Uncovering a Role for the Dorsal Hippocampal Commissure in Recognition Memory.

The dorsal hippocampal commissure (DHC) is a white matter tract that provides interhemispheric connections between temporal lobe brain regions. Despite the importance of these regions for learning and memory, there is scant evidence of a role for the DHC in successful memory performance. We used diffusion-weighted magnetic resonance imaging (DW-MRI) and white matter tractography to reconstruct the DHC in both humans (in vivo) and nonhuman primates (ex vivo). Across species, our findings demonstrate a close consistency between the known anatomy and tract reconstructions of the DHC. Anterograde tract-tracer techniques also highlighted the parahippocampal origins of DHC fibers in nonhuman primates. Finally, we derived diffusion tensor MRI metrics from the DHC in a large sample of human subjects to investigate whether interindividual variation in DHC microstructure is predictive of memory performance. The mean diffusivity of the DHC correlated with performance in a standardized recognition memory task, an effect that was not reproduced in a comparison commissure tract-the anterior commissure. These findings highlight a potential role for the DHC in recognition memory, and our tract reconstruction approach has the potential to generate further novel insights into the role of this previously understudied white matter tract in both health and disease.

Distribution and Morphology of Cortical Terminals in the Cat Thalamus from the Anterior Ectosylvian Sulcus.

Two main types of cortical terminals have been identified in the cat thalamus. Large (type II) have been proposed to drive the response properties of thalamic cells while smaller (type I) are believed to modulate those properties. Among the cat's visual cortical areas, the anterior ectosylvian visual area (AEV) is considered as one of the highest areas in the hierarchical organization of the visual system. Whereas the connections from the AEV to the thalamus have been recognized, their nature (type I or II) is presently not known. In this study, we assessed and compared the relative contribution of type I and type II inputs to thalamic nuclei originating from the AEV. The anterograde tracer BDA was injected in the AEV of five animals. Results show that (1) both type I and II terminals from AEV are present in the Lateral Posterior- Pulvinar complex, the lateral median suprageniculate complex and the medial and dorsal geniculate nuclei (2) type I terminals significantly outnumber the type II terminals in almost all nuclei studied. Our results indicate that neurons in the AEV are more likely to modulate response properties in the thalamus rather than to determine basic organization of receptive fields of thalamic cells.

Uncertainty about the intensity of impending pain increases ensuing pain responses in congenital blindness.

We have shown that congenitally blind individuals are more sensitive to painful heat compared to their sighted counterparts. This hypersensitivity might be at least partly mediated by psychological and cognitive factors, such as pain expectation and anxiety. Here we investigate whether uncertainty about the intensity of a pending painful stimulus affects pain differently in congenitally blind and sighted control subjects. We measured pain and anxiety in a group of 11 congenitally blind and 11 age- and sex-matched normal sighted control participants. Painful stimuli were delivered under two psychological conditions, whereby participants were either certain or uncertain about the intensity of a pending noxious stimuli. Although both blind and sighted participants had increased anxiety ratings in the uncertain condition, pain ratings increased only in the congenitally blind participants. Our data therefore indicate that increased anxiety levels have a stronger influence on the perceived pain intensity in blind individuals, possibly because they allocate greater attention to signals of external threat.

Thalamocortical Connectivity and Microstructural Changes in Congenital and Late Blindness.

There is ample evidence that the occipital cortex of congenitally blind individuals processes nonvisual information. It remains a debate whether the cross-modal activation of the occipital cortex is mediated through the modulation of preexisting corticocortical projections or the reorganisation of thalamocortical connectivity. Current knowledge on this topic largely stems from anatomical studies in animal models. The aim of this study was to test whether purported changes in thalamocortical connectivity in blindness can be revealed by tractography based on diffusion-weighted magnetic resonance imaging. To assess the thalamocortical network, we used a clustering method based on the thalamic white matter projections towards predefined cortical regions. Five thalamic clusters were obtained in each group representing their cortical projections. Although we did not find differences in the thalamocortical network between congenitally blind individuals, late blind individuals, and normal sighted controls, diffusion tensor imaging (DTI) indices revealed significant microstructural changes within thalamic clusters of both blind groups. Furthermore, we find a significant decrease in fractional anisotropy (FA) in occipital and temporal thalamocortical projections in both blind groups that were not captured at the network level. This suggests that plastic microstructural changes have taken place, but not in a degree to be reflected in the tractography-based thalamocortical network.

Melatonin and cortisol profiles in the absence of light perception.

As light plays an important role in the synchronisation of the internal biological clock to the environmental day/night schedule, we compared the 24-h profiles of biological circadian markers in blind and normal sighted individuals. Salivary melatonin and cortisol concentrations were collected every two hours in eleven blind subjects, reporting no conscious light perception, and eleven age- and sex-matched normal sighted controls. Timing of melatonin onset and associated cortisol quiescence period confirm an increased incidence of abnormal circadian patterns in blindness. Additionally, blind subjects showed a greater overall melatonin concentration throughout the 24-h period. Cortisol profiles, including concentration and morning cortisol peaks, on the other hand, did not differ between blind and sighted individuals. These findings support previous reports of an increase in abnormal circadian rhythms and the absence of the entrainment properties of light in blindness.

Altered sleep-wake patterns in blindness: a combined actigraphy and psychometric study.

OBJECTIVE: Light plays an important role in the synchronization of the internal biological clock and the environmental day/night pattern. Thus, absence of vision is often associated with both increases in reported sleep disturbances and incidence of free-running circadian rhythms. In this study we discuss variability in the sleep-wake pattern between blind and normal-sighted individuals. METHODS: Thirty-day actigraphy recordings were collected from 11 blind individuals without residual light perception and 11 age- and sex-matched normal-sighted controls. From these recordings, we extracted parameters of sleep and wake, including episodes of rest, day-time and night-time sleep periods, and the number of awakenings throughout sleep. A measure of sleep efficiency was derived from these measures for each night-time sleep episode. We also examined complementary measures of sleep quality, using the Pittsburgh Sleep Quality Index, and chronotype, using the Morningness-Eveningness Questionnaire. RESULTS: Although no group differences were found when averaging over the entire recording period, we found a greater variability throughout the 30-days in both sleep efficiency and timing of the night-time sleep episode in blind participants as compared to sighted control participants. We also confirm previous reports of reduced sleep quality in blind individuals. Notably, the variability in sleep efficiency and in the timing of sleep correlated with the severity of sleep disturbances. CONCLUSION: The timing and physiology of sleep are strongly dependent on the endogenous circadian phase; therefore, observed findings support the hypothesis of free-running circadian rhythms as a dominant factor for the sleep disturbances experienced in blindness.

Pain hypersensitivity in congenital blindness is associated with faster central processing of C-fibre input.

BACKGROUND: We have recently shown that visual deprivation from birth exacerbates responses to painful thermal stimuli. However, the mechanisms underlying pain hypersensitivity in congenital blindness are unclear. METHODS: To study the contribution of Aδ- and C-fibres in pain perception, we measured thresholds and response times to selective C- and Aδ-fibre activation in congenitally blind, late blind and normally sighted participants. Ultrafast constant-temperature heat pulses were delivered to the hand with a CO2 laser using an interleaved adaptive double staircase procedure. Participants were instructed to respond as quickly as possible when detecting a laser-induced sensation. We used a 650 ms cut-off criterion to distinguish fast Aδ- from slow C-fibre-mediated sensations. RESULTS: Congenitally blind participants showed significantly faster reaction times to C- but not to Aδ-fibre-mediated sensations. In contrast, thresholds for Aδ- and C-fibre stimulation did not differ between groups. Late blind individuals did not differ from sighted controls in any aspect. A follow-up experiment using only suprathreshold stimuli for Aδ- and C-fibre activation confirmed these findings and further showed that congenitally blind individuals detected significantly more C-fibre-mediated stimuli than sighted controls. A decomposition analysis of the reaction times indicated that the faster response times in the congenitally blind are due to more efficient central processing of C-fibre-mediated sensations. CONCLUSION: The increased sensitivity to painful thermal stimulation in congenital blindness may be due to more efficient central processing of C-fibre-mediated input, which may help to avoid impending dangerous encounters with stimuli that threaten the bodily integrity. WHAT DOES THIS STUDY ADD?: Hypersensitivity to heat pain in congenital blindness is associated with faster responses to C-fibre activation, likely caused by more efficient central processing of C-fibre-mediated input.

Neural correlates of taste perception in congenital blindness.

Sight is undoubtedly important for the perception and the assessment of the palatability of tastants. Although many studies have addressed the consequences of visual impairment on food selection, feeding behavior, eating habits and taste perception, nothing is known about the neural correlates of gustation in blindness. In the current study we examined brain responses during gustation using functional magnetic resonance imaging (fMRI). We scanned nine congenitally blind and 14 age- and sex-matched blindfolded sighted control subjects, matched in age, gender and body mass index (BMI), while they made judgments of either the intensity or the (un)pleasantness of different tastes (sweet, bitter) or artificial saliva that were delivered intra-orally. The fMRI data indicated that during gustation, congenitally blind individuals activate less strongly the primary taste cortex (right posterior insula and overlying Rolandic operculum) and the hypothalamus. In sharp contrast with results of multiple other sensory processing studies in congenitally blind subjects, including touch, audition and smell, the occipital cortex was not recruited during taste processing, suggesting the absence of taste-related compensatory crossmodal responses in the occipital cortex. These results underscore our earlier behavioral demonstration that congenitally blind subjects have a lower gustatory sensitivity compared to normal sighted individuals. We hypothesize that due to an underexposure to a variety of tastants, training-induced crossmodal sensory plasticity to gustatory stimulation does not occur in blind subjects.

The endocannabinoid system within the dorsal lateral geniculate nucleus of the vervet monkey.

The endocannabinoid system mainly consists of cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), their endogenous ligands termed endocannabinoids (eCBs), and the enzymes responsible for the synthesis and degradation of eCBs. These cannabinoid receptors have been well characterized in rodent and monkey retinae. Here, we investigated the expression and localization of the eCB system beyond the retina, namely the first thalamic relay, the dorsal lateral geniculate nucleus (dLGN), of vervet monkeys using immunohistochemistry methods. Our results show that CB1R is expressed throughout the dLGN with more prominent labeling in the magnocellular layers. The same pattern is observed for the degradation enzyme, fatty acid amide hydrolase (FAAH). However, the synthesizing enzyme N-acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD) is expressed homogenously throughout the dLGN with no preference for any of the layers. These proteins are weakly expressed in the koniocellular layers. These results suggest that the presence of the eCB system throughout the layers of the dLGN may represent a novel site of neuromodulatory action in normal vision. The larger amount of CB1R in the dLGN magnocellular layers may explain some of the behavioral effects of cannabinoids associated with the integrity of the dorsal visual pathway that plays a role in visual-spatial localization and motion perception.

Expression and localization of the cannabinoid receptor type 1 and the enzyme fatty acid amide hydrolase in the retina of vervet monkeys.

The presence of a widespread endocannabinoid (eCB) system within the nervous system, including the retina, has been demonstrated in recent years. Expression patterns of the cannabinoid receptor type 1 (CB1R) and enzyme fatty acid amide hydrolase (FAAH) are available for rodents, but data for humans and monkeys are scarce. We, therefore, thoroughly examined the distribution pattern of CB1R and FAAH throughout the retina of the vervet monkey (Chlorocebus sabeus) using confocal microscopy. Our results demonstrate that CB1R and FAAH are expressed throughout the retina, from the foveal pit to the far periphery. CB1R and FAAH are present in the photoreceptor, outer plexiform, inner nuclear, inner plexiform, and retinal ganglion cell layers (PRL, OPL, INL, IPL, and RGCL, respectively). More specifically, in PRL, CB1R and FAAH are preferentially expressed in cones of the central retina. In OPL, these two components of the eCB system are concentrated not only in the cone pedicles but also in rod spherules with, however, a less intense staining pattern. Triple-labeling immunofluorescence revealed that both cone and rod bipolar cells express CB1R and FAAH. Heavy staining is detected in RGC somas and axons. Neither CB1R nor FAAH are found in the retinal glia, the Müller cells. These data indicate that the eCB system is present throughout the primate retina and is ideally positioned to modulate central and peripheral retinal functions.

Fatty acid amide hydrolase expression during retinal postnatal development in rats.

The endocannabinoid (eCB) system is thought to participate in developmental processes in the CNS. The rodent retina represents a valuable model to study CNS development because it contains well-identified cell types with established developmental timelines. The distribution of cannabinoid receptor type 1 (CB1R) was recently revealed in the developing retina; however, the expression patterns of other elements of this system remain unknown. In this study, we investigated the expression pattern of the degradative enzyme fatty acid amide hydrolase (FAAH), a key regulator of the eCB system, in the rat retina during postnatal development. To identify the cells expressing the enzyme, co-stainings were carried out for FAAH and retinal cell type markers. FAAH was expressed at postnatal day (P) 1 in ganglion and cholinergic amacrine cells. In the course of development, it appeared in cones, horizontal, and bipolar cells. For most cell types (horizontal, cholinergic amacrine cells, and cone bipolar cells), FAAH was transiently expressed, suggesting an important redistribution of the enzyme during postnatal development and thus a potential role of the eCB system in developmental processes. Our results also indicated that, in the adult retina, FAAH is expressed in cones, rod bipolar cells, and some retinal ganglion cells. The presence of FAAH in adult animals supports the hypothesis that the eCB system is involved in retinal functions. Overall these results indicate that, as shown in other structures of the brain, the eCB system could play an instrumental role in the development and function of the retina.

Neural correlates of olfactory processing in congenital blindness.

Adaptive neuroplastic changes have been well documented in congenitally blind individuals for the processing of tactile and auditory information. By contrast, very few studies have investigated olfactory processing in the absence of vision. There is ample evidence that the olfactory system is highly plastic and that blind individuals rely more on their sense of smell than the sighted do. The olfactory system in the blind is therefore likely to be susceptible to cross-modal changes similar to those observed for the tactile and auditory modalities. To test this hypothesis, we used functional magnetic resonance imaging to measure changes in the blood-oxygenation level-dependent signal in congenitally blind and blindfolded sighted control subjects during a simple odor detection task. We found several group differences in task-related activations. Compared to sighted controls, congenitally blind subjects more strongly activated primary (right amygdala) and secondary (right orbitofrontal cortex and bilateral hippocampus) olfactory areas. In addition, widespread task-related activations were found throughout the whole extent of the occipital cortex in blind but not in sighted participants. The stronger recruitment of the occipital cortex during odor detection demonstrates a preferential access of olfactory stimuli to this area when vision is lacking from birth. This finding expands current knowledge about the supramodal function of the visually deprived occipital cortex in congenital blindness, linking it also to olfactory processing in addition to tactile and auditory processing.

Altered expression of parvalbumin and calbindin in interneurons within the primary visual cortex of neonatal enucleated hamsters.

In the present study, we tested the hypothesis that the expression of calcium binding proteins (CaBPs), parvalbumin (PV), calretinin (CR) and calbindin (CB), is dependent upon sensory experience as emphasized in visual deprivation and deafferentation studies. The expression of CaBPs was studied in interneurons within the primary and extrastriate visual cortices (V1, V2M, V2L) and auditory cortex (AC) of adult hamsters enucleated at birth. The effects of enucleation were mainly confined to area V1 where there was a significant volume reduction (26%) and changes in the laminar distribution of PV and CB immunoreactive (IR) cells. The density of PV-IR cell bodies was significantly increased in layer IV and reduced in layer V. Moreover, the density of CB-IR neurons was inferior in layer V of V1 in enucleated hamsters (EH) compared to controls. These results suggest that some features of the laminar distribution of specific CaBPs, in primary sensory cortices, are dependent upon or modulated by sensory input.

Complex motion sensitivity of neurons, in the visual part of the anterior ectosylvian cortex in cats.

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.

TMS of the occipital cortex induces tactile sensations in the fingers of blind Braille readers.

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.

Complex motion selectivity in PMLS cortex following early lesions of primary visual cortex in the cat.

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.

rTMS of the occipital cortex abolishes Braille reading and repetition priming in blind subjects.

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.

Distribution, morphology, and synaptic targets of corticothalamic terminals in the cat lateral posterior-pulvinar complex that originate from the posteromedial lateral suprasylvian cortex.

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.

Global motion integration in the postero-medial part of the lateral suprasylvian cortex in the cat.

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.

Stereoscopic processing in the human brain as a function of binocular luminance rivalry.

We investigated the neural substrates of a recent model of human stereodepth perception by obtaining measurements of regional cerebral blood flow (rCBF) using PET. Subjects experienced the perceptual properties of stereopsis by viewing rival-luminance stereograms displaying an identical random-dot pattern in their central portion while the backgrounds exhibited correspondent dots contrasting in black/white luminance. The stereoscopic vision induced by retinal luminance rivalry coincided with a significant elevation of rCBF in the dorsal visual pathway. Area V5 (MT) was activated bilaterally by the experimental condition while the remaining active loci were restricted to the right hemisphere. The neural sites that responded to this novel stereoscopic stimulus are similar to those activated by traditional stereograms containing horizontal disparities.