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We review our recent behavioural and imaging studies testing the consequences of congenital blindness on the chemical senses in comparison with the condition of anosmia. We found that congenitally blind (CB) subjects have increased sensitivity for orthonasal odorants and recruit their visually deprived occipital cortex to process orthonasal olfactory stimuli. In sharp contrast, CB perform less well than sighted controls in taste and retronasal olfaction, i.e. when processing chemicals inside the mouth. Interestingly, CB do not recruit their occipital cortex to process taste stimuli. In contrast to these findings in blindness, congenital anosmia is associated with lower taste and trigeminal sensitivity, accompanied by weaker activations within the 'flavour network' upon exposure to such stimuli. We conclude that functional adaptations to congenital anosmia or blindness are quite distinct, such that CB can train their exteroceptive chemical senses and recruit normally visual cortical areas to process chemical information from the surrounding environment.

Cannabinoids exert their actions mainly through two receptors, the cannabinoid CB1 receptor (CB1R) and cannabinoid CB2 receptor (CB2R). In recent years, the G-protein coupled receptor 55 (GPR55) was suggested as a cannabinoid receptor based on its activation by anandamide and tetrahydrocannabinol. Yet, its formal classification is still a matter of debate. CB1R and CB2R expression patterns are well described for rodent and monkey retinas. In the monkey retina, CB1R has been localized in its neural (cone photoreceptor, horizontal, bipolar, amacrine and ganglion cells) and CB2R in glial components (Müller cells). The aim of this study was to determine the expression pattern of GPR55 in the monkey retina by using confocal microscopy. Our results show that GPR55 is strictly localized in the photoreceptor layer of the extrafoveal portion of the retina. Co-immunolabeling of GPR55 with rhodopsin, the photosensitive pigment in rods, revealed a clear overlap of expression throughout the rod structure with most prominent staining in the inner segments. Additionally, double-label of GPR55 with calbindin, a specific marker for cone photoreceptors in the primate retina, allowed us to exclude expression of GPR55 in cones. The labeling of GPR55 in rods was further assessed with a 3D visualization in the XZ and YZ planes thus confirming its exclusive expression in rods. These results provide data on the distribution of GPR55 in the monkey retina, different than CB1R and CB2R. The presence of GPR55 in rods suggests a function of this receptor in scotopic vision that needs to be demonstrated.

Vision is important for avoiding encounters with objects in the environment that may imperil physical integrity. We tested whether, in the absence of vision, a lower pain threshold would arise from an adaptive shift to other sensory channels. We therefore measured heat and cold pain thresholds and responses to suprathreshold heat stimuli in 2 groups of congenitally blind and matched normal-sighted participants. We also assessed detection thresholds for innocuous warmth and cold, and participants' attitude toward painful encounters in daily life. Our results show that, compared to sighted subjects, congenitally blind subjects have lower heat pain thresholds, rate suprathreshold heat pain stimuli as more painful, and have increased sensitivity for cold pain stimuli. Thresholds for nonpainful thermal stimulation did not differ between groups. The results of the pain questionnaires further indicated that blind subjects are more attentive to signals of external threats. These findings indicate that the absence of vision from birth induces a hypersensitivity to painful stimuli, lending new support to a model of sensory integration of vision and pain processing., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

The ActiveAx technique fits the minimal model of white matter diffusion to diffusion MRI data acquired using optimized protocols that provide orientationally invariant indices of axon diameter and density. We investigated how limitations of the available maximal gradient strength (Gmax) on a scanner influence the sensitivity to a range of axon diameters. Multishell high-angular-diffusion-imaging (HARDI) protocols for Gmax of 60, 140, 200, and 300 mT/m were optimized for the pulsed-gradient-spin-echo (PGSE) sequence. Data were acquired on a fixed monkey brain and Monte-Carlo simulations supported the results. Increasing Gmax reduces within-voxel variation of the axon diameter index and improves contrast beyond what is achievable with higher signal-to-noise ratio. Simulations reveal an upper bound on the axon diameter (∼10 μm) that pulsed-gradient-spin-echo measurements are sensitive to, due to a trade-off between short T2 and the long diffusion time needed to probe larger axon diameters. A lower bound (∼2.5 μm) slightly dependent on Gmax was evident, below which axon diameters are identifiable as small, but impossible to differentiate. These results emphasize the key-role of Gmax for enhancing contrast between axon diameter distributions and are, therefore, relevant in general for microstructure imaging methods and highlight the need for increased Gmax on future commercial systems., (Copyright © 2012 Wiley Periodicals, Inc.)

Navigation of retinal projections towards their targets is regulated by guidance molecules and growth cone transduction mechanisms. Here, we present in vitro and in vivo evidences that the cannabinoid receptor 2 (CB2R) is expressed along the retino-thalamic pathway and exerts a modulatory action on axon guidance. These effects are specific to CB2R since no changes were observed in mice where the gene coding for this receptor was altered (cnr2 (-/-)). The CB2R induced morphological changes observed at the growth cone are PKA dependent and require the presence of the netrin-1 receptor, Deleted in Colorectal Cancer. Interfering with endogenous CB2R signalling using pharmacological agents increased retinal axon length and induced aberrant projections. Additionally, cnr2 (-/-) mice showed abnormal eye-specific segregation of retinal projections in the dorsal lateral geniculate nucleus (dLGN) indicating CB2R's implication in retinothalamic development. Overall, this study demonstrates that the contribution of endocannabinoids to brain development is not solely mediated by CB1R, but also involves CB2R.

Cross-modal activity in visual cortex of blind subjects has been reported during performance of variety of non-visual tasks. A key unanswered question is through which pathways non-visual inputs are funneled to the visual cortex. Here we used tomographic analysis of single trial magnetoencephalography (MEG) data recorded from one congenitally blind and two sighted subjects after stimulation of the left and right median nerves at three intensities: below sensory threshold, above sensory threshold and above motor threshold; the last sufficient to produce thumb twitching. We identified reproducible brain responses in the primary somatosensory (S1) and motor (M1) cortices at around 20 ms post-stimulus, which were very similar in sighted and blind subjects. Time-frequency analysis revealed strong 45-70 Hz activity at latencies of 20-50 ms in S1 and M1, and posterior parietal cortex Brodmann areas (BA) 7 and 40, which compared to lower frequencies, were substantially more pronounced in the blind than the sighted subjects. Critically, at frequencies from α-band up to 100 Hz we found clear, strong, and widespread responses in the visual cortex of the blind subject, which increased with the intensity of the somatosensory stimuli. Time-delayed mutual information (MI) revealed that in blind subject the stimulus information is funneled from the early somatosensory to visual cortex through posterior parietal BA 7 and 40, projecting first to visual areas V5 and V3, and eventually V1. The flow of information through this pathway occurred in stages characterized by convergence of activations into specific cortical regions. In sighted subjects, no linked activity was found that led from the somatosensory to the visual cortex through any of the studied brain regions. These results provide the first evidence from MEG that in blind subjects, tactile information is routed from primary somatosensory to occipital cortex via the posterior parietal cortex.

The presence of the cannabinoid receptor type 1 (CB1R) has been largely documented in the rodent and primate retinae in recent years. There is, however, some controversy concerning the presence of the CB2 receptor (CB2R) within the central nervous system. Only recently, CB2R has been found in the rodent retina, but its presence in the primate retina has not yet been demonstrated. The aim of this study was twofold: 1) to characterize the distribution patterns of CB2R in the monkey retina and compare this distribution with that previously reported for CB1R and 2) to resolve the controversy on the presence of CB2R in the neural component of the retina. We therefore thoroughly examined the cellular localization of CB2R in the vervet monkey (Chlorocebus sabeus) retina, using confocal microscopy. Our results demonstrate that CB2R, like CB1R, is present throughout the retinal layers, but with striking dissimilarities. Double labeling of CB2R and glutamine synthetase shows that CB2R is restricted to Müller cell processes, extending from the internal limiting membrane, with very low staining, to the external limiting membrane, with heavy labeling. We conclude that CB2R is indeed present in the retina but exclusively in the retinal glia, whereas CB1R is expressed only in the neuroretina. These results extend our knowledge on the expression and distribution of cannabinoid receptors in the monkey retina, although further experiments are still needed to clarify their role in retinal functions., (Copyright © 2013 Wiley Periodicals, Inc.)

Sight is undoubtedly not only important for food identification and selection but also for the modulation of gustatory sensitivity. We can, therefore, assume that taste sensitivity and eating habits are affected by visual deprivation from birth. We measured taste detection and identification thresholds of the 5 basic tastants in 13 congenitally blind and 13 sighted control subjects. Participants also answered several eating habits questionnaires, including the Food Neophobia Scale, the Food Variety Seeking Tendency Scale, the Intuitive Eating Scale, and the Body Awareness Questionnaire. Our behavioral results showed that compared with the normal sighted, blind subjects have increased thresholds for taste detection and taste identification. This finding is at odds with the superior performance of congenitally blind subjects in several tactile, auditory and olfactory tasks. Our psychometric data further indicate that blind subjects more strongly rely on internal hunger and satiety cues, instead of external contextual or emotional cues, to decide when and what to eat. We suggest that the lower taste sensitivity observed in congenitally blind individuals is due to various blindness-related obstacles when shopping for food, cooking and eating out, all of which contribute to underexpose the gustatory system to a larger variety of taste stimuli.

Despite their lack of vision, congenitally blind subjects are able to build and manipulate cognitive maps for spatial navigation. It is assumed that they thereby rely more heavily on echolocation, proprioceptive signals and environmental cues such as ambient temperature and audition to compensate for their lack of vision. Little is known, however, about the neural mechanisms underlying spatial navigation in blind individuals in settings where these cues are absent. We therefore measured behavioural performance and blood oxygenation-level dependant (BOLD) responses using functional magnetic resonance imaging (fMRI) in congenitally blind and blindfolded sighted participants while they navigated through a tactile multiple T-maze. Both groups learned the maze task at a similar pace. In blind participants, tactile maze navigation was associated with increased BOLD responses in the right hippocampus and parahippocampus, occipital cortex and fusiform gyrus. Blindfolded sighted controls did not show increased BOLD responses in these areas; instead they activated the caudate nucleus and thalamus. Both groups activated the precuneus during tactile maze navigation. We conclude that cross-modal plastic processes allow for the recruitment of the hippocampal complex and visual cortex in congenital blindness., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We used functional MRI (fMRI) to test the hypothesis that blind subjects recruit the ventral visual stream during nonhaptic tactile-form recognition. Congenitally blind and blindfolded sighted control subjects were scanned after they had been trained during four consecutive days to perform a tactile-form recognition task with the tongue display unit (TDU). Both groups learned the task at the same rate. In line with our hypothesis, the fMRI data showed that during nonhaptic shape recognition, blind subjects activated large portions of the ventral visual stream, including the cuneus, precuneus, inferotemporal (IT), cortex, lateral occipital tactile vision area (LOtv), and fusiform gyrus. Control subjects activated area LOtv and precuneus but not cuneus, IT and fusiform gyrus. These results indicate that congenitally blind subjects recruit key regions in the ventral visual pathway during nonhaptic tactile shape discrimination. The activation of LOtv by nonhaptic tactile shape processing in blind and sighted subjects adds further support to the notion that this area subserves an abstract or supramodal representation of shape. Together with our previous findings, our data suggest that the segregation of the efferent projections of the primary visual cortex into a dorsal and ventral visual stream is preserved in individuals blind from birth.

Behavioural recovery in children who undergo medically required hemispherectomy showcase the remarkable ability of the cerebral cortex to adapt and reorganize following insult early in life. Case study data suggest that lesions sustained early in childhood lead to better recovery compared to those that occur later in life. In these children, it is possible that neural reorganization had begun prior to surgery but was masked by the dysfunctional hemisphere. The degree of neural reorganization has been difficult to study systematically in human infants. Here we present a 20-year culmination of data on our nonhuman primate model (Chlorocebus sabeus) of early-life hemispherectomy in which behavioral recovery is interpreted in light of plastic processes that lead to the anatomical reorganization of the early-damaged brain. The model presented here suggests that significant functional recovery occurs after the removal of one hemisphere in monkeys with no preexisting neurological dysfunctions. Human and primate studies suggest a critical role for subcortical and brainstem structures as well as corticospinal tracts in the neuroanatomical reorganization which result in the remarkable behavioral recovery following hemispherectomy. The non-human primate model presented here offers a unique opportunity for studying the behavioral and functional neuroanatomical reorganization that underlies developmental plasticity.

Early loss of a given sensory input in mammals causes anatomical and functional modifications in the brain via a process called cross-modal plasticity. In the past four decades, several animal models have illuminated our understanding of the biological substrates involved in cross-modal plasticity. Progressively, studies are now starting to emphasise on cell-specific mechanisms that may be responsible for this intermodal sensory plasticity. Inhibitory interneurons expressing γ-aminobutyric acid (GABA) play an important role in maintaining the appropriate dynamic range of cortical excitation, in critical periods of developmental plasticity, in receptive field refinement, and in treatment of sensory information reaching the cerebral cortex. The diverse interneuron population is very sensitive to sensory experience during development. GABAergic neurons are therefore well suited to act as a gate for mediating cross-modal plasticity. This paper attempts to highlight the links between early sensory deprivation, cortical GABAergic interneuron alterations, and cross-modal plasticity, discuss its implications, and further provide insights for future research in the field.

During object manipulation the brain integrates the visual, auditory, and haptic experience of an object into a unified percept. Previous brain imaging studies have implicated for instance the dorsal part of the lateral occipital complex in visuo-tactile and the posterior superior temporal sulcus in audio-visual integration of object-related inputs (Amedi et al., 2005). Yet it is still unclear which brain regions represent object-specific information of all three sensory modalities. To address this question, we performed two complementary functional magnetic resonance imaging experiments. In the first experiment, we identified brain regions which were consistently activated by unimodal visual, auditory, and haptic processing of manipulable objects relative to non-object control stimuli presented in the same modality. In the second experiment, we assessed regional brain activations when participants had to match object-related information that was presented simultaneously in two or all three modalities. Only a well-defined region in left fusiform gyrus (FG) showed an object-specific activation during unisensory processing in the visual, auditory, and tactile modalities. The same region was also consistently activated during multisensory matching of object-related information across all three senses. Taken together, our results suggest that this region is central to the recognition of manipulable objects. A putative role of this FG region is to unify object-specific information provided by the visual, auditory, and tactile modalities into trisensory object representations., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Diffusion anisotropy monitored with diffusion-weighted magnetic resonance imaging (DWMRI) is a sensitive marker to monitor developmental or pathological microstructural changes in spinal cord. The white matter is often treated as a unidirectional axonal bundle but collateral fibers branching off the main spinal pathways contradicts this assumption and affects the diffusion anisotropy. It is the aim of this study to investigate to what extent collateral fibers are apparent in diffusion tensor data and if collaterals can be detected as individual fiber directions using crossing fiber detection techniques. We calculate the diffusion tensor and the persistent angular structure (PAS), a multi-fiber reconstruction technique, from high quality post mortem data of a perfusion-fixed vervet monkey cervical spinal cord sample and simulated crossing fiber data. Our results show that (i) cylindrical geometry in the white matter of the spinal cord is an invalid assumption due to collateral fibers. We also demonstrate that (ii) collateral fibers can be resolved as distinct peaks in the water diffusion propagator in white matter using multi-fiber models. Finally, we show that (iii) crossing fibers are mainly located laterally and increase towards the cervical enlargement., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Vision allows for obstacle detection and avoidance. The compensatory mechanisms involved in maintaining these functions in blind people using their remaining intact senses are poorly understood. We investigated the ability of congenitally blind participants to detect and avoid obstacles using the tongue display unit, a sensory substitution device that uses the tongue as a portal to the brain. We found that congenitally blind were better than sighted control participants in detecting and avoiding obstacles using the tongue display unit. Obstacles size and avoidance strategy had a significant effect on performance: large obstacles were better detected than small ones and step-around obstacles were better avoided than step-over ones. These data extend our earlier findings that when using a sensory substitution device, blind participants outperform sighted controls not only in a virtual navigation task but also during effective navigation within a human-sized obstacle course.

It is generally acknowledged that people blind from birth develop supra-normal sensory abilities in order to compensate for their visual deficit. While extensive research has been done on the somatosensory and auditory modalities of the blind, information about their sense of smell remains scant. The goal of this study was therefore to compare odor perception and odor awareness in a group of 11 congenitally blind and 14 sighted control subjects. We measured odor detection threshold, odor discrimination and odor identification using the Sniffin'Sticks test. Participants also filled in the Odor Awareness Scale (OAS) to assess consciousness of olfactory sensations. Our data showed that blind subjects had a lower odor detection threshold compared to the sighted. However, no group differences were found for odor discrimination and odor identification. Interestingly, the OAS revealed that blind participants scored higher for odor awareness. The largest group differences were found for items of the OAS that measure responses to body odors and fragrances. We conclude that blind subjects rely more on their sense of smell than the sighted in order to assess their environment and to recognize places and other people., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Vision plays a central role in how we represent and interact with the world around us. The primacy of vision is structurally imbedded in cortical organization as about one-third of the cortical surface in primates is involved in visual processes. Consequently, the loss of vision, either at birth or later in life, affects brain organization and the way the world is perceived and acted upon. In this paper, we address a number of issues on the nature of consciousness in people deprived of vision. Do brains from sighted and blind individuals differ, and how? How does the brain of someone who has never had any visual perception form an image of the external world? What is the subjective correlate of activity in the visual cortex of a subject who has never seen in life? More in general, what can we learn about the functional development of the human brain in physiological conditions by studying blindness? We discuss findings from animal research as well from recent psychophysical and functional brain imaging studies in sighted and blind individuals that shed some new light on the answers to these questions.

Vision plays a central role in how we represent and interact with the world around us. Roughly, one-third of the cortical surface in primates is involved in visual processes. The loss of vision, either at birth or later in life, must therefore have profound consequences on brain organization and on the way the world is perceived and acted upon. In this chapter, we formulate a number of critical questions. Do blind individuals indeed develop supra-normal capacities for the remaining senses in order to compensate for their loss of vision? Do brains from sighted and blind individuals differ, and how? How does the brain of someone who has never had any visual perception form an image of the external world? We discuss findings from animal research as well from recent psychophysical and functional brain imaging studies in sighted and blind individuals that shed some new light on the answers to these questions., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Vision is undoubtedly important for navigation although not essential as blind individuals outperform their blindfolded seeing counterparts in a variety of navigational tasks. It is believed that the blind's superior performance is because of their efficient use of proprioceptive signals and environmental cues such as temperature and echolocation. We hypothesize that by limiting these cues, blind individuals will lose their advantage compared with controls in spatial navigation tasks. We therefore evaluated the performance of blind and sighted individuals in small-scale, tactile multiple T mazes. Our results show that blindfolded sighted controls outperformed blind participants in the route-learning tasks. This suggests that, contrary to indoor large-scale spaces, navigational skills inside small-scale spaces benefit from visual experience.

This paper proposes and tests a technique for imaging orientationally invariant indices of axon diameter and density in white matter using diffusion magnetic resonance imaging. Such indices potentially provide more specific markers of white matter microstructure than standard indices from diffusion tensor imaging. Orientational invariance allows for combination with tractography and presents new opportunities for mapping brain connectivity and quantifying disease processes. The technique uses a four-compartment tissue model combined with an optimized multishell high-angular-resolution pulsed-gradient-spin-echo acquisition. We test the method in simulation, on fixed monkey brains using a preclinical scanner and on live human brains using a clinical 3T scanner. The human data take about one hour to acquire. The simulation experiments show that both monkey and human protocols distinguish distributions of axon diameters that occur naturally in white matter. We compare the axon diameter index with the mean axon diameter weighted by axon volume. The index differs from this mean and is protocol dependent, but correlation is good for the monkey protocol and weaker, but discernible, for the human protocol where greater diffusivity and lower gradient strength limit sensitivity to only the largest axons. Maps of axon diameter and density indices from the monkey and human data in the corpus callosum and corticospinal tract reflect known trends from histology. The results show orientationally invariant sensitivity to natural axon diameter distributions for the first time with both specialist and clinical hardware. This demonstration motivates further refinement, validation, and evaluation of the precise nature of the indices and the influence of potential confounds., (Copyright 2010 Elsevier Inc. All rights reserved.)

Visual impairment is commonly reported as a consequence of heavy prenatal ethanol exposure in humans. Children generally display characteristic cranio-facial dysmorphology and represent typical severe cases of foetal alcohol syndrome. Binge-like rodent model systems have concluded that third trimester equivalent ethanol exposure results in widespread apoptosis in the visual system from the retina to the visual cortex. Neither clinical nor animal studies address the consequences of more moderate prenatal ethanol exposure on the visual system. The current study uses a naturalistic and voluntary consumption approach in non-human primates (Chlorocebus sabeus) in order to more closely model prenatal ethanol consumption patterns in humans. Pregnant vervet monkeys voluntarily drank on average 2.418 +/- 0.296 g etoh/kg/day four times a week during the third trimester. Using unbiased stereology, we estimated the neuronal and glial population of the parvocellular (P) and magnocellular (M) layers of the lateral geniculate nucleus (LGN) following foetal alcohol exposure (FAE) in infant subjects. Layer volume and total number of neurons and glia in the LGN of the FAE subjects were not significantly different from age-matched control subjects. The M neuronal soma size of FAE subjects, however, was significantly reduced to resemble the size of the P-neurons. These results suggest that alterations at the level of morphology and anatomy of the M-neurons may lead to behavioural deficits associated with the integrity of the dorsal visual pathway.

The motion-sensitive middle temporal cortex (hMT+ complex) responds also to non-visual motion stimulation conveyed through the tactile and auditory modalities, both in sighted and in congenitally blind individuals. This indicates that hMT+ is truly responsive to motion-related information regardless of visual experience and the sensory modality through which such information is carried to the brain. Here we determined whether the hMT+ complex responds to motion perception per se, that is, motion not perceived through the visual, haptic or aural modalities. Using functional magnetic resonance imaging (fMRI), we investigated brain responses in eight congenitally blind and nine sighted volunteers who had been trained to use the tongue display unit (TDU), a sensory substitution device which converts visual information into electrotactile pulses delivered to the tongue, to resolve a tactile motion discrimination task. Stimuli consisted of either static dots, dots moving coherently or dots moving in random directions. Both groups learned the task at the same rate and activated the hMT+ complex during tactile motion discrimination, although at different anatomical locations. Furthermore, the congenitally blind subjects showed additional activations within the dorsal extrastriate cortical pathway. These results extend previous data in support of the supramodal functional organization of hMT+ complex by showing that this cortical area processes motion-related information per se, that is, motion stimuli that are not visual in nature and that are administered to body structures that, in humans, are not primarily devoted to movement perception or spatial location, such as the tongue. In line with previous studies, the differential activations between sighted and congenitally blind individuals indicate that lack of vision leads to functional rearrangements of these supramodal cortical areas., (Copyright 2010 Elsevier Inc. All rights reserved.)

Despite the importance of vision for spatial navigation, blind subjects retain the ability to represent spatial information and to move independently in space to localize and reach targets. However, the neural correlates of navigation in subjects lacking vision remain elusive. We therefore used functional MRI (fMRI) to explore the cortical network underlying successful navigation in blind subjects. We first trained congenitally blind and blindfolded sighted control subjects to perform a virtual navigation task with the tongue display unit (TDU), a tactile-to-vision sensory substitution device that translates a visual image into electrotactile stimulation applied to the tongue. After training, participants repeated the navigation task during fMRI. Although both groups successfully learned to use the TDU in the virtual navigation task, the brain activation patterns showed substantial differences. Blind but not blindfolded sighted control subjects activated the parahippocampus and visual cortex during navigation, areas that are recruited during topographical learning and spatial representation in sighted subjects. When the navigation task was performed under full vision in a second group of sighted participants, the activation pattern strongly resembled the one obtained in the blind when using the TDU. This suggests that in the absence of vision, cross-modal plasticity permits the recruitment of the same cortical network used for spatial navigation tasks in sighted subjects.

Hemiparesis, unilateral weakness or partial paralysis, is a common outcome following hemispherectomy in humans. We use the non-human primate as an invaluable translational model for our understanding of developmental plasticity in response to hemispherectomy. Three infant vervet monkeys (Chlorocebus sabeus) underwent hemispherectomy at a median age of 9 weeks and two additional monkeys at 48 months. Gross motor assessment was conducted in a large open field that contained a horizontal bar spanning the width of the cage. Subjects were assessed yearly following surgery in infantile lesions for a period of 3 years. Adult-lesioned subjects were assessed 40 months following surgery. Shortly after surgery both infant and adult-lesioned subjects were unable to move the contralateral side of their body, but all subjects were able to walk within 6 months following surgery. At each time point the lower limb gait was normal in infant-lesioned subjects with no apparent limp or dragging, however the upper limb demonstrated significant impairment. Horizontal bar crossing was significantly impaired during the first 24 months following surgery. Adult-lesioned subjects also displayed upper limb movement impairments similar to infant-lesioned subjects. In addition the adult-lesioned subjects displayed a noticeable lower limb limp, which was not observed in the infant-lesioned group. Both groups at each time point showed a propensity for ipsiversive turning. The upper limb gait impairment and horizontal bar crossing of lesioned subjects are reminiscent of hemiparesis seen in hemisperectomized humans with the young-lesioned subjects showing a greater propensity for recovery., ((c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Primary Objective: Olfactory functions are not systematically evaluated following traumatic brain injury (TBI). This study aimed at comparing two smell tests that are used in a clinical setting., Research Design: The University of Pennsylvania Smell Identification Test (UPSIT) and the Alberta Smell Test were compared in terms of assessment time, cost and diagnosis. Parameters associated with olfactory loss such as injury severity, type of cerebral lesion and depressive data were considered. Forty-nine TBI patients admitted to an outpatient rehabilitation programme took part in this experiment., Results: The scores of the two smell tests were significantly correlated. Both tests indicated that patients with frontal lesion performed significantly worse than patients with other types of lesion. Mood and injury severity were not associated with olfactory impairment when age was taken into account. Between 40-44% of the patients showing olfactory impairments were not aware of their deficit., Conclusions: Since a significant proportion of the patients showing olfactory impairments were not aware of their deficit, it is recommended than clinicians systematically evaluate olfactory functions using the Alberta Smell test. To refine their diagnosis, the UPSIT can also be used.

Immunohistochemistry (IHC) is one of the most widely used laboratory techniques for the detection of target proteins in situ. Questions concerning the expression pattern of a target protein across the entire brain are relatively easy to answer when using IHC in small brains, such as those of rodents. However, answering the same questions in large and convoluted brains, such as those of primates presents a number of challenges. Here we present a systematic approach for immunodetection of target proteins in an adult monkey brain. This approach relies on the tissue embedding and sectioning methodology of NeuroScience Associates (NSA) as well as tools developed specifically for batch-staining of free-floating sections. It results in uniform staining of a set of sections which, at a particular interval, represents the entire brain. The resulting stained sections can be subjected to a wide variety of analytical procedures in order to measure protein levels, the population of neurons expressing a certain protein.

Unbiased stereology is a method for accurately and efficiently estimating the total neuron number (or other cell type) in a given area of interest(1). To achieve this goal 6-10 systematic sections should be probed covering the entire structure. Typically this involves processing 1/5 sections which leaves a significant amount of material unprocessed. In order to maximize the material, we propose an inexpensive method for preserving fixed tissue as part of a long-term storage research plan. As tissue is sliced and processed for the desired stain or antibody, alternate sections should be systematically placed in antigen preserve at -20 degrees C for future processing. Using 24-well plates, sections can be placed in order for future retrieval. Using this method, tissue can be stored and processed for immunohistochemistry over the course of years.

The use of non-human primates provides an excellent translational model for our understanding of developmental and aging processes in humans(1-6). In addition, the use of non-human primates has recently afforded the opportunity to naturally model complex psychiatric disorders such as alcohol abuse(7). Here we describe a technique for blocking the brain in the coronal plane of the vervet monkey (Chlorocebus aethiops sabeus) in the intact skull in stereotaxic space. The method described here provides a standard plane of section between blocks and subjects and minimizes partial sections between blocks. Sectioning a block of tissue in the coronal plane also facilitates the delineation of an area of interest. This method provides manageable sized blocks since a single hemisphere of the vervet monkey yields more than 1200 sections when slicing at 50 microm. Furthermore by blocking the brain into 1cm blocks, it facilitates penetration of sucrose for cyroprotection and allows the block to be sliced on a standard cryostat.

The visual system in humans is considered the gateway to the world and plays a principal role in the plethora of sensory, perceptual and cognitive processes. It is therefore not surprising that quality of vision is tied to quality of life . Despite widespread clinical and basic research surrounding the causes of visual disorders, many forms of visual impairments, such as retinitis pigmentosa and macular degeneration, lack effective treatments. Non-human primates have the closest general features of eye development to that of humans. Not only do they have a similar vascular anatomy, but amongst other mammals, primates have the unique characteristic of having a region in the temporal retina specialized for high visual acuity, the fovea(1). Here we describe a general technique for dissecting the primate retina to provide tissue for retinal histology, immunohistochemistry, laser capture microdissection, as well as light and electron microscopy. With the extended use of the non-human primate as a translational model, our hope is that improved understanding of the retina will provide insights into effective approaches towards attenuating or reversing the negative impact of visual disorders on the quality of life of affected individuals.

The non-human primate is an important translational species for understanding the normal function and disease processes of the human brain. Unbiased stereology, the method accepted as state-of-the-art for quantification of biological objects in tissue sections, generates reliable structural data for biological features in the mammalian brain. The key components of the approach are unbiased (systematic-random) sampling of anatomically defined structures (reference spaces), combined with quantification of cell numbers and size, fiber and capillary lengths, surface areas, regional volumes and spatial distributions of biological objects within the reference space. Among the advantages of these stereological approaches over previous methods is the avoidance of all known sources of systematic (non-random) error arising from faulty assumptions and non-verifiable models. This study documents a biological application of computerized stereology to estimate the total neuronal population in the frontal cortex of the vervet monkey brain (Chlorocebus aethiops sabeus), with assistance from two commercially available stereology programs, BioQuant Life Sciences and Stereologer (Figure 1). In addition to contrast and comparison of results from both the BioQuant and Stereologer systems, this study provides a detailed protocol for the Stereologer system.

We used positron emission tomography to investigate whether tactile motion discrimination activates the dorsal visual stream in congenitally blind (CB) participants compared with sighted controls. The tactile stimuli consisted of either static dots, dots moving coherently in one of two possible directions, or in random directions. Although CB and sighted controls performed equally well on the motion discrimination task, only CB showed increased activation in the right middle temporal area. In addition, CB also activated other visual areas including the cuneus and extrastriate area V3. These results indicate that the dorsal visual pathway is activated by tactile motion stimuli in CB, therefore providing additional support for the cross-modal plasticity hypothesis.

Children with fetal alcohol spectrum disorders (FASD) show behavioral and intellectual impairments that indicate frontal lobe dysfunction, but the extent of damage to this region has not been clarified by brain imaging studies. This study uses the St Kitts vervet monkey, a species that voluntarily consumes beverage alcohol, to examine the effects of prenatal ethanol exposure. Pregnant vervets were allowed to drink the equivalent of 3-5 standard drinks four times a week during the third trimester. Using unbiased stereology, we estimated neuronal reduction and found significantly fewer cells in the frontal lobes of FASD offspring as well as an increased density of interstitial white matter neurons. These cytoarchitectonic effects are consistent with the behavioral and cognitive changes observed in FASD.

During development, retinal ganglion cells (RGCs) extend their axons toward their thalamic and mesencephalic targets. Their navigation is largely directed by guidance cues present in their environment. Since cAMP is an important second messenger that mediates the neural response to guidance molecules and its intracellular levels seem to decrease significantly following birth, we tested whether modulation of the cAMP/protein kinase A (PKA) pathway would affect the normal development of RGC axons. At postnatal day 1, hamsters received a unilateral intraocular injection of either 0.9% saline solution, 12 mM of the membrane-permeable cAMP analogue (dibutyryl cAMP; db-cAMP), or 10 microM of the PKA inhibitor KT5720. Intraocular elevation of cAMP significantly accelerated RGC axonal growth while inhibition of PKA activity decreased it. Moreover, when highly purified RGC cultures were treated with forskolin (an activator of adenylate cyclase) or cAMP analogues (db-cAMP and Sp-cAMP), neurite length, growth cone (GC) surface area and GC filopodia number were significantly increased. This indicates that intraocular elevation of cAMP acts directly on RGCs. Since these effects were prevented by PKA inhibitors, it demonstrates that cAMP also exerts its action via the PKA pathway. Taken together, these results suggest that the cAMP/PKA cascade is essential for the normal development of retinothalamic projections.

We used whole brain MRI voxel-based morphometry (VBM) to study the anatomical organization of the visual system in congenitally blind (CB) adults. Eleven CB without a history of visual perception were compared with 21 age- and sex-matched normal-sighted controls (NS). CB showed significant atrophy of the geniculo-striate system, encompassing the optic nerves, the optic chiasm, the optic radiations and the primary visual cortex (BA17). The volume decrease in BA17 reached 25% in both hemispheres. The pulvinar and its projections to the associative visual areas were also dramatically altered, BA18/19 and the middle temporal cortex (MT) showing volume reductions of up to 20%. Additional significant white matter alterations were observed in the inferior longitudinal tract and in the posterior part of the corpus callosum, which links the visual areas of both hemispheres. Our data indicate that the afferent projections to the visual cortex in CB are largely atrophied. Despite the massive volume reductions in the occipital lobes, there is compelling evidence from the literature (reviewed in Noppeney 2007; Ptito and Kupers 2005) that blind subjects activate their visual cortex when performing tasks that involve somatosensory or auditory inputs, suggesting a reorganization of the neural pathways that transmit sensory information to the visual cortex.

In cats, it is generally believed that the visual part of the anterior ectosylvian cortex (AEV) is involved in motion integration. It receives a substantial proportion of its afferents from cortical (e.g. lateral suprasylvian cortex) and subcortical (e.g. lateral posterior-pulvinar complex) areas known to participate in complex motion analysis. It has been established that a subset of AEV neurons can code the veridical motion of a moving plaid pattern (pattern-motion selectivity). In our study, we have further investigated the possibility that AEV neurons may play a role in higher-order motion processing by studying their responses to complex stimuli which necessitate higher order spatial and temporal integration. Experiments were performed in anesthetized adult cats. Classical receptive fields were stimulated with (1) complex random-dot kinematograms (RDKs), where the individual elements of the pattern do not provide coherent motion cues; (2) optic flow fields which require global spatial integration. We report that a large proportion of AEV neurons were selective to the direction and speed of RDKs. Close to two-thirds of the cells were selective to the direction of optic flow fields with about equal proportions being selective to contraction and expansion. The complex RDK and optic flow responsive units could not be systematically characterized based on their responses to plaid patterns; they were either pattern- or component-motion selective. These findings support the proposal that AEV is involved in higher-order motion processing. Our data suggest that the AEV may be more involved in the analysis of motion of visual patterns in relation to the animal's behavior rather than the analysis of the constituents of the patterns.

Various non-visual inputs produce cross-modal responses in the visual cortex of early blind subjects. In order to determine the qualitative experience associated with these occipital activations, we systematically stimulated the entire occipital cortex using single pulse transcranial magnetic stimulation (TMS) in early blind subjects and in blindfolded seeing controls. Whereas blindfolded seeing controls reported only phosphenes following occipital cortex stimulation, some of the blind subjects reported tactile sensations in the fingers that were somatotopically organized onto the visual cortex. The number of cortical sites inducing tactile sensations appeared to be related to the number of hours of Braille reading per day, Braille reading speed and dexterity. These data, taken in conjunction with previous anatomical, behavioural and functional imaging results, suggest the presence of a polysynaptic cortical pathway between the somatosensory cortex and the visual cortex in early blind subjects. These results also add new evidence that the activity of the occipital lobe in the blind takes its qualitative expression from the character of its new input source, therefore supporting the cortical deference hypothesis.

This study compares the 'tactile-visual' acuity of the tongue for 15 early blind participants with that of 24 age-matched and sex-matched sighted controls. Snellen's tumbling E test was used to assess 'visual' acuity using the tongue display unit. The tongue display unit is a sensory substitution device that converts a visual stimulus grabbed by a camera into electro-tactile pulses delivered to the tongue via a grid made out of electrodes. No overall significant difference was found in thresholds between early blind (1/206) and sighted control (1/237) participants. We found, however, a larger proportion of early blind in the two highest visual acuity categories (1/150 and 1/90). These results extend earlier findings that it is possible to measure visual acuity in the blind individuals using the tongue. Moreover, our data demonstrate that a subgroup of early blind participants is more efficient than controls in conveying visual information through the tongue.

This study compares hippocampal volumes of early blind and sex/age-matched sighted controls through volumetric and localization analyses. Early blind individuals showed a significantly smaller right posterior hippocampus compared with controls. No differences in total hippocampal volumes were found between groups and there were no within-group differences for left versus right hippocampus. Sex, age and total brain grey matter volume had no effect on hippocampal volumes. Although extensive navigational training results in structural enhancement of the hippocampus for the sighted, the reduction of the posterior hippocampus in early blind individuals suggests the implication of this region in visual spatial memory.

To study the functional involvement of the visual cortex in Braille reading, we applied repetitive transcranial magnetic stimulation (rTMS) over midoccipital (MOC) and primary somatosensory (SI) cortex in blind subjects. After rTMS of MOC, but not SI, subjects made significantly more errors and showed an abolishment of the improvement in reading speed following repetitive presentation of the same word list, suggesting a role of the visual cortex in repetition priming in the blind.

In the cat, the analysis of visual motion cues has generally been attributed to the posteromedial lateral suprasylvian cortex (PMLS) (Toyama et al., 1985; Rauschecker et al., 1987; Rauschecker, 1988; Kim et al., 1997). The responses of neurons in this area are not critically dependent on inputs from the primary visual cortex (VC), as lesions of VC leave neuronal response properties in PMLS relatively unchanged (Spear & Baumann, 1979; Spear, 1988; Guido et al., 1990b). However, previous studies have used a limited range of visual stimuli. In this study, we assessed whether neurons in PMLS cortex remained direction-selective to complex motion stimuli following a lesion of VC, particularly to complex random dot kinematograms (RDKs). Unilateral aspiration of VC was performed on post-natal days 7-9. Single unit extracellular recordings were performed one year later in the ipsilateral PMLS cortex. As in previous studies, a reduction in the percentage of direction selective neurons was observed with drifting sinewave gratings. We report a previously unobserved phenomenon with sinewave gratings, in which there is a greater modulation of firing rate at the temporal frequency of the stimulus in animals with a lesion of VC, suggesting an increased segregation of ON and OFF sub-regions. A significant portion of neurons in PMLS cortex were direction selective to simple (16/18) and complex (11/16) RDKs. However, the strength of direction selectivity to both stimuli was reduced as compared to normals. The data suggest that complex motion processing is still present, albeit reduced, in PMLS cortex despite the removal of VC input. The complex RDK motion selectivity is consistent with both geniculo-cortical and extra-geniculate thalamo-cortical pathways in residual direction encoding.

After loss of a particular sensory channel, the deprived cortex can be activated by inputs from other sensory modalities. It is not known whether activation of the rewired cortex evokes subjective experiences characteristic of that cortex or consistent with the rerouted sensory information. In a previous study, blind subjects were trained to perform visual tasks with a tongue display unit, a sensory substitution device that translates visual displays into electrotactile tongue stimulation. This cross-modal sensory stimulation activated their visual cortices. We now extend this finding by using transcranial magnetic stimulation to examine the perceptual correlates of training-induced plastic responses. We find that blind subjects proficient with the use of the tongue display unit report somatopically organized tactile sensations that are referred to the tongue when transcranial magnetic stimulation is applied over the occipital cortex. No such sensations were evoked in trained, blindfolded, seeing control subjects who performed the sensory substitution task equally well. These data show that the perceptual correlate of activity in a given cortical area reflects the characteristics of its novel sensory input source.

The lateral posterior (LP) nucleus is a higher order thalamic nucleus that is believed to play a key role in the transmission of visual information between cortical areas. Two types of cortical terminals have been identified in higher order nuclei, large (type II) and smaller (type I), which have been proposed to drive and modulate, respectively, the response properties of thalamic cells (Sherman and Guillery [1998] Proc. Natl. Acad. Sci. U. S. A. 95:7121-7126). The aim of this study was to assess and compare the relative contribution of driver and modulator inputs to the LP nucleus that originate from the posteromedial part of the lateral suprasylvian cortex (PMLS) and area 17. To achieve this goal, the anterograde tracers biotinylated dextran amine (BDA) or Phaseolus vulgaris leucoagglutinin (PHAL) were injected into area 17 or PMLS. Results indicate that area 17 injections preferentially labelled large terminals, whereas PMLS injections preferentially labelled small terminals. A detailed analysis of PMLS terminal morphology revealed at least four categories of terminals: small type I terminals (57%), medium-sized to large singletons (30%), large terminals in arrangements of intermediate complexity (8%), and large terminals that form arrangements resembling rosettes (5%). Ultrastructural analysis and postembedding immunocytochemical staining for gamma-aminobutyric acid (GABA) distinguished two types of labelled PMLS terminals: small profiles with round vesicles (RS profiles) that contacted mostly non-GABAergic dendrites outside of glomeruli and large profiles with round vesicles (RL profiles) that contacted non-GABAergic dendrites (55%) and GABAergic dendritic terminals (45%) in glomeruli. RL profiles likely include singleton, intermediate, and rosette terminals, although future studies are needed to establish definitively the relationship between light microscopic morphology and ultrastructural features. All terminals types appeared to be involved in reciprocal corticothalamocortical connections as a result of an intermingling of terminals labelled by anterograde transport and cells labelled by retrograde transport. In conclusion, our results indicate that the origin of the driver inputs reaching the LP nucleus is not restricted to the primary visual cortex and that extrastriate visual areas might also contribute to the basic organization of visual receptive fields of neurons in this higher order nucleus., (2006 Wiley-Liss, Inc.)

In cats, the postero-medial part of lateral suprasylvian cortex (PMLS) is generally considered a key area for motion processing. While behavioral studies have indeed supported the role of PMLS cortex in higher order motion integration (Cereb Cortex 6:814-822, 1996), there is no evidence that individual PMLS cells can perform such analysis (Vis Neurosci 5:463-468, 1990; J Neurophysiol 63:1529-1543, 1990). Given the fundamental importance of understanding the neural substrate subtending higher order motion processing, we investigated whether PMLS neurons can signal the direction of motion of complex random dot kinematograms (RDKs) wherein comprising elements do not provide any local coherent motion cues. Results indicated that most PMLS cells (82%) can integrate the displacement of individual elements into a global motion percept. Their large receptive fields allowed the integration of motion for elements separated by large spatial intervals (up to 4 degrees ). In most cases, the analysis of complex RDK motion necessitated the contribution of the area of the visual field beyond the classical receptive field. None of the complex RDK-sensitive cells were found to be pattern-motion selective when tested with plaid patterns. Our results provide the first evidence that receptive fields of PMLS neurons can perform global motion analysis and support the behavioral evidence that this area is implicated in complex motion processing (Cereb Cortex 6:814-822, 1996). It also further corroborates the findings that PMLS neurons cannot signal the true direction of a plaid pattern (Vis Neurosci 5:463-468, 1990; J Neurophysiol 63:1529-1543, 1990). Providing that these same neurons can signal the direction of complex RDKs, there may be distinct cortical mechanisms for processing different types of complex motion.

The development of the corpus callosum (CC) and the anterior commissure (CA) is well known in a wide variety of species. No study, however, has described the development of the commissure of the superior colliculus (CSC) from embryonic state to adulthood in mammals. In this study, by using the lipophylic tracer DiI, we investigated the ontogeny of this mesencephalic commissure in the hamster at various ages. The development of axonal terminals, growth cone morphologies, and axons branching were described for the superior colliculus (SC) contralateral to the tracer injection. The first CSC axons cross the midline at embryonic day 11 (E-11) and grow further into the intermediate layers of the contralateral SC between E-12 and E-14. There is little axon growth therein between E-14 and the day of birth (P-0). Growth cones at the tip of these axons adopt complex morphologies at E-12 and progressively simplify until P-0. Pioneer axons are clearly visible between E-14 and P-1. These are followed by other axons progressively more numerous between P-0 and P-5. Axons do not show any branching until P-2. Between P-3 and P-9, the axons progressively arborize in the intermediate layers. Some axons reach the superficial layers at P-5, and they become more numerous around P-11, and only a few axons remain therein by P-21. Myelinated axons appear at P11 and are very dense at P-21. Our results indicate that the CSC follows developmental schemes similar to those of the CC and the AC but that initial axon midline crossing occurs earlier., (J. Comp. Neurol. 494:887-902, 2006. (c) 2005 Wiley-Liss, Inc.)

The brain shows a remarkable capacity to reorganize itself following early sensory deprivation or neonatal brain damage. Using two models of deprivation, we will show that the brain does indeed adjust to the loss of either the visual cortex (which receives most of the retinal inputs through the lateral geniculate bodies of the thalamus) or the eyes (which provide the major input to the visual cortex) through cross-modal plastic processes. Hamsters, deprived of their visual system at birth, develop novel and permanent retinal projections to the auditory thalamus. These projections form functional synapses and project to the auditory cortex. When trained on a visual discrimination task, the "rewired" hamsters perform as well as normal hamsters. Lesions of the auditory cortex produce cortical blindness. Congenitally blind human subjects, trained to discriminate the orientation of a stimulus applied to the tongue via an electrotactile device, show activation of their visual cortex, whereas trained blindfolded controls show only activation of the somatosensory cortex representing the tongue. We propose that in blind subjects, there is an unmasking of existing cortico-cortical (parieto-occipital) connections, enabling transfer of somatosensory information to visual cortex.

On the basis of anatomical and physiological data obtained on animal models, we recently proposed that neurons in the main visual extrageniculate nuclei complex, the pulvinar, are actively involved in higher-order visual processing. Pulvinar neurons have been shown to integrate the component signals of a plaid pattern into a coherent global percept (pattern-motion selectivity). Using positron emission tomography (PET), we have investigated the possibility that the human pulvinar is also involved in plaid-defined higher-order motion integration. Plaid patterns were presented to normal observers in two conditions (coherent vs. transparent) created by varying the relative spatial frequency of the two gratings comprising the plaid. Regions of interest analysis revealed a significant activation of the pulvinar in the coherent condition supporting the notion that the human pulvinar nucleus is involved in higher-order motion processing. Plaid pattern activation was also observed in the medial temporal gyrus (area MT/V5), a motion area with strong anatomical connections to the pulvinar. These data provide the first direct evidence that the human pulvinar is involved in complex motion integration, as previously shown in animal models, and further support the existence of cortico-thalamo-cortical computational networks involved in higher-order visual processing.

The morphology and distribution of neurons immunoreactive (ir) to parvalbumin (PV), calretinin (CR) and calbindin (CB) were studied in the primary visual (V1) and auditory (A1) cortices of hamsters. Cortical cell populations were labelled immunohistochemically using a glucose oxidase-diaminobenzidine-nickel combined revelation method. Quantitative analysis revealed significant differences between V1 and A1 in the density and distribution of their neuronal population. CBir cells exhibited several typologies in both cortical regions. Most cells were multipolar even though many of them had bitufted or bipolar morphologies. These cells were distributed in layers II/III and in layer V of both A1 and V1, but were more numerous in layer V of V1. CRir cells were of the fusiform type with long bipolar dendritic arbours. These were similarly distributed in both cortices with a peak in superficial layers II/III. PVir cells were also found in both cortices and had round or oval-shaped somata with multipolar processes. They were mostly located in layer V for V1 and in layers III/IV for A1. Visual and auditory primary cortices can thus be differentiated on the basis of their immunoreactivity to specific calcium binding proteins.