Neurotechnology: expanding opportunities for funding at the National Institute of Mental Health.

The National Institute of Mental Health recognizes the importance that creative development of technology and methodology play in brain and behavioral science research. This institute is making major efforts to support such development through specific initiatives, like the Human Brain Project. In addition, this Institute is actively building bridges between business and academic research communities to make optical use of funds for the research and development of commercially viable technologies relevant to all aspects of the Institute's mission through the Small Business Innovation Research and Small Business Technology Transfer Programs. Together, these efforts will culminate in a more vigorous scientific enterprise, and ultimately benefit the entire mental health community and society.

The Human Brain Project: an international resource.

As the amount of basic neuroscientific information increases dramatically, its day-to-day integration and application becomes an increasing difficulty. Technological advances, particularly in computer and information sciences, should allow this information 'explosion' to become more manageable. To this end, the Human Brain Project, an initiative of several NIH Institutes and other United States Government agencies, is being developed to provide a computer database that will allow neuroscientists access to information at all levels of integration, from genes to behavior. In this article Michael Huerta, Stephen Koslow and Alan Leshner outline the genesis and ideas behind the initiative and discuss its future development.

Changes in the cortical map of the hand following postnatal median nerve injury in monkeys: modification of somatotopic aggregates.

Median nerves to the hands of 8-15-d-old marmoset monkeys were transected and precluded from regeneration by ligation. Following periods of 0.4-1.5 years, features of organization in the cortical area 3b hand map were assessed neurophysiologically, and compared to features in normally reared monkeys. Cortical features in monkeys with both histories were similar in certain respects. (1) Receptive field organization was similar in terms of tactile thresholds and receptive field size, continuity, and glabrous-hairy specificity. (2) Somatotopic organization was similar in terms of the continuity of the glabrous representation, and progressions of receptive field shifts across some parts of the hand map. (3) Finally, the overall size of the hand map did not change. In contrast, other cortical features clearly differed following these developmental histories. (1) Neurons at virtually all recording sites in normal hand maps responded to light mechanical stimulation, whereas, following injury, neurons at about 8% of the recording sites responded only to high-intensity stimuli. (2) Somatotopic organization differed in terms of the presence or absence of the representation of skin autonomously innervated by the median nerve, the number and continuity of representations of hairy skin, and the spatial interfacing of representations. (3) Finally, there were differences in the areas and widths of representations of parts of the hand. The overall impression is that there is a correspondence between the cortical features that changed most after injury, and the features that varied most in individual normal monkeys: in both circumstances the most variable features involved properties of spatial patterning across large aggregates of neurons as reflected by the size, shape, continuity, and interfacing of representations. A hypothesis is proposed that suggests that the cortical hand map normally consists of a number of representations that are capable of developing and surviving somewhat autonomously of each other. The features of spatial patterning in the mosaiclike map of these representations are influenced by postnatal availability of inputs from intact hand nerves.

Changes in the cortical map of the hand following postnatal ulnar and radial nerve injury in monkeys: organization and modification of nerve dominance aggregates.

The ulnar and radial nerves to the hands of 12-31-d-old marmoset monkeys were transected and ligated, and the monkeys were subsequently reared for periods of 1.4-1.6 years with only median nerve innervation to the hand. Features of organization in the cortical area 3b hand map were then assessed with neurophysiological mapping procedures, and compared to features in monkeys that had undergone either a normal postnatal development with three intact hand nerves, or an abnormal development with two intact nerves due to postnatal injury of the median nerve. A systematic comparison of cortical organization in these monkeys led to three main findings. First, some features of organization show little or no change when monkeys are reared with one, two, or three hand nerves. These features include receptive field size and the overall size of the hand map. Second, other features are, in contrast, clearly altered in an injury-dependent manner. These features include cortical neuronal thresholds to light tactile stimuli, and the spatial location, size, shape, continuity, and somatotopic interfacing of representations of the parts of the hand. Finally, estimates of the peripheral innervation territories of the hand nerves, and of the corresponding distributions of cortical neurons activated by inputs from these territories, indicate that the normal hand map contains bandlike aggregates of neurons that are dominantly activated by inputs from each nerve. Postnatal nerve injuries alter the size of these nerve dominance aggregates.

Differential thalamic connectivity of rostral and caudal parts of cortical area Fr2 in rats.

Thalamocortical connections were studied after injections of retrograde tracers were made into rostral or caudal parts of cortical area Fr2 in adult rats. The data reveal that both rostral Fr2 (rFr2) and caudal Fr2 (cFr2) receive input from the centrolateral, central medial, interanteromedial, mediodorsal, paracentral, parafascicular, posterior, reuniens, rhomboid, ventrolateral, ventromedial and zona incerta nuclei. In addition, cFr2, but not rFr2, receives input from the anteromedial, anteroventral, laterodorsal and lateral posterior nuclei. These findings provide further evidence that Fr2 is connectionally and functionally heterogeneous, with rFr2 connected with somatomotor-related nuclei and with cFr2 connected with somatomotor- and visuomotor-related nuclei.

Projection of the mammalian superior colliculus upon the dorsal lateral geniculate nucleus: organization of tectogeniculate pathways in nineteen species.

Anterograde and retrograde transport methods have been used to analyze the projection of the superior colliculus upon the dorsal lateral geniculate nucleus in 19 mammalian species. Our retrograde findings reveal that tectogeniculate neurons are relatively small, and lie dorsally within the superficial gray. These small tectogeniculate neurons are spatially related to a dense tier of W-cell retinal input. Our anterograde tracing results show that tectogeniculate axons are visuotopically distributed to small-celled regions of the lateral geniculate in all nineteen species. In the majority of these species, the small-celled, tectally innervated regions of the lateral geniculate lie adjacent to the optic tract and contain W-cell-like neurons. Our findings suggest that neuroanatomical demonstration of the tectogeniculate projection is a relatively simple and straightforward way of revealing regions of the lateral geniculate which contain W-cells. This is true even in species in which the lateral geniculate lacks obvious cellular laminae, and in regions of the lateral geniculate where W-cells are few in number. The present data are especially interesting in light of the cortical projections of tectally innervated, small-celled regions of the lateral geniculate to the patches or puffs within layer III of area 17. Since these regions of small-celled geniculocortical axons are co-extensive with zones ("blobs") rich in cytochrome oxidase, it might be that information carried over the tectogeniculate circuitry plays an important role in the functions of the blob system.

Nigrotectal projections in the primate Galago crassicaudatus.

The pattern of the nigrotectal projection in Galago crassicaudatus was determined using retrograde and anterograde transport methods. These experiments revealed that pars reticulata and pars lateralis of the substantia nigra project to all layers of the ipsilateral and contralateral superior colliculus, except to layer I. The nigrotectal projection is not homogeneous, but is concentrated in particular collicular layers and sublayers, and the intensity and laminar distribution of the projection varies along the rostral-caudal dimension of the superior colliculus. The ipsilateral and contralateral nigrotectal projections are generally similar, except that a tier of dense label which is prominent in the ventral part of much of the ipsilateral layer IV is not obvious contralaterally; moreover, the contralateral projection is much sparser than the ipsilateral. Deposits of tracers at different medial-lateral locations within the substantia nigra did not result in different laminar patterns of anterogradely transported label in the superior colliculus. Based on the known connections and functions of the collicular layers and sublayers, the pattern and distribution of the nigrotectal projection suggests that the substantia nigra may use this pathway to gain access to particular components of vision- and visuomotor-related networks.

Primary motor cortex receives input from area 3a in macaques.

Intracortical microstimulation was used to define topographic sectors and the rostral border of primary motor cortex in adult macaques (Macaca mulatta). In the same animals, injections of fluorescent tracers were made within defined regions of primary motor cortex. Retrogradely labeled neurons were topographically distributed in area 3a, with most neurons located in layer III, and fewer neurons situated in layers V and IV. These findings suggest that muscle afferent information, thought to be important in a closed-loop mode of function, may reach primary motor cortex directly from cortical area 3a.

Supplementary eye field as defined by intracortical microstimulation: connections in macaques.

In macaques, the frontal eye field and the recently defined supplementary eye field play a role in the production of eye movements. Whereas the structure and function of the frontal eye field are well understood, little is known about the supplementary eye field. The goal of this study was to determine the connections of the physiologically defined supplementary eye field. In each case, the location of the supplementary eye field was determined by using intracortical microstimulation, the borders were marked with small electrolytic lesions, and horseradish peroxidase conjugated to wheat germ agglutinin was injected into the supplementary eye field. After the tissue was incubated with tetramethyl benzidine, it was determined that in three cases the injection site was confined to the physiologically defined supplementary eye field. The present results indicate that the supplementary eye field is reciprocally connected with the claustrum, ventral anterior nucleus, including pars magnocellularis, nucleus X, posterior subdivision of the ventral lateral nucleus, multiform, parvocellular, magnocellular, and densocellular subdivisions of the medial dorsal nucleus, central lateral nucleus, parafascicular nucleus, and suprageniculate-limitans complex. The supplementary eye field projects to the putamen, caudate, reticular nucleus of the thalamus, central densocellular nucleus, zona incerta, subthalamic nucleus, rostral interstitial nucleus of the medial longitudinal fasciculus, parvocellular part of the red nucleus, intermediate and deep layers of the superior colliculus, central gray, cuneiform nucleus, mesencephalic reticular formation, pontine gray, nucleus reticularis tegmenti pontis, and nucleus reticularis pontis oralis. The supplementary eye field is reciprocally and bilaterally connected with periprincipal and inferior prefrontal cortex, with periarcuate cortex, including the frontal eye field, the frontal ventral region, and with postarcuate premotor cortex, and cortex surrounding the supplementary eye field, including the supplementary motor area. The supplementary eye field is also reciprocally connected ipsilaterally with cortex in and around the cingulate sulcus and the intraparietal sulcus, whereas cortex within the superior temporal sulcus projects to the supplementary eye field. The connections of the physiologically defined supplementary eye field are compared to previously demonstrated connections of the supplementary motor region and of the physiologically defined frontal eye field. Comparisons between the connections of the frontal and supplementary eye fields reveal that both regions are connected with structures related to visuomotor functions, but the frontal eye field has more extensive connections with vision-related structures, and the supplementary eye field has more extensive connections with structures related to prefrontal and skeletomotor functions. Such connectional differences suggest functional differences between these two sensorimotor regions of the frontal lobe.

Neuroanatomical studies of the nigrotectal projection in the cat.

We have used retrograde and anterograde transport methods to analyze the nigrotectal projection in the cat. This projection arises from both pars reticulata (SNr) and pars lateralis (SNl) and distributes to all cellular laminae of the superior colliculus. This extensive nigrotectal innervation is not a simple, single circuit. Rather it appears to consist of several parallel channels, with each taking origin from a particular zone of the substantia nigra and terminating within specific collicular laminae and/or sublaminae. For instance, only neurons within the SNl project to the stratum griseum superficiale; such neurons also project diffusely to all other tectal laminae. Cells in the most lateral portion of the SNr project to a horizontal, patchy tier in the interface region between the stratum opticum and the stratum griseum intermediate (SGI). Finally, more medially placed neurons within the SNr project to a horizontal patchy tier within the middle of the SGI and to a wedge-shaped locus in the stratum griseum profundum. Our findings provide an anatomical substrate for electrophysiological data (Karabelas and Moschovakis: J. Comp. Neurol. 239: 309-329, '85) showing a widespread distribution of nigrorecipient tectal neurons in the cat.

Frontal eye field as defined by intracortical microstimulation in squirrel monkeys, owl monkeys, and macaque monkeys. II. Cortical connections.

Physiological (intracortical microstimulation) and anatomical (transport of horseradish peroxidase conjugated to wheat germ agglutinin as shown by tetramethyl benzidine) approaches were combined in the same animals to reveal the locations, extents, and cortical connections of the frontal eye fields (FEF) in squirrel, owl, and macaque monkeys. In some of the same owl and macaque monkeys, intracortical microstimulation was also used to evoke eye movements from dorsomedial frontal cortex (the supplementary motor area). In addition, in all of the owl and squirrel monkeys, intracortical microstimulation was also used to evoke body movements from the premotor and motor cortex situated between the central dimple and the FEF. These microstimulation data were directly compared to the distribution of anterogradely and retrogradely transported label resulting from injections of tracer into the FEF in each monkey. Since the injection sites were limited to the physiologically defined FEF, the demonstrated connections were solely those of the FEF. To aid in the interpretation of areal patterns of connections, the relatively smooth cortex of owl and squirrel monkeys was unfolded, flattened, and cut parallel to the flattened surface. Cortex of macaque monkeys, which has numerous deep sulci, was cut coronally. Reciprocal connections with the ipsilateral frontal lobe were similar in all three species: dorsomedial cortex (supplementary motor area), cortex just rostral (periprincipal prefrontal cortex) to the FEF, and cortex just caudal (premotor cortex) to the FEF. In squirrel and owl monkeys, extensive reciprocal connections were made with cortex throughout the caudal half of the lateral fissure and, to a much lesser extent, cortex around the superior temporal sulcus. In macaque monkeys, only sparse connections were present with cortex of the lateral fissure, but extensive and dense connections were made with cortex throughout the caudal one-third to one-half of the superior temporal sulcus. In addition, very dense reciprocal connections were made with the cortex of the lateral, or inferior, bank of the intraparietal sulcus. Contralateral reciprocal connections in all three species were virtually limited to regions that correspond in location to the FEF and the supplementary motor area. The results of this study reveal connections between the physiologically defined frontal eye field and cortical regions known to participate in higher order visual processing, short-term memory, multimodal, visuomotor, and skeletomotor functions.(ABSTRACT TRUNCATED AT 400 WORDS)

Somatotopic organization of the third somatosensory area (SIII) in cats.

Multiunit microelectrode recording techniques were used to study the location and organization of the third somatosensory area (SIII) in cats. Representations of all major contralateral body parts were found in a small region of cortex along the lateral wing of the ansate sulcus and between the lateral sulcus and the suprasylvian sulcus. The systematic map of the body surface included forepaw and face regions previously identified as parts of SIII. The forepaw representation was generally buried on the rostral bank of the lateral wing of the ansate sulcus. The representations of the face and mystacial vibrissae were largely exposed on the rostral suprasylvian gyrus, but part of the representation of the face was also buried in the lateral wing of the ansate sulcus. Representations of the trunk and hindlimb extended from the suprasylvian gyrus onto the medial bank of the suprasylvian sulcus. We had expected to find these latter body parts in more medial cortex just caudal to the representation of these parts in the first somatosensory area (SI). Instead, neurons in penetrations in cortex caudal to the SI trunk and hindlimb representations were unresponsive to tactile stimulation. The unexpected location of the hindlimb in SIII led us to determine whether the proposed parts of SIII had similar cortical and thalamic connections. Injected anatomical tracers revealed that the representations of both the forelimb and hindlimb were interconnected with SI and a region of the thalamus just dorsal to the ventroposterior nucleus. Similarities in patterns of connections of forelimb and hindlimb portions of SIII supported the conclusion that SIII as presented here is a functional unit of cortex. We conclude that SIII has a somatotopic organization that does not parallel that in SI, and that SIII is not entirely coextensive with either area 5 or area 5a of Hassler and Muhs-Clement (1964).

Frontal eye field as defined by intracortical microstimulation in squirrel monkeys, owl monkeys, and macaque monkeys: I. Subcortical connections.

Intracortical microstimulation was used to define the borders of the frontal eye fields in squirrel, owl, and macaque monkeys. The borders were marked with electrolytic lesions, and horseradish peroxidase conjugated to wheat germ agglutinin was injected within the field. Following tetramethyl benzidine histochemistry, afferent and efferent connections of the frontal eye field with subcortical structures were studied. Most connections were ipsilateral and were similar in all primates studied. These include reciprocal connections with the following nuclei: medial dorsal (lateral parts), ventral anterior (especially with pars magnocellularis), central lateral, paracentral, ventral lateral, parafascicular, medial pulvinar, limitans, and suprageniculate. The frontal eye field also projects to the ipsilateral pretectal nuclei, subthalamic nucleus, nucleus of the posterior commissure, superior colliculus (especially layer four), zona incerta, rostral interstitial nucleus of the medial longitudinal fasciculus, nucleus Darkschewitsch, dorsomedial parvocellular red nucleus, interstitial nucleus of Cajal, basilar pontine nuclei, and bilaterally to the paramedian pontine reticular formation and the nucleus reticularis tegmenti pontis. Many of these structures also receive input from deeper layers of the superior colliculus and are known to participate in visuomotor function. These results reveal connections that account for the parallel influence of the superior colliculus and the frontal eye field on visuomotor function; suggest that there has been little evolutionary change in subcortical connections, and therefore function, of the frontal eye fields since the time that these lines of primates diverged; and support the conclusion that the frontal eye fields are homologous in New and Old World monkeys.

Studies on the evolution of multiple somatosensory representations in primates: the organization of anterior parietal cortex in the New World Callitrichid, Saguinus.

Because members of the New World family, Callithricidae, are generally regarded as the most primitive of monkeys, we studied the organization of somatosensory cortex in the tamarin (Saguinus) in hopes of better understanding differences in the organization of anterior parietal cortex in primates and how these differences relate to phylogeny. In most prosimian primates only one complete representation of cutaneous receptors has been found in the region of primary cortex, S-I, while in all Old and New World monkeys studied to date, two cutaneous representations exist in distinct architectonic fields, areas 3b and 1. In detailed microelectrode mapping studies in anesthetized tamarins, only one complete representation responsive to low-threshold cutaneous stimulation was evident in the S-I region. This topographic representation was in a parietal koniocortical field that architectonically resembles area 3b of other monkeys, and the general somatotopic organization of the field was similar to that of area 3b of other monkeys. Cortex rostral to the single representation was generally unresponsive to somatosensory stimuli, or required more intense stimulation for neural activation. Cortex caudal to the representation, in the region of area 1 of other monkeys, was generally either unresponsive or responded to only high-threshold stimulation, although some recording sites were activated by low-threshold tactile stimulation. The present evidence, together with that from previous studies, suggests that the single, complete body surface representation in Saguinus is homologous to the S-I representation found in some prosimians (Galago, Perodicticus) and the area 3b cutaneous representation found in New World Cebidae (Aotus, Saimiri, and Cebus) and Old World Macaca. Cortex rostral to S-I in Saguinus has the appearance of areas 3a and 4 of other primates. The cortex caudal to S-I in Saguinus, while resembling area 1 in some ways, does not have all of the features of area 1 of other monkeys. In particular, the field was not easily activated by low-threshold cutaneous stimuli, as area 1 is in other monkeys, and therefore a second cutaneous representation of all body parts was not demonstrated. Thus, cortex in the expected location of area 1 of Saguinus was not as responsive as area 1 of other monkeys, and it somewhat resembled the high-threshold fringe zones found caudal to S-I in anesthetized prosimians and some nonprimates. The results raise the possibility that the area 1 cutaneous representation that is characteristic of other New World monkeys and Old World monkeys evolved from a less responsive precursor along the caudal border of S-I in early monkeys.

Hypothalamic and ventral thalamic projections to the superior colliculus in the cat.

The present report describes the organization of collicular afferents that arise within either the hypothalamus or the ventral thalamus. Following the placement of large injections of WGA-HRP into the superior colliculus of the cat, retrogradely labeled neurons are located within the reticular nucleus of the thalamus, the zona incerta, the fields of Forel, and throughout the hypothalamus. Although the dorsal hypothalamic area contains the largest number of labeled hypothalamic neurons, labeled cells are also found within the periventricular, paraventricular, dorsomedial, ventromedial, posterior, lateral, and anterior hypothalamic nuclei. A strikingly similar pattern of distribution of labeled neurons is also observed following placement of small injections of WGA-HRP that are restricted within the stratum griseum intermedium (SGI). In contrast, hypothalamic and ventral thalamic labeling is not seen after placement of injections within the stratum griseum superficiale. Following the placement of injections of tritiated anterograde tracers within the dorsal hypothalamic area, transported label is organized in two bands of clusters over the SGI. When injections of tritiated tracers are placed within the zona incerta, terminal label is also located over the SGI; however, the distribution of silver grains does not appear as clusters or distinct puffs. On the basis of the comparison of the cellular types that give rise to these projections and the differences in terminal distribution, we suggest that the hypothalamic and ventral thalamic projections to the superior colliculus are totally separate and unrelated pathways. The functional implications of the hypothalamotectal pathway are also discussed.

The trigemino-olivary projection in the cat: contributions of individual subnuclei.

Anterograde autoradiographic methods were used to determine the projection of the principal sensory trigeminal nucleus and of each of the three spinal trigeminal subnuclei to the inferior olivary complex in the cat. Our data reveal that the principal sensory trigeminal nucleus does not contribute to the trigemino-olivary pathway. Each spinal trigeminal subnucleus has a unique contribution to this pathway: pars oralis projects sparsely to the border between the dorsal accessory and principal olives (DAO-PO), pars interpolaris projects mostly to the rostral medial DAO, and pars caudalis projects mostly to the rostral medial part of the ventral leaf of PO and slightly to the caudal medial accessory olive. In the light of recent physiological and anatomical findings, our data indicate that information from each spinal trigeminal subnucleus reaches a different segment of the contralateral inferior olivary complex, which in turn distributes differentially to the cerebellar cortex.

Transient tectogeniculate projections in neonatal kittens: an autoradiographic study.

By using anterograde transport autoradiography, the present experiments demonstrated that the pattern of tectogeniculate projections in young (birth-14 postnatal days) kittens is strikingly different from that present in adult cats. Rather than being confined to the ventral C laminae, the neonatal projection extended across all layers of the lateral geniculate nucleus. This projection, like that in the adult cat, originates from cells in superficial laminae and is visuotopically organized. Thus, labeling only a portion of the superior colliculus with tritiated leucine produced a topographically appropriate strip of labeling in the ipsilateral lateral geniculate nucleus that encompassed all laminae and was especially dense in all interlaminar zones. Transported label also invaded the medial interlaminar nucleus (MIN). The loss of tectogeniculate projections in the neonate from MIN and the dorsal laminae and interlaminar zones of the lateral geniculate nucleus does not appear to begin until 1-2 weeks postnatal. Once initiated, however, the process is nearly completed by 21 days postnatal. It is not yet known whether the loss of these "anomalous" projections is due to the pruning of axonal collaterals, cell death, or a combination of the two processes. However, by comparing these data with those from other laboratories, it does appear that the loss of tectogeniculate projections depends on the presence of the two eyes and may reflect the differential laminar distribution of W-, X-, and Y-cell types. The protracted postnatal anatomical maturation of tectogeniculate projections differs substantially from the earlier maturing patterns apparent in all other tectofugal pathways.

Subcortical connections of area 17 in the tree shrew: an autoradiographic analysis.

The present anterograde autoradiographic study reveals several targets of the striate cortex (area 17) of the tree shrew which were not previously observed in studies which used anterograde degeneration methods; our data also confirm several previous findings. The results are discussed in the context of these projections modulating ascending visual information (claustrum, lateral intermediate nucleus, pulvinar, dorsal lateral geniculate, cells of the external medullary lamina, reticular nucleus of the thalamus, superficial collicular layers, and the anterior and posterior pretectal nuclei) or visuomotor information (putamen, caudate, ventral lateral geniculate, pontine gray, and the anterior and posterior pretectal nuclei).

A variant of the mammalian somatotopic map in a bat.

Two ordered representations of the body surface, S-I and S-II, have been described on the cortical surface of the brains of a variety of mammals; additional separate topographical maps have been found in the somatosensory cortex of the cat and monkey. Except for minor variations in the placement of the body parts, the basic somatotopy of the maps is remarkably consistent across species. As the reasons for this consistency and the minor variations are unclear, we examined the somatotopy of the bat, whose body plan has been modified extensively so that the forelimb can be used for flight. We report here that in both S-I and S-II of the grey-headed flying fox, not only is the representation of the distal forelimb displaced from its usual position on the map, but the digits are directed caudally instead of rostrally as they are in all other mammals studied. The variant somatotopy appears to reflect the postural differences between flying and walking mammals, supporting the notion that topographical maps may have functional significance apart from their point-to-point connections with the sensory periphery.