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The posterior parietal cortex (PPC) of squirrel monkeys contains subregions where long trains of intracortical microstimulation evoke complex, behaviorally meaningful movements. Recently, we showed that such stimulation of a part of the PPC in the caudal lateral sulcus (LS) elicits eye movements in these monkeys. Here, we studied the functional and anatomical connections of this oculomotor region we call parietal eye field (PEF) with frontal eye field (FEF) and other cortical regions in 2 squirrel monkeys. We demonstrated these connections with intrinsic optical imaging and injections of anatomical tracers. Optical imaging of frontal cortex during stimulation of the PEF evoked focal functional activation within FEF. Tracing studies confirmed the functional PEF-FEF connections. Moreover, tracer injections revealed PEF connections with other PPC regions on the dorsolateral and medial brain surface, cortex in the caudal LS, and visual and auditory cortical association areas. Subcortical projections of PEF were primarily with superior colliculus, and pontine nuclei as well as nuclei of the dorsal posterior thalamus and caudate. These findings suggest that PEF in squirrel monkey is homologous to lateral intraparietal (LIP) area of macaque, supporting the notion that these brain circuits are organized similarly to mediate ethologically relevant oculomotor behaviors.

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.

Advances in optical technology have revolutionized studies of brain function in freely behaving mice. Here, we describe an optical imaging and stimulation device for use in primates that easily attaches to an intracranial chamber. It consists of affordable commercially available or 3D-printed components: a monochromatic camera, a small standard lens, a wireless μLED stimulator powered by an induction coil, and an LED array for illumination. We show that the intrinsic imaging performance of this device is comparable to a standard benchtop system in revealing the functional organization of the visual cortex for awake macaques in a primate chair or under anesthesia. Imaging revealed neural modulatory effects of wireless focal optogenetic stimulation aimed at identified functional domains. With a 1 to 2 cm field of view, 100× larger than previously used in primates without head restraint, our device permits widefield optical imaging and optogenetic stimulation for ethological studies in primates.

Significance: We present a new optical method for modulating cortical activity in multiple locations and across multiple time points with high spatial and temporal precision. Our method uses infrared light and does not require dyes or transgenic modifications. It is compatible with a number of other stimulation and recording techniques. Aim: Infrared neural stimulation (INS) has been largely confined to single point stimuli. In this study, we expand upon this approach and develop a rapidly switched fiber array capable of generation of stimulus patterns. Our prototype is capable of stimulating at nine separate locations but is easily scalable. Approach: Our device is made of commercially available components: a solid-state infrared laser, a piezoelectric fiber coupled optical switch, and 200-μm diameter optical fibers. We validate it using intrinsic optical signal imaging of INS responses in macaque and squirrel monkey sensory cortical areas. Results: We demonstrate that our switched array can consistently generate responses in primate cortex, consistent with earlier single channel INS investigations. Conclusions: Our device can successfully target the cortical surface, either at one specific region or multiple points spread out across different areas. It is compatible with a host of other imaging and stimulation modalities.

Gene drive organisms (GDOs), whose genomes have been genetically engineered to spread a desired allele through a population, have the potential to transform the way societies address a wide range of daunting public health and environmental challenges. The development, testing, and release of GDOs, however, are complex and often controversial. A key challenge is to clarify the appropriate roles of developers and others actively engaged in work with GDOs in decision-making processes, and, in particular, how to establish partnerships with relevant authorities and other stakeholders. Several members of the gene drive community previously proposed safeguards for laboratory experiments with GDOs (1) that, in the absence of national or international guidelines, were considered essential for responsible laboratory work to proceed. Now, with GDO development advancing in laboratories (2–5), we envision similar safeguards for the potential next step: ecologically and/or genetically confined field trials to further assess the performance of GDOs. A GDO's propensity to spread necessitates well-developed criteria for field trials to assess its potential impacts (6). We, as a multidisciplinary group of GDO developers, ecologists, conservation biologists, and experts in social science, ethics, and policy, outline commitments below that we deem critical for responsible conduct of a field trial and to ensure that these technologies, if they are introduced, serve the public interest.

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.

To map in vivo cortical circuitry at the mesoscale we applied a novel approach to map inter-areal functional connectivity. Electrical intracortical microstimulation (ICMS) in conjunction with optical imaging of intrinsic signals (OIS) was used map functional connections in somatosensory cortical areas in anesthetized squirrel monkeys. ICMS produced activations that were focal and that displayed responses which were stimulation intensity dependent. ICMS in supragranular layers of Brodmann areas 3b, 1, 2, 3a, and M1 evoked inter-areal activation patterns that were topographically appropriate and appeared consistent with known anatomical connectivity. Specifically, ICMS revealed area 3b connections with area 1; area 1 connections with areas 2 and 3a; area 2 connections with areas 1, 3a, and M1; area 3a connections with areas M1, 1, and 2; and M1 connections with areas 3a, 1, and 2. These somatosensory connectivity patterns were reminiscent of feedforward patterns observed anatomically, although feedback contributions are also likely present. Further consistent with anatomical connectivity, intra-areal and intra-areal patterns of activation were patchy with patch sizes of 200–300 μm. In summary, ICMS with OIS is a novel approach for mapping inter-areal and intra-areal connections in vivo. Comparisons with feedforward and feedback anatomical connectivity is discussed.

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.

Non-human primates (NHPs) are vital models for neuroscience research. These animals have been widely used in behavioral, electrophysiological, molecular, and more recently, multimodal neuroimaging and neuro-engineering studies. Several RF coil arrays have been designed for functional, high-resolution brain magnetic resonance imaging (MRI), but few have been designed to accommodate multimodal devices. In the present study, a 16-channel array coil was constructed for brain imaging of macaques at 3 Tesla (3 T). To construct this coil, a close-fitting helmet-shaped form was designed to host 16 coil loops for whole-brain coverage. This assembly is mountable onto stereotaxic head frame bars, and the coil functions while the monkey is in the sphinx position with a clear line of vision of stimuli presented from outside of the MRI system. In addition, 4 openings were allocated in the coil housing, allowing multimodal devices to directly access visual cortical regions such as V1-V4 and MT. Coil performance was evaluated in an anesthetized macaque by quantifying and comparing signal-to-noise ratios (SNRs), noise correlations, and g-factor maps to a vendor-supplied human pediatric coil frequently used for NHP MRI. The result from in vivo experiments showed that the NHP coil was well-decoupled, had higher SNRs in cortical regions, and improved data acquisition acceleration capability compared with a vendor-supplied human pediatric coil that has been frequently used in macaque MRI studies. Furthermore, whole-brain anatomic imaging, diffusion tensor imaging and functional brain imaging have also been conducted: the details of brain anatomical structure, such as cerebellum and brainstem, can be clearly visualized in T2-SPACE images; b0 SNR calculated from b0 maps was higher than the human pediatric coil in all regions of interest (ROIs); the time-course SNR (tSNR) map calculated for GRE-EPI images demonstrates that the presented coil can be used for high-resolution functional imaging at 3 T.

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.

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.

Optogenetics has revolutionized neuroscience in small laboratory animals, but its effect on animal models more closely related to humans, such as non-human primates (NHPs), has been mixed. To make evidence-based decisions in primate optogenetics, the scientific community would benefit from a centralized database listing all attempts, successful and unsuccessful, of using optogenetics in the primate brain. We contacted members of the community to ask for their contributions to an open science initiative. As of this writing, 45 laboratories around the world contributed more than 1,000 injection experiments, including precise details regarding their methods and outcomes. Of those entries, more than half had not been published. The resource is free for everyone to consult and contribute to on the Open Science Framework website. Here we review some of the insights from this initial release of the database and discuss methodological considerations to improve the success of optogenetic experiments in NHPs. ispartof: NEURON vol:108 issue:6 ispartof: location:United States status: published

Introduction: The close functional relationship between areas 3b and 1 of the somatosensory cortex is based on their reciprocal connections indicating that tactile sensation depends on the interaction of these two areas. Aim: The aim of the authors was to explore this neuronal circuit at the level of the distal finger pad representation. Method: The study was made by bidirectional tract tracing aided by neurophysiological mapping in squirrel monkeys (Saimiri sciureus). Results: Inter-areal connections between the two areas preferred the homologues representations. However, intra-areal connections were formed between the neighboring finger pad representations supporting the physiological observations. Interestingly, the size of the local input area of the injected cortical micro-region, which differed in the two areas, represented the same skin area. Conclusions: The authors propose that intra-areal connections are important in integrating information across fingers, while inter-areal connections are important in maintaining input localization during hand movement. Orv. Hetil., 2016, 157(33), 1320–1325.

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.

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.

In rats, navigating through an environment requires continuous information about objects near the head. Sensory information such as object location and surface texture are encoded by spike firing patterns of single neurons within rat barrel cortex. Although there are many studies using single-unit electrophysiology, much less is known regarding the spatiotemporal pattern of activity of populations of neurons in barrel cortex in response to whisker stimulation. To examine cortical response at the population level, we used voltage-sensitive dye (VSD) imaging to examine ensemble spatiotemporal dynamics of barrel cortex in response to stimulation of single or two adjacent whiskers in urethane-anesthetized rats. Single whisker stimulation produced a poststimulus fluorescence response peak within 12–16 ms in the barrel corresponding to the stimulated whisker (principal whisker). This fluorescence subsequently propagated throughout the barrel field, spreading anisotropically preferentially along a barrel row. After paired whisker stimulation, the VSD signal showed sublinear summation (less than the sum of 2 single whisker stimulations), consistent with previous electrophysiological and imaging studies. Surprisingly, we observed a spatial shift in the center of activation occurring over a 10- to 20-ms period with shift magnitudes of 1–2 barrels. This shift occurred predominantly in the posteromedial direction within the barrel field. Our data thus reveal previously unreported spatiotemporal patterns of barrel cortex activation. We suggest that this nontopographical shift is consistent with known functional and anatomic asymmetries in barrel cortex and that it may provide an important insight for understanding barrel field activation during whisking behavior.

The close functional relationship between areas 3b and 1 of the somatosensory cortex is based on their reciprocal connections indicating that tactile sensation depends on the interaction of these two areas.The aim of the authors was to explore this neuronal circuit at the level of the distal finger pad representation.The study was made by bidirectional tract tracing aided by neurophysiological mapping in squirrel monkeys (Saimiri sciureus).Inter-areal connections between the two areas preferred the homologues representations. However, intra-areal connections were formed between the neighboring finger pad representations supporting the physiological observations. Interestingly, the size of the local input area of the injected cortical micro-region, which differed in the two areas, represented the same skin area.The authors propose that intra-areal connections are important in integrating information across fingers, while inter-areal connections are important in maintaining input localization during hand movement. Orv. Hetil., 2016, 157(33), 1320-1325.

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 (

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.

In the visual and auditory systems specialized neural pathways use motion cues to track object motion and self-motion, and use differential motion cues for figure-ground segregation. To examine the neural circuits that encode motion in the somatosensory system, we have developed neuroimaging methods to study motion processing in human and nonhuman primates. We have implemented stimulus presentation paradigms to examine neural encoding of apparent motion percepts. These paradigms are designed to be compatible with fMRI, optical imaging, and electrophysiological methods, thereby permitting direct comparison of data derived across neurofunctional scales. An additional motivation for using a common tactile motion stimulation paradigm is to bridge two disparate bodies of work, that derived from neuroimaging studies in humans and another from neuroimaging, neurophysiological and neuroanatomical studies in monkeys. Here, we demonstrate that such an approach through the use of optical imaging and 9.4 Tesla fMRI experiments in monkeys, and 7 Tesla fMRI experiments in humans is effective in revealing neural regions activated by tactile motion stimuli. These methods span spatial scales capable of detecting 100 μm sized domains to those that would reveal global whole brain circuits. Armed with such capabilities, our long-term goals are to identify directionally selective areas and directionally se-lective functional domains and understand the global pathways within which they reside. Such knowledge would have great impact on our thinking regarding not only tactile motion processing, but also general strategies underlying somatosensory cortical processing.

(2011). Golgi: A Biography of the Founder of Modern Neuroscience, Translated by Aldo Badiani and Henry A. Buchtel, edited by Paolo Mazzarello. Psychiatry: Vol. 74, No. 2, pp. 169-172.

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.

This commentary builds on the papers presented at the Vanderbilt Conference by emphasizing the importance of better understanding the process of change-making if real change in the real world is to be achieved. The commentary reviews several frameworks and research findings related to achieving large-scale sustainable change that benefits children and families. It calls for the application of systems thinking as a complement to the more micro-level research that was presented at the Vanderbilt conference. Such an approach would have implications for framing of the issue, for the strategies that are taken to try to achieve change, and for research/evaluation methods for studying complex, dynamic, nonlinear systems.

Lysyl oxidase acts as both a matrix modifying enzyme and an oncogene suppressor. It is synthesized as a 50-kDa proenzyme, secreted, and processed into an approximately 30 kDa mature, active enzyme and an 18-kDa propeptide. The tumor suppressive effect of lysyl oxidase appears to be exerted within the cell, so the subcellular localization of protein forms was investigated. Propeptide-specific antibody detected 50-kDa proenzyme in cytoplasmic and nuclear extracts of non-transformed mouse fibroblasts, but free 18-kDa propeptide was not detected in any extract. Antibody to epitope near the N-terminus of mature lysyl oxidase detected the proenzyme product in non-transformed cells, and a 30-kDa cytoplasmic protein in both non-transformed and transformed cells. RNA interference reduced the expression of lysyl oxidase mRNA and 50-kDa proenzyme in non-transformed cells, but had no effect on 30-kDa protein, indicating that although this protein displays a lysyl oxidase epitope, it is not derived from lysyl oxidase message. The absence of both free 18-kDa propeptide and mature lysyl oxidase within non-transformed cells suggests that cellular reversion after restoration of lysyl oxidase gene expression is mediated by the 50-kDa proenzyme within cells.

Stimulation of the skin evokes topographically organized activation in somatosensory cortex. This representation is context dependent, however, since a different cortical topography is observed in area 3b when stimulated with complex tactile stimuli that evoke the von Békésy funneling illusion. Here we report on the population responses, as observed with intrinsic optical imaging, of area 1 and area 3b in the anesthetized squirrel monkey to pressure indentation of distal finger pads. Individual finger pad stimulation revealed that area 1 exhibited a smaller magnification factor than 3b, as evidenced by a smaller area of activation elicited by distal finger pad stimulation. Effects of paired finger pad stimulation produced largely similar effects in area 1 and area 3b. Paired finger pad stimulation produced reductions in the area of digit activation in area 1, suggesting the presence of lateral inhibition and funneling of information in area 1. Suppressive effects were stronger for paired stimulations at adjacent than at nonadjacent sites. Single-unit recordings revealed a mixture of either a summation or a suppression of the response to paired finger stimulation, compared with single finger pad stimulation of the primary digit. However, the average population response showed that paired finger pad stimulation resulted in response suppression. Based on this study and previous studies, we suggest the presence of at least three distinct ranges of lateral inhibition in areas 3b and 1.

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.