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Human functional magnetic resonance imaging (fMRI) and behavioral studies have established the roles of cortical areas along the Sylvian fissure in sensing subjective pain. Yet, little is known about how sensory aspects of painful information are represented and processed by neurons in these regions and how their electrophysiological activities are related to fMRI signals. The current study aims to partially address this critical knowledge gap by performing fMRI-guided microelectrode mapping and recording studies in the homologous region of the parietal operculum in squirrel monkeys under light anesthesia. In each animal studied (n = 8), we detected mesoscale mini-networks for heat nociception in cortical regions around the lateral sulcus. Within the network, we discovered a ∼1.5 × 1.5-mm2-sized cortical patch that solely contained heat nociceptive neurons that aligned with the heat fMRI activation locus. These neurons responded slowly to thermal (heat and cold) nociceptive stimuli exclusively, continued firing for several seconds after the succession of stimulation, and exhibited multidigit receptive fields and high spontaneous firing rates. Similar to the fMRI responses, increasing temperatures in the nociceptive range led to a nonlinear increase in firing rates. The finding of a clustering of heat nociceptive neurons provides novel insights into the unique functional organization of thermal nociception in the S2 subregion of the primate brain. With fMRI, it supports the existence of a modality-preferred heat nociceptive patch that is spatially separated and intermingled with touch patches containing neurons with comparable receptive fields and the presence of functionally distinct mini-networks in primate opercular cortex.

Long-train intracortical microstimulation (ICMS) of motor (M1) and posterior parietal cortices (PPC) in primates reveals cortical domains for different ethologically relevant behaviors. How functional domains interact with each other in producing motor behaviors is not known. In this study, we tested our hypothesis that matching domains interact to produce a specific complex movement, whereas connections between nonmatching domains are involved in suppression of conflicting motor outputs to prevent competing movements. In anesthetized galagos, we used 500-ms trains of ICMS to evoke complex movements from a functional domain in M1 or PPC while simultaneously stimulating another mismatched or matched domain. We considered movements of different and similar directions evoked from chosen cortical sites distant or close to each other. Their trajectories and speeds were analyzed and compared with those evoked by simultaneous stimulation. Stimulation of two sites evoking same or complementary movements produced a similar but more pronounced movement or a combined movement, respectively. Stimulation of two sites representing movements of different directions resulted in partial or total suppression of one of these movements. Thus interactions between domains in M1 and PPC were additive when they were functionally matched across fields or antagonistic between functionally conflicting domains, especially in PPC, suggesting that mismatched domains are involved in mutual suppression. Simultaneous stimulation of unrelated domains (forelimb and face) produced both movements independently. Movements produced by the simultaneous stimulation of sites in domains of two cerebral hemispheres were largely independent, but some interactions were observed. NEW & NOTEWORTHY Long trains of electrical pulses applied simultaneously to two sites in motor cortical areas (M1, PPC) have shown that interactions of functionally matched domains (evoking similar movements) within these areas were additive to produce a specific complex movement. Interactions between functionally mismatched domains (evoking different movements) were mostly antagonistic, suggesting their involvement in mutual suppression of conflicting motor outputs to prevent competing movements. Simultaneous stimulation of unrelated domains (forelimb and face) produced both movements independently.

In cortical circuitry, synaptic communication across areas is based on two types of axon terminals, small and large, with modulatory and driving roles, respectively. In contrast, it is not known whether similar synaptic specializations exist for intra-areal projections. Using anterograde tracing and three-dimensional reconstruction by electron microscopy (3D-EM), we asked whether large boutons form synapses in the circuit of somatosensory cortical areas 3b and 1. In contrast to observations in macaque visual cortex, light microscopy showed both small and large boutons not only in inter-areal pathways, but also in long-distance intrinsic connections. 3D-EM showed that correlation of surface and volume provides a powerful tool for classifying cortical endings. Principal component analysis supported this observation and highlighted the significance of the size of mitochondria as a distinguishing feature of bouton type. The larger mitochondrion and higher degree of perforated postsynaptic density associated with large rather than to small boutons support the driver-like function of large boutons. In contrast to bouton size and complexity, the size of the postsynaptic density appeared invariant across the bouton types. Comparative studies in human supported that size is a major distinguishing factor of bouton type in the cerebral cortex. In conclusion, the driver-like function of the large endings could facilitate fast dissemination of tactile information within the intrinsic and inter-areal circuitry of areas 3b and 1.

Motor cortex (M1) and somatosensory cortex (S1) are central to arm and hand control. Efforts to understand encoding in M1 and S1 have focused on temporal relationships between neural activity and movement features. However, it remains unclear how the neural activity is spatially organized within M1 and S1. Optical imaging methods are well-suited for revealing the spatio-temporal organization of cortical activity, but their application is sparse in monkey sensorimotor cortex. Here, we investigate the effectiveness of intrinsic signal optical imaging (ISOI) for measuring cortical activity that supports arm and hand control in a macaque monkey. ISOI revealed spatial domains that were active in M1 and S1 in response to instructed reaching and grasping. The lateral M1 domains overlapped the hand representation and contained a population of neurons with peak firing during grasping. In contrast, the medial M1 domain overlapped the arm representation and a population of neurons with peak firing during reaching. The S1 domain overlapped the hand representations of areas 1 and 2 and a population of neurons with peak firing upon hand contact with the target. Our single unit recordings indicate that ISOI domains report the locations of spatial clusters of functionally related neurons. ISOI is therefore an effective tool for surveilling the neocortex for “hot zones” of activity that supports movement. Combining the strengths of ISOI with other imaging modalities (e.g., fMRI, 2-photon) and with electrophysiological methods can open new frontiers in understanding the spatio-temporal organization of cortical signals involved in movement control.

Decades of studies in non-human primates (NHPs) have been conducted in conditions of strict experimental control of perception and behavior in order to understand the functions of the brain. For instance, experiments focused on visual perception often involve head fixation, unnaturally long eye fixation periods, and attention to locations away from the center of gaze. These paradigms require long training periods (months to a year). While such studies have advanced our knowledge of brain function tremendously, a recurring question is how relevant the gathered data are to natural behavior. The availability of cutting-edge technologies and computational power can free us from the limitations of classical experimental paradigms and usher in a new generation of neuroscience questions focused on how the brain functions in real world settings. Here we demonstrate a small head-mounted multimodal device for stimulating and recording domain-based cortical activity in NHPs. This device consists of an intrinsic optical signal imaging camera and a wireless LED stimulator. To evaluate the functionality of this device, we compared its imaging performance in vivo to that of current benchtop intrinsic imaging systems and demonstrated the efficacy of wireless optogenetic stimulation while conducting awake intrinsic imaging. Our device device has been constructed from off the shelf components and offers multiareal and targeted stimulation and recording capabilities in minimally restrained subjects. It has a potential to contribute to our understanding of cortical encoding of perception and behavior and could have clinical relevance for the development of brain-machine interfaces.

Zika virus infection during pregnancy is associated with miscarriage and with a broad spectrum of fetal and neonatal developmental abnormalities collectively known as congenital Zika syndrome (CZS). Symptomology of CZS includes malformations of the brain and skull, neurodevelopmental delay, seizures, joint contractures, hearing loss and visual impairment. Previous studies of Zika virus in pregnant rhesus macaques (Macaca mulatta) have described injury to the developing fetus and pregnancy loss, but neonatal outcomes following fetal Zika virus exposure have yet to be characterized in nonhuman primates. Herein we describe the presentation of rhesus macaque neonates with a spectrum of clinical outcomes, including one infant with CZS-like symptoms including cardiomyopathy, motor delay and seizure activity following maternal infection with Zika virus during the first trimester of pregnancy. Further characterization of this neonatal nonhuman primate model of gestational Zika virus infection will provide opportunities to evaluate the efficacy of pre- and postnatal therapeutics for gestational Zika virus infection and CZS.

Significance Primate visual cortex is organized into columns that process different features of a visual scene, such as color, orientation preference, and ocular dominance. Until now, their small size has made it difficult to modulate them directly. Here, we report for the first time that focal targeting of light-sensitive ion channels (channelrhodopsins) in macaques using lentiviral vectors allows one to stimulate functional domains. We show that such targeted stimulation leads to selective activation of anatomically connected neighboring domains with similar function. Such a fine-scale optical stimulation approach is capable of mapping functionally specific domain-based neuronal networks. Its potential for linking such networks to optogenetic modulation of perception and behavior opens doors for developing targeted, domain-based neuroprosthetics., In primates, visual perception is mediated by brain circuits composed of submillimeter nodes linked together in specific networks that process different types of information, such as eye specificity and contour orientation. We hypothesized that optogenetic stimulation targeted to cortical nodes could selectively activate such cortical networks. We used viral transfection methods to confer light sensitivity to neurons in monkey primary visual cortex. Using intrinsic signal optical imaging and single-unit electrophysiology to assess effects of targeted optogenetic stimulation, we found that (i) optogenetic stimulation of single ocular dominance columns (eye-specific nodes) revealed preferential activation of nearby same-eye columns but not opposite-eye columns, and (ii) optogenetic stimulation of single orientation domains increased visual response of matching orientation domains and relatively suppressed nonmatching orientation selectivity. These findings demonstrate that optical stimulation of single nodes leads to modulation of functionally specific cortical networks related to underlying neural architecture.

We have developed INS-fMRI as a rapid and high-resolution method for mapping functional brain networks in vivo., We have developed a way to map brain-wide networks using focal pulsed infrared neural stimulation in ultrahigh-field magnetic resonance imaging (MRI). The patterns of connections revealed are similar to those of connections previously mapped with anatomical tract tracing methods. These include connections between cortex and subcortical locations and long-range cortico-cortical connections. Studies of local cortical connections reveal columnar-sized laminar activation, consistent with feed-forward and feedback projection signatures. This method is broadly applicable and can be applied to multiple areas of the brain in different species and across different MRI platforms. Systematic point-by-point application of this method may lead to fundamental advances in our understanding of brain connectomes.

After lesions of the somatosensory dorsal column (DC) pathway, the cortical hand representation can become unresponsive to tactile stimuli, but considerable responsiveness returns over weeks of post-lesion recovery. The reactivation suggests that preserved subthreshold sensory inputs become potentiated and axon sprouting occurs over time to mediate recovery. Here, we studied the recovery process in 3 squirrel monkeys, using high-resolution cerebral blood volume-based functional magnetic resonance imaging (CBV-fMRI) mapping of contralateral somatosensory cortex responsiveness to stimulation of distal finger pads with low and high level electrocutaneous stimulation (ES) before and 2, 4, and 6 weeks after a mid-cervical level contralateral DC lesion. Both low and high intensity ES of digits revealed the expected somatotopy of the area 3b hand representation in pre-lesion monkeys, while in areas 1 and 3a, high intensity stimulation was more effective in activating somatotopic patterns. Six weeks post-lesion, and irrespective of the severity of loss of direct DC inputs (98%, 79%, 40%), somatosensory cortical area 3b of all three animals showed near complete recovery in terms of somatotopy and responsiveness to low and high intensity ES. However there was significant variability in the patterns and amplitudes of reactivation of individual digit territories within and between animals, reflecting differences in the degree of permanent and/or transient silencing of primary DC and secondary inputs 2 weeks post-lesion, and their spatio-temporal trajectories of recovery between 2 and 6 weeks. Similar variations in the silencing and recovery of somatotopy and responsiveness to high intensity ES in areas 3a and 1 are consistent with individual differences in damage to and recovery of DC and spinocuneate pathways, and possibly the potentiation of spinothalamic pathways. Thus, cortical deactivation and subsequent reactivation depends not only on the degree of DC lesion, but also on the severity and duration of loss of secondary as well as primary inputs revealed by low and high intensity ES.

Functions of the cerebral cortex emerge via interactions of horizontally distributed neuronal populations within and across areas. However, the connectional underpinning of these interactions is not well understood. The present study explores the circuitry of column-size cortical domains within the hierarchically organized somatosensory cortical areas 3b and 1 using tract tracing and optical intrinsic signal imaging (OIS). The anatomical findings reveal that feedforward connections exhibit high topographic specificity, while intrinsic and feedback connections have a more widespread distribution. Both intrinsic and inter-areal connections are topographically oriented across the finger representations. Compared to area 3b, the low clustering of connections and small cortical magnification factor supports that the circuitry of area 1 scaffolds a sparse functional representation that integrates peripheral information from a large area that is fed back to area 3b. Fast information exchange between areas is ensured by thick axons forming a topographically organized, reciprocal pathway. Moreover, the highest density of projecting neurons and groups of axon arborization patches corresponds well with the size and locations of the functional population response reported by OIS. The findings establish connectional motifs at the mesoscopic level that underpin the functional organization of the cerebral cortex.

Inter-areal and ipsilateral cortical responses to tactile stimulation have not been well described in human S1 cortex. By taking advantage of the high signal-to-noise ratio at 7 T, we quantified blood oxygenation level dependent (BOLD) response patterns and time courses to tactile stimuli on individual distal finger pads at a fine spatial scale, and examined whether there are inter-areal (area 3b versus area 1) and interhemispheric response differences to unilateral tactile stimulation in healthy human subjects. We found that 2-Hz tactile stimulation of individual fingertips evoked detectable BOLD signal changes in both contralateral and ipsilateral area 3b and area 1. Contralateral digit activations were organized in an orderly somatotopic manner, and BOLD responses in area 3b were more digit selective than those in area 1. However, the area of cortex that was responsive to stimulation of a single digit (stimulus-response field) was similar across areas. In the ipsilateral hemisphere, response magnitudes in both areas 3b and 1 were significantly weaker than those of the contralateral hemisphere. Digit activations exhibited no clear somatotopic organizational pattern in either area 3b or area 1, yet digit selectivity was retained in area 1 but not in area 3b. The observation of distinct digit-selective responses of contralateral area 3b versus area 1 supports a higher order function of contralateral area 1 in spatial integration. In contrast, ipsilateral cortices may play a less discriminative role in the perception of unilateral tactile sensation in humans.

Infrared neural stimulation (INS) is an alternative neurostimulation modality that uses pulsed infrared light to evoke spatially precise neural activity that does not require direct contact with neural tissue. With these advantages INS has the potential to increase our understanding of specific neural pathways and impact current diagnostic and therapeutic clinical applications. In order to develop this technique, we investigate the feasibility of INS (λ = 1.875 μm, fiber diameter = 100–400 μm) to activate and modulate neural activity in primary visual cortex (V1) of Macaque monkeys. Infrared neural stimulation was found to evoke localized neural responses as evidenced by both electrophysiology and intrinsic signal optical imaging (OIS). Single unit recordings acquired during INS indicated statistically significant increases in neuron firing rates that demonstrate INS evoked excitatory neural activity. Consistent with this, INS stimulation led to focal intensity-dependent reflectance changes recorded with OIS. We also asked whether INS is capable of stimulating functionally specific domains in visual cortex and of modulating visually evoked activity in visual cortex. We found that application of INS via 100 μm or 200 μm fiber optics produced enhancement of visually evoked OIS response confined to the eye column where INS was applied and relative suppression of the other eye column. Stimulating the cortex with a 400 μm fiber, exceeding the ocular dominance width, led to relative suppression, consistent with involvement of inhibitory surrounds. This study is the first to demonstrate that INS can be used to either enhance or diminish visual cortical response and that this can be done in a functional domain specific manner. INS thus holds great potential for use as a safe, non-contact, focally specific brain stimulation technology in primate brains.

Understanding cortical organization is key to understanding brain function. Distinct neural networks underlie the functional organization of the cerebral cortex; however, little is known about how different nodes in the cortical network interact during perceptual processing and motor behavior. To study cortical network function we examined whether the optical imaging of intrinsic signals (OIS) reveals the functional patterns of activity evoked by electrical cortical microstimulation. We examined the effects of current amplitude, train duration, and depth of cortical stimulation on the hemodynamic response to electrical microstimulation (250-Hz train, 0.4-ms pulse duration) in anesthetized New World monkey somatosensory cortex. Electrical stimulation elicited a restricted cortical response that varied according to stimulation parameters and electrode depth. Higher currents of stimulation recruited more areas of cortex than smaller currents. The largest cortical responses were seen when stimulation was delivered around cortical layer 4. Distinct local patches of activation, highly suggestive of local projections, around the site of stimulation were observed at different depths of stimulation. Thus we find that specific electrical stimulation parameters can elicit activation of single cortical columns and their associated columnar networks, reminiscent of anatomically labeled networks. This novel functional tract tracing method will open new avenues for investigating relationships of local cortical organization.

To understand manual tactile functions in primates, it is essential to explore the interactions between the finger pad representations in somatosensory cortex. To this end, we used optical imaging and electrophysiological mapping to guide neuroanatomical tracer injections into distal digit tip representations of Brodmann area 3b in the squirrel monkey. Retrogradely labeled cell densities and anterogradely labeled fibers and terminal patches in somatosensory areas were plotted and quantified with respect to tangential distribution. Within area 3b, reciprocal patchy distribution of anterograde and retrograde labeling spanned the representation of the distal pad of multiple digits, indicating strong cross-digit connectivity. Inter-areal connections revealed bundles of long-range fibers projecting anteroposteriorly, connecting area 3b with clusters of labeled neurons and terminal axon arborizations in area 1. Inter-areal linkage appeared to be largely confined to the representation of the injected finger. These findings provide the neuroanatomical basis for the interaction between distal finger pad representations observed by recent electrophysiological studies. We propose that intra-areal connectivity may be heavily involved in interdigit integration such as shape discrimination, whereas long-range inter-areal connections may subserve active touch in a digit-specific manner.

Functional magnetic resonance imaging (fMRI) at high magnetic field strength can suffer from serious degradation of image quality because of motion and physiological noise, as well as spatial distortions and signal losses due to susceptibility effects. Overcoming such limitations is essential for sensitive detection and reliable interpretation of fMRI data. These issues are particularly problematic in studies of awake animals. As part of our initial efforts to study functional brain activations in awake, behaving monkeys using fMRI at 4.7 T, we have developed acquisition and analysis procedures to improve image quality with encouraging results. We evaluated the influence of two main variables on image quality. First, we show how important the level of behavioral training is for obtaining good data stability and high temporal signal-to-noise ratios. In initial sessions, our typical scan session lasted 1.5 h, partitioned into short (

How are characteristics of communities associated with the implementation of the principles of systems of care (SOC)? This study uses multilevel modeling with a stratified random sample (N = 225) of US counties to explore community-level predictors of the implementation factors of the System of Care Implementation Survey. A model composed of community-level social indicators fits well with 5 of 14 factors identified as relevant for effective SOCs. As hypothesized, community disadvantage was negatively and residential stability positively associated with the implementation of SOC principles. Designation as a mental health professional shortage area was positively related to some implementation scores, as was the percentage of minority residents, while rurality was not significantly associated with any of the factors. Given the limitations of the study, the results should be interpreted with caution, but suggest that further research is merited to clarify these relationships that could inform efforts directed at promoting SOCs.

A major impediment to obtaining national information on systems of care implementation has been the lack of a psychometrically sound large-scale survey instrument. The present study provided information on the factorial and concurrent validity of the Systems of Care Implementation Survey scales. Multilevel confirmatory factor analysis and multilevel regression analysis were used to test these indicators of internal and external validity. Two hundred twenty-five counties were randomly selected and stratified by population size and poverty level. Nine hundred ten informants responded to the survey questionnaire, M = 4.04 informants per county (SD = 3.17). Results indicated that all models had at least adequate fit to the data, with nine of the 14 factor models having excellent fit. Overall, 11 of the 14 factors had some indication that receiving federal funding to create systems of care was associated with higher scores on the factors. Implications for future research were discussed.

The results of a survey to measure the implementation of the systems of care (SOC) approach in a nationally representative sample of counties are presented. The results from 910 informants within 225 counties reveal a moderate level of implementation of SOC factors, with the level of poverty and population size influencing implementation. Furthermore, mental health informants generally tended to rate the implementation of systems of care greater than administrators associated with the school system, other family serving agency personnel or family members. Family members and school personnel tended to rate the implementation lowest, while staff from the other child serving agencies tended to rate the implementation closer to mental health administrators. A quarter of the counties (26%) surveyed rated themselves as having adequate levels of implementation on 11 or more of the 14 factors, while 75% rated themselves as having adequate levels of implementation on six or more of the 14 factors measured. Implications for federal policies regarding systems of care implementation are discussed.

Interferons were first described by Isaacs & Lindenmann working at the National Institute for Medical Research, Mill Hill in 1957 [1]. Thus, the fiftieth year of their discovery is being celebrated this year at Oxford in a meeting of the International Society for Interferon and Cytokine Research. This then is an appropriate time to review the clinical applications of the interferons. To accomplish this coherently it is necessary also to review briefly what led to the discovery of interferons, why their clinical applications were so slow in coming, and the impact of interferon research on the biomedical sciences.

Throughout the country, there is considerable inconsistency in how states regulate residential treatment programs for youth. In states with little oversight, the health and safety of youth are unprotected and they may be subject to substandard treatment, rights violations, and/or abuse. Three initiatives to address this issue are reported: (1) an Internet survey of youth who are former residents, (2) a four-state pilot study of how states regulate and monitor residential programs, and (3) a bridge-building conference between residential treatment providers and mental health leaders. Recommendations address the next steps for lawmakers, lawyers, judges, mental health and education professionals, and parents.

There are currently largescale efforts underway to understand the brain as connection machine. However, there has been little emphasis on understanding connection patterns between functionally specific cortical columns. Here, we review development and application of focal electrical and optical stimulation methods combined with optical imaging and fMRI mapping in the nonhuman primate. These new approaches, when applied systematically on a large scale, will elucidate functionally specific intra-areal and inter-areal network connection patterns. Such functionally specific network data can provide accurate views of brain network topology.

Background Functional brain mapping via cortical microstimulation is a widely used clinical and experimental tool. However, data are traditionally collected point by point, making the technique very time consuming. Moreover, even in skilled hands, consistent penetration depths are difficult to achieve. Finally, the effects of microstimulation are assessed behaviorally, with no attempt to capture the activity of the local cortical circuits being stimulated. New method We propose a novel method for functional brain mapping, which combines the use of a microelectrode array with intrinsic optical imaging. The precise spacing of electrodes allows for fast, accurate mapping of the area of interest in a regular grid. At the same time, the optical window allows for visualization of local neural connections when stimulation is combined with intrinsic optical imaging. Results We demonstrate the efficacy of our technique using the primate motor cortex as a sample application, using a combination of microstimulation, imaging and electrophysiological recordings during wakefulness and under anesthesia. Comparison with current method: We find the data collected with our method is consistent with previous data published by others. We believe that our approach enables data to be collected faster and in a more consistent fashion and makes possible a number of studies that would be difficult to carry out with the traditional approach. Conclusions Our technique allows for simultaneous modulation and imaging of cortical sensorimotor networks in wakeful subjects over multiple sessions which is highly desirable for both the study of cortical organization and the design of brain machine interfaces.

Interferon regulatory factor (IRF)-1 expression was surveyed in nontransformed and oncogene-transformed mouse fibroblasts, using Western immunoblot with an IRF- 1-specific antiserum, to examine possible differences resulting from cellular transformation. Ten additional proteins that reacted with the IRF-1 antibody and that underwent specific competition by peptide antigen were observed in extracts of both nontransformed and oncogene-transformed cell lines. Cross-reacting proteins were also observed in mouse macrophage extracts. Protein was captured from fibroblast nuclear extracts, using oligonucleotides representing IRF-binding sequences linked to magnetic beads. Captured proteins were eluted and analyzed by immunoblot with anti-IRF-1. Along with 43-kDa IRF-1, 4 of the 7 nuclearly located cross-reacting proteins (97, 90, 66, and 33 kDa) were found to complex with the IRF binding element. These proteins, with an epitope in common with the IRF-1 C-terminal region and IRF element DNA sequence-binding capability, may represent new members of the IRF family.

In April 2002, the President's New Freedom Commission on Mental Health was created by executive order to study the mental health care delivery system in our nation and to make recommendations for improvements so that individuals with serious mental disorders can live, work, learn, and fully participate in their homes and communities. In its report, "Achieving the Promise: Transforming Mental Health Care in America," the commission provided strategies to address critical infrastructure, practice, and research issues. This article focuses on the work of the commission's Subcommittee on Children and Families, describing its vision for mental health service delivery for children and providing suggestions for strengthening community-based care for youths with or at risk of behavioral health disorders. Training, research, practice, and policy implications for psychologists are discussed.

Interferon (IFN) regulatory factor-1 (IRF-1) deregulation in ras-transformed mouse fibroblasts (RS485) was studied. Treatment with the proteasome inhibitor MG132 did not alter the constitutive IRF-1 protein levels in RS485 but significantly increased them in nontransformed NIH 3T3 cells at 4 h after serum stimulation of synchronized cultures. Because IRF-1 protein levels in NIH 3T3 are minimal at 4 h after serum starvation, the cyclic expression of IRF-1 in NIH 3T3 appears to be partially due to proteasome activity; however, proteasome activity in RS485 did not appear to be defective. In NIH 3T3 and RS485 cells treated with cycloheximide, there were similar rapid drops in IRF-1 protein levels, and the addition of MG132 along with cycloheximide prevented protein loss in both cell lines. Northern blot analyses of synchronized cultures showed that the IRF-1 message closely mirrored the protein expression pattern in both NIH 3T3 and RS485 cells. In synchronized cells treated with the transcription inhibitor actinomycin D, IRF-1 mRNA half-life was only marginally longer in ras-transformed fibroblasts than in the nontransformed cells, and this difference would contribute minimally to protein overexpression. These findings indicate that IRF-1 deregulation in RS485 cells occurs primarily at the transcriptional level.

We used intrinsic signal optical imaging to obtain maps of human somatosensory cortex during electrocutaneous stimulation of the face during a neurosurgical procedure for epilepsy. We found that human face somatotopy is organized like the macaque or cebus monkey, with peri-orbital skin located medial to peri-buccal skin, and that cortical magnification in the human is comparable to that in non-human primates. This study demonstrates that intrinsic signal imaging can be performed on humans during operative procedures with sufficient spatial resolution to reveal high-resolution topographic maps.

Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that has been historically associated with type I IFN activation and antioncogenic properties. We studied IRF-1 expression and DNA-binding capacity in nontransformed and transformed mouse fibroblasts. A 43-kDa nuclear IRF-1 protein was expressed biphasically during the cell cycle in primary mouse embryo fibroblasts, nontransformed NIH 3T3 cells, and ras revertants. IRF-1 expression became constitutive in ras-transformed NIH 3T3 cells and in cells transformed by oncogenes ets, fes, fos, her-2/neu, met, mos, raf, or trk, suggesting that deregulated IRF-1 expression may be associated with loss of growth control. Lysyl oxidase (LO), a ras suppressor that is downregulated in ras transformants, is an IRF-1 target gene, but it is not stimulated by abundant IRF-1 present in transformants, while another IRF-1 target gene (iNOS) is transcribed. IRF-1 from either normal or ras-transformed cells bound to IRF elements in the IFN-beta and LO promoters. IRF-1 in transformants can, therefore, bind to but not transactivate the LO promoter, and the presence of IRF-1 is not sufficient to suppress ras transformation. LO expression may effect the regulated expression of IRF-1: a ras revertant, which was generated by stable transfection of LO cDNA, regained the normal biphasic IRF-1 pattern. A mainly cytoplasmic, constitutively expressed 46-kDa protein with immunologic identity to the 43-kDa nuclear IRF-1 was also present in normal and transformed cells, but as it did not bind to the IRF elements, its function is unclear.

In this article we comment on the other articles in this issue, which describe the national evaluation of the Comprehensive Community Mental Health Services for Children and Their Families Program. The commentary focuses on 4 major themes. The first theme is the complexity of community-based systems of care and the special challenge that this presents for their evaluation. The second theme is the need for theories of change for systems of care to be more clearly developed and elucidated. The third theme discusses the implications of the diversity of the population served for the development of interventions and for the application of interventions that have been tested on other populations. The fourth theme examines strategies for conducting evaluations, given the constraints that exist in large evaluations of community-wide interventions.

Intrinsic signal optical imaging (ISOI) within the first decade of its use in humans showed its capacity as a precise functional mapping tool. It is a powerful tool that can be used intraoperatively to help a surgeon to directly identify functional areas of the cerebral cortex. Its use is limited to the intraoperative setting as it requires a craniotomy and durotomy for direct visualization of the brain. It has been applied in humans to study language, somatosensory and visual cortices, cortical hemodynamics, epileptiform activity, and lesion delineation. Despite studies showing clear evidence of its usefulness in clinical care, its clinical use in humans has not grown. Impediments imposed by imaging in a human operating room setting have hindered such work. However, recent studies have been aimed at overcoming obstacles in clinical studies establishing the benefits of its use to patients. This review provides a description of ISOI and its use in human studies with an emphasis on the challenges that have hindered its widespread use and the recent studies that aim to overcome these hurdles. Clinical studies establishing the benefits of its use to patients would serve as the impetus for continued development and use in humans.

Reflex responses to electrocutaneous stimulation of the tail were characterized in awake cats, before and after transection of the spinal cord at sacrocaudal levels S3-Ca1 Consistent with effects of spinal transection at higher levels, postoperative cutaneous reflexes were initially depressed, and the tail was flaccid. Recovery ensued over the course of 70–90 days after sacrocaudal transection. Preoperative and chronic postlesion reflexes elicited by electrocutaneous stimulation were graded in amplitude as a function of stimulus intensity. Chronic postlesion testing of electrocutaneous reflexes revealed greater than normal peak amplitudes, peak latencies, total amplitudes (power), and durations, particularly for higher stimulus intensities. Thus, sacrocaudal transection produced effects representative of the spastic syndrome. In contrast, exaggerated reflex responsivity did not develop for a group of cats that received transplants of fetal spinal cord tissue within sacrocaudal transection cavities at the time of injury, in conjunction with long-term immunosuppression by cyclosporine. We conclude that gray matter replacement and potential neuroprotective actions of the grafts and/or immunosuppression prevent development of the spastic syndrome. This argues that the spastic syndrome does not result entirely from interruption of long spinal pathways.

A dorsal column (DC) lesion has lasting effects on behavioral tasks that require temporal processing of tactile information (e.g., frequency and duration discrimination). The present experiments describe physiological correlates of these deficits in temporal discrimination. Compound action potentials evoked by electrocutaneous stimulation were recorded from the major white matter subdivisions of the spinal cord in anesthetized monkeys, and relationships between stimulation frequency and evoked potential (EP) amplitude were determined for the ascending pathways. At 10 pulses per second (Hz) EPs recorded in the lateral spinal columns were attenuated slightly (by 15% or less, relative to 1.5 Hz), whereas potentials recorded from the DCs were not attenuated. The attenuation increased with stimulation frequencies up to 50 Hz, reaching 80% for the anterolateral column and 38% for the dorsolateral column, but only 15% for the DC. Epidural EPs were recorded, before and after interruption of the contralateral DC, from awake animals with electrodes chronically implanted over primary somatosensory cortex (SI). Following the lesion. EP responses to 1.5-Hz stimulation were 46% of preoperative responses to the same stimulus. At 10 Hz, EP amplitudes were attenuated even more, to 27% of the preoperative amplitude at 1.5 Hz. Principal components analysis was employed to quantify alterations in EP conformation and stimulus frequency was varied from 1.5 to 10 Hz, before and after a DC lesion. Interruption of the DC resulted in a significant decrease in the information provided by the EP about changes in stimulus frequency. EPs were also recorded from different locations along the anterior-posterior dimension of the hindlimb region of SI in lightly anesthetized animals. Principal components analysis revealed that there was less information present in the EP about changes in stimulus frequency (1.5-10 Hz) at all recording locations in animals with a DC lesion, compared with the cortex of normal animals. The DC lesion significantly decreased the amplitude of cortical EPs evoked by repetitive stimulation. At 10 Hz the EP was nearly buried in noise, consistent with behavioral deficits in discrimination of the duration of 10 Hz stimulation following interruption of the DC. Also, significantly less information was present in the cortical EPs about changes in stimulus frequency in the absence of intact DCs, which is consistent with deficits in frequency discrimination. This reduction could be explained in part by a lesser capacity of spinal pathways in the lateral column to follow repetitive stimulation above 10 Hz. However, more rostral manifestations of a DC lesion, at either the thalamus or the cortex, are likely to contribute to the reduced capacity of animals with DC lesions to make temporal discriminations.

Using double immunofluorescence, we have shown previously that interferon (IFN) treatment inhibits the transport of herpes simplex virus-1 (HSV-1) gD from the Golgi complex to the plasma membrane in the virus infected and gD cDNA transfected LMtk-cells. In the present study, we quantitated the gD protein on the cell surface and localized the gD protein in the trans-Golgi network (TGN). The results showed 10-fold less fluorescence for the gD protein on the cell surface in IFN-treated LMtk-cells. Subcellular fractionation studies demonstrated that gD was associated with TGN-enriched membranes. Gold labeling for DAMP distribution using electron microscopy showed that IFN raised the pH of TGN. IFNs induced alkalinization of TGN may be related to the block in the transport of HSV-1 gD. Earlier we reported that a subeffective dose of chloroquine (CHL) or IFN does not change the pHi. However, both CHL and IFN together raise the pHi significantly. To study the biologic significance of the finding, the effect of these subeffective doses of IFN and CHL on the antiviral activity and the transport of the gD protein was studied. Results suggested that CHL enhance the antiviral activity of IFN against HSV-1 and concomitantly increase the inhibition of HSV-1 gD transport. This IFN-induced increase in pHi of the TGN may also explain the inhibitory effect of IFN reported on the terminal steps of some of the enveloped viruses.

There were seven workshops that primarily concerned the biological effects of the interferons and the other cytokines. These were: Workshop 6, The refractory state in the response to interferons (IFNs) and antibodies in treated patients; Workshop 7, IFNs, multiple sclerosis, and the nervous system; Workshop 9, Viral inhibition of the response to IFNs and other cytokines; Workshop 10, Cell growth inhibition by IFNs and other cytokines; Workshop 12, Cytokines and cell death; Workshop 13, Interactions between cytokines; and, Workshop 14, Cytokine gene therapy. Summaries of each of these sessions follow.

The specific purpose of the study was to compile descriptive data on children with serious emotional disturbance (SED), including (a) demographic and family characteristics, (b) level of psychological and adaptive functioning, (c) services received, and (d) outcomes or how the children fared over time. The sample consisted of 812 children, ages 8 to 18 years (M = 13.89 years, SD = 2.35), who had been identified as having SED and were being served by either mental health (46%) or public school (54%) systems in accordance with P.L. 94–142. Data were collected annually during a 7-year period. Results indicated that, at entry into the study, the children already had serious problems in many domains and the problems remained serious for these children at the end of the study.

The cardiosynchronous signal obtained through Radio Frequency Impedance Interrogation (RFII) is a non-invasive method for monitoring hemodynamics with potential applications in combat triage and biometric identification. The RFII signal is periodic in nature dominated by the heart beat cycle. The first step in both of these applications is to segment the signal by identifying a fiducial point in each heart beat cycle. A continuous wavelet transform was utilized to locate the fiducial points with high temporal resolution. Cepstral Analysis was used to estimate the average heart rate to focus on the appropriate portion of the time-frequency spectrum. Robust heartbeats from RFII signals collected from four subjects were segmented using this method.

The group therapy literature on male sexual abuse is very preliminary and concerned solely with short-term support models. This paper describes a long-term psychodynamic therapy group for male survivors that has been running successfully in a clinic setting for almost three years. This combined group and individual treatment approach presupposes the selection of men who are capable of using group process to explore basic personality and relationship problems. With sexually abused men, certain treatment issues are paramount. These concern the safety of group boundaries, power and control, facilitating intimacy, handling shame and guilt, and the effects of trauma. Special attention is given to the gender-related dynamics and conflicts that occur in a group of male survivors with a male leader.

OBJECTIVE: The US Surgeon General has called for new approaches to close the mental health services gap for the large proportion of US children with significant mental health needs who have not received evaluation or services within the previous 6 to 12 months. In response, investigators sought to develop brief, easily understood, scientifically derived “warning signs” to help parents, teachers, and the lay public to more easily recognize children with unmet mental health needs and bring these children to health care providers' attention for evaluation and possible services. METHOD: Analyses of epidemiologic data sets from >6000 children and parents were conducted to (1) determine the frequency of common but severely impairing symptom profiles, (2) examine symptom profile frequencies according to age and gender, (3) evaluate positive predictive values of symptom profiles relative to Diagnostic and Statistical Manual of Mental Disorders diagnoses, and (4) examine whether children with 1 or more symptom profiles receive mental health services. RESULTS: Symptom-profile frequencies ranged from 0.5% to 2.0%, and 8% of the children had 1 or more symptom profile. Profiles generated moderate-to-high positive predictive values (52.7%–75.4%) for impairing psychiatric diagnoses, but fewer than 25% of children with 1 or more profiles had received services in the previous 6 months. CONCLUSIONS: Scientifically robust symptom profiles that reflect severe but largely untreated mental health problems were identified. Used as “action signs,” these profiles might help increase public awareness about children's mental health needs, facilitate communication and referral for specific children in need of evaluation, and narrow the child mental health services gap.

The posterior parietal cortex (PPC) of monkeys and prosimian galagos contains a number of subregions where complex, behaviorally meaningful movements, such as reaching, grasping, and body defense, can be evoked by electrical stimulation with long trains of electrical pulses through microelectrodes. Shorter trains of pulses evoke no or simple movements. One possibility for the difference in effectiveness of intracortical microstimulation is that long trains activate much larger regions of the brain. Here, we show that long-train stimulation of PPC does not activate widespread regions of frontal motor and premotor cortex but instead, produces focal, somatotopically appropriate activations of frontal motor and premotor cortex. Shorter stimulation trains activate the same frontal foci but less strongly, showing that longer stimulus trains do not produce less specification. Because the activated sites in frontal cortex correspond to the locations of direct parietal–frontal anatomical connections from the stimulated PPC subregions, the results show the usefulness of optical imaging in conjunction with electrical stimulation in showing functional pathways between nodes in behavior-specific cortical networks. Thus, long-train stimulation is effective in evoking ethologically relevant sequences of movements by activating nodes in a cortical network for a behaviorally relevant period rather than spreading activation in a nonspecific manner.

The children’s system of care framework has been extensively implemented in the U.S. Since its inception in 1993, the Comprehensive Community Mental Health Services for Children and Their Families Program has invested in excess of $1 billion supporting the development of systems of care in 164 grantee sites across the country. Despite these efforts to implement children’s systems of care nationally, little is known about the extent to which the principles and values actually have been put into practice outside of the funded grantee sites. This paper describes the development of the Systems of Care Implementation Survey, a measure designed specifically for the first ever study assessing the level of implementation of factors contributing to effective children’s systems of care in a nationally representative sample of counties throughout the U.S.

Non-contact, non-invasive monitoring of hemodynamic parameters has long been deemed to be important to medical monitoring in a variety of environments. Radio Frequency Impedance Interrogation (RFII) measures hemodynamic function via resonance frequency coupling to a hydrophilic protein molecule. We examined the use of RFII for hemodynamic monitoring of human subjects during Lower Body Negative Pressure (LBNP) and physiological hemodynamic maneuvers using valsalva and orthostatic position changes in this small pilot study. Results demonstrate a high degree of correlation between stroke volume waveform amplitude (R2 = 0.92) and RFII derived R-R interval (R2 = 0.99) and classic electrocardiogram (ECG). These results suggest that RFII may be of great utility in the pre-hospital triage setting and for in-hospital patient monitoring.

H-Ras functions as a signal switch molecule in numerous signaling pathways in the cytoplasm, requiring H-Ras localization to the inner surface of the cytoplasmic membrane, and H-Ras is considered to be a cytoplasmic protein. Immunoblot studies of cells transformed by overexpression of c-H-ras indicated that H-Ras protein was present in both cytoplasmic and nuclear extracts, suggesting a possible correlation of nuclear H-Ras and cellular transformation. Unexpectedly, additional studies revealed that H-Ras protein was also present in the nuclei of nontransformed and primary mouse cells, which do not overexpress H-Ras. Mouse fibroblast NIH 3T3 cells, L cells, and a primary fibroblast line all had H-Ras present in both cytoplasmic and nuclear extracts. Nuclear extracts of cells synchronized by growth without serum displayed an increasing amount of H-Ras and cyclin D1 as cells grew after serum addition. Treatment with farnesyltransferase inhibitor caused loss of H-Ras from the nucleus. Immunofluorescence in situ studies of nuclei from synchronized cultures showed that H-Ras protein appeared in and disappeared from the nuclei as the cells moved through the growth cycle. This cycling occurred in both nontransformed and ras-transformed cells. Flow cytometry measurements on parallel cultures revealed that the time point at which the greatest percentage of cells were in S phase, for each line, corresponded to appearance of a noticeably stronger in situ signal for H-Ras. H-Ras may participate in nuclear signaling pathways associated with replication in addition to its cytoplasmic signaling functions.

This paper reviews changes in approaches to serving children with emotional disorders and their families over the last decade. The implications of these changes for the professional mental health disciplines in general, and for academic training programs in particular, are then examined. Proposals are made for changes in curricula and increased faculty development; policy issues concerning academic training programs are re-examined.

Pulsed infrared light has shown promise as an alternative to electrical stimulation in applications where contact free or high spatial precision stimulation are desired. Infrared neural stimulation (INS) is well characterized in the peripheral nervous system; however, to date, research has been limited in the central nervous system. In this study, pulsed infrared light (λ=1.875 μm, pulse width=250 μs, radiant exposure=0.01–0.55 J/cm2, fiber size=400 μm, repetition rate=50–200 Hz) was used to stimulate the somatosensory cortex of anesthetized rats, and its efficacy was assessed using intrinsic optical imaging and electrophysiology techniques. INS was found to evoke an intrinsic response of similar magnitude to that evoked by tactile stimulation (0.3–0.4% change in intrinsic signal magnitude). A maximum deflection in the intrinsic signal was measured to range from 0.05% to 0.4% in response to INS, and the activated region of cortex measured approximately 2 mm in diameter. The intrinsic signal magnitude increased with faster laser repetition rates and increasing radiant exposures. Single unit recordings indicated a statistically significant decrease in neuronal firing that was observed at the onset of INS stimulation (0.5 s stimulus) and continued up to 1 s after stimulation onset. The pattern of neuronal firing differed from that observed during tactile stimulation, potentially due to a different spatial integration field of the pulsed infrared light compared to tactile stimulation. The results demonstrate that INS can be used safely and effectively to manipulate neuronal firing.

This study aimed to evaluate the ability of BOLD signals at high MRI field (7 Tesla) to map fine-scale single-digit activations in subdivisions (areas 3b and 1) of the human primary somatosensory cortex (SI) in individual subjects. We acquired BOLD-fMRI data from cortical areas around the central suclus in six healthy human subjects while stimulating individual finger pads with 2 Hz air puffs. Discrete, single-digit responses were identified in an area along the posterior bank of the central sulcus corresponding to area 3b and in an area along the crest of the postcentral gyrus corresponding to area 1. In single subjects, activations of digits 1 to 4 in both areas 3b and 1 were organized in a somatotopic manner. The separation of digit representations was measured for adjacent digits, and was approximately 1.6 times greater in area 3b than in area 1. Within individual subjects, the cortical responses to single-digit stimulations and the magnitude of the BOLD signals were reproducible across imaging runs and were comparable across subjects. Our findings demonstrate that BOLD-fMRI at 7 T is capable of revealing the somatotopic organization of single-digit activations with good within-subject reliability and reproducibility, and activation maps can be acquired within a reasonably short time window, which are essential characteristics for several neurological applications within patient populations.