Modular Organization of Signal Transmission in Primate Somatosensory Cortex.

Axonal patches are known as the major sites of synaptic connections in the cerebral cortex of higher order mammals. However, the functional role of these patches is highly debated. Patches are formed by populations of nearby neurons in a topographic manner and are recognized as the termination fields of long-distance lateral connections within and between cortical areas. In addition, axons form numerous boutons that lie outside the patches, whose function is also unknown. To better understand the functional roles of these two distinct populations of boutons, we compared individual and collective morphological features of axons within and outside the patches of intra-areal, feedforward, and feedback pathways by way of tract tracing in the somatosensory cortex of New World monkeys. We found that, with the exception of tortuosity, which is an invariant property, bouton spacing and axonal convergence properties differ significantly between axons within patch and no-patch domains. Principal component analyses corroborated the clustering of axons according to patch formation without any additional effect by the type of pathway or laminar distribution. Stepwise logistic regression identified convergence and bouton density as the best predictors of patch formation. These findings support that patches are specific sites of axonal convergence that promote the synchronous activity of neuronal populations. On the other hand, no-patch domains could form a neuroanatomical substrate to diversify the responses of cortical neurons.

Magnetic resonance temperature imaging of laser-induced thermotherapy using proton resonance frequency shift: evaluation of different sequences in phantom and porcine brain at 7 T.

PURPOSE: The present study aimed to evaluate magnetic resonance (MR) thermometry using proton resonance frequency shift (PRFS) during laser-induced thermotherapy (LITT), and to compare the results of using different sequences at a field strength of 7-Tesla to identify the optimal for use in ablation so that the surrounding healthy tissues may be protected from damaging in real time. MATERIALS AND METHODS: LITT was applied to agarose gel phantoms and ex-vivo porcine brains. We reconstructed both magnitude and phase images to perform MR thermometry based on PRFS methods. We tested four different sequences: a gradient-echo (GRE), a segmented gradient-echo echoplanar imaging (EPI-GRE), a fast-low angle shot (FLASH), and a true fast imaging with steady precession (TRUFI). Temperature was monitored and verified using a fiber-optic thermometry device. RESULTS: All sequences showed good linear correlations (R = 0.97-0.99) between the measured temperature and the calculated MR-thermometry measurements. The phantom/porcine brain experiments revealed the temperature precisions at 1.53/0.69 °C (GRE), 0.61/0.43 °C (EPI-GRE), 1.64/1.32 °C (FLASH), and 0.58/1.52 °C (TRUFI), respectively. Furthermore, we performed a Bland-Altman analysis and the temperature accuracies were found to be - 1.32/- 0.60 °C (GRE), 0.42/- 0.33 °C (EPI-GRE), - 1.28/- 0.98 °C (FLASH), and 0.14/0.46 °C (TRUFI) in the phantom/porcine brain experiments, respectively. CONCLUSIONS: Our experiments recommend that EPI-GRE sequence be the best of the all sequences for MR temperature imaging with PRFS in the LITT on 7 T magnetic resonance imaging (MRI) systems because of its relatively higher precision and accuracy.

Head-mounted optical imaging and optogenetic stimulation system for use in behaving primates.

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.

Fiberoptic array for multiple channel infrared neural stimulation of the brain.

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 - µ m 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.

Synaptic organization of cortico-cortical communication in primates.

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.

Virtual reality therapy for upper limb rehabilitation in patients with stroke: a meta-analysis of randomized clinical trials.

Background: Stroke is a major cause of life-long disability in adults, associated with poor quality of life. Virtual reality (VR)-based therapy systems are known to be helpful in improving motor functions following stroke, but recent clinical findings have not been included in the previous publications of meta-analysis studies.Aims: This meta-analysis was based on the available literature to evaluate the therapeutic potential of VR as compared to dose-matched conventional therapies (CT) in patients with stroke.Methods: We retrieved relevant articles in EMBASE, MEDLINE, PubMed, and Web of Science published between 2010 and February 2019. Peer-reviewed randomized controlled trials that compared VR with CT were included.Results: A total of 27 studies met the inclusion criteria. The analysis indicated that the VR group showed statistically significant improvement in the recovery of UL function (Fugl-Meyer Upper Extremity [FM-UE]: n = 20 studies, Mean Difference [MD] = 3.84, P = .01), activity (Box and Block Test [BBT]: n = 13, MD = 3.82, P = .04), and participation (Motor Activity Log [MAL]: n = 6, MD = 0.8, P = .0001) versus the control group.Conclusion: VR appears to be a promising therapeutic technology for UL motor rehabilitation in patients with stroke.

Solving visual correspondence between the two eyes via domain-based population encoding in nonhuman primates.

Stereoscopic vision depends on correct matching of corresponding features between the two eyes. It is unclear where the brain solves this binocular correspondence problem. Although our visual system is able to make correct global matches, there are many possible false matches between any two images. Here, we use optical imaging data of binocular disparity response in the visual cortex of awake and anesthetized monkeys to demonstrate that the second visual cortical area (V2) is the first cortical stage that correctly discards false matches and robustly encodes correct matches. Our findings indicate that a key transformation for achieving depth perception lies in early stages of extrastriate visual cortex and is achieved by population coding.

Review of functional and clinical relevance of intrinsic signal optical imaging in human brain mapping.

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.

Intrinsic signal optical imaging of visual brain activity: Tracking of fast cortical dynamics.

Hemodynamic-based brain imaging techniques are typically incapable of monitoring brain activity with both high spatial and high temporal resolutions. In this study, we have used intrinsic signal optical imaging (ISOI), a relatively high spatial resolution imaging technique, to examine the temporal resolution of the hemodynamic signal. We imaged V1 responses in anesthetized monkey to a moving light spot. Movies of cortical responses clearly revealed a focus of hemodynamic response traveling across the cortical surface. Importantly, at different locations along the cortical trajectory, response timecourses maintained a similar tri-phasic shape and shifted sequentially across cortex with a predictable delay. We calculated the time between distinguishable timecourses and found that the temporal resolution of the signal at which two events can be reliably distinguished is about 80 milliseconds. These results suggest that hemodynamic-based imaging is suitable for detecting ongoing cortical events at high spatial resolution and with temporal resolution relevant for behavioral studies.

Spatial Distribution of Attentional Modulation at Columnar Resolution in Macaque Area V4.

Attention to a location in a visual scene affects neuronal responses in visual cortical areas in a retinotopically specific manner. Optical imaging studies have revealed that cortical responses consist of two components of different sizes: the stimulus-nonspecific global signal and the stimulus-specific mapping signal (domain activity). It remains unclear whether either or both of these components are modulated by spatial attention. In this study, to determine the spatial distribution of attentional modulation at columnar resolution, we performed cerebral blood volume (CBV)-based optical imaging in area V4 of monkeys performing a color change detection task in which spatial attention was manipulated. We found that spatial attention enhanced global signals of the hemodynamic responses, but did not affect stimulus-selective domain activities. These results indicate the involvement of global signals in neural processing of spatial attention. We propose that global signals reflect the neural substrate of the normalization pool in normalization models of attention.

[Neuronal connections within the hand representation in areas 3b and 1 of the somatosensory cortex in primates]. / Neuronalis összeköttetések a szomatoszenzoros kérgi área 3b és área 1 kézreprezentációs területén foemlosökben.

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.

Microelectrode array stimulation combined with intrinsic optical imaging: A novel tool for functional brain mapping.

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.

An Orientation Map for Motion Boundaries in Macaque V2.

The ability to extract the shape of moving objects is fundamental to visual perception. However, where such computations are processed in the visual system is unknown. To address this question, we used intrinsic signal optical imaging in awake monkeys to examine cortical response to perceptual contours defined by motion contrast (motion boundaries, MBs). We found that MB stimuli elicit a robust orientation response in area V2. Orientation maps derived from subtraction of orthogonal MB stimuli aligned well with the orientation maps obtained with luminance gratings (LGs). In contrast, area V1 responded well to LGs, but exhibited a much weaker orientation response to MBs. We further show that V2 direction domains respond to motion contrast, which is required in the detection of MB in V2. These results suggest that V2 represents MB information, an important prerequisite for shape recognition and figure-ground segregation.

Specificity of V1-V2 orientation networks in the primate visual cortex.

The computation of texture and shape involves integration of features of various orientations. Orientation networks within V1 tend to involve cells which share similar orientation selectivity. However, emergent properties in V2 require the integration of multiple orientations. We now show that, unlike interactions within V1, V1-V2 orientation interactions are much less synchronized and are not necessarily orientation dependent. We find V1-V2 orientation networks are of two types: a more tightly synchronized, orientation-preserving network and a less synchronized orientation-diverse network. We suggest that such diversity of V1-V2 interactions underlies the spatial and functional integration required for computation of higher order contour and shape in V2.

Resolving the organization of the territory of the third visual area: a new proposal.

In primates, the cortex adjoining the rostral border of V2 has been variously interpreted as belonging to a single visual area, V3, with dorsal V3 (V3d) representing the lower visual quadrant and ventral V3 (V3v) representing the upper visual quadrant, V3d and V3v constituting separate, incomplete visual areas, V3d and ventral posterior (VP), or V3d being divided into several visual areas, including a dorsomedial (DM) visual area, a medial visual area (M), and dorsal extension of VP (or VLP). In our view, the evidence from V1 connections strongly supports the contention that V3v and V3d are parts of a single visual area, V3, and that DM is a separate visual area along the rostral border of V3d. In addition, the retinotopy revealed by V1 connection patterns, microelectrode mapping, optical imaging mapping, and functional magnetic resonance imaging (fmri) mapping indicates that much of the proposed territory of V3d corresponds to V3. Yet, other evidence from microelectrode mapping and anatomical connection patterns supports the possibility of an upper quadrant representation along the rostral border of the middle of dorsal V2 (V2d), interpreted as part of DM or DM plus DI, and along the midline end of V2d, interpreted as the visual area M. While the data supporting these different interpretations appear contradictory, they also seem, to some extent, valid. We suggest that V3d may have a gap in its middle, possibly representing part of the upper visual quadrant that is not part of DM. In addition, another visual area, M, is likely located at the DM tip of V3d. There is no evidence for a similar disruption of V3v. For the present, we favor continuing the traditional concept of V3 with the possible modification of a gap in V3d in at least some primates.

Optogenetic Activation of Normalization in Alert Macaque Visual Cortex.

Normalization has been proposed as a canonical computation that accounts for a variety of nonlinear neuronal response properties associated with sensory processing and higher cognitive functions. A key premise of normalization is that the excitability of a neuron is inversely proportional to the overall activity level of the network. We tested this by optogenetically activating excitatory neurons in alert macaque primary visual cortex and measuring changes in neuronal activity as a function of stimulation intensity, with or without variable-contrast visual stimulation. Optogenetic depolarization of excitatory neurons either facilitated or suppressed baseline activity, consistent with indirect recruitment of inhibitory networks. As predicted by the normalization model, neurons exhibited sub-additive responses to optogenetic and visual stimulation, which depended lawfully on stimulation intensity and luminance contrast. We conclude that the normalization computation persists even under the artificial conditions of optogenetic stimulation, underscoring the canonical nature of this form of neural computation.

Infrared neural stimulation of primary visual cortex in non-human primates.

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=1.875µm, fiber diameter=100-400µm) 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 100µm or 200µm 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 400µm 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.

Connectivity of somatosensory cortical area 1 forms an anatomical substrate for the emergence of multifinger receptive fields and complex feature selectivity in the squirrel monkey (Saimiri sciureus).

Converging evidence shows that interaction of digit-specific input, which is required to form global tactile percepts, begins as early as area 3b in the primary somatosensory cortex with the involvement of intrinsic lateral connections. How tactile processing is further elaborated in area 1, the next stage of the somatosensory cortical hierarchy, is less understood. This question was investigated by studying the tangential distribution of intrinsic and interareal connections of finger representations of area 1. Retrogradely labeled cell densities and anterogradely labeled fibers and terminal patches were plotted and quantified with respect to the hand representation by combining tract tracing with electrophysiological mapping and intrinsic signal optical imaging in somatosensory areas. Intrinsic connections of distal finger pad representations of area 1 spanned the representation of multiple digits indicating strong cross-digit connectivity. Area 1 distal finger pad regions also established high-density connections with homotopic regions of areas 3b and 2. Although similar to area 3b, connections of area 1 distributed more widely and covered a larger somatotopic representation including more proximal parts of the finger representations. The lateral connectivity pattern of area 1 is a suitable anatomical substrate of the emergence of multifinger receptive fields, complex feature selectivity, and invariant stimulus properties of the neurons.