonance Imaging, Radiation Therapy, Medicine, and 15 moreBrain Tumor, Glioma, Animals, Male, Magnetic Resonance, Rat Brain, High Resolution, Blood Flow, Dissolved Oxygen, Cerebral Blood Flow, Mr Imaging, High Spatial Resolution, Blood Vessel, Brain Neoplasms, and High magnetic field
Research Interests: Cartography, Chemistry, Metabolism, Magnetic Resonance Imaging, Medicine, and 15 moreBrain Mapping, Cross Correlation, Brain, Flow, Brain Circulation, Animals, Male, Exploration, Clinical Sciences, Correlation coefficient, Cerebral Blood Flow, Laser Doppler Flowmetry, Cerebral Blood Volume, Cardiovascular medicine and haematology, and Electric stimulation
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Research Interests: Chemistry, Biomedical Engineering, Magnetic Resonance Imaging, Microcirculation, Functional MRI, and 15 moreMedicine, Magnetic field, Anisotropy, Brain Mapping, Brain, Animals, Male, Magnetic Resonance, Image Enhancement, Rats, Oxygen, Time Dependent, Diffusion Weighted MRI, Spin Echo, and Electric stimulation
In vivo tractography based on diffusion magnetic resonance imaging (dMRI) has opened new doors to study structure-function relationships in the human brain. Initially developed to map the trajectory of major white matter tracts, dMRI is... more
In vivo tractography based on diffusion magnetic resonance imaging (dMRI) has opened new doors to study structure-function relationships in the human brain. Initially developed to map the trajectory of major white matter tracts, dMRI is used increasingly to infer long-range anatomical connections of the cortex. Because axonal projections originate and terminate in the gray matter but travel mainly through the deep white matter, the success of tractography hinges on the capacity to follow fibers across this transition. Here we demonstrate that the complex arrangement of white matter fibers residing just under the cortical sheet poses severe challenges for long-range tractography over roughly half of the brain. We investigate this issue by comparing dMRI from very-high-resolution ex vivo macaque brain specimens with histological analysis of the same tissue. Using probabilistic tracking from pure gray and white matter seeds, we found that ∼50% of the cortical surface was effectively in...
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One of the great strengths of the mouse model is the wide array of genetic tools that have been developed. Striking examples include methods for directed modification of the genome, and for regulated expression or inactivation of genes.... more
One of the great strengths of the mouse model is the wide array of genetic tools that have been developed. Striking examples include methods for directed modification of the genome, and for regulated expression or inactivation of genes. Within neuroscience, it is now routine to express reporter genes, neuronal activity indicators, and opsins in specific neuronal types in the mouse. However, there are considerable anatomical, physiological, cognitive, and behavioral differences between the mouse and the human that, in some areas of inquiry, limit the degree to which insights derived from the mouse can be applied to understanding human neurobiology. Several recent advances have now brought into reach the goal of applying these tools to understanding the primate brain. Here we describe these advances, consider their potential to advance our understanding of the human brain and brain disorders, discuss bioethical considerations, and describe what will be needed to move forward.
Research Interests: Cognitive Science, Primates, Brain, Humans, Mice, and 5 moreAnimals, Biological evolution, Genes, Neuron, and Neurosciences
Research Interests: Cognitive Science, Biomedical Engineering, Auditory Perception, Depression, Nonparametric Statistics, and 63 moreDiabetes, Magnetic Resonance Imaging, Imaging, Epilepsy, Drug interactions, Manganese, Catheterization, Molecular Neurobiology, Brain Mapping, Hippocampus, Hearing, Brain, Tinnitus, Humans, Thalamus, Noise, Mice, Blood brain barrier, Animals, Calcium channels, Spinal Cord, Neuroimage, Male, Three Dimensional Imaging, Temporal Lobe Epilepsy, Heart, Neuronal Plasticity, Mental Disorders, Brain Ischemia, Medical Physiology, Neurons, Epilepsia, Nerve Regeneration, Clinical Sciences, Dentate Gyrus, Pituitary Gland, Entorhinal Cortex, Biological systems, Early Detection, Image Enhancement, Rats, Pilocarpine, Solutions, Animal models, Reproducibility of Results, Wistar Rats, Neural pathways, Manganese Compounds, Sensitivity and Specificity, Thoracic Vertebrae, Spinal Cord Injuries, Axons, Olfactory Pathways, Neurosciences, Predictive value of tests, Contrast Media, Biochemistry and cell biology, Mannitol, Salicylates, Interferon Alpha, Motor activity, Chlorides, and Cycloheximide
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Report overall long-term results of stage 0 rectal cancer following neoadjuvant chemoradiation and compare long-term results between operative and nonoperative treatment. Two-hundred sixty-five patients with distal rectal adenocarcinoma... more
Report overall long-term results of stage 0 rectal cancer following neoadjuvant chemoradiation and compare long-term results between operative and nonoperative treatment. Two-hundred sixty-five patients with distal rectal adenocarcinoma considered resectable were treated by neoadjuvant chemoradiation (CRT) with 5-FU, Leucovorin and 5040 cGy. Patients with incomplete clinical response were referred to radical surgical resection. Patients with incomplete clinical response treated by surgery resulting in stage p0 were compared to patients with complete clinical response treated by nonoperative treatment. Statistical analysis was performed using chi2, Student t test and Kaplan-Meier curves. Overall and disease-free 10-year survival rates were 97.7% and 84%. In 71 patients (26.8%) complete clinical response was observed following CRT (Observation group). Twenty-two patients (8.3%) showed incomplete clinical response and pT0N0M0 resected specimens (Resection group). There were no differences between patient's demographics and tumor's characteristics between groups. In the Resection group, 9 definitive colostomies and 7 diverting temporary ileostomies were performed. Mean follow-up was 57.3 months in Observation Group and 48 months in Resection Group. There were 3 systemic recurrences in each group and 2 endorectal recurrences in Observation Group. Two patients in the Resection group died of the disease. Five-year overall and disease-free survival rates were 88% and 83%, respectively, in Resection Group and 100% and 92% in Observation Group. Stage 0 rectal cancer disease is associated with excellent long-term results irrespective of treatment strategy. Surgical resection may not lead to improved outcome in this situation and may be associated with high rates of temporary or definitive stoma construction and unnecessary morbidity and mortality rates.
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Quantitative magnetic resonance measurements of regional tissue perfusion can be obtained using magnetically labeled arterial water as a diffusable tracer. Continuous labeling is achieved in flowing spins using adiabatic inversion. The... more
Quantitative magnetic resonance measurements of regional tissue perfusion can be obtained using magnetically labeled arterial water as a diffusable tracer. Continuous labeling is achieved in flowing spins using adiabatic inversion. The effects of continuous labeling of proximal arterial spins and T1 relaxation in distal tissue magnetization result in a steady-state change in tissue magnetization which is tissue specific, i.e., it can be quantified in units of blood flow per gram of tissue per unit time. This magnetization is sampled using standard imaging sequences. The theoretical basis for this method, including the effects of macromolecular spin saturation, is reviewed. Recent results demonstrating the successful implementation of this technique in vitro and in vivo in rat brain, heart, and kidney, and in human brain and kidney are presented, as well as the use of a separate RF coil for arterial labeling to produce selective perfusion images in rat brain. This approach allows quantitative perfusion images to be obtained completely non-invasively at the resolution of 1H MRI, and is useful in the clinical and investigational evaluation of organ physiology.
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Research Interests: Comparative Anatomy, Neuroscience, Cognitive Science, Magnetic Resonance Imaging, Visual Cortex, and 14 moreBrain Mapping, Cerebral Cortex, Female, Animals, Male, Neuronal Plasticity, Primary visual cortex, Time Factors, Neural pathways, Auditory Cortex, Callithrix, Species Specificity, Statistical Methods for Neuroscience, and Neurosciences
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Supplemental material, MSJ822408_supplementary_tables for The spectrum of spinal cord lesions in a primate model of multiple sclerosis by Jennifer A Lefeuvre, Joseph R Guy, Nicholas J Luciano, Seung-Kwon Ha, Emily Leibovitch, Mathieu D... more
Supplemental material, MSJ822408_supplementary_tables for The spectrum of spinal cord lesions in a primate model of multiple sclerosis by Jennifer A Lefeuvre, Joseph R Guy, Nicholas J Luciano, Seung-Kwon Ha, Emily Leibovitch, Mathieu D Santin, Afonso C Silva, Steven Jacobson, Stéphane Lehéricy, Daniel S Reich and Pascal Sati in Multiple Sclerosis Journal
The corpus callosum (CC), the anterior (AC), and the posterior (PC) commissures are the principal axonal fiber bundle pathways that allow bidirectional communication between the brain hemispheres. Here, we used the Allen mouse brain... more
The corpus callosum (CC), the anterior (AC), and the posterior (PC) commissures are the principal axonal fiber bundle pathways that allow bidirectional communication between the brain hemispheres. Here, we used the Allen mouse brain connectivity atlas and high-resolution diffusion-weighted MRI (DWI) to investigate interhemispheric fiber bundles in C57bl6/J mice, the most commonly used wild-type mouse model in biomedical research. We identified 1) commissural projections from the primary motor area through the AC to the contralateral hemisphere; and 2) intrathalamic interhemispheric fiber bundles from multiple regions in the frontal cortex to the contralateral thalamus. This is the first description of direct interhemispheric corticothalamic connectivity from the orbital cortex. We named these newly identified crossing points thalamic commissures. We also analyzed interhemispheric connectivity in the Balb/c mouse model of dysgenesis of the corpus callosum (CCD). Relative to C57bl6/J,...
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The rapid adoption of marmosets in neuroscience has created a demand for three dimensional (3D) atlases of the brain of this species to facilitate data integration in a common reference space. We report on a new open access template of... more
The rapid adoption of marmosets in neuroscience has created a demand for three dimensional (3D) atlases of the brain of this species to facilitate data integration in a common reference space. We report on a new open access template of the marmoset cortex (the Nencki–Monash, or NM template), representing a morphological average of 20 brains of young adult individuals, obtained by 3D reconstructions generated from Nissl-stained serial sections. The method used to generate the template takes into account morphological features of the individual brains, as well as the borders of clearly defined cytoarchitectural areas. This has resulted in a resource which allows direct estimates of the most likely coordinates of each cortical area, as well as quantification of the margins of error involved in assigning voxels to areas, and preserves quantitative information about the laminar structure of the cortex. We provide spatial transformations between the NM and other available marmoset brain t...
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Research Interests: Chemistry, Biomedical Engineering, Magnetic Resonance Imaging, Flow Cytometry, Biology, and 15 moreCell Migration, Apoptosis, Manganese, Humans, Iron Oxide, Clinical Sciences, Image Enhancement, Lymphocytes, Contrast Media, Cytotoxic T cells, Cell Labeling, Chlorides, Magnetic resonance image, Lymphocyte, and human lymphocyte
Functional magnetic resonance imaging (fMRI) rests on the assumption that regional brain activity is closely coupled to regional cerebral blood flow (rCBF) in vivo. To test the degree of coupling, cortical brain activity was locally... more
Functional magnetic resonance imaging (fMRI) rests on the assumption that regional brain activity is closely coupled to regional cerebral blood flow (rCBF) in vivo. To test the degree of coupling, cortical brain activity was locally stimulated in rats by reversed microdialysis infusion of picrotoxinin, a γ-aminobutyric acid-A antagonist. Before and during the first 30 minutes of infusion, simultaneous fMRI (rCBF) and neurochemical (interstitial glutamate concentration) measures of brain activity were highly correlated (r = 0.83). After 30 minutes of picrotoxinin-induced stimulation, glutamate levels decreased but rCBF remained elevated, suggesting that additional factors modulate the relationship between neuronal neurotransmitters and hemodynamics at these later stages.
Research Interests: Neuroscience, Chemistry, Neurology, Metabolism, Magnetic Resonance Imaging, and 15 moreMedicine, Brain Mapping, Glutamate, Brain, Flow, Brain Circulation, Animals, Male, Magnetic Resonance, Clinical Sciences, Microdialysis, Cerebral, Neurosciences, Glutamic Acid, and Cardiovascular medicine and haematology
The common marmoset (Callithrix jacchus) has garnered interest recently as a powerful model for the future of neuroscience research. Much of this excitement has centered on the species' reproductive biology and compatibility with gene... more
The common marmoset (Callithrix jacchus) has garnered interest recently as a powerful model for the future of neuroscience research. Much of this excitement has centered on the species' reproductive biology and compatibility with gene editing techniques, which together have provided a path for transgenic marmosets to contribute to the study of disease as well as basic brain mechanisms. In step with technical advances is the need to establish experimental paradigms that optimally tap into the marmosets' behavioral and cognitive capacities. While conditioned task performance of a marmoset can compare unfavorably with rhesus monkey performance on conventional testing paradigms, marmosets' social behavior and cognition are more similar to that of humans. For example, marmosets are among only a handful of primates that, like humans, routinely pair bond and care cooperatively for their young. They are also notably pro-social and exhibit social cognitive abilities, such as imit...
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FP %vol FN %vol TP %vol Lesion Volume Marmoset 1 26.8% 36.4% 63.7% 27.2 Marmoset 2 10.7% 0.8% 99.2% 18.1 Marmoset 3 2.8% 20.9% 79.1% 96.5 Average 8.4% 21.3% 78.7% 47.3 Table 1. %vol corresponds to % relative to lesion volume from gold... more
FP %vol FN %vol TP %vol Lesion Volume Marmoset 1 26.8% 36.4% 63.7% 27.2 Marmoset 2 10.7% 0.8% 99.2% 18.1 Marmoset 3 2.8% 20.9% 79.1% 96.5 Average 8.4% 21.3% 78.7% 47.3 Table 1. %vol corresponds to % relative to lesion volume from gold standard. All values are the average across the three follow-up scans. 1395 Automated Lesion Segmentation in a Marmoset Model of Multiple Sclerosis via Subtraction MRI Colin Shea, Pascal Sati, Joseph Guy, Emily Leibovitch, Steven Jacobson, Afonso Silva, and Daniel S. Reich NINDS, NIH, Bethesda, Maryland, United States
The primate auditory cortex is organized into a network of anatomically and functionally distinct processing fields. Because of its tonotopic properties, the auditory core has been the main target of neurophysiological studies ranging... more
The primate auditory cortex is organized into a network of anatomically and functionally distinct processing fields. Because of its tonotopic properties, the auditory core has been the main target of neurophysiological studies ranging from sensory encoding to perceptual decision-making. By comparison, the auditory belt has been less extensively studied, in part due to the fact that neurons in the belt areas prefer more complex stimuli and integrate over a wider frequency range than neurons in the core, which prefer pure tones of a single frequency. Complementary approaches, such as functional magnetic resonance imaging (fMRI), allow the anatomical identification of both the auditory core and belt and facilitate their functional characterization by rapidly testing a range of stimuli across multiple brain areas simultaneously that can be used to guide subsequent neural recordings. Bridging these technologies in primates will serve to further expand our understanding of primate auditio...