Central fatigue induced by short-lasting finger tapping and isometric tasks: A study of silent periods evoked at spinal and supraspinal levels.

The neural substrates of fatigue induced by muscular activity have been addressed in depth in relation to isometric tasks. For these activities, when fatigue develops, it has been noted that the duration of the silent periods (SPs) increases in response to both transcranial magnetic stimulation (TMS) of primary motor cortex or electric cervicomedullary stimulation (CMS). However, fatigue is known to be task-dependent and the mechanisms giving rise to a decrease in motor performance during brief, fast repetitive tasks have been less studied. We hypothesized that fatigue induced by repetitive fast finger tapping may have physiological mechanisms different from those accounting for fatigue during an isometric contraction, even in cases of matched effort durations. In these tasks, we examined the contribution of spinal and supraspinal motor circuits to the production of fatigue. The tapping rate and maximal voluntary contractions (MVC), and TMS- and CMS-evoked SPs were obtained at the time of fatigue, and while subjects maintained maximal muscle activation after fast finger-tapping (or isometric activity) of different durations (10 or 30s). Results showed different mechanisms of fatigue triggered by isometric contraction and repetitive movements, even of short duration. Short-lasting repetitive movements induce fatigue within intracortical inhibitory circuits. They increased TMS-SPs, but not CMS-SPs. On the other hand, isometric contraction had a clear impact on spinal circuits. The consideration of these differences might help to optimize the study of fatigue in physiological conditions and neurological disorders.

Anandamide activation of CB1 receptors increases spontaneous bursting and oscillatory activity in the thalamus.

The endocannabinoid system is a modulatory system that has been strongly associated with the regulation of functions as learning and memory, pain perception and sensory physiology in many areas of the central nervous system. However, although a role in sensory processing has been demonstrated at the level of the thalamus, the influence of the endocannabinoid system on thalamic rhythms and oscillations has been less studied, despite the fact that such activities are significant characteristics of the thalamic state. The present work aimed to characterize the role of anandamide (AEA) - one of the endogenous CB1 receptor agonists - and AM251 - a CB1 antagonist - in the modulation of burst firing and oscillatory activity present in the dLGN of the anesthetized rat. Administration of AEA (0.5mg/kg iv) increased the number of bursts in the majority of the cells tested and induced the appearance of a slow delta-like (1.5Hz) oscillatory activity. These effects were CB1-mediated, as demonstrated by the complete antagonism during the co-application of AM251 (0.5mg/kg iv). Thus, by demonstrating that the AEA-mediated activation of CB1 receptors increases spontaneous bursting and oscillatory activity in the thalamus our study infers that endocannabinoids could have a role in processes controlling the sleep-wake cycle and level of arousal.

Responses of primate LGN cells to moving stimuli involve a constant background modulation by feedback from area MT.

The feedback connections from the cortical middle temporal (MT) motion area, to layer 6 of the primary visual cortex (V1), have the capacity to drive a cascaded feedback influence from the layer 6 cortico-geniculate cells back to the lateral geniculate nucleus (LGN) relay cells. This introduces the possibility of a re-entrant motion signal affecting the relay of the retinal input through the LGN to the visual cortex. The question is whether the response of LGN cells to moving stimuli involves a component derived from this feedback. By producing a reversible focal pharmacological block of the activity of an MT direction column we show the presence of such an influence from MT on the responses of magno, parvo and koniocellular cells in the macaque LGN. The pattern of effect in the LGN reflects the direction bias of the MT location inactivated. This suggests a moving stimulus is captured by iterative interactions in the circuit formed by visual cortical areas and visual thalamus.

Touch responses made to remembered and visual target locations in the dark: a human psychophysical study.

UNLABELLED: Saccadic eye movements made to remembered locations in the dark show a distinct up-shift in macaque monkey, and slight upward bias in humans (Gnadt et al. 1991). This upward bias created in the visual spatial mapping of a saccade may be translated downstream in a hand/touch movement. This error could possibly reveal (a) information about the frames of reference used in each scenario and (b) the sources of this error within the brain. This would suggest an early planning stage if they are shared, or a later stage if the errors are distinct. METHODS: Eight human subjects performed touch responses to a touch screen monitor to both visual and remembered target locations. The subjects used a high-resolution touch-screen monitor, a bite bar and chin-rest for restricting head movements during responses. All target locations were 20 degrees vectors from the central starting position in horizontal, vertical and oblique planes of motion. RESULTS: Subjects were accurate to both visual and remembered target locations with little variance. Subject means showed no significant differences between control and memory trials; however, a distinct asymmetry was observed between cardinal and oblique planes during memory trials. Subjects consistently made errors to oblique locations during touches made to the remembered location that was not evident in control conditions. This error pattern revealed a strong hypermetric tendency for oblique planes of touches made to a remembered location.

Surround suppression in primate V1.

We investigated the spatial organization of surround suppression in primate primary visual cortex (V1). We utilized drifting stimuli, configured to extend either from within the classical receptive field (CRF) to surrounding visual space, or from surrounding visual space into the CRF or subdivided to generate direction contrast, to make a detailed examination of the strength, spatial organization, direction dependence, mechanisms, and laminar distribution of surround suppression. Most cells (99/105, 94%) through all cortical layers, exhibited suppression (mean reduction 67%) to uniform stimuli exceeding the CRF, and 43% exhibited a more than 70% reduction. Testing with an annulus revealed two different patterns of surround influence. Some cells (37% of cells), classical surround suppression (CSS) cells exhibited responses to an annulus encroaching on the CRF that were less than the plateau in the spatial summation curve. The majority (63%), center-gated surround suppression (CGSS) cells, showed responses to annuli that equaled or exceeded the plateau in the spatial summation curve. Analysis suggested the CSS mechanism was implemented in all cells while the CGSS mechanism was implemented in varying strength across the sample with the extreme reflected in cells that gave larger responses to annuli than to a center stimulus. Reversing the direction of motion of the portion of the stimulus surrounding the CRF revealed four different patterns of effect: no reduction in the degree of suppression (22% of cells), a reduction in surround suppression (41%), a facilitation of the response above the level to the inner stimulus alone (37%), and a facilitation of the response above that to the inner stimulus alone that also exceeded the values associated with an optimal inner stimulus. The facilitatory effects were only seen for reverse direction interfaces between the central and surrounding stimulus at diameters equal to or more than the CRF size. The zones driving the suppressive influences and the direction contrast facilitation were often spatially heterogeneous and for a number of cells bore strong comparison with the class of behavior reported for surround mechanisms in MT. This suggests a potential role, for example, in extracting information about motion contrast in the representation of the three dimensional structure of moving objects.

A possible role for nitric oxide at the sleep/wake interface.

Cholinergic neurotransmission is known to have important arousal/activating functions. The neurons responsible for those actions also release the atypical neuromodulator nitric oxide (NO), which has been shown in previous studies to be involved in the modulation of sleep/wake states. The present investigation, using an animal model (anesthetized cat) tests the hypothesis that NO cooperates with ACh in controlling rhythmic neuronal activity, which may play a role in sleep/wake transition. We have used extracellular singleunit recording of neurons in the dorsal thalamus and visual cortex with simultaneous iontophoretic application of drugs acting upon the NO system: the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine (L-NOArg), NO donors, and 8-bromo-cGMP (which mimics the action of NO). Local inhibition of NOS significantly reduced the activity of recorded cells in both thalamus and visual cortex. The opposite effect was achieved with NO donors application. In cortex, ejection of 8-bromo-cGMP or the NO donor diethylamine-nitric oxide (DEA-NO) increased cell firing. Furthermore, the rhythmic firing pattern present in these cortical neurons was disrupted. Taken together, these findings suggest that the NO system collaborates with cholinergic neurotransmission. This collaboration might be involved in the control of different patterns of electrogenic activity during various states of the sleep-wake cycle, via the ability of the NO system to modify rhythmic activity of neurons.

Visual response augmentation in cat (and macaque) LGN: potentiation by corticofugally mediated gain control in the temporal domain.

Visual responses of neurons are dependent on the context of a stimulus, not only in spatial terms but also temporally, although evidence for temporally separate visual influences is meagre, based mainly on studies in the higher cortex. Here we demonstrate temporally induced elevation of visual responsiveness in cells in the lateral geniculate nucleus (LGN) of cat and monkey following a period of high intensity (elevated contrast) stimulation. This augmentation is seen in 40-70% (monkey-cat) of cells tested and of all subtypes. Peaking at approximately 3 min following the period of intense stimulation, it can last for 10-12 min and can be repeated and summed in time. Furthermore, it is dependent on corticofugal input, is seen even when high contrast stimuli of orthogonal orientation are used and therefore results from a/any prior increase in activity in the retino-geniculo-striate pathway. We suggest that this reflects a general mechanism for control of visual responsiveness; both a flexible and dynamic means of changing effectiveness of thalamic activity as visual input changes, but also a mechanism which is an emergent property of the thalamo-cortico-thalamic loop.

The primate pulvinar nuclei: vision and action.

The pulvinar nuclei of the thalamus are proportionately larger in higher mammals, particularly in primates, and account for a quarter of the total mass. Traditionally, these nuclei have been divided into oral (somatosensory), superior and inferior (both visual) and medial (visual, multi-sensory) divisions. With reciprocal connections to vast areas of cerebral cortex, and input from the colliculus and retina, they occupy an analogous position in the extra-striate visual system to the lateral geniculate nucleus in the primary visual pathway, but deal with higher-order visual and visuomotor transduction. With a renewed recent interest in this thalamic nuclear collection, and growth in our knowledge of the cortex with which it communicates, perhaps the time is right to look to new dimensions in the pulvinar code.

Effects of feedback projections from area 18 layers 2/3 to area 17 layers 2/3 in the cat visual cortex.

In the absence of a direct geniculate input, area 17 cells in the cat are nevertheless able to respond to visual stimuli because of feedback connections from area 18. Anatomic studies have shown that, in the cat visual cortex, layer 5 of area 18 projects to layer 5 of area 17, and layers 2/3 of area 18 project to layers 2/3 of area 17. What is the specific role of these connections? Previous studies have examined the effect of area 18 layer 5 blockade on cells in area 17 layer 5. Here we examine whether the feedback connections from layers 2/3 of area 18 influence the orientation tuning and velocity tuning of cells in layers 2/3 of area 17. Experiments were carried out in anesthetized and paralyzed cats. We blocked reversibly a small region (300 microm radius) in layers 2/3 of area 18 by iontophoretic application of GABA and recorded simultaneously from cells in layers 2/3 of area 17 while stimulating with oriented sweeping bars. Area 17 cells showed either enhanced or suppressed visual responses to sweeping bars of various orientations and velocities during area 18 blockade. For most area 17 cells, orientation bandwidths remained unaltered, and we never observed visual responses during blockade that were absent completely in the preblockade condition. This suggests that area 18 layers 2/3 modulate visual responses in area 17 layers 2/3 without fundamentally altering their specificity.

Separate body- and world-referenced representations of visual space in parietal cortex.

In order to direct a movement towards a visual stimulus, visual spatial information must be combined with postural information. For example, directing gaze (eye plus head) towards a visible target requires the combination of retinal image location with eye and head position to determine the location of the target relative to the body. Similarly, world-referenced postural information is required to determine where something lies in the world. Posterior parietal neurons recorded in monkeys combine visual information with eye and head position. A population of such cells could make up a distributed representation of target location in an extraretinal frame of reference. However, previous studies have not distinguished between world-referenced and body-referenced signals. Here we report that modulations of visual signals (gain fields) in two adjacent cortical fields, LIP and 7a, are referenced to the body and to the world, respectively. This segregation of spatial information is consistent with a streaming of information, with one path carrying body-referenced information for the control of gaze, and the other carrying world-referenced information for navigation and other tasks that require an absolute frame of reference.

Functional magnetic resonance imaging in macaque cortex.

The ability to use fMRI in a monkey model would bridge the gap between the fMRI demonstration of cerebral activation in humans and the cumulative wealth of monkey data on the functional organization of the brain from single electrode mapping, radioisotope and histology studies. We report a new technique for fMRI in an awake co-operative rhesus macaque (Macaca mulatta) in a conventional clinical 1.5T MR scanner and present the first fMRI images from a macaque. Good resolution, signal-to-noise ratio and BOLD response (2.6-4.6%) have been achieved using the manufacturer's standard volume knee coil. T1 values of macaque gray and white matter (1490 ms, 1010 ms respectively) are higher than human brain, whereas T2 values are lower (55 ms, 48 ms respectively). An MR-compatible design for restraining the monkey is also described, along with a suitable EPI sequence for BOLD images, optimized for monkey T2, with voxel sizes from 29 to 61 microl, and MPRAGE sequence for anatomical studies with 0.8 mm isotropic resolution, optimized for monkey T1.

Enhanced visual responses in cat dLGN--potentiation by priming with excitatory amino acids.

Sustained iontophoresis of NMDA potentiated visual responses for minutes after the application in 16 of 38 cells (42%), peaking 3 min after the end of the application and declining to control levels within 12 min. Potentiation was also seen after application of ACPD (36%, n = 14) and AMPA (29%, n = 14), but not after application of ACh (n = 20). ACh also excites dLGN cells, but does not interact with amino acid receptors, and ACh receptors are not directly involved in the transmission of visual information. We suggest that this modulation is a form of visually induced potentiation which permits dynamic modification of the strength of visual information to be relayed to the cortex depending upon the history of previous activity levels.

Actions of compounds manipulating the nitric oxide system in the cat primary visual cortex.

1. We iontophoretically applied NG-nitro-L-arginine (L-NOArg), an inhibitor of nitric oxide synthase (NOS), to cells (n = 77) in area 17 of anaesthetized and paralysed cats while recording single-unit activity extracellularly. In twenty-nine out of seventy-seven cells (38%), compounds altering NO levels affected visual responses. 2. In twenty-five out of twenty-nine cells, L-NOArg non-selectively reduced visually elicited responses and spontaneous activity. These effects were reversed by co-application of L-arginine (L-Arg), which was without effect when applied alone. Application of the NO donor diethylamine-nitric oxide (DEA-NO) produced excitation in three out of eleven cells, all three cells showing suppression by L-NOArg. In ten cells the effect of the soluble analogue of cGMP, 8-bromo-cGMP, was tested. In three of those in which L-NOArg application reduced firing, 8-bromo-cGMP had an excitatory effect. In six out of fifteen cells tested, L-NOArg non-selectively reduced responses to NMDA and alpha-amino-3-hydroxy-5-methylisoxasole-4-propionic acid (AMPA). Again, co-application of L-Arg reversed this effect, without enhancing activity beyond control values. 3. In a further subpopulation of ten cells, L-NOArg decreased responses to ACh in five. 4. In four out of twenty-nine cells L-NOArg produced the opposite effect and increased visual responses. This was reversed by co-application of L-Arg. Some cells were also affected by 8-bromo-cGMP and DEA-NO in ways opposite to those described above. It is possible that the variety of effects seen here could also reflect trans-synaptic activation, or changes in local circuit activity. However, the most parsimonious explanation for our data is that NO differentially affects the activity of two populations of cortical cells, in the main causing a non-specific excitation.

An unusual effect of application of the amino acid L-arginine on cat visual cortical cells.

Iontophoretic application of L-arginine (L-Arg) resulted in a profound decrease in visually elicited and spontaneous activity in 22 of 77 (29%) cells in area 17 of the anaesthetized/paralysed cat. Duration was long, and cells did not recover pre-application activity levels, indicating permanent decline. This effect was obtained without change in the extracellularly recorded wave-form, demonstrating that this did not result from depolarization block. In the remaining 55 cells, application of L-Arg alone, at levels capable of eliciting inhibition as described above, was without effect. In 29 cells, L-Arg application was able to reverse the effect of inhibition of nitric oxide (NO) production. Populations of cells showing the depressive effect described above and those affected by NO modulation levels were mutually exclusive.

Further observations on the role of nitric oxide in the feline lateral geniculate nucleus.

We have examined the responses of a population of 77 cells in the dorsal lateral geniculate nucleus (dLGN) of the anaesthetized, paralysed cat. Here the synthetic enzyme for the production of nitric oxide, nitric oxide synthase, is found only in the presynaptic terminals of the cholinergic input from the brainstem. In our hands, iontophoretic application of inhibitors of this enzyme resulted both in significant decreases in visual responses and decreased responses to exogenous application of NMDA, effects which were reversed by coapplication of the natural substrate for nitric oxide synthase, L-arginine, but not the biologically inactive isomer, D-arginine. Nitroprusside and S-nitroso-N-acetylpenicillamine (SNAP), nitric oxide donors, but not L-arginine, were able to increase markedly both spontaneous activity and the responsiveness to NMDA application. Furthermore, SNAP application facilitated visual responses. Responses of cells in animals without retinal, cortical and parabrachial input to the LGN suggest a postsynaptic site of action of nitric oxide. This modulation of the gain of visual signals transmitted to the cortex suggests a completely novel pathway for nitric oxide regulation of function, as yet described only in primary sensory thalamus of the mammalian central nervous system.

Visual cortical mechanisms detecting focal orientation discontinuities.

Neurons in the primary visual cortex (V1) respond in well defined ways to stimuli within their classical receptive field, but these responses can be modified by stimuli overlying the surrounding area. For example patch-suppressed cells respond to gratings of a specific orientation within their classical receptive field, but the response diminishes if the grating is expanded to cover the surrounding area. We report here more complex effects in many such cells. When stimulated at their optimal orientation, introducing a surrounding field at a significantly different (for example, orthogonal) orientation enhanced their output by both a disinhibitory mechanism and an active facilitatory mechanism producing 'supra-optimal' responses. Importantly, some cells responded well if the orientations of centre and surround stimuli were swapped. The output reflected the discontinuity because neither stimulus component alone was effective. Under these stimulus conditions simultaneously recorded cells with orthogonally oriented receptive fields showed correlated firing consistent with neuronal binding to the configuration. We propose a mechanism integrating orientation-dependent information over adjacent areas of visual space to represent focal orientation discontinuities such as junctions or corners.

Differential properties of cells in the feline primary visual cortex providing the corticofugal feedback to the lateral geniculate nucleus and visual claustrum.

We have examined the responses of 141 layer VI cells in the feline visual cortex. Within this group we compared the responses of a subpopulation of cells checked for connectivity by electrical stimulation in the dLGN and the visual claustrum. The antidromically identified corticogeniculate projecting cells had relatively short receptive fields, as judged from length response curves, measured quantitatively, and were located at the "short" end of the receptive field length spectrum seen in the general population. Of the 17 corticogeniculate projecting cells, 71% were S type cells, which were typically monocular and directionally selective, with relatively long latencies following electrical stimulation. The remaining 29% were C type cells, also directionally selective, but with a wider spread of ocular dominance preferences and shorter latencies following electrical stimulation. S and C type subpopulations did not differ in their receptive field lengths. The mean receptive field length for this subpopulation was 2.2 degrees +/- 0.27, the shortest field being 1 degrees and the longest 5 degrees. The five layer VI cells activated by electrical stimulation from electrodes within the dorsocaudal (visual) claustrum all had much longer receptive field lengths than the corticogeniculate population, often 10 degrees or longer and were monocular and directionally selective S type cells. These data indicate that the information carried in the corticogeniculate stream (and that from layer VI directly to layer IV carried by axon collaterals) is relatively tightly focused in spatial terms whilst the less spatially focused, long receptive field output from layer VI projects to the claustrum.

Non-length-tuned cells in layers II/III and IV of the visual cortex: the effect of blockade of layer VI on responses to stimuli of different lengths.

We have previously shown, using a local inactivation technique, that layer VI provides a facilitatory input to the majority of hypercomplex cells located in layer IV above, and hence to layers II/III, which in many cases enhances length selectivity. However, many cells in these layers are not tuned for stimulus length, being equally responsive to long and short stimuli. Thus it is important to known whether layer VI can influence the responses of these cells. We have now used a similar paradigm of iontophoretic application of GABA to examine the effect of blockade of layer VI on the length tuning profiles of these cells in layers II-IV. During the blockade of layer VI, the most common effect, seen in 41% of the cells, was inhibition of visual responses, (i.e. commensurate with loss of a facilitatory input). An increase in response magnitude was found in 21% of the population, and responses were unaffected in 36% of cells tested. This suggests that the predominant influence of local regions of layer VI on this cell type, located in layers II/III and IV, is facilitatory, with a smaller proportion of cells receiving an inhibitory input. Such effects were seen even with the shortest lengths tested, suggesting once more that elements of layer VI are responsive to stimuli much shorter than was previously accepted. Thus these data suggest that layer VI plays a role in the generation of the response dynamics of non-length-tuned cells in overlying layers II/III and IV.

The role of nitric oxide in the transformation of visual information within the dorsal lateral geniculate nucleus of the cat.

We have shown that application of an inhibitor of the enzyme nitric oxide synthase (NOS) effectively suppresses the visual responses of relay cells in the dorsal lateral geniculate nucleus (dLGN) of the anaesthetized paralysed cat. Such suppression seems to result from a specific reduction in transmission via N-methyl-D-aspartic acid (NMDA) receptors, since iontophoretic application of the inhibitor of NOS selectively and in a dose-dependent manner decreased the responses to exogenously applied NMDA. Responses to other exogenously applied amino acid agonists, such as quisqualate (Quis), kainate (Kain) and alpha-amino-3-hydroxy-5-5-methyl-4-isoxazole-propionic acid (AMPA) were largely unaffected. Furthermore, the excitatory action of acetylcholine (ACh), normally co-localized with NOS in axonal terminals within the dLGN arising from the brainstem, was also unaffected. Unlike some other actions of nitric oxide (NO), this role seems not to involve an increase in production of cyclic guanosine-3',5'-mono-phosphate (cGMP), since application of the membrane permeable cGMP analogue 8-bromo-cGMP did not alter the suppressive effect of NOS inhibitors on either visual or NMDA evoked responses. We conclude that the normal function of NO at this level of the visual system is permissive, allowing full expression of NMDA mediated visually elicited information.

Effects of vasoactive intestinal polypeptide on the response properties of cells in area 17 of the cat visual cortex.

1. Vasoactive intestinal polypeptide (VIP) was iontophoretically applied to a population of 90 single cells in the primary visual cortex (area 17) of the cat. Response magnitude, response selectivity, spontaneous activity, and the ratio between the visual response and spontaneous activity (signal-to-noise ratio) of the cells were assessed quantitatively before and during drug application. 2. VIP had little effect in the absence of visual stimulation, with only 29/90 (32%) of the cells showing a change of even 1 sp/s in their spontaneous activity. In contrast it had a clear effect on the visual responses of the majority (73/90, 81%) of the cells tested. 3. VIP produced a substantial change (i.e., > or = 40%) in optimal response magnitude for 57 of the affected cells. Of these 65% were facilitated, usually with no change or an improvement in signal-to-noise ratio and direction selectivity. The remaining cells were inhibited, with more variable effects on their visual response characteristics, and were found predominantly in the superficial laminae. 4. The effects of VIP bore a remarkable resemblance to those reported previously for the muscarinic action of acetylcholine (ACh). VIP and a muscarinic cholinergic agonist, either ACh or acetyl-beta-methacholine (MeCh), were therefore applied in turn to a group of 40 cells. In 23 cases VIP and the muscarinic agonist were also applied simultaneously. 5. The effects of VIP and the cholinergic agonist matched in 92% of the cases where both drugs were effective. That is to say, cells that were facilitated by VIP were facilitated also by ACh or MeCh, and vice versa. In many instances there was a clear similarity in the pattern as well as the direction of the effects produced by the two substances. The result of simultaneous application was generally additive. 6. These data suggest that VIP and ACh activate very similar postsynaptic mechanisms, and share a closely related function at the level of individual cortical cells. Thus VIP may facilitate the responses of both the excitatory and the inhibitory components of the cortical circuit, leading to an overall increase in responsiveness and selectivity. In contrast to the cholinergic input from the basal forebrain, however, the VIP-positive cortical cells are likely to exert a very localized influence, over a circumscribed region of the cortex, in response to the presence of an effective visual stimulus.