Kadharbatcha Saleem
National Institutes of Health, Laboratory of Neuropsychology, Department Member
High-resolution imaging studies have consistently shown that in cortical tissue water diffuses preferentially along radial and tangential orientations with respect to the cortical surface, in agreement with histology. These dominant... more
High-resolution imaging studies have consistently shown that in cortical tissue water diffuses preferentially along radial and tangential orientations with respect to the cortical surface, in agreement with histology. These dominant orientations do not change significantly even if the relative contributions from microscopic water pools to the net voxel signal vary across experiments that use different diffusion times, b-values, TEs, and TRs. With this in mind, we propose a practical new framework for imaging non-parametric diffusion tensor distributions (DTDs) by constraining the microscopic diffusion tensors of the DTD to be diagonalized using the same orthonormal reference frame of the mesoscopic voxel. In each voxel, the constrained DTD (cDTD) is completely determined by the correlation spectrum of the microscopic principal diffusivities associated with the axes of the voxel reference frame. Consequently, all cDTDs are inherently limited to the domain of positive definite tensors...
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Neural tissue microstructure plays a key role in developmental, physiological and pathophysiological processes. In the continuing quest to characterize it at ever finer length scales, we use a novel diffusion tensor distribution (DTD)... more
Neural tissue microstructure plays a key role in developmental, physiological and pathophysiological processes. In the continuing quest to characterize it at ever finer length scales, we use a novel diffusion tensor distribution (DTD) paradigm to probe microstructural features much smaller than the nominal MRI voxel size. We first assume the DTD is a normal tensor variate distribution constrained to lie on the manifold of positive definite matrices, characterized by a mean and covariance tensor. We then estimate the DTD using Monte Carlo signal inversion combined with parsimonious model selection framework that exploits a hierarchy of symmetries of mean and covariance tensors. High resolution multiple pulsed field gradient (mPFG) MRI measurements were performed on a homogeneous isotropic diffusion phantom (PDMS) for control, and excised visual cortex and spinal cord of macaque monkey to investigate the capabilities of DTD MRI in revealing neural tissue microstructural features using...
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Anatomical Accuracy of Diffusion MRI Tractography: Testing the Fundamental Limits Cibu P Thomas, Frank Q Ye, Mustafa Okan Irfanoglu, Pooja D Modi, Kadharbatcha S Saleem, David A Leopold, and Carlo Pierpaoli National Institute of Child... more
Anatomical Accuracy of Diffusion MRI Tractography: Testing the Fundamental Limits Cibu P Thomas, Frank Q Ye, Mustafa Okan Irfanoglu, Pooja D Modi, Kadharbatcha S Saleem, David A Leopold, and Carlo Pierpaoli National Institute of Child Health and Human Development, Bethesda, Maryland, United States, Center for Neuroscience and Regenerative Medicine, USUHS, Bethesda, Maryland, United States, National Institute of Mental Health, Bethesda, Maryland, United States
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In the primate auditory cortex, information flows serially in the mediolateral dimension from core, to belt, to parabelt. In the caudorostral dimension, stepwise serial projections convey information through the primary, rostral, and... more
In the primate auditory cortex, information flows serially in the mediolateral dimension from core, to belt, to parabelt. In the caudorostral dimension, stepwise serial projections convey information through the primary, rostral, and rostrotemporal (AI, R, and RT) core areas on the supratemporal plane, continuing to the rostrotemporal polar area (RTp) and adjacent auditory-related areas of the rostral superior temporal gyrus (STGr) and temporal pole. In addition to this cascade of corticocortical connections, the auditory cortex receives parallel thalamocortical projections from the medial geniculate nucleus (MGN). Previous studies have examined the projections from MGN to auditory cortex, but most have focused on the caudal core areas AI and R. In this study, we investigated the full extent of connections between MGN and AI, R, RT, RTp, and STGr using retrograde and anterograde anatomical tracers. Both AI and R received nearly 90% of their thalamic inputs from the ventral subdivisi...
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A combined MRI and Histology: Atlas of the Rhesus monkey brain in stereotaxic coordinates is designed to provide an easy to use resource/reference for anatomical, physiological, and functional imaging (fMRI, PET and MEG) studies in... more
A combined MRI and Histology: Atlas of the Rhesus monkey brain in stereotaxic coordinates is designed to provide an easy to use resource/reference for anatomical, physiological, and functional imaging (fMRI, PET and MEG) studies in primates. We hope that this book will ...
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The use of standard anatomical templates is common in human neuroimaging, as it facilitates data analysis and comparison across subjects and studies. For non-human primates, previous in vivo templates have lacked sufficient contrast to... more
The use of standard anatomical templates is common in human neuroimaging, as it facilitates data analysis and comparison across subjects and studies. For non-human primates, previous in vivo templates have lacked sufficient contrast to reliably validate known anatomical brain regions and have not provided tools for automated single-subject processing. Here we present the "National Institute of Mental Health Macaque Template", or NMT for short. The NMT is a high-resolution in vivo MRI template of the average macaque brain generated from 31 subjects, as well as a neuroimaging tool for improved data analysis and visualization. From the NMT volume, we generated maps of tissue segmentation and cortical thickness. Surface reconstructions and transformations to previously published digital brain atlases are also provided. We further provide an analysis pipeline using the NMT that automates and standardizes the time-consuming processes of brain extraction, tissue segmentation, and...
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Rapid, serial, and humane collection of cerebrospinal fluid (CSF) in nonhuman primates (NHP) is an essential element of numerous research studies and is currently accomplished via two different models. The CSF reservoir model (FR)... more
Rapid, serial, and humane collection of cerebrospinal fluid (CSF) in nonhuman primates (NHP) is an essential element of numerous research studies and is currently accomplished via two different models. The CSF reservoir model (FR) combines a catheter in the 4th ventricle with a flexible silastic reservoir to permit circulating CSF flow. The CSF lateral port model (LP) consists of a lateral ventricular catheter and an IV port that provides static access to CSF and volume restrictions on sample collection. The FR model is associated with an intensive, prolonged recovery and frequent postsurgical hydrocephalus and nonpatency, whereas the LP model is associated with an easier recovery. To maximize the advantages of both systems, we developed the CSF lateral reservoir model (LR), which combines the beneficial features of the 2 previous models but avoids their limitations by using a reservoir for circulating CSF flow combined with catheter placement in the lateral ventricle. Nine adult male rhesus monkeys were utilized in this study. Pre-surgical MRI was performed to determine the coordinates of the lateral ventricle and location of choroid plexus (CP). The coordinates were determined to avoid the CP and major blood vessels. The predetermined coordinates were 100% accurate, according to MRI validation. The LR system functioned successfully in 67% of cases for 221 d, and 44% remain functional at 426 to 510 d postoperatively. Compared with established models, our LR model markedly reduced postoperative complications and recovery time. Development of the LR model was successful in rhesus macaques and is a useful alternative to the FR and LP methods of CSF collection from nonhuman primates.
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ABSTRACT BACKGROUND: The overall outcome for children with diffuse intrinsic pontine gliomas remains poor. We hypothesize that the lack of efficacy of any chemotherapy agents for this disease is related to differences in the blood-brain... more
ABSTRACT BACKGROUND: The overall outcome for children with diffuse intrinsic pontine gliomas remains poor. We hypothesize that the lack of efficacy of any chemotherapy agents for this disease is related to differences in the blood-brain barrier (BBB) throughout the central nervous system, with certain areas crucial to basic functioning (such as the pons) having a more restrictive BBB. We developed a novel animal model in rhesus macaques (Macaca mulatta) using microdialysis (MD), a continuous sampling technique based on diffusion, to simultaneously measure drug penetration into the cerebral cortex, pons, and CSF. METHODS: Custom made MD probes (CMA, Solna, Sweden) were stereotactically placed into the frontal cortex and pons of 4 adult male rhesus macaques based on coordinates determined by pre-surgical MRI. After completion of in vivo retrodialysis, an intravenous infusion of temozolomide was administered. Single continuous MD samples from the pons and cortex were collected over 4 hours with concurrent serial plasma and CSF samples. Post-surgical MRI was obtained for 2 animals and post-mortem pathology was performed on all 4 animals to confirm probe placement. Temozolomide concentrations for all samples were quantified using HPLC/tandem mass spectroscopy. RESULTS: Microdialysis probe placement was tolerated in all four animals with confirmation of proper placement into the pons and cortex in 3 of 4 animals. Measurable drug quantities were present in both the pons and cerebral cortex for samples analyzed to date. CONCLUSIONS: We have developed a new animal model using MD to assess differences in drug penetration within the CNS. We were able to confirm in 3 of 4 animals proper placement of both MD probes using either MRI or gross pathology. Temozolomide drug concentrations can be quantified within the pons and cortex using microdialysis; further pharmacokinetic assessment, assay development and survival studies will be done to validate this animal model.
The macaque orbitofrontal cortex (OFC) is essential for selecting goals based on current, updated values of expected reward outcomes. As monkeys consume a given type of reward to satiety, its value diminishes, and OFC damage impairs the... more
The macaque orbitofrontal cortex (OFC) is essential for selecting goals based on current, updated values of expected reward outcomes. As monkeys consume a given type of reward to satiety, its value diminishes, and OFC damage impairs the ability to shift goal choices away from devalued outcomes. To examine the contributions of OFC's components to goal selection, we reversibly inactivated either its anterior (area 11) or posterior (area 13) parts. We found that neurons in area 13 must be active during the selective satiation procedure to enable the updating of outcome valuations. After this updating has occurred, however, area 13 is not needed to select goals based on this knowledge. In contrast, neurons in area 11 do not need to be active during the value-updating process. Instead, inactivation of this area during choices causes an impairment. These findings demonstrate selective and complementary specializations within the OFC.
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We examined the connections between the anterior inferotemporal cortex and the superior temporal sulcus (STS) in the macaque monkey by injecting Phaseolus vulgaris leucoagglutinin (PHA-L) or wheat germ agglutinin conjugated to horseradish... more
We examined the connections between the anterior inferotemporal cortex and the superior temporal sulcus (STS) in the macaque monkey by injecting Phaseolus vulgaris leucoagglutinin (PHA-L) or wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) into the dorsoanterior and ventroanterior subdivisions of TE (TEad and TEav, respectively) and observing the labeled terminals and cell bodies in STS. We found a clear dichotomy in the connections of the rostral part of STS: the injections into TEad resulted in a dense distribution of labeled terminals and cell bodies in the upper bank of rostral STS, whereas labeling was confined to the lower bank and fundus of rostral STS after injections into TEav. The distribution of labeling in the rostral STS was discontinuous from the distribution of labeling surrounding the injection sites: the lower bank of the rostral STS was spared from labeling in the TEad injection cases, and TEad had only sparse distribution in the TEav injection ...
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Corticostriatal and corticoamygdalar projections arising from area TE of the macaque monkey were studied by focal injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin into the dorsolateral and ventromedial subdivisions... more
Corticostriatal and corticoamygdalar projections arising from area TE of the macaque monkey were studied by focal injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin into the dorsolateral and ventromedial subdivisions of the anterior TE (TEad and TEav, respectively). This approach yielded several new results. First, the global distributions of labeled terminals revealed that both TEad and TEav projected to the ventrocaudal striatum, including the tail of the caudate nucleus and the adjacent ventral putamen, and the dorsolateral aspect of the deep amygdaloid nuclei. TEav also projected to the medial basal nucleus of the amygdala and the ventral striatum. Second, the reconstructed single axons (n = 18) demonstrated that some axons originating from TEav or TEad projected simultaneously to the ventrocaudal striatum and the dorsolateral aspect of the deep amygdaloid nuclei by giving off collaterals. TEav axons projected to the medial basal nucleus of the amygdala also...
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Pediatric diffuse intrinsic pontine gliomas are aggressive brainstem tumors that fail to respond to treatment. We hypothesize that the protective features of the pons may hinder chemotherapeutic agents from entering pontine tissue... more
Pediatric diffuse intrinsic pontine gliomas are aggressive brainstem tumors that fail to respond to treatment. We hypothesize that the protective features of the pons may hinder chemotherapeutic agents from entering pontine tissue compared with cortical brain tissue. To test this hypothesis, we developed a unique nonhuman primate model using microdialysis, a continuous in vivo extracellular sampling technique, to compare drug exposure concurrently in pontine tissue, cortical tissue, CSF, and plasma after intravenous administration of chemotherapeutic agents. The surgical coordinates and approach for microdialysis cannula-probe placement were determined in 5 adult male rhesus monkeys (Macaca mulatta) by using MRI. Microdialysis cannulas-probes were implanted stereotactically in the brain, retrodialysis was performed to measure relative recovery, and a 1-h intravenous infusion of temozolomide was administered. Continuous microdialysis samples were collected from the pons and cortex ov...
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Rapid, serial, and humane collection of cerebrospinal fluid (CSF) in nonhuman primates (NHP) is an essential element of numerous research studies and is currently accomplished via two different models. The CSF reservoir model (FR)... more
Rapid, serial, and humane collection of cerebrospinal fluid (CSF) in nonhuman primates (NHP) is an essential element of numerous research studies and is currently accomplished via two different models. The CSF reservoir model (FR) combines a catheter in the 4th ventricle with a flexible silastic reservoir to permit circulating CSF flow. The CSF lateral port model (LP) consists of a lateral ventricular catheter and an IV port that provides static access to CSF and volume restrictions on sample collection. The FR model is associated with an intensive, prolonged recovery and frequent postsurgical hydrocephalus and nonpatency, whereas the LP model is associated with an easier recovery. To maximize the advantages of both systems, we developed the CSF lateral reservoir model (LR), which combines the beneficial features of the 2 previous models but avoids their limitations by using a reservoir for circulating CSF flow combined with catheter placement in the lateral ventricle. Nine adult ma...
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Fronto-limbic circuits in the primate brain are responsible for executive function, learning and memory, and emotions, including fear. Consequently, changes in gene expression in cortical and subcortical brain regions housing these... more
Fronto-limbic circuits in the primate brain are responsible for executive function, learning and memory, and emotions, including fear. Consequently, changes in gene expression in cortical and subcortical brain regions housing these circuits are associated with many important psychiatric and neurological disorders. While high quality gene expression profiles can be identified in brains from model organisms, primate brains have unique features such as Brodmann Area 25, which is absent in rodents, yet profoundly important in primates, including humans. The potential insights to be gained from studying the human brain are complicated by the fact that the post-mortem interval (PMI) is variable, and most repositories keep solid tissue in the deep frozen state. Consequently, sampling the important medial and internal regions of these brains is difficult. Here we describe a novel method for obtaining discrete regions from the fronto-limbic circuits of a 4 year old and a 5 year old, male, intact, frozen non-human primate (NHP) brain, for which the PMI is exactly known. The method also preserves high quality RNA, from which we use transcriptional profiling and a new algorithm to identify region-exclusive RNA signatures for Area 25 (NFκB and dopamine receptor signaling), the anterior cingulate cortex (LXR/RXR signaling), the amygdala (semaphorin signaling), and the hippocampus (Ca(++) and retinoic acid signaling). The RNA signatures not only reflect function of the different regions, but also include highly expressed RNAs for which function is either poorly understood, or which generate proteins presently lacking annotated functions. We suggest that this new approach will provide a useful strategy for identifying changes in fronto-limbic system biology underlying normal development, aging and disease in the human brain.
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Research Interests: Cognitive Science, Animal Behavior, Magnetic Resonance Imaging, Prefrontal Cortex, Brain Mapping, and 17 moreThalamus, wheat germ agglutinin (WGA), Animals, Substantia nigra, Neurons, Neurotoxins, Globus Pallidus, Time Factors, Neuron, Basal ganglia, Macaca Mulatta, Neural pathways, Manganese Compounds, Macaque Monkey, Neurosciences, Chlorides, and Magnetic resonance image
Research Interests: Cognitive Science, Computer Graphics, Biomedical Engineering, Magnetic Resonance Imaging, Visual Cortex, and 16 moreBrain Mapping, Temporal Lobe, Fourier Analysis, Brain, Cerebral Cortex, Animals, Male, Magnetic Resonance, Clinical Sciences, Parietal Lobe, Rhesus Monkey, Neocortex, Macaca Mulatta, Ease of Use, Frontal Lobe, and Occipital Lobe
The division of cortical visual processing into distinct dorsal and ventral streams is a key framework that has guided visual neuroscience. The characterization of the ventral stream as a... more
The division of cortical visual processing into distinct dorsal and ventral streams is a key framework that has guided visual neuroscience. The characterization of the ventral stream as a 'What' pathway is relatively uncontroversial, but the nature of dorsal stream processing is less clear. Originally proposed as mediating spatial perception ('Where'), more recent accounts suggest it primarily serves non-conscious visually guided action ('How'). Here, we identify three pathways emerging from the dorsal stream that consist of projections to the prefrontal and premotor cortices, and a major projection to the medial temporal lobe that courses both directly and indirectly through the posterior cingulate and retrosplenial cortices. These three pathways support both conscious and non-conscious visuospatial processing, including spatial working memory, visually guided action and navigation, respectively.
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Genetic control over morphological variability of primary sulci and gyri is of great interest in the evolutionary, developmental and clinical neurosciences. Primary structures emerge early in development and their morphology is thought to... more
Genetic control over morphological variability of primary sulci and gyri is of great interest in the evolutionary, developmental and clinical neurosciences. Primary structures emerge early in development and their morphology is thought to be related to neuronal differentiation, development of functional connections and cortical lateralization. We measured the proportional contributions of genetics and environment to regional variability, testing two theories regarding regional modulation of genetic influences by ontogenic and phenotypic factors. Our measures were surface area, and average length and depth of eleven primary cortical sulci from high-resolution MR images in 180 pedigreed baboons. Average heritability values for sulcal area, depth and length (h(2)(Area)=.38+/-.22; h(2)(Depth)=.42+/-.23; h(2)(Length)=.34+/-.22) indicated that regional cortical anatomy is under genetic control. The regional pattern of genetic contributions was complex and, contrary to previously proposed ...