Selective stimulation of neurons in visual cortex enables segregation of slow and fast connections.

Organization of the central visual pathway is generally studied from a perspective of feedforward processes. However, there are horizontal connections and also strong feedback from extra striate to visual cortex. Here, we use visual stimuli designed to maximize relative differential involvements of these three main types of connections. The approach relies on differences between stimulation within the classical receptive field (CRF) and that of the surround region. Although previous studies have used similar approaches, they were limited primarily to spatial segregation of neural connections. Our experimental design provides clear segregation of fast and slow components of surround modulation. We assume these are mediated by feedback and horizontal connections, respectively, but other factors may be involved. Our results imply that both horizontal and feedback connections contribute to integration of visual information outside the CRF and provide suppressive or facilitative modulation. For a given cell, modulation may change in strength and sign from suppression to facilitation or the reverse depending on surround parameters. Sub-threshold input from the CRF surround increases local field potential (LFP) power in distinct frequency ranges which differ for suppression and facilitation. Horizontal connections have delayed CRF-surround modulation and are sensitive to position changes in the surround. Therefore, surround information beyond the CRF is initially processed by fast connections which we consider to be feedback, whereas spatially tuned mechanisms are relatively slow and presumably mediated by horizontal connections. Overall, results suggest that convergent fast (feedforward) inputs determine size and structure of the CRFs of recipient cells in visual cortex. And fast connections from extra striate regions (feedback) plus slow-tuned connections (horizontal) within visual cortex contribute to spatial influences of CRF surround activation.

Binocular activation elicits differences in neurometabolic coupling in visual cortex.

Non-invasive brain imaging requires comprehensive interpretation of hemodynamic signals. In functional magnetic resonance imaging, blood oxygen level dependent (BOLD) signals are used to infer neural processes. This necessitates a clear understanding of how BOLD signals and neural activity are related. One fundamental question concerns the relative importance of synaptic activity and spiking discharge. Although these two components are related, most previous work shows that synaptic activity is better reflected in the BOLD signal. However, the mechanisms of this relationship are not clear. The BOLD signal depends on relative changes in cerebral blood flow and cerebral metabolic rate of oxygen. Oxygen metabolism changes are difficult to measure with current imaging techniques, but it is possible to obtain direct quantitative simultaneous in vivo measurement of tissue oxygen and co-localized underlying neural activity. Here, we use this approach with a specific binocular stimulus protocol in order to activate inhibitory and excitatory neuronal pathways in the visual cortex. During excitatory binocular interaction, we find that metabolic, spiking, and local field potential responses are correlated. However, during suppressive binocular interaction, spiking activity and local field potentials (LFP) are dissociated while only the latter is coupled with metabolic response. These results suggest that inhibitory connections may be a key factor in the dissociation between LFP and spiking activity, which may contribute substantially to the close coupling between the BOLD signal and synchronized synaptic activity in the brain.

Spatial summation of neurometabolic coupling in the central visual pathway.

Noninvasive neural imaging has become an important tool in both applied and theoretical applications. The hemodynamic properties that are measured in functional magnetic resonance imaging (fMRI), for example, are generally used to infer neuronal characteristics. In an attempt to provide empirical data to connect the hemodynamic measurements with neural function, we have conducted previous studies in which neural activity and tissue oxygen metabolic functions are determined together in co-localized regions of the central visual pathway. A basic question in this procedure is whether oxygen responses are coupled linearly in space and time with neural activity. We have previously examined temporal factors, and in the current study, spatial characteristics are addressed. We have recorded from neurons in the lateral geniculate nucleus (LGN) and striate cortex in anesthetized cats. In both structures, there is a classical receptive field (CRF) within which a neuron can be activated. There is also a region outside the CRF from which stimulation cannot activate the cell directly but can influence the response elicited from the CRF. In this investigation we have used several specific spatial stimulus patterns presented to either the CRF or the surrounding region or to both areas together in order to determine spatial response patterns. Within the CRF, we find that neural and metabolic responses sum in a nonlinear fashion but changes in these two measurements are closely coupled. For stimuli that extend beyond the CRF, neural activity is generally reduced while oxygen response exhibits uncoupled changes.

Beyond the classical receptive field in the visual cortex.

We have investigated the organization of regions outside the classical receptive field (CRF) for neurons in the visual cortex. First, we have determined the incidence and nature of interactions from outside the CRF. We find interaction from regions outside the CRF for a majority of cortical cells and it is almost always of a suppressive nature. Second, we have determined that most interaction is from specific well-defined regions outside the CRF. These regions are generally as effective as what is found for a complete annulus. Third, it is possible to reverse the inhibition from outside the CRF by the addition of a second grating that is orthogonal to the preferred orientation. This disinhibition may completely offset the suppressive influence of the surround. Additional experiments suggest that this process is not necessarily involved in figure/ground analysis.

Joint-encoding of motion and depth by visual cortical neurons: neural basis of the Pulfrich effect.

Motion and stereoscopic depth are fundamental parameters of the structural analysis of visual scenes. Because they are defined by a difference in object position, either over time or across the eyes, a common neural machinery may be used for encoding these attributes. To examine this idea, we analyzed responses of binocular complex cells in the cat striate cortex to stimuli of various intra- and interocular spatial and temporal shifts. We found that most neurons exhibit space-time-oriented response profiles in both monocular and binocular domains. This indicates that these neurons encode motion and depth jointly, and it explains phenomena such as the Pulfrich effect. We also found that the relationship between neuronal tuning of motion and depth conforms to that predicted by the use of motion parallax as a depth cue. These results demonstrate a joint-encoding of motion and depth at an early cortical stage.

An international perspective on Tourette syndrome: selected findings from 3,500 individuals in 22 countries.

We have established a multisite, international database of 3,500 individuals diagnosed with Tourette syndrome (TS). The male:female ratio is 4.3:1 for the total sample, with wide variation among sites; the male excess occurs at every site. Anger control problems, sleep difficulties, coprolalia, and self-injurious behavior only reach impressive levels in individuals with comorbidity. Anger control problems are strongly correlated with comorbidity, regardless of site, region, or whether assessed by neurologists or psychiatrists. The mean age at onset of tics is 6.4 years. At all ages, about 12% of individuals with TS have no reported comorbidity. The most common reported comorbidity is attention-deficit-hyperactivity disorder. Males are more likely to have comorbid disorders than females. The earlier the age at onset, the greater the likelihood of a positive family history of tics. An understanding of the factors producing these and other variations might assist in better subtyping of TS. Because behavioral problems are associated with comorbidity, their presence should dictate a high index of suspicion of the latter, whose treatment may be at least as important as tic reduction. The established database can be used as the entry point for further research when large samples are studied and generalizability of results is important.

Clinical trials of controlled-release melatonin in children with sleep-wake cycle disorders.

This is the first study to examine effective doses of controlled-release (CR) melatonin in children with chronic sleep wake cycle disorders. All 42 subjects had severe neurodevelopmental difficulties. Initially, a randomized double-blinded cross-over design was used in 16 children, comparing the effectiveness of fast-release (FR) and CR melatonin. In the remainder of the patients, the CR melatonin was studied on a clinical basis. The effectiveness of treatment was assessed by sleep charts and clinical follow-up. Emphasis was placed on the judgement of the parents, who had guidance from the physicians. The average final CR melatonin dose in the 42 patients was 5.7 mg (2-12 mg). The studies showed that the FR melatonin was most effective when there was only delayed sleep onset, but CR formulations were more useful for sleep maintenance. Children appeared to require higher doses than adults.

Suppression outside the classical cortical receptive field.

The important visual stimulus parameters for a given cell are defined by the classical receptive field (CRF). However, cells are also influenced by visual stimuli presented in areas surrounding the CRF. The experiments described here were conducted to determine the incidence and nature of CRF surround influences in the primary visual cortex. From extracellular recordings in the cat's striate cortex, we find that for over half of the cells investigated (56%, 153/271), the effect of stimulation in the surround of the CRF is to suppress the neuron's activity by at least 10% compared to the response to a grating presented within the CRF alone. For the remainder of the cells, the interactions were minimal and a few were of a facilitatory nature. In this paper, we focus on the suppressive interactions. Simple and complex cell types exhibit equal incidences of surround suppression. Suppression is observed for cells in all layers, and its degree is strongly correlated between the two eyes for binocular neurons. These results show that surround suppression is a prevalent form of inhibition and may play an important role in visual processing.

Contrast gain control in the visual cortex: monocular versus binocular mechanisms.

In this study, we compare binocular and monocular mechanisms underlying contrast encoding by binocular simple cells in primary visual cortex. At mid to high levels of stimulus contrast, contrast gain of cortical neurons typically decreases as stimulus contrast is increased (). We have devised a technique by which it is possible to determine the relative contributions of monocular and binocular processes to such reductions in contrast gain. First, we model the simple cell as an adjustable linear mechanism with a static output nonlinearity. For binocular cells, the linear mechanism is sensitive to inputs from both eyes. To constrain the parameters of the model, we record from binocular simple cells in striate cortex. To activate each cell, drifting sinusoidal gratings are presented dichoptically at various relative interocular phases. Stimulus contrast for one eye is varied over a large range whereas that for the other eye is fixed. We then determine the best-fitting parameters of the model for each cell for all of the interocular contrast ratios. This allows us to determine the effect of contrast on the contrast gain of the system. Finally, we decompose the contrast gain into monocular and binocular components. Using the data to constrain the model for a fixed contrast in one eye and increased contrasts in the other eye, we find steep reductions in monocular gain, whereas binocular gain exhibits modest and variable changes. These findings demonstrate that contrast gain reductions occur primarily at a monocular site, before convergence of information from the two eyes.

Linear and nonlinear contributions to orientation tuning of simple cells in the cat's striate cortex.

Orientation selectivity is one of the most conspicuous receptive-field (RF) properties that distinguishes neurons in the striate cortex from those in the lateral geniculate nucleus (LGN). It has been suggested that orientation selectivity arises from an elongated array of feedforward LGN inputs (Hubel & Wiesel, 1962). Others have argued that cortical mechanisms underlie orientation selectivity (e.g. Sillito, 1975; Somers et al., 1995). However, isolation of each mechanism is experimentally difficult and no single study has analyzed both processes simultaneously to address their relative roles. An alternative approach, which we have employed in this study, is to examine the relative contributions of linear and nonlinear mechanisms in sharpening orientation tuning. Since the input stage of simple cells is remarkably linear, the nonlinear contribution can be attributed solely to cortical factors. Therefore, if the nonlinear component is substantial compared to the linear contribution, it can be concluded that cortical factors play a prominent role in sharpening orientation tuning. To obtain the linear contribution, we first measure RF profiles of simple cells in the cat's striate cortex using a binary m-sequence noise stimulus. Then, based on linear spatial summation of the RF profile, we obtain a predicted orientation-tuning curve, which represents the linear contribution. The nonlinear contribution is estimated as the difference between the predicted tuning curve and that measured with drifting sinusoidal gratings. We find that measured tuning curves are generally more sharply tuned for orientation than predicted curves, which indicates that the linear mechanism is not enough to account for the sharpness of orientation-tuning. Therefore, cortical factors must play an important role in sharpening orientation tuning of simple cells. We also examine the relationship of RF shape (subregion aspect ratio) and size (subregion length and width) to orientation-tuning halfwidth. As expected, predicted tuning halfwidths are found to depend strongly on both subregion length and subregion aspect ratio. However, we find that measured tuning halfwidths show only a weak correlation with subregion aspect ratio, and no significant correlation with RF length and width. These results suggest that cortical mechanisms not only serve to sharpen orientation tuning, but also serve to make orientation tuning less dependent on the size and shape of the RF. This ensures that orientation is represented equally well regardless of RF size and shape.

Asymmetric suppression outside the classical receptive field of the visual cortex.

Areas beyond the classical receptive field (CRF) can modulate responses of the majority of cells in the primary visual cortex of the cat (). Although general characteristics of this phenomenon have been reported previously, little is known about the detailed spatial organization of the surrounds. Previous work suggests that the surrounds may be uniform regions that encircle the CRF or may be limited to the "ends" of the CRF. We have examined the spatial organization of surrounds of single-cell receptive fields in the primary visual cortex of anesthetized, paralyzed cats. The CRF was stimulated with an optimal drifting grating, whereas the surround was probed with a second small grating patch placed at discrete locations around the CRF. For most cells that exhibit suppression, the surrounds are spatially asymmetric, such that the suppression originates from a localized region. We find a variety of suppressive zone locations, but there is a slight bias for suppression to occur at the end zones of the CRF. The spatial pattern of suppression is independent of the parameters of the suppressive stimulus used, although the effect is clearest with iso-oriented surround stimuli. A subset of cells exhibit axially symmetric or uniform surround fields. These results demonstrate that the surrounds are more specific than previously realized, and this specialization has implications for the processing of visual information in the primary visual cortex. One possibility is that these localized surrounds may provide a substrate for figure-ground segmentation of visual scenes.

Stereoscopic vision: Which parts of the brain are involved?

Neurons of the visual system that exhibit depth specificity are prevalent in the medial temporal region of the cerebral cortex. Electrical activation of these cells can bias an observer's depth estimates, indicating that they play an important role in depth perception.

Neural mechanisms for processing binocular information II. Complex cells.

Complex cells in the striate cortex exhibit extensive spatiotemporal nonlinearities, presumably due to a convergence of various subunits. Because these subunits essentially determine many aspects of a complex cell receptive field (RF), such as tuning for orientation, spatial frequency, and binocular disparity, examination of the RF properties of subunits is important for understanding functional roles of complex cells. Although monocular aspects of these subunits have been studied, little is known about their binocular properties. Using a sophisticated RF mapping technique that employs binary m-sequences, we have examined binocular interactions exhibited by complex cells in the cat's striate cortex and the binocular RF properties of their underlying functional subunits. We find that binocular interaction RFs of complex cells exhibit subregions that are elongated along the frontoparallel axis at different binocular disparities. Therefore responses of complex cells are largely independent of monocular stimulus position or phase as long as the binocular disparity of the stimulus is kept constant. The binocular interaction RF is well described by a sum of binocular interaction RFs of underlying functional subunits, which exhibit simple cell-like RFs and a preference for different monocular phases but the same binocular disparity. For more than half of the complex cells examined, subunits of each cell are consistent with the characteristics specified by an energy model, with respect to the number of subunits as well as relationships between the subunit properties. Subunits exhibit RF binocular disparities that are largely consistent with a phase mechanism for encoding binocular disparity. These results indicate that binocular interactions of complex cells are derived from simple cell-like subunits, which exhibit multiplicative binocular interactions. Therefore binocular interactions of complex cells are also multiplicative. This suggests that complex cells compute something analogous to an interocular cross-correlation of images for a local region of visual space. The result of this computation can be used for solving the stereo correspondence problem.

Neural mechanisms for processing binocular information I. Simple cells.

The visual system integrates information from the left and right eyes and constructs a visual world that is perceived as single and three dimensional. To understand neural mechanisms underlying this process, it is important to learn about how signals from the two eyes interact at the level of single neurons. Using a sophisticated receptive field (RF) mapping technique that employs binary m-sequences, we have determined the rules of binocular interactions exhibited by simple cells in the cat's striate cortex in relation to the structure of their monocular RFs. We find that binocular interaction RFs of most simple cells are well described as the product of left and right eye RFs. Therefore the binocular interactions depend not only on binocular disparity but also on monocular stimulus position or phase. The binocular interaction RF is consistent with that predicted by a model of a linear binocular filter followed by a static nonlinearity. The static nonlinearity is shown to have a shape of a half-power function with an average exponent of approximately 2. Although the initial binocular convergence of signals is linear, the static nonlinearity makes binocular interaction multiplicative at the output of simple cells. This multiplicative binocular interaction is a key ingredient for the computation of interocular cross-correlation, an algorithm for solving the stereo correspondence problem. Therefore simple cells may perform initial computations necessary to solve this problem.

Neural mechanisms for encoding binocular disparity: receptive field position versus phase.

The visual system uses binocular disparity to discriminate the relative depth of objects in space. Because the striate cortex is the first site along the central visual pathways at which signals from the left and right eyes converge onto a single neuron, encoding of binocular disparity is thought to begin in this region. There are two possible mechanisms for encoding binocular disparity through simple cells in the striate cortex: a difference in receptive field (RF) position between the two eyes (RF position disparity) and a difference in RF profiles between the two eyes (RF phase disparity). Although there is evidence that supports each of these schemes, both mechanisms have not been examined in a single study to determine their relative roles. In this study, we have measured RF position and phase disparities of individual simple cells in the cat's striate cortex to address this issue. Using a sophisticated RF mapping technique that employs binary m-sequences, we have obtained left and right eye RF profiles of two or more cells recorded simultaneously. A version of the reference-cell method was used to estimate RF position disparity. We find that RF position disparities generally are limited to values that are not sufficient to encode large binocular disparities. In contrast, RF phase disparities cover a wide range of binocular disparities and exhibit dependencies on RF orientation and spatial frequency in a manner expected for a mechanism that encodes binocular disparity. These results suggest that binocular disparity is encoded mainly through RF phase disparity. However, RF position disparity may play a significant role for cells with high spatial frequency selectivity that are constrained to have only small RF phase disparities.

Waiting times for appointments with orthopaedic surgeons in Victoria: 1995-97.

BACKGROUND: A number of different models have been proposed for determining surgical workforce requirements. METHODS: In 1995 the Workforce Subcommittee of the Victorian Regional Branch of the Australian Orthopaedic Association commenced a prospective evaluation of waiting times for both urgent and nonurgent appointments with orthopaedic surgeons in Victoria. RESULTS: The results for the 3 years, 1995-97, show no significant change in the waiting time for nonurgent appointments and no difference between metropolitan and rural areas. The waiting time for an urgent appointment increased from 1995 to 1997 for the state of Victoria and for metropolitan Melbourne but not for rural areas. However, the median waiting time for an urgent appointment did not change. CONCLUSION: Overall the waiting times were found to be satisfactory by previously reported standards.

Melatonin treatment of non-epileptic myoclonus in children.

Oral melatonin (MLT) has been used by our Vancouver research group in the treatment of paediatric sleep disorders since 1991; slightly over 200 children, mainly with multiple disabilities, who frequently had seizures, have been treated. Three children with markedly delayed sleep onset due to recurring myoclonus were also referred for MLT treatment: two had non-epileptic, and one had epileptic and non-epileptic myoclonus. Low doses of oral MLT (3 to 5 mg) unexpectedly abolished their myoclonus and allowed them to sleep. There were no adverse effects. It appears that certain types of myoclonus, which might be resistant to conventional anticonvulsant medications, may respond to MLT but the mechanism of action is unclear. Further research on this novel treatment is urgently needed.

Functional micro-organization of primary visual cortex: receptive field analysis of nearby neurons.

It is well established that multiple stimulus dimensions (e.g., orientation and spatial frequency) are mapped onto the surface of striate cortex. However, the detailed organization of neurons within a local region of striate cortex remains unclear. Within a vertical column, do all neurons have the same response selectivities? And if not, how do they most commonly differ and why? To address these questions, we recorded from nearby pairs of simple cells and made detailed spatiotemporal maps of their receptive fields. From these maps, we extracted and analyzed a variety of response metrics. Our results provide new insights into the local organization of striate cortex. First, we show that nearby neurons seldom have very similar receptive fields, when these fields are characterized in space and time. Thus, there may be less redundancy within a column than previously thought. Moreover, we show that correlated discharge increases with receptive field similarity; thus, the local dissimilarity between neurons may allow for noise reduction by response pooling. Second, we show that several response variables are clustered within striate cortex, including some that have not received much attention such as response latency and temporal frequency. We also demonstrate that other parameters are not clustered, including the spatial phase (or symmetry) of the receptive field. Third, we show that spatial phase is the single parameter that accounts for most of the difference between receptive fields of nearby neurons. We consider the implications of this local diversity of spatial phase for population coding and construction of higher-order receptive fields.