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Papers by james fallon

Auditory-visual interaction in cat orbital-insular cortex

Neuroscience Letters, 1977

ABSTRACT

Experimental Neurology, 1975

Near total lesions of occipital cortex were made in rhesus monkeys and the subsequent anterograde... more Near total lesions of occipital cortex were made in rhesus monkeys and the subsequent anterograde degeneration was analyzed using the Fink-Heimer technique. In addition to degenerated terminal endings seen in parietal, temporal and frontal cortices, sparse to moderately dense pericellular and terminal degeneration was seen in posterior portions of ventral orbital cortex and the inferior prefrontal convexity (lateral orbital cortex). These results indicate that activity from the visual cortex may directly influence cells of the frontal orbital cortex.

The island of Calleja complex of rat basal forebrain. I. Light and electron microscopic observations

The Journal of Comparative Neurology, 1982

An analysis of the cells and their processes within the island of Calleja complexes (ICC) was mad... more An analysis of the cells and their processes within the island of Calleja complexes (ICC) was made in light and electron microscopic preparations to determine synaptic relationships within this part of the basal forebrain. The light microscopic preparations showed that the ICC contained two cell types, granule cells and large cells. In electron microscopic preparations, the somata of granule cells were grouped together and were directly apposed to other somata of granule cells. Specialized junctions (4-6 nm wide) that occurred at sites of somal apposition suggested ephaptic coupling of granule cells. The granule cell somata had nuclei that contained clumps of heterochromatin adjacent to smooth nuclear envelopes. The perikaryal cytoplasm of these cells consisted of a relatively thin rim containing few organelles. Spinous dendrites of small diameter were occasionally found in continuity with these cells. Axon terminals rarely formed synapses with the somata of granule cells, but were more frequently found to synapse on their dendrites and dendritic spines. These features for granule cells are similar to those for medium-sized spiny neurons in the neostriatum. The somata of the large cells were found either within the core or along the dorsal margin of the ICC. The large cells had infolded nuclei and an abundant perikaryal cytoplasm that contained many organelles. Large diameter dendrites that tapered down to smaller diameters emanated in many directions from these somata. Axon terminals covered nearly the entire surface of these somata and dendrites where they commonly formed symmetric synaptic junctions. These characteristics of large cells indicate a resemblance to the large cells in the globus pallidus and ventral pallidum. Therefore, the ICC have ultrastructural features found in both the neostriatum and globus pallidus.

How the Brain Develops and How It Functions

For many models of the cerebral cortex, particularly developmental ones, knowledge of cortical st... more For many models of the cerebral cortex, particularly developmental ones, knowledge of cortical structure is essential to a proper understanding of its functional capacities. We have studied the microscopic neuroanatomic changes of the postnatal human cerebral cortex during its development from birth to 72 mo. The microscopic structural changes we have identified to date are complex, yet well organized, and mathematically describable. The discoveries to date arising from analyses of the Conel data include: 1. That the total number of cortical neurons increases by 1/3 from term birth to 3 mo, then decreases back to the birth value by 15 mo, then increases by approximately 70% above the birth value from 15 to 72 mo. 2. Based on 35 cortical areas, the mean number of neurons under 1 mm2 of cortical surface extending the depth of the cortex decreases by 50% from term birth to 15 mo, then from 15 to 72 mo, increases by 70% above the value at 15 mo. Both of the previous findings provided the first evidence for postnatal mammalian (human) neocortical neurogenesis. These findings have received subsequent support from studies demonstrating cortical neurogenesis in adult macaque monkeys. 3. That changes in total cortical neuron number from birth to 72 mo inversely correlate strongly (ρ = −0.73) with the number of new behaviors acquired during this time. The correlation appears strongest when there is a time delay, suggesting that changes in cortical neuron number precede the appearance of newly acquired behaviors. 4. That each of 35 cortical areas analyzed show characteristic increases and decreases in neuron number in a wave-like fashion from birth to 72 mo, suggesting local regulatory control of both neuronal cell death and neurogenesis. The changes in neuron number appear to follow gradients that correspond to functional cortical systems, including frontal (motor, dorsolateral prefrontal, and orbitofrontal, separately), visual (ventral and dorsal streams, separately), and auditory systems. 5. That within any given cortical area from birth to 72 mo, there are functionally related shifts in the relative numbers of neurons in the six cortical layers. Since each of the six cortical layers has a specific function with specific communication to other layers, the neocortex can create 720 variations (6!) in its function just by changing the relative power of the six cortical layers in all possible permutations. The data clearly show that only a few of these permutations are actually used. It appears that the function of secondary association neocortical areas or higher are most developed when layers III and VI have the most neurons, and that the function of primary sensory, 1st order association, or transitional (i.e., cingulate) neocortical areas are most developed when layers III and IV have the most neurons. Layer III is primarily responsible for long distance cortico-cortical communication; layer IV is primarily responsible for receiving thalamic sensory information from the environment plus feedforward cortico-cortical communication; and layer VI is primarily responsible for sending cortical information back to the thalamus and receiving feedback cortico-cortical information. In this chapter, we present the data and studies that formed the basis for the above discoveries in postnatal human cerebral cortex from birth to 72 mo. These data have particular relevance to those interested in building computational models of cortical development and provide a basis for concomitant cortical electrophysiological and behavioral developmental changes. Computational models incorporating such knowledge may provide a mechanistic understanding of how the brain develops and how it functions.

Estimating cortical connectivity for developing human cerebral cortex

Neurocomputing, 2000

ABSTRACT Cortical connectivity for human cerebral cortex was estimated for 31 cortical areas usin... more ABSTRACT Cortical connectivity for human cerebral cortex was estimated for 31 cortical areas using microscopic anatomical data of the number of neurons, myelinated axon density, and dendrite fiber density. Estimated connections agree with known connections derived from imaging and tracing studies. Also some unusual connections, which have been recently confirmed by other studies, were estimated.

Modeling neuron spatial distribution and morphology in the developing human cerebral cortex

Neurocomputing, 2000

... Additional context-sensitive features to accommodate segment retraction, differential growth ... more ... Additional context-sensitive features to accommodate segment retraction, differential growth rates in adjacent dendritic arbors, and the synchronized growth of neuronal forests are being examined. ... A neuron visualizer allows a 3D interactive display of neurons in the ...

Psychiatry Research: Neuroimaging, 2015

The aim of the study was to examine functional brain activity in response to unpleasant images in... more The aim of the study was to examine functional brain activity in response to unpleasant images in individuals with the 7-repeat (7R) allele compared to individuals with the 4-repeat (4R) allele of the dopamine receptor D4 (DRD4) gene (VNTR in exon 3). Based on the response ready hypothesis, individuals with the DRD4-4R/7R genotype were expected to show greater functional brain activity in response to unpleasant compared to neutral stimuli in specific regions of the frontal, temporal, parietal and limbic lobes, which form the networks involved in attentional, emotional, and preparatory responses. Functional Magnetic Resonance Imaging activity was studied in 26 young adults (13 with the DRD4-4R/7R genotype and 13 with the DRD4-4R/4R genotype). Participants were asked to look at and subjectively rate unpleasant and neutral images. Results showed increased brain activity in response to unpleasant images compared to neutral images in the right temporal lobe in participants with the DRD4-4R/7R genotype versus participants with the DRD4-4R/4R genotype. The increase in right temporal lobe activity in individuals with DRD4-4R/7R suggests greater involvement in processing negative emotional stimuli. Intriguingly, no differences were found between the two genotypes in the subjective ratings of the images. The findings corroborate the response ready hypothesis, which suggests that individuals with the 7R allele are more responsive to negative emotional stimuli compared to individuals with the 4R allele of the DRD4 gene.

The Journal of Neuroscience, 1986

Previous results from immunocytochemical and retrograde transport studies indicated that some GAB... more Previous results from immunocytochemical and retrograde transport studies indicated that some GABAergic neurons in the hilus of the dentate gyrus may have axonal projections through the hippocampal commissure. This study has utilized a combined immunocytochemical and retrograde transport method as well as 2 anterograde electron-microscopic methods to determine the existence of this projection in rats. Combined tracer and immunofluorescence studies showed several double-labeled GABAergic neurons in the hilus contralateral to the injection site. The electron-microscopic studies revealed both degenerating and HRP-labeled commissural axons that formed symmetric synapses, the type shown to be formed by GABAergic terminals in the hippocampus. These data demonstrate a GABAergic component within the hippocampal commissural pathway and add further evidence that cortical GABAergic terminals are not derived exclusively from intrinsic neurons. Previous immunocytochemical results have indicated that neurons containing glutamate decarboxylase (GAD) are found throughout the hippocampal dentate gyrus (Ribak et al., 1978). GAD is the synthesizing enzyme for the neurotransmitter GABA, which is known to have an inhibitory effect in the neocortex and hippocampal allocortex (Alger and Nicoll, 1982; Curtis et al., 1970; KmjeviC, 1974). A more recent study has shown that the hilar GAD-positive neurons display a wide variety of shapes and sizes (Seress and Ribak, 1983). In addition, a quantitative assessment of these neurons indicated that at least 60% of the total number of hilar neurons are GABAergic. These data, taken

CYBERCHILD: A database of the microscopic development of the postnatal human cerebral cortex from birth to 72 months

Neurocomputing, 2000

We introduce a database of the microscopic, laminar development of ∼73% of postnatal human cerebr... more We introduce a database of the microscopic, laminar development of ∼73% of postnatal human cerebral cortical areas from 0 to 72 months. These data have yielded important findings, such as overturning the dogma of no postnatal neurogenesis in humans. To facilitate their use in computational models, the data are being interfaced with GENESIS.

CYBERCHILD: A database of the microscopic development of the postnatal human cerebral cortex from birth to 72 months

Neurocomputing, 2000

We introduce a database of the microscopic, laminar development of ∼73% of postnatal human cerebr... more We introduce a database of the microscopic, laminar development of ∼73% of postnatal human cerebral cortical areas from 0 to 72 months. These data have yielded important findings, such as overturning the dogma of no postnatal neurogenesis in humans. To facilitate their use in computational models, the data are being interfaced with GENESIS.

Pediatric and Developmental Pathology, 1999

From 1939 to 1967, J.L. Conel quantitatively studied the microscopic features of the developing h... more From 1939 to 1967, J.L. Conel quantitatively studied the microscopic features of the developing human cerebral cortex and published the findings in eight volumes. We have constructed a database using his neuroanatomical measurements (neuronal packing density, myelinated large fiber density, large proximal dendrite density, somal breadth and height, and total cortical and cortical layer thickness) at the eight age periods (0 [term birth], 1, 3, 6, 15, 24, 48, and 72 postnatal months) he studied. In this report, we examine changes in neuron numbers over the eight age-points for 35 von Economo areas for which Conel gave appropriate data. From birth to 3 months postnatal age, total cortical neuron number increases 23–30%, then falls to within 3.5% of the birth value at 24 months, supporting our previous work showing that the observed decrease in the number of neurons per column of cortex under a 1-mm2 cortical surface from birth to 15 months is almost entirely due to cortical surface ex...

MRI white matter diffusion anisotropy and PET metabolic rate in schizophrenia

…, 1998

A disturbance in the frontal-striatal-thalamic circuitry has been proposed for schizophrenia, but... more A disturbance in the frontal-striatal-thalamic circuitry has been proposed for schizophrenia, but this concept has been based primarily on indirect evidence from psychopharmacology and analogies with animal research. Diffusion tensor imaging, a new MRI technique that permits direct assessment of the large axon masses stretching from the prefrontal cortex to the striatum, was used to study white matter axon bundles. Diffusion tensor images, high-resolution structural MRI and positron emission tomography scans with 18-fluorodexoyglucose were obtained on five patients with schizophrenia and six age- and sex-matched normal controls. Significantly lower diffusion anisotropy in the white matter of the prefrontal cortex in schizophrenic patients than in normal controls was observed in statistical probability maps. Co-registered PET scans revealed significantly lower correlation coefficients between metabolic rates in the prefrontal cortex and striatum in patients than in controls. These twin findings provide convergent evidence for diminished fronto-striatal connectivity in schizophrenia.

Brain Sciences

System-specific brain responses—time-locked to rapid eye movements (REMs) in sleep—are characteri... more System-specific brain responses—time-locked to rapid eye movements (REMs) in sleep—are characteristically widespread, with robust and clear activation in the primary visual cortex and other structures involved in multisensory integration. This pattern suggests that REMs underwrite hierarchical processing of visual information in a time-locked manner, where REMs index the generation and scanning of virtual-world models, through multisensory integration in dreaming—as in awake states. Default mode network (DMN) activity increases during rest and reduces during various tasks including visual perception. The implicit anticorrelation between the DMN and task-positive network (TPN)—that persists in REM sleep—prompted us to focus on DMN responses to temporally-precise REM events. We timed REMs during sleep from the video recordings and quantified the neural correlates of REMs—using functional MRI (fMRI)—in 24 independent studies of 11 healthy participants. A reanalysis of these data reveal...

Current Biology

Highlights d We use fossil skull data to derive an index of endocranial shape in human MRI scans ... more Highlights d We use fossil skull data to derive an index of endocranial shape in human MRI scans d In 4,468 Europeans, we screen introgressed Neandertal SNPs for association with the index d Lead SNPs consistently associate with reduced globularity in five separate subsamples d These SNPs affect neural expression of two genes linked to neurogenesis and myelination

Frontiers in Psychology

The neural correlates of rapid eye movements (REMs) in sleep are extraordinarily robust; includin... more The neural correlates of rapid eye movements (REMs) in sleep are extraordinarily robust; including REM-locked multisensory-motor integration and accompanying activation in the retrosplenial cortex, the supplementary eye field and areas encompassing cholinergic basal nucleus (Hong et al., 2009). The phenomenology of REMs speaks to the notion that perceptual experience in both sleep and wakefulness is a constructive process-in which we generate predictions of sensory inputs and then test those predictions through actively sampling the sensorium with eye movements. On this view, REMs during sleep may index an internalized active sampling or 'scanning' of selfgenerated visual constructs that are released from the constraints of visual input. If this view is correct, it renders REMs an ideal probe to study consciousness as "an exclusively internal affair" (Metzinger, 2009). In other words, REMs offer a probe of active inferencein the sense of predictive coding-when the brain is isolated from the sensorium in virtue of the natural blockade of sensory afferents during REM sleep. Crucially, REMs are temporally precise events that enable powerful inferences based on time series analyses. As a natural, task-free probe, (REMs) could be used in non-compliant subjects, including infants and animals. In short, REMs constitute a promising probe to study the ontogenetic and phylogenetic development of consciousness and perhaps the psychopathology of schizophrenia and autism, which have been considered in terms of aberrant predictive coding.

The Journal of comparative neurology, Jan 15, 2016

Epigenetic programming and reprogramming are at the heart of cellular differentiation and represe... more Epigenetic programming and reprogramming are at the heart of cellular differentiation and represent developmental and evolutionary mechanisms in both germline and somatic cell lines. Only about 2% of our genome is composed of protein-coding genes, while the remaining 98%, once considered "junk" DNA, codes for regulatory/epigenetic elements that control how genes are expressed in different tissues and across time from conception to death. While we already know that epigenetic mechanisms are at play in cancer development and in regulating metabolism (cellular and whole body), the role of epigenetics in the developing prenatal and postnatal brain, and in maintaining a proper brain activity throughout the various stages of life, in addition to having played a critical role in human evolution, is a relatively new domain of knowledge. Here we present the current state-of-the-art techniques and results of these studies within the domain of emotions, and then speculate on how geno...

Method for correlating differential brain images and genotypes; genes that correlate with differential brain images

Methods of assigning quantitative phenotype measurement summary statistics to differential brain ... more Methods of assigning quantitative phenotype measurement summary statistics to differential brain image information associated with neuropsychiatric disorders are provided. Summary statistics are correlated to genotype information to identify loci that correlate with differential brain image phenotypes. Methods of identifying modulators of genes at the loci are provided, as well as modulators identified by the methods. Systems for correlating polymorphisms and differential brain image phenotypes, for identifying modulators and for ...

Methods for treating a neurological disorder by peripheral administration of a transforming growth factor alpha (TGF-a)

Regulation of Anaesthesia

A PET study of the pathophysiology of negative symptoms in schizophrenia. Positron emission tomography

The American Journal of Psychiatry, 2002

Positron emission tomography (PET) was used to compare cerebral metabolic patterns in schizophren... more Positron emission tomography (PET) was used to compare cerebral metabolic patterns in schizophrenic subjects with predominantly negative symptoms (alogia, affective flattening, avolition, and attentional impairment) and in those with predominantly positive symptoms. Fourteen right-handed male subjects with DSM-IV schizophrenia were assigned to groups with predominantly negative or predominantly positive symptoms on the basis of their post-drug-washout scores on the Positive and Negative Syndrome Scale. The patients were compared to seven age- and gender-matched normal volunteers. PET scans with [(18)F]fluorodeoxyglucose were obtained during a degraded Continuous Performance Task to measure absolute glucose metabolic rates. Statistical parametric mapping was used to estimate the regional metabolic differences between groups. The subjects with predominantly negative symptoms had significant differences in glucose metabolic rates, compared to both the subjects with predominantly positive symptoms and the normal subjects. Negative symptom subjects had a lower glucose metabolic rate in the right hemisphere, especially in the temporal and ventral prefrontal cortices, compared to the other groups, and higher metabolic rates in the cerebellar cortex and in the lower deep cerebellar nuclei. Negative symptom subscale scores were negatively correlated with glucose metabolic rates for most of the brain areas that differentiated subjects with predominantly negative symptoms from those with predominantly positive symptoms. Schizophrenic subjects with predominantly negative symptoms have greater metabolic abnormalities than subjects with predominantly positive symptoms, particularly in frontal, temporal, and cerebellar circuitry. These results are consistent with abnormalities in corticocortical, corticobasal ganglia, mesocortical dopamine, and cerebellar-thalamic-prefrontal circuits, which may underlie the negative symptoms of schizophrenia.

Auditory-visual interaction in cat orbital-insular cortex

Neuroscience Letters, 1977

ABSTRACT

Experimental Neurology, 1975

Near total lesions of occipital cortex were made in rhesus monkeys and the subsequent anterograde... more Near total lesions of occipital cortex were made in rhesus monkeys and the subsequent anterograde degeneration was analyzed using the Fink-Heimer technique. In addition to degenerated terminal endings seen in parietal, temporal and frontal cortices, sparse to moderately dense pericellular and terminal degeneration was seen in posterior portions of ventral orbital cortex and the inferior prefrontal convexity (lateral orbital cortex). These results indicate that activity from the visual cortex may directly influence cells of the frontal orbital cortex.

The island of Calleja complex of rat basal forebrain. I. Light and electron microscopic observations

The Journal of Comparative Neurology, 1982

An analysis of the cells and their processes within the island of Calleja complexes (ICC) was mad... more An analysis of the cells and their processes within the island of Calleja complexes (ICC) was made in light and electron microscopic preparations to determine synaptic relationships within this part of the basal forebrain. The light microscopic preparations showed that the ICC contained two cell types, granule cells and large cells. In electron microscopic preparations, the somata of granule cells were grouped together and were directly apposed to other somata of granule cells. Specialized junctions (4-6 nm wide) that occurred at sites of somal apposition suggested ephaptic coupling of granule cells. The granule cell somata had nuclei that contained clumps of heterochromatin adjacent to smooth nuclear envelopes. The perikaryal cytoplasm of these cells consisted of a relatively thin rim containing few organelles. Spinous dendrites of small diameter were occasionally found in continuity with these cells. Axon terminals rarely formed synapses with the somata of granule cells, but were more frequently found to synapse on their dendrites and dendritic spines. These features for granule cells are similar to those for medium-sized spiny neurons in the neostriatum. The somata of the large cells were found either within the core or along the dorsal margin of the ICC. The large cells had infolded nuclei and an abundant perikaryal cytoplasm that contained many organelles. Large diameter dendrites that tapered down to smaller diameters emanated in many directions from these somata. Axon terminals covered nearly the entire surface of these somata and dendrites where they commonly formed symmetric synaptic junctions. These characteristics of large cells indicate a resemblance to the large cells in the globus pallidus and ventral pallidum. Therefore, the ICC have ultrastructural features found in both the neostriatum and globus pallidus.

How the Brain Develops and How It Functions

For many models of the cerebral cortex, particularly developmental ones, knowledge of cortical st... more For many models of the cerebral cortex, particularly developmental ones, knowledge of cortical structure is essential to a proper understanding of its functional capacities. We have studied the microscopic neuroanatomic changes of the postnatal human cerebral cortex during its development from birth to 72 mo. The microscopic structural changes we have identified to date are complex, yet well organized, and mathematically describable. The discoveries to date arising from analyses of the Conel data include: 1. That the total number of cortical neurons increases by 1/3 from term birth to 3 mo, then decreases back to the birth value by 15 mo, then increases by approximately 70% above the birth value from 15 to 72 mo. 2. Based on 35 cortical areas, the mean number of neurons under 1 mm2 of cortical surface extending the depth of the cortex decreases by 50% from term birth to 15 mo, then from 15 to 72 mo, increases by 70% above the value at 15 mo. Both of the previous findings provided the first evidence for postnatal mammalian (human) neocortical neurogenesis. These findings have received subsequent support from studies demonstrating cortical neurogenesis in adult macaque monkeys. 3. That changes in total cortical neuron number from birth to 72 mo inversely correlate strongly (ρ = −0.73) with the number of new behaviors acquired during this time. The correlation appears strongest when there is a time delay, suggesting that changes in cortical neuron number precede the appearance of newly acquired behaviors. 4. That each of 35 cortical areas analyzed show characteristic increases and decreases in neuron number in a wave-like fashion from birth to 72 mo, suggesting local regulatory control of both neuronal cell death and neurogenesis. The changes in neuron number appear to follow gradients that correspond to functional cortical systems, including frontal (motor, dorsolateral prefrontal, and orbitofrontal, separately), visual (ventral and dorsal streams, separately), and auditory systems. 5. That within any given cortical area from birth to 72 mo, there are functionally related shifts in the relative numbers of neurons in the six cortical layers. Since each of the six cortical layers has a specific function with specific communication to other layers, the neocortex can create 720 variations (6!) in its function just by changing the relative power of the six cortical layers in all possible permutations. The data clearly show that only a few of these permutations are actually used. It appears that the function of secondary association neocortical areas or higher are most developed when layers III and VI have the most neurons, and that the function of primary sensory, 1st order association, or transitional (i.e., cingulate) neocortical areas are most developed when layers III and IV have the most neurons. Layer III is primarily responsible for long distance cortico-cortical communication; layer IV is primarily responsible for receiving thalamic sensory information from the environment plus feedforward cortico-cortical communication; and layer VI is primarily responsible for sending cortical information back to the thalamus and receiving feedback cortico-cortical information. In this chapter, we present the data and studies that formed the basis for the above discoveries in postnatal human cerebral cortex from birth to 72 mo. These data have particular relevance to those interested in building computational models of cortical development and provide a basis for concomitant cortical electrophysiological and behavioral developmental changes. Computational models incorporating such knowledge may provide a mechanistic understanding of how the brain develops and how it functions.

Estimating cortical connectivity for developing human cerebral cortex

Neurocomputing, 2000

ABSTRACT Cortical connectivity for human cerebral cortex was estimated for 31 cortical areas usin... more ABSTRACT Cortical connectivity for human cerebral cortex was estimated for 31 cortical areas using microscopic anatomical data of the number of neurons, myelinated axon density, and dendrite fiber density. Estimated connections agree with known connections derived from imaging and tracing studies. Also some unusual connections, which have been recently confirmed by other studies, were estimated.

Modeling neuron spatial distribution and morphology in the developing human cerebral cortex

Neurocomputing, 2000

... Additional context-sensitive features to accommodate segment retraction, differential growth ... more ... Additional context-sensitive features to accommodate segment retraction, differential growth rates in adjacent dendritic arbors, and the synchronized growth of neuronal forests are being examined. ... A neuron visualizer allows a 3D interactive display of neurons in the ...

Psychiatry Research: Neuroimaging, 2015

The aim of the study was to examine functional brain activity in response to unpleasant images in... more The aim of the study was to examine functional brain activity in response to unpleasant images in individuals with the 7-repeat (7R) allele compared to individuals with the 4-repeat (4R) allele of the dopamine receptor D4 (DRD4) gene (VNTR in exon 3). Based on the response ready hypothesis, individuals with the DRD4-4R/7R genotype were expected to show greater functional brain activity in response to unpleasant compared to neutral stimuli in specific regions of the frontal, temporal, parietal and limbic lobes, which form the networks involved in attentional, emotional, and preparatory responses. Functional Magnetic Resonance Imaging activity was studied in 26 young adults (13 with the DRD4-4R/7R genotype and 13 with the DRD4-4R/4R genotype). Participants were asked to look at and subjectively rate unpleasant and neutral images. Results showed increased brain activity in response to unpleasant images compared to neutral images in the right temporal lobe in participants with the DRD4-4R/7R genotype versus participants with the DRD4-4R/4R genotype. The increase in right temporal lobe activity in individuals with DRD4-4R/7R suggests greater involvement in processing negative emotional stimuli. Intriguingly, no differences were found between the two genotypes in the subjective ratings of the images. The findings corroborate the response ready hypothesis, which suggests that individuals with the 7R allele are more responsive to negative emotional stimuli compared to individuals with the 4R allele of the DRD4 gene.

The Journal of Neuroscience, 1986

Previous results from immunocytochemical and retrograde transport studies indicated that some GAB... more Previous results from immunocytochemical and retrograde transport studies indicated that some GABAergic neurons in the hilus of the dentate gyrus may have axonal projections through the hippocampal commissure. This study has utilized a combined immunocytochemical and retrograde transport method as well as 2 anterograde electron-microscopic methods to determine the existence of this projection in rats. Combined tracer and immunofluorescence studies showed several double-labeled GABAergic neurons in the hilus contralateral to the injection site. The electron-microscopic studies revealed both degenerating and HRP-labeled commissural axons that formed symmetric synapses, the type shown to be formed by GABAergic terminals in the hippocampus. These data demonstrate a GABAergic component within the hippocampal commissural pathway and add further evidence that cortical GABAergic terminals are not derived exclusively from intrinsic neurons. Previous immunocytochemical results have indicated that neurons containing glutamate decarboxylase (GAD) are found throughout the hippocampal dentate gyrus (Ribak et al., 1978). GAD is the synthesizing enzyme for the neurotransmitter GABA, which is known to have an inhibitory effect in the neocortex and hippocampal allocortex (Alger and Nicoll, 1982; Curtis et al., 1970; KmjeviC, 1974). A more recent study has shown that the hilar GAD-positive neurons display a wide variety of shapes and sizes (Seress and Ribak, 1983). In addition, a quantitative assessment of these neurons indicated that at least 60% of the total number of hilar neurons are GABAergic. These data, taken

CYBERCHILD: A database of the microscopic development of the postnatal human cerebral cortex from birth to 72 months

Neurocomputing, 2000

We introduce a database of the microscopic, laminar development of ∼73% of postnatal human cerebr... more We introduce a database of the microscopic, laminar development of ∼73% of postnatal human cerebral cortical areas from 0 to 72 months. These data have yielded important findings, such as overturning the dogma of no postnatal neurogenesis in humans. To facilitate their use in computational models, the data are being interfaced with GENESIS.

CYBERCHILD: A database of the microscopic development of the postnatal human cerebral cortex from birth to 72 months

Neurocomputing, 2000

We introduce a database of the microscopic, laminar development of ∼73% of postnatal human cerebr... more We introduce a database of the microscopic, laminar development of ∼73% of postnatal human cerebral cortical areas from 0 to 72 months. These data have yielded important findings, such as overturning the dogma of no postnatal neurogenesis in humans. To facilitate their use in computational models, the data are being interfaced with GENESIS.

Pediatric and Developmental Pathology, 1999

From 1939 to 1967, J.L. Conel quantitatively studied the microscopic features of the developing h... more From 1939 to 1967, J.L. Conel quantitatively studied the microscopic features of the developing human cerebral cortex and published the findings in eight volumes. We have constructed a database using his neuroanatomical measurements (neuronal packing density, myelinated large fiber density, large proximal dendrite density, somal breadth and height, and total cortical and cortical layer thickness) at the eight age periods (0 [term birth], 1, 3, 6, 15, 24, 48, and 72 postnatal months) he studied. In this report, we examine changes in neuron numbers over the eight age-points for 35 von Economo areas for which Conel gave appropriate data. From birth to 3 months postnatal age, total cortical neuron number increases 23–30%, then falls to within 3.5% of the birth value at 24 months, supporting our previous work showing that the observed decrease in the number of neurons per column of cortex under a 1-mm2 cortical surface from birth to 15 months is almost entirely due to cortical surface ex...

MRI white matter diffusion anisotropy and PET metabolic rate in schizophrenia

…, 1998

A disturbance in the frontal-striatal-thalamic circuitry has been proposed for schizophrenia, but... more A disturbance in the frontal-striatal-thalamic circuitry has been proposed for schizophrenia, but this concept has been based primarily on indirect evidence from psychopharmacology and analogies with animal research. Diffusion tensor imaging, a new MRI technique that permits direct assessment of the large axon masses stretching from the prefrontal cortex to the striatum, was used to study white matter axon bundles. Diffusion tensor images, high-resolution structural MRI and positron emission tomography scans with 18-fluorodexoyglucose were obtained on five patients with schizophrenia and six age- and sex-matched normal controls. Significantly lower diffusion anisotropy in the white matter of the prefrontal cortex in schizophrenic patients than in normal controls was observed in statistical probability maps. Co-registered PET scans revealed significantly lower correlation coefficients between metabolic rates in the prefrontal cortex and striatum in patients than in controls. These twin findings provide convergent evidence for diminished fronto-striatal connectivity in schizophrenia.

Brain Sciences

System-specific brain responses—time-locked to rapid eye movements (REMs) in sleep—are characteri... more System-specific brain responses—time-locked to rapid eye movements (REMs) in sleep—are characteristically widespread, with robust and clear activation in the primary visual cortex and other structures involved in multisensory integration. This pattern suggests that REMs underwrite hierarchical processing of visual information in a time-locked manner, where REMs index the generation and scanning of virtual-world models, through multisensory integration in dreaming—as in awake states. Default mode network (DMN) activity increases during rest and reduces during various tasks including visual perception. The implicit anticorrelation between the DMN and task-positive network (TPN)—that persists in REM sleep—prompted us to focus on DMN responses to temporally-precise REM events. We timed REMs during sleep from the video recordings and quantified the neural correlates of REMs—using functional MRI (fMRI)—in 24 independent studies of 11 healthy participants. A reanalysis of these data reveal...

Current Biology

Highlights d We use fossil skull data to derive an index of endocranial shape in human MRI scans ... more Highlights d We use fossil skull data to derive an index of endocranial shape in human MRI scans d In 4,468 Europeans, we screen introgressed Neandertal SNPs for association with the index d Lead SNPs consistently associate with reduced globularity in five separate subsamples d These SNPs affect neural expression of two genes linked to neurogenesis and myelination

Frontiers in Psychology

The neural correlates of rapid eye movements (REMs) in sleep are extraordinarily robust; includin... more The neural correlates of rapid eye movements (REMs) in sleep are extraordinarily robust; including REM-locked multisensory-motor integration and accompanying activation in the retrosplenial cortex, the supplementary eye field and areas encompassing cholinergic basal nucleus (Hong et al., 2009). The phenomenology of REMs speaks to the notion that perceptual experience in both sleep and wakefulness is a constructive process-in which we generate predictions of sensory inputs and then test those predictions through actively sampling the sensorium with eye movements. On this view, REMs during sleep may index an internalized active sampling or 'scanning' of selfgenerated visual constructs that are released from the constraints of visual input. If this view is correct, it renders REMs an ideal probe to study consciousness as "an exclusively internal affair" (Metzinger, 2009). In other words, REMs offer a probe of active inferencein the sense of predictive coding-when the brain is isolated from the sensorium in virtue of the natural blockade of sensory afferents during REM sleep. Crucially, REMs are temporally precise events that enable powerful inferences based on time series analyses. As a natural, task-free probe, (REMs) could be used in non-compliant subjects, including infants and animals. In short, REMs constitute a promising probe to study the ontogenetic and phylogenetic development of consciousness and perhaps the psychopathology of schizophrenia and autism, which have been considered in terms of aberrant predictive coding.

The Journal of comparative neurology, Jan 15, 2016

Epigenetic programming and reprogramming are at the heart of cellular differentiation and represe... more Epigenetic programming and reprogramming are at the heart of cellular differentiation and represent developmental and evolutionary mechanisms in both germline and somatic cell lines. Only about 2% of our genome is composed of protein-coding genes, while the remaining 98%, once considered "junk" DNA, codes for regulatory/epigenetic elements that control how genes are expressed in different tissues and across time from conception to death. While we already know that epigenetic mechanisms are at play in cancer development and in regulating metabolism (cellular and whole body), the role of epigenetics in the developing prenatal and postnatal brain, and in maintaining a proper brain activity throughout the various stages of life, in addition to having played a critical role in human evolution, is a relatively new domain of knowledge. Here we present the current state-of-the-art techniques and results of these studies within the domain of emotions, and then speculate on how geno...

Method for correlating differential brain images and genotypes; genes that correlate with differential brain images

Methods of assigning quantitative phenotype measurement summary statistics to differential brain ... more Methods of assigning quantitative phenotype measurement summary statistics to differential brain image information associated with neuropsychiatric disorders are provided. Summary statistics are correlated to genotype information to identify loci that correlate with differential brain image phenotypes. Methods of identifying modulators of genes at the loci are provided, as well as modulators identified by the methods. Systems for correlating polymorphisms and differential brain image phenotypes, for identifying modulators and for ...

Methods for treating a neurological disorder by peripheral administration of a transforming growth factor alpha (TGF-a)

Regulation of Anaesthesia

A PET study of the pathophysiology of negative symptoms in schizophrenia. Positron emission tomography

The American Journal of Psychiatry, 2002

Positron emission tomography (PET) was used to compare cerebral metabolic patterns in schizophren... more Positron emission tomography (PET) was used to compare cerebral metabolic patterns in schizophrenic subjects with predominantly negative symptoms (alogia, affective flattening, avolition, and attentional impairment) and in those with predominantly positive symptoms. Fourteen right-handed male subjects with DSM-IV schizophrenia were assigned to groups with predominantly negative or predominantly positive symptoms on the basis of their post-drug-washout scores on the Positive and Negative Syndrome Scale. The patients were compared to seven age- and gender-matched normal volunteers. PET scans with [(18)F]fluorodeoxyglucose were obtained during a degraded Continuous Performance Task to measure absolute glucose metabolic rates. Statistical parametric mapping was used to estimate the regional metabolic differences between groups. The subjects with predominantly negative symptoms had significant differences in glucose metabolic rates, compared to both the subjects with predominantly positive symptoms and the normal subjects. Negative symptom subjects had a lower glucose metabolic rate in the right hemisphere, especially in the temporal and ventral prefrontal cortices, compared to the other groups, and higher metabolic rates in the cerebellar cortex and in the lower deep cerebellar nuclei. Negative symptom subscale scores were negatively correlated with glucose metabolic rates for most of the brain areas that differentiated subjects with predominantly negative symptoms from those with predominantly positive symptoms. Schizophrenic subjects with predominantly negative symptoms have greater metabolic abnormalities than subjects with predominantly positive symptoms, particularly in frontal, temporal, and cerebellar circuitry. These results are consistent with abnormalities in corticocortical, corticobasal ganglia, mesocortical dopamine, and cerebellar-thalamic-prefrontal circuits, which may underlie the negative symptoms of schizophrenia.