A frontoparietal network for volitional control of gaze following.

Gaze following is a major element of non-verbal communication and important for successful social interactions. Human gaze following is a fast and almost reflex-like behaviour, yet it can be volitionally controlled and suppressed to some extent if inappropriate or unnecessary, given the social context. In order to identify the neural basis of the cognitive control of gaze following, we carried out an event-related fMRI experiment, in which human subjects' eye movements were tracked while they were exposed to gaze cues in two distinct contexts: A baseline gaze following condition in which subjects were instructed to use gaze cues to shift their attention to a gazed-at spatial target and a control condition in which the subjects were required to ignore the gaze cue and instead to shift their attention to a distinct spatial target to be selected based on a colour mapping rule, requiring the suppression of gaze following. We could identify a suppression-related blood-oxygen-level-dependent (BOLD) response in a frontoparietal network comprising dorsolateral prefrontal cortex (dlPFC), orbitofrontal cortex (OFC), the anterior insula, precuneus, and posterior parietal cortex (PPC). These findings suggest that overexcitation of frontoparietal circuits in turn suppressing the gaze following patch might be a potential cause of gaze following deficits in clinical populations.

Parietal blood oxygenation level-dependent response evoked by covert visual search reflects set-size effect in monkeys.

Distinguishing a target from distractors during visual search is crucial for goal-directed behaviour. The more distractors that are presented with the target, the larger is the subject's error rate. This observation defines the set-size effect in visual search. Neurons in areas related to attention and eye movements, like the lateral intraparietal area (LIP) and frontal eye field (FEF), diminish their firing rates when the number of distractors increases, in line with the behavioural set-size effect. Furthermore, human imaging studies that have tried to delineate cortical areas modulating their blood oxygenation level-dependent (BOLD) response with set size have yielded contradictory results. In order to test whether BOLD imaging of the rhesus monkey cortex yields results consistent with the electrophysiological findings and, moreover, to clarify if additional other cortical regions beyond the two hitherto implicated are involved in this process, we studied monkeys while performing a covert visual search task. When varying the number of distractors in the search task, we observed a monotonic increase in error rates when search time was kept constant as was expected if monkeys resorted to a serial search strategy. Visual search consistently evoked robust BOLD activity in the monkey FEF and a region in the intraparietal sulcus in its lateral and middle part, probably involving area LIP. Whereas the BOLD response in the FEF did not depend on set size, the LIP signal increased in parallel with set size. These results demonstrate the virtue of BOLD imaging in monkeys when trying to delineate cortical areas underlying a cognitive process like visual search. However, they also demonstrate the caution needed when inferring neural activity from BOLD activity.

The dependencies of fronto-parietal BOLD responses evoked by covert visual search suggest eye-centred coding.

Visual scenes explored covertly are initially represented in a retinal frame of reference (FOR). On the other hand, 'later' stages of the cortical network allocating spatial attention most probably use non-retinal or non-eye-centred representations as they may ease the integration of different sensory modalities for the formation of supramodal representations of space. We tested if the cortical areas involved in shifting covert attention are based on eye-centred or non-eye-centred coding by using functional magnetic resonance imaging. Subjects were scanned while detecting a target item (a regularly oriented 'L') amidst a set of distractors (rotated 'L's). The array was centred either 5° right or left of the fixation point, independent of eye-gaze orientation, the latter varied in three steps: straight relative to the head, 10° left or 10° right. A quantitative comparison of the blood-oxygen-level-dependent (BOLD) responses for the three eye-gaze orientations revealed stronger BOLD responses in the right intraparietal sulcus (IPS) and the right frontal eye field (FEF) for search in the contralateral (i.e. left) eye-centred space, independent of whether the array was located in the right or left head-centred hemispace. The left IPS showed the reverse pattern, i.e. an activation by search in the right eye-centred hemispace. In other words, the IPS and the right FEF, members of the cortical network underlying covert search, operate in an eye-centred FOR.

Frontal, Parietal, and Temporal Brain Areas Are Differentially Activated When Disambiguating Potential Objects of Joint Attention.

Humans establish joint attention with others by following the other's gaze. Previous work has suggested that a cortical patch (gaze-following patch, GFP) close to the posterior superior temporal sulcus (pSTS) may serve as a link between the extraction of the other's gaze direction and the resulting shifts of attention, mediated by human lateral intraparietal area (hLIP). However, it is not clear how the brain copes with situations in which information on gaze direction alone is insufficient to identify the target object because more than one may lie along the gaze vector. In this fMRI study, we tested human subjects on a paradigm that allowed the identification of a target object based on the integration of the other's gaze direction and information provided by an auditory cue on the relevant object category. Whereas the GFP activity turned out to be fully determined by the use of gaze direction, activity in hLIP reflected the total information needed to pinpoint the target. Moreover, in an exploratory analysis, we found that a region in the inferior frontal junction (IFJ) was sensitive to the total information on the target. An examination of the BOLD time courses in the three identified areas suggests functionally complementary roles. Although the GFP seems to primarily process directional information stemming from the other's gaze, the IFJ may help to analyze the scene when gaze direction and auditory information are not sufficient to pinpoint the target. Finally, hLIP integrates both streams of information to shift attention to distinct spatial locations.

Normal spatial attention but impaired saccades and visual motion perception after lesions of the monkey cerebellum.

Lesions of the cerebellum produce deficits in movement and motor learning. Saccadic dysmetria, for example, is caused by lesions of the posterior cerebellar vermis. Monkeys and patients with such lesions are unable to modify the amplitude of saccades. Some have suggested that the effects on eye movements might reflect a more global cognitive deficit caused by the cerebellar lesion. We tested that idea by studying the effects of vermis lesions on attention as well as saccadic eye movements, visual motion perception, and luminance change detection. Lesions in posterior vermis of four monkeys caused the known deficits in saccadic control. Attention tested by examination of acuity threshold changes induced by prior cueing of the location of the targets remained normal after vermis lesions. Luminance change detection was also unaffected by the lesions. In one case, after a lesion restricted to lobulus VIII, the animal had impaired visual motion perception.

Optimizing visual motion perception during eye movements.

We usually perceive a stationary, stable world and we are able to correctly estimate the direction of heading from optic flow despite coherent visual motion induced by eye movements. This astonishing example of perceptual invariance results from a comparison of visual information with internal reference signals predicting the visual consequences of an eye movement. Here we demonstrate that the reference signal predicting the consequences of smooth-pursuit eye movements is continuously calibrated on the basis of direction-selective interactions between the pursuit motor command and the rotational flow induced by the eye movement, thereby minimizing imperfections of the reference signal and guaranteeing an ecologically optimal interpretation of visual motion.

Binding of signals relevant for action: towards a hypothesis of the functional role of the pontine nuclei.

If numbers matter, the projection that connects the cerebral cortex to the cerebellum is probably one of the most-important pathways through the CNS. Its extensive development as one ascends the phylogenetic scale parallels that of the cerebral hemispheres and the cerebellum, and it accompanies improvements in motor skills, suggesting that this system might have a decisive role in the generation of skilled movement. This article focuses on the pontine nuclei (PN), which are intercalated in the cerebro-cerebellar pathway, a large nuclear complex in the ventral brainstem of mammals, whose raison d'être has as yet not been examined. By considering recent morphological and electrophysiological findings, this article argues that the PN are an interface that is needed to accommodate the grossly different computational principles governing the cerebral cortex and the cerebellum.

Transient change in GABA(A) receptor subunit mRNA expression in Lurcher cerebellar nuclei during Purkinje cell degeneration.

BACKGROUND: Lurcher mice suffer from a complete Purkinje cell (PC) loss in the first four postnatal weeks. Parallel to this degeneration, GABAergic synapses in the deep cerebellar nuclei (DCN), the major recipient of the inhibitory PC projection, increase synaptic conductance. Here, we further investigated this phenomenon, using real-time RT-PCR to assess GABAA receptor subunit gene expression during PC degeneration. RESULTS: We observed a specific reduction in gamma2 subunit gene expression, while alpha1-5, beta1-2, gamma1,3 and delta subunits were unaffected. We made two further specific findings. First, the difference in gene expression was shown in tissue from DCN only. Neither the hippocampus nor coronal sections through the forebrain showed such effects. Furthermore, the involvement of different levels of corticosterone, a possible humeral trigger for differences in gene expression, could be excluded. Second, like the known potentiation of GABAergic synapses, the gamma2 down-regulation was present only after the onset of degeneration at p14. The difference in gamma2 mRNA expression, however, appeared transient, since it was no longer detectable in adult Lurcher mice. CONCLUSION: In conclusion, the down-regulation of gamma2 subunits may be related to differences in synaptic efficacy and, as such, may reflect the initial phase of adaptive responses of DCN tissue to massive GABAergic deafferentation. Its transient course, however, does not support the idea that modulations in GABAergic transmission are at the basis of the well-known DCN-based functional benefit of Lurcher mice present throughout their life.

Saccadic dysmetria and adaptation after lesions of the cerebellar cortex.

We studied the effects of small lesions of the oculomotor vermis of the cerebellar cortex on the ability of monkeys to execute and adapt saccadic eye movements. For saccades in one horizontal direction, the lesions led to an initial gross hypometria and a permanent abolition of the capacity for rapid adaptation. Mean saccade amplitude recovered from the initial hypometria, although variability remained high. A series of hundreds of repetitive saccades in the same direction resulted in gradual decrement of amplitude. Saccades in other directions were less strongly affected by the lesions. We suggest the following. (1) The cerebellar cortex is constantly recalibrating the saccadic system, thus compensating for rapid biomechanical changes such as might be caused by muscle fatigue. (2) A mechanism capable of slow recovery from dysmetria is revealed despite the permanent absence of rapid adaptation.

Responses of Visual-Tracking Neurons from Cortical Area MST-I to Visual, Eye and Head Motion.

Thirty-one neurons which exhibited ocular pursuit-related activity [visual-tracking (VT) neurons] were found clustered within area MST-I (the lateral part of area MST) of two rhesus monkeys. Their responses were studied to determine whether this activity was correlated only with pursuit eye movement or with head movement as well. The latter hypothesis appeared to be preferable since visual, eye movement and head movement inputs were found to be mapped in register onto most of these cells. First, in each cell tested (n=19) the pursuit response persisted even in the absence of retinal image motion, offering clear evidence for non-visual input. Second, 22 of the 31 cells were directionally responsive to moving visual stimuli and in 20 of these the preferred directions for the visual motion and pursuit responses agreed closely. Responses were also obtained from many of the same cells during suppression of both the horizontal and the vertical vestibulo-ocular reflex (VOR). In each case, where directional visual, pursuit and VOR suppression responses were each obtained, vector addition of responses during suppression of the horizontal and vertical VOR resulted in an estimated preferred direction for head rotation which was closely aligned with the preferred direction previously obtained for eye motion or visual motion. In addition, the preferred direction of head movement was conserved even when the VOR was elicited by passive head rotation in complete darkness, although the responses in this instance were, on average, only 62% of those obtained during VOR suppression. Our interpretation is that, at present, MST-I VT neurons are best described as encoding the direction of target motion in space-centred coordinates by integrating inputs reflecting retinal image motion plus eye and head movement.

Morphology, number, and distribution of putative GABA-ergic neurons in the basilar pontine gray of the monkey.

We used an antibody raised against the inhibitory transmitter gamma-aminobutyric acid (GABA) in the basilar pontine gray (bpg) of the monkey. Somata, dendrites, and a plexus of probably axonal fibers exhibited GABA-like immunoreactivity. Labeled neurons were small with oval, triangular, or circular soma shape. They gave rise to 2 to 4 dendrites with little branching. No axons were seen issuing from the soma. Occasionally, appendages consisting of spheroidal bodies positioned at the distal end of tenuous stalks and (in 1 cell) axonlike processes were observed to originate from dendrites. According to their morphology, we suggest that these putative GABA-ergic neurons may correspond to the type II neurons observed in Golgi material. The average number of putative GABA-ergic cells in 40-micron sections was about 30/mm2. When compared with Nissl-stained sections, these amounted to about 5% of all cells. There was no substantial variation in average density in different parts of the bpg. However, labeled cells tended to lie in clusters, perhaps related to the well-established input-output compartments of the bpg. The demonstration of a significant population of putative inhibitory neurons challenges the traditional view of the bpg, which suggests that this brainstem cell group functions as a simple relay exchanging signals between cortex and cerebellum.

Brainstem afferents to the lateral mesencephalic tegmental region of the cat.

The lateral mesencephalic tegmental region (LTR) is a part of the midbrain reticular formation characterized by the presence of neurons exhibiting head movement-related discharge modulation. In addition, the LTR contains directionally selective visual units. Possible sources for these vestibular and visual signals were studied by retrograde axonal transport of horseradish peroxidase and three different fluorescent tracers (rhodamine, fast blue, and fluorogold) injected into various parts of the LTR. All injections into the LTR traced afferents from the vestibular nuclei and from the nucleus prepositus hypoglossi. Predominant projections were derived from the ipsilateral nucleus prepositus hypoglossi and the ipsilateral medial vestibular nucleus, whereas the observed inputs from the inferior, lateral, and superior vestibular nuclei were much weaker. Further inputs to the LTR originated in the deep and intermediate layers of the ipsilateral superior colliculus and the ipsilateral periaqueductal gray, the contralateral LTR, and the contralateral marginal nucleus of the brachium conjunctivum. Tracer deposits in medial parts of the tegmentum neighboring the LTR never produced the pattern of afferents observed after injections into the LTR. Our results suggest that afferents from the deeper layers of the superior colliculus are probably the source of visual signals in the LTR and that head movement-related responses are likely to be derived from the nucleus prepositus hypoglossi and the medial vestibular nucleus.

Comparison of projection neurons in the pontine nuclei and the nucleus reticularis tegmenti pontis of the rat.

Dendritic features of identified projection neurons in two precerebellar nuclei, the pontine nuclei (PN) and the nucleus reticularis tegmenti pontis (NRTP) were established by using a combination of retrograde tracing (injection of fluorogold or rhodamine labelled latex micro-spheres into the cerebellum) with subsequent intracellular filling (lucifer yellow) in fixed slices of pontine brainstem. A multivariate analysis revealed that parameters selected to characterize the dendritic tree such as size of dendritic field, number of branching points, and length of terminal dendrites did not deviate significantly between different regions of the PN and the NRTP. On the other hand, projection neurons in ventral regions of the PN were characterized by an irregular coverage of their distal dendrites by appendages while those in the dorsal PN and the NRTP were virtually devoid of them. The NRTP, dorsal, and medial PN tended to display larger somata and more primary dendrites than ventral regions of the PN. These differences, however, do not allow the differentiation of projection neurons within the PN from those in the NRTP. They rather reflect a dorso-ventral gradient ignoring the border between the nuclei. Accordingly, a cluster analysis did not differentiate distinct types of projection neurons within the total sample. In both nuclei, multiple linear regression analysis revealed that the size of dendritic fields was strongly correlated with the length of terminal dendrites while it did not depend on other parameters of the dendritic field. Thus, larger dendritic fields seem not to be accompanied by a higher complexity but rather may be used to extend the reach of a projection neuron within the arrangement of afferent terminals. We suggest that these similarities within dendritic properties in PN and NRTP projection neurons reflect similar processing of afferent information in both precerebellar nuclei.

Patterns of projections from the pontine nuclei and the nucleus reticularis tegmenti pontis to the posterior vermis in the rhesus monkey: a study using retrograde tracers.

In an attempt to estimate the relative importance of the various afferent systems impinging on the oculomotor regions of the posterior cerebellar vermis of rhesus monkeys in quantitative terms, we made small injections of the retrograde tracers fast blue, fluorogold, and cholera toxin into different parts of a region of the posterior vermis, spanning lobuli VI through VIII. We found that the vast majority of cells retrogradely labeled by injections of lobulus VII and its vicinity lay in the pontine nuclei (PN), the nucleus reticularis tegmenti pontis (NRTP), and subnuclei a and b of the medial accessory olive. The remaining retrogradely labeled cells were distributed among a number of other brainstem nuclei or regions including the paramedian pontine reticular formation (PPRF). A quantitative analysis showed that the projection from the NRTP to the posterior vermis was focused on lobulus VII. While the projection from the PN as a whole demonstrated a preference for the more caudal parts of the posterior vermis, a closer look at the different regions of the PN revealed that cells located in the dorsal parts of the PN showed the same preference for lobulus VII as cells in the NRTP. The dorsal PN are a major gateway for cortical input to the cerebellum, related to visual processing and visually guided eye movements. Conversely, the NRTP, likewise involved in visually guided eye movements, is much more dependent on subcortical afferents. The observed convergence of input derived from the dorsal PN and the NRTP in oculomotor lobulus VII therefore suggests that a major function of this part of the vermis might be the integration of cortical and subcortical signals important for visually guided eye movements.

Morphology and mosaics of VIP-like immunoreactive neurons in the retina of the rhesus monkey.

Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide that has been demonstrated to reside in cells ( = VIP+ cells) of the retinae of various vertebrate species. In an attempt to study the morphology and distribution of VIP+ cells in the retina of the rhesus monkey in more detail, we subjected VIP+ cells observed in cryostat sections or wholemounts rhesus monkey retinae to a quantitative analysis. VIP+ cells were found to reside in the innermost row of the inner nuclear layer (INL) and in the ganglion cell layer (GCL) in similar numbers (estimate: 50 cells/mm2 at 6-10 mm eccentricity each) and only on rare occasions (12% of all VIP+ cells) in varying positions within the inner plexiform layer (IPL). Somata of VIP+ cells were circular and had a mean diameter of 9.1 microns. They gave rise to 1-3 main dendrites, which were usually oriented toward the IPL. Main dendrites ramified widely into thin fibers (dendritic field diameter less than = 1 mm), carrying varicose swellings. The fibers that contributed to one and the same plexus of VIP+ fibers preferred the middle third of the IPL, independent of the positions of the parent somata. A quantitative analysis of nearest-neighbour distances in the retinal wholemount preparation suggested that VIP+ cells in the GCL and in the INL might be distributed according to 2 independent mosaics. A comparison with Golgi-stained material leads to the tentative equation of VIP+ cells with the "spiny" A12 amacrine cell of Mariani ('90). Whereas the low density and large dendritic field size of VIP+ cells might suggest a more widespread function, the varicose dendritic morphology seems to be more compatible with functionally independent dendritic subunits mediating localized effects.

Pharmacological modulation of on and off ganglion cells in the cat retina.

We studied the effects of 2-amino-4-phosphonobutyric acid and 2-amino-4-phosphonovaleric acid, which are antagonists to excitatory amino acids, on brisk-sustained(X) and brisk-transient(Y) ganglion cells in the cat retina. The ganglion cells were recorded extracellularly with a multibarreled electrode in the intact eye in vivo and drugs were applied iontophoretically. We found contrasting effects of 2-amino-4-phosphonobutyric acid and 2-amino-4-phosphonovaleric acid on ON- and OFF-centre cells irrespective of the brisk-sustained(X)/brisk-transient(Y) dichotomy. The maintained discharge and the light response of ON-centre cells decreased during 2-amino-4-phosphonobutyric acid and 2-amino-4-phosphonovaleric acid application, whereas the maintained discharge of OFF-centre cells increased. The light response of OFF-centre cells was not significantly affected. 2-Amino-4-phosphonovaleric acid was generally less potent than 2-amino-4-phosphonobutyric acid. It was shown in the mudpuppy retina [Slaughter and Miller (1981) Science, N.Y. 211, 182-185; Slaughter and Miller (1981) Invest. ophthal. Vis. Sci. 20, 44] that 2-amino-4-phosphonobutyric and 2-amino-4-phosphonovaleric acid selectively block the response of ON-bipolar cells. Assuming that these drugs act on the same synaptic sites in the cat retina, one expects a block of ON-centre ganglion cells. Moreover, the drug response of OFF-centre ganglion cells is then consistent with Sterling's hypothesis [Sterling (1983) A. Rev. Neurosci. 6, 149-185] that OFF-ganglion cells receive a direct inhibitory input from ON-bipolars. For some period 19 out of 108 cells responded to 2-amino-4-phosphonobutyric acid and 2-amino-4-phosphonovaleric acid in an opposite way to that described above: ON-centre cells increased and OFF-centre cells decreased their maintained discharge. It is proposed that this "reverse response" may be mediated by autoreceptors to excitatory amino acids or due to different receptor sites triggering antagonistic response mechanisms.

Cholecystokinin in the cat retina. Action of exogenous CCK8 and localization of cholecystokinin-like immunoreactivity.

The effects of applying cholecystokinin (CCK8) iontophoretically onto cat retinal ganglion cells were studied in the optically intact eye of the cat. CCK8 suppressed both the maintained and the light evoked discharge of brisk ganglion cells, irrespective of their being on- or off-center, brisk-transient, or brisk-sustained and independent of the state of light adaptation. The inhibitory action of CCK8 in the cat retina is opposite from its excitatory action in other parts of the brain. Using an antiserum to cholecystokinin, immunoreactivity was localized in horizontal cells and amacrine cells of the cat retina. Inconsistently immunoreactivity also was found in ganglion cells and fibers.

Action of iontophoretically applied dopamine on cat retinal ganglion cells.

Iontophoretically applied dopamine reversibly altered both the spontaneous firing rates and the light evoked responses of retinal ganglion cells in the intact eye of the cat. The effects of dopamine were the same for all cell classes encountered: on brisk-transient, off brisk-transient, on brisk-sustained, off brisk-sustained, sluggish and non-concentrically organized cells. Dopamine reduced the spontaneous firing rates of all cells. In response to light stimulation, the inhibitory response phase (light off in on ganglion cells, light on in off ganglion cells) was also reduced by dopamine. However, the excitatory response phase (light on in on ganglion cells, light off in off ganglion cells) was only consistently reduced for optimal spot stimulation: for wholefield or annular stimulation the excitatory response phase was reduced in 76% of cells, whereas for the remaining cells it was unchanged or even increased. The net effect of these alterations was to cause a shift in the centre surround balance of the cell output in favour of the centre for 82% of concentrically organized cells. These results are discussed in the context of present anatomical knowledge.

Localization of aspartate aminotransferase and cytochrome oxidase in the cat retina.

Using immunohistochemical techniques, we demonstrate aspartate aminotransferase (AAT)-like immunoreactivity in cone pedicles and ganglion cells of the cat retina. An identical pattern was seen when we stained for cytochrome oxidase activity, a marker for neurons which have a high metabolic activity. Tetrodotoxin selectively blocked the cytochrome oxidase labeling of ganglion cells. AAT is a key enzyme in the metabolism of aspartate and glutamate and has been proposed as a marker for neurons which use aspartate/glutamate as a neurotransmitter. Due to the close correlation between AAT-like immunoreactivity and cytochrome oxidase activity, we suggest that, at least in the retina, AAT-like immunoreactivity in fact labels cells which have a high metabolic activity.

Modification of the Filehne illusion by conditioning visual stimuli.

During smooth pursuit eye movements made across a stationary background an illusory motion of the background is perceived (Filehne illusion). The present study was undertaken in order to test if the Filehne illusion can be influenced by information unrelated to the retinal image slip prevailing and to the eye movement being executed. The Filehne illusion was measured in eight subjects by determining the amount of external background motion required to compensate for the illusory background motion induced by 12 deg/sec rightward smooth pursuit. Using a two-alternative forced-choice method, test trials, which yielded the estimate of the Filehne illusion, were randomly interleaved with conditioning trials, in which high retinal image slip was created by background stimuli moving at a constant horizontal velocity. There was a highly reproducible monotic relationship between the size and direction of the Filehne illusion and the velocity of the background stimulus in the conditioning trials with the following extremes: large Filehne illusions with illusory motion to the right occurred for conditioning stimuli moving to the left, i.e. opposite to the direction of eye movement in the test trials, while conversely, conditioning stimuli moving to the right yielded Filehne illusions close to zero. Additional controls suggest that passive motion aftereffects are unlikely to account for the modulation of the Filehne illusion by the conditioning stimulus. We hypothesize that this modification might reflect the dynamic character of the networks elaborating spatial constancy.