Using perceptual signatures to define and dissociate condition-specific neural etiology: autism and fragile X syndrome as model conditions.

The functional link between genetic alteration and behavioral end-state is rarely straightforward and never linear. Cases where neurodevelopmental conditions defined by a distinct genetic etiology share behavioral phenotypes are exemplary, as is the case for autism and Fragile X Syndrome (FXS). In this paper and its companion paper, we propose a method for assessing the functional link between genotype and neural alteration across these target conditions by comparing their perceptual signatures. In the present paper, we discuss how such signatures can be used to (1) define and differentiate various aspects of neural functioning in autism and FXS, and subsequently, (2) to infer candidate causal (genetic) mechanisms based on such signatures (see companion paper, this issue).

Associating neural alterations and genotype in autism and fragile x syndrome: incorporating perceptual phenotypes in causal modeling.

We have previously described (see companion paper, this issue) the utility of using perceptual signatures for defining and dissociating condition-specific neural functioning underlying early visual processes in autism and FXS. These perceptually-driven hypotheses are based on differential performance evidenced only at the earliest stages of visual information processing, mediated by local neural network functioning. In this paper, we first review how most large-scale neural models are unable to address atypical low-level perceptual functioning in autism, and then suggest how condition-specific, local neural endophenotypes (described in our companion paper) can be incorporated into causal models to infer target candidate gene or gene clusters that are implicated in autism's pathogenesis. The usefulness of such a translational research approach is discussed.

Can anchor models explain inverted-U effects in facial judgments?

Researchers in a variety of disciplines have found that participants take less time and generate less diversity of responses when judging stimuli towards the ends of a scale than when judging those near the center. Three types of models, connectionist, exemplar, and anchor models, can account for these inverted-U effects. Anchor models assume that stimuli near the ends of the scale are used as anchors to compare with the other stimuli, implying that anchor representations are activated for each judgment. Therefore, participants should learn the anchors better than the other stimuli. Participants were 40 students from the Department of Psychology at McGill University (5 men; M age = 20.5 yr.; SD = 1.7). The experiment involved two tasks: first participants judged facial gender and then performed a recognition task. The results showed no correlation between the position on the gender scale and recognition accuracy. Several hypotheses were offered to explain these results.

Batch immunostaining for large-scale protein detection in the whole monkey brain.

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

Dorsal-ventral integration in the recognition of motion-defined unfamiliar faces.

The primate visual system is organized into two parallel anatomical pathways, both originating in early visual areas but terminating in posterior parietal or inferior temporal regions. Classically, these two pathways have been thought to subserve spatial vision and visual guided actions (dorsal pathway) and object identification (ventral pathway). However, evidence is accumulating that dorsal visual areas may also represent many aspects of object shape in absence of demands for attention or action. Dorsal visual areas exhibit selectivity for three-dimensional cues of depth and are considered necessary for the extraction of surfaces from depth cues and can carry out cognitive functions with such cues as well. These results suggest that dorsal visual areas may participate in object recognition, but it is unclear to what capacity. Here, we tested whether three-dimensional structure-from-motion (SFM) cues, thought to be computed exclusively by dorsal stream mechanisms, are sufficient to drive complex object recognition. We then tested whether recognition of such stimuli relies on dorsal stream mechanisms alone, or whether dorsal-ventral integration is invoked. Results suggest that such cues are sufficient to drive unfamiliar face recognition in normal participants and that ventral stream areas are necessary for both identification and learning of unfamiliar faces from SFM cues.

Whole-brain expression analysis of FMRP in adult monkey and its relationship to cognitive deficits in fragile X syndrome.

Fragile X syndrome (FXS) is one of the most prevalent forms of heritable mental retardation and developmental delay in males. The syndrome is caused by the silencing of a single gene (fragile X mental retardation-1; FMR1) and the lack of expression of its protein product (fragile X mental retardation-1 protein; FMRP). Recent work has linked the high expression levels of FMRP in the magnocellular layers of lateral geniculate nucleus (M-LGN) of the visual system to a specific reduction of perceptual function known to be mediated by that neural structure. This finding has given rise to the intriguing notion that FMRP expression level may be used as an index of susceptibility of specific brain regions to the observed perceptual and cognitive deficits in FXS. We undertook a comprehensive expression profiling study of FMRP in the monkey to obtain further insight into the link between FMPR expression and the behavioural impact of its loss in FXS. We report here the first 3D whole-brain map of FMRP expression in the Old-World monkey and show that certain brain structures display high FMRP levels, such as the cerebellum, striatum, and temporal lobe structures. This finding provides support for the notion that FMRP expression loss is linked to behavioural and cognitive impairment associated with these structures. We argue that whole-brain FMRP expression mapping may be used to formulate and test new hypotheses about other forms of impairments in FXS that were not specifically examined in this study.

Inverted-U effects generalize to the judgment of subjective properties of faces.

Researchers studying absolute identification have long known that it takes more time to identify a stimulus in the middle of a range than one at the extremes. That is, there is an inverted-U relation between mean response time and response position. In this task, an inverted-U relation also exists between response uncertainty and response position. Similarly, an inverted-U relation between mean response time and response position has been found for psychometric measures involving questions about the self. However, psychophysicists explain these inverted-U effects differently than do self-schema researchers. We propose an integrative framework in which task constraints explain these effects. To verify the generality of these inverted-U effects, we hypothesized that they would exist in three tasks having similar constraints--in this case, tasks involving the judgment of subjective properties of faces on a Likert-type scale. Our results are consistent with this hypothesis. We discuss the relevance of the results for other applications of Likert-type scales.

Imagine Jane and identify John: face identity aftereffects induced by imagined faces.

It is not known whether prolonged exposure to perceived and imagined complex visual images produces similar shifts in subsequent perception through selective adaptation. This question is important because a positive finding would suggest that perception and imagery of visual stimuli are mediated by shared neural networks. In this study, we used a selective adaptation procedure designed to induce high-level face-identity aftereffects--a phenomenon in which extended exposure to a particular face facilitates recognition of subsequent faces with opposite features while impairing recognition of all other faces. We report here that adaptation to either real or imagined faces produces a similar shift in perception and that identity boundaries represented in real and imagined faces are equivalent. Together, our results show that identity information contained in imagined and real faces produce similar behavioral outcomes. Our findings of high-level visual aftereffects induced by imagined stimuli can be taken as evidence for the involvement of shared neural networks that mediate perception and imagery of complex visual stimuli.

Gene profiling of pooled single neuronal cell bodies from laser capture microdissected vervet monkey lateral geniculate nucleus hybridized to the Rhesus Macaque Genome Array.

This report is based on an ongoing study to examine gene expression differences in monkey lateral geniculate nucleus (LGN). Here, samples from an Old World species, the vervet monkey (Cercopithecus aethiops), were cross-hybridized to the Rhesus Macaque Genome Array (Affymetrix). Microarray analysis was performed using laser capture microdissected populations of individual neuronal cell bodies isolated from the LGN compared to heterogeneous samples from whole lamina. Our results indicated that cross-species hybridization of microdissected brain tissue samples from vervet monkeys to the Rhesus array produced reliable and biologically relevant data sets. We present the first list of genes enriched in the large neuronal cell bodies of the LGN. We found that these cell bodies are concentrated with genes involved in metabolic processes and protein synthesis, whereas signaling molecules including chemokines and integrins were expressed at higher levels within heterogeneous samples. Our data set also provides support for a contribution of Wnt signaling in adult monkey LGN.

Differences in attentional involvement underlying the perception of distinctive and typical faces.

Differences in human faces can be evaluated along a continuum that ranges from 'distinctive' to 'typical.' We examined processing differences between distinctive and typical faces by two attentional tasks that induce attentional blink (AB). Given that AB is believed to reflect temporal or capacity limits of attention, stimuli that survive AB are believed to be associated with greater processing efficiency. In a change-detection task, participants were required to detect changes in the two pairs of faces that were presented in rapid succession. Changes involving the distinctive face of a pair were more likely to be detected than those involving a typical face. In a face-identification task, distinctive faces embedded in a rapid serial visual presentation (RSVP) stream were identified with a greater accuracy than typical faces. Together, our results suggest that distinctive faces are associated with greater processing efficiency and may be explained in terms of perceptual salience, a stimulus dimension known to attract attention.

Activity of common marmosets (Callithrix jacchus) in limited spaces: hand movement characteristics.

The increasing popularity of marmoset monkeys (Callithrix jacchus) in anatomical, behavioral, and electrophysiological studies has called for a detailed analysis of their natural behavior within limited spaces. In the present study, the authors analyzed hand movements during horizontal and vertical progressions in a cylinder. The trajectory of each hand covered the entire cylinder floor during horizontal progressions and the entire cylinder wall during vertical progressions. Different marmosets have different patterns of hand movement. The average maximum angle of hand movements for all marmosets during horizontal and vertical progressions oscillates, although the average over time is constant and similar for both hands, whereas head movements during horizontal progressions become smaller with successive progressions. Another observed difference between rats and monkeys was in the size of head and hand movements at the beginning of each experimental session. During the 1st horizontal progression, all marmosets moved their heads to a greater extent than their hands. This sequential head and hand movement is referred as bistable behavior. The bistable pattern of motor behavior, which was also observed in successive progressions, may be derived from an inherent fear of predators or exploratory interest of a novel environment.

Dynamic changes in CREB phosphorylation and neuroadaptive gene expression in area V1 of adult monkeys after monocular enucleation.

Our understanding of the molecular events that emerge after change in sensory input remains elusive, especially with regard to mature area V1. Here, we characterized P-CREB expression in area V1 of monkeys at multiple time-points after monocular enucleation (ME) to assess the possible contribution of CREB in visually deprived neocortex. Immunoblot assays and immunostainings showed that P-CREB is dynamically regulated in adult area V1, reaching a peak level between 5 and 30 days after ME, and becoming reduced at the 90-day post-ME time-point. This striking temporal increase in P-CREB level was paralleled by a concomitant increase of two CREB-regulated pro-survival effectors, namely Bcl-2 and Bcl-w. We present our results in the context of recent advances about adult visual neocortex and propose that ME induces a multifaceted CREB-mediated response that favors intrinsic stability of neurons and facilitates mature cortical networks to reorganize over a prolonged period.

Neuroanatomical, molecular genetic, and behavioral correlates of fragile X syndrome.

Fragile X syndrome (FXS) is a leading cause of inherited mental retardation. In the vast majority of cases, this X-linked disorder is due to a CGG expansion in the 5' untranslated region of the fmr-1 gene and the resulting decreased expression of its associated protein, FMRP. FXS is characterized by a number of cognitive, behavioral, anatomical, and biological abnormalities. FXS provides a unique opportunity to study the consequence of mutation in a single gene on the development and proper functioning of the CNS. The current focus on the role of FMRP in neuronal maturation makes it timely to assemble the extant information on how reduced expression of the fmr-1 gene leads to neuronal dysmorphology. The purpose of this review is to summarize recent genetic, neuroanatomical, and behavioral studies of fragile X syndrome and to offer potential mechanisms to account for the pleiotropic phenotype of this disorder.

Representations of familiar and unfamiliar faces as revealed by viewpoint-aftereffects.

A viewpoint-dependent aftereffect occurs after prolonged viewing of a stimulus of a particular orientation, with the result that the test image is perceived to be facing away from the adapting orientation. Prior psychophysical work has led to the suggestion that the visual brain encodes a limited range of viewpoint information with regard to complex images. In this study, we investigated whether familiar faces were susceptible to a viewpoint aftereffect. Familiar faces are believed to be represented in a view-invariant manner, whereas unfamiliar faces are represented in a viewpoint-dependent manner. Adaptation to both familiar and unfamiliar faces influenced the perception of viewpoint of subsequent face images. However, category-specific transfer of a repulsive viewpoint-dependent aftereffect was observed with unfamiliar faces. Our results suggest that neural networks that mediate viewpoint information are also involved in view-invariant representation of familiar faces.

Quantification of three-dimensional exploration in the cylinder test by the common marmoset (Callithrix jacchus).

The increasing trend in use of marmoset monkeys in behavioral studies has necessitated a greater understanding of their natural behavior, especially within confined spatial environments. One way to approach this issue is to examine locomotor and exploratory strategies using the cylinder test, as done recently for the rat by Gharbawie et al. [Gharbawie OA, Whishaw PA, Whishaw IQ. The topography of three-dimensional exploration: a new quantification of vertical and horizontal exploration, postural support, and exploratory bouts in the cylinder test. Behav Brain Res 2004;151:125-35]. We have used this paradigm in conjunction with Eshkol-Wachmann movement analysis in marmoset monkeys. We provide evidence that marmosets display systematic changes in both horizontal and vertical progressions during exploration. Quantitative analysis and comparison with the extant data in rats showed both similarities and differences. For example, both species display horizontal and vertical scanning movements, although the variability is considerably greater for the marmoset. The horizontal progressions consist of head scans, turning, and stepping. The amplitude of these progressions oscillates and decreases with trial duration. Vertical progressions, which consist of rears, head scans, and descent, also strongly oscillate but with constant mean amplitude during a trial. The difference between the two species is most evident in locomotor behavior. Rats use their forepaws primarily for postural support and follow forequarter movements while body weight shifts are generated by the hind limbs. Marmosets, however, can hold a vertical position without hand support and display more complex movement characteristics during exploration. The data from this study should be of use in designing experiments in which marmosets are engaged in free-roaming behavior within a confined space.

Patchy organization and asymmetric distribution of the neural correlates of face processing in monkey inferotemporal cortex.

BACKGROUND: It is believed that a face-specific system exists within the primate ventral visual pathway that is separate from a domain-general nonface object coding system. In addition, it is believed that hemispheric asymmetry, which was long held to be a distinct feature of the human brain, can be found in the brains of other primates as well. We show here for the first time by way of a functional imaging technique that face- and object-selective neurons form spatially distinct clusters at the cellular level in monkey inferotemporal cortex. We have used a novel functional mapping technique that simultaneously generates two separate activity profiles by exploiting the differential time course of zif268 mRNA and protein expression. RESULTS: We show that neurons activated by face stimulation can be visualized at cellular resolution and distinguished from those activated by nonface complex objects. Our dual-activity maps of face and object selectivity show that face-selective patches of various sizes (mean, 22.30 mm2; std, 32.76 mm2) exist throughout the IT cortex in the context of a large expanse of cortical territory that is responsive to visual objects. CONCLUSIONS: These results add to recent findings that face-selective patches of various sizes exist throughout area IT and provide the first direct anatomical evidence at cellular resolution for a hemispheric asymmetry in favor of the right hemisphere. Together, our results support the notion that human and monkey brains share a similarity in both anatomical organization and distribution of function with respect to high-level visual processing.

Recognizing faces defined by texture gradients.

Texture gradients can reveal surface orientation in a manner similar to shape from shading, and therefore provide an important cue for object recognition. In this study, we tested whether a complex 3-D object, such as a face, can be identified from texture gradients alone. The stimuli were laser-scanned faces for which the texture element was a fractal-noise pattern mapped onto the 3-D surface. An eight-alternative forced choice task was used in which participants matched a face defined by texture gradients to one of eight faces defined by shape from shading (Experiment 1) or by texture gradients (Experiment 2). On average, participants scored 24% and 18%, respectively, above chance in these experiments. Although this performance was much poorer than the performance based entirely on shape-from-shading stimuli (Experiment 3), the results suggest that texture gradient information may be used to recover surface geometry of complex objects.

Face recognition is affected by similarity in spatial frequency range to a greater degree than within-category object recognition.

Previous studies have suggested that face identification is more sensitive to variations in spatial frequency content than object recognition, but none have compared how sensitive the 2 processes are to variations in spatial frequency overlap (SFO). The authors tested face and object matching accuracy under varying SFO conditions. Their results showed that object recognition was more robust to SFO variations than face recognition and that the vulnerability of faces was not due to reliance on configural processing. They suggest that variations in sensitivity to SFO help explain the vulnerability of face recognition to changes in image format and the lack of a middle-frequency advantage in object recognition.

Microarray analysis of developmental plasticity in monkey primary visual cortex.

We performed microarray gene expression analyses on the visual cortex of Old-World monkeys (Cercopithicus aethiops) in an effort to identify transcripts associated with developmental maturation and activity-driven changes during the visual critical period. Samples derived from normal animals and those subjected to monocular enucleation (ME) were hybridized to human Affymetrix HG-U95Av2 oligonucleotide microarrays (N = 12) and the results were independently validated by real-time quantitative RT-PCR. To identify genes exhibiting significant expression differences among our samples, the microarray hybridization data were processed with two software packages that use different analytical models (Affymetrix MicroArray Suite 5.0, dChip 1.2). We identified 108 transcripts within diverse functional categories that differed in their visual cortical expression at the height of the critical period when compared to adults. The expression levels of four transcripts were also globally modulated following ME during the critical period. These transcripts are particularly sensitive to ME during the critical period but are not significantly modulated in ME adults. Three of the ME-driven genes (NGFI-B, egr3, NARP) are known immediate-early genes (IEG) while the other (DUSP6) is a phosphatase that can regulate IEG expression. The putative biological significance of the ME-driven and developmentally regulated genes is discussed with respect to the critical period for activity-dependent visual cortical neuroplasticity.

Cellular-resolution activity mapping of the brain using immediate-early gene expression.

Immediate-Early Genes are a class of genes that are rapidly up-regulated following neural stimulation. Due to their quality as potential activity markers in the CNS, they have been used extensively in functional mapping studies. At least three genes have been popularly used, including zif268 (Egr1, NGFI, Krox-24, or ZENK), c-fos and recently, Arc. A number of techniques have been developed in applying IEG labelling for the development of functional maps, thus overcoming some of the earlier limitations of this approach. Current developments highlight the future prospects of cellular-resolution functional activity mapping of the brain.