Gaze following requires early visual experience.

Gaze understanding­a suggested precursor for understanding others' intentions­requires recovery of gaze direction from the observed person's head and eye position. This challenging computation is naturally acquired at infancy without explicit external guidance, but can it be learned later if vision is extremely poor throughout early childhood? We addressed this question by studying gaze following in Ethiopian patients with early bilateral congenital cataracts diagnosed and treated by us only at late childhood. This sight restoration provided a unique opportunity to directly address basic issues on the roles of "nature" and "nurture" in development, as it caused a selective perturbation to the natural process, eliminating some gaze-direction cues while leaving others still available. Following surgery, the patients' visual acuity typically improved substantially, allowing discrimination of pupil position in the eye. Yet, the patients failed to show eye gaze-following effects and fixated less than controls on the eyes­two spontaneous behaviors typically seen in controls. Our model for unsupervised learning of gaze direction explains how head-based gaze following can develop under severe image blur, resembling preoperative conditions. It also suggests why, despite acquiring sufficient resolution to extract eye position, automatic eye gaze following is not established after surgery due to lack of detailed early visual experience. We suggest that visual skills acquired in infancy in an unsupervised manner will be difficult or impossible to acquire when internal guidance is no longer available, even when sufficient image resolution for the task is restored. This creates fundamental barriers to spontaneous vision recovery following prolonged deprivation in early age.

Performance comparison: exome sequencing as a single test replacing Sanger sequencing.

Next generation sequencing tests are used routinely as first-choice tests in the clinic. However, systematic performance comparing the results of exome sequencing as a single test replacing Sanger sequencing of targeted gene(s) is still lacking. Performance comparison data are critically important for clinical case management. In this study, we compared Sanger-sequencing results of 258 genes to those obtained from next generation sequencing (NGS) using two exome-sequencing enrichment kits: Agilent-SureSelectQXT and Illumina-Nextera. Sequencing was performed on leukocytes and buccal-derived DNA from a single individual, and all 258 genes were sequenced a total of 11 times (using different sequencing methods and DNA sources). Sanger sequencing was completed for all exons, including flanking ± 8 bp regions. For the 258 genes, NGS mean coverage was > 20 × for > 98 and > 91% of the regions targeted by SureSelect and Nextera, respectively. Overall, 449 variants were identified in at least one experiment, and 407/449 (90.6%) were detected by all. Of the 42 discordant variants, 23 were determined as true calls, summing-up to a truth set of 430 variants. Sensitivity of true-variant detection was 99% for Sanger sequencing and 97-100% for the NGS experiments. Mean false-positive rates were 3.7E-6 for Sanger sequencing, 2.5E-6 for SureSelect-NGS and 5.2E-6 for Nextera-NGS. Our findings suggest a high overall concordance between Sanger sequencing and NGS performances. Both methods demonstrated false-positive and false-negative calls. High clinical suspicion for a specific diagnosis should, therefore, override negative results of either Sanger sequencing or NGS.

Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome.

OBJECTIVE: To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome. METHODS: Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression. RESULTS: All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth. INTERPRETATION: DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646-655.

Practice improves peri-saccadic shape judgment but does not diminish target mislocalization.

Visual sensitivity is markedly reduced during an eye movement. Peri-saccadic vision is also characterized by a mislocalization of the briefly presented stimulus closer to the saccadic target. These features are commonly viewed as obligatory elements of peri-saccadic vision. However, practice improves performance in many perceptual tasks performed at threshold conditions. We wondered if this could also be the case with peri-saccadic perception. To test this, we used a paradigm in which subjects reported the orientation (or location) of an ellipse briefly presented during a saccade. Practice on peri-saccadic orientation discrimination led to long-lasting gains in that task but did not alter the classical mislocalization of the visual stimulus. Shape discrimination gains were largely generalized to other untrained conditions when the same stimuli were used (discrimination during a saccade in the opposite direction or at a different stimulus location than previously trained). However, performance dropped to baseline level when participants shifted to a novel Vernier discrimination task under identical saccade conditions. Furthermore, practice on the location task did not induce better stimulus localization or discrimination. These results suggest that the limited visual information available during a saccade may be better used with practice, possibly by focusing attention on the specific target features or a better readout of the available information. Saccadic mislocalization, by contrast, is robust and resistant to top-down modulations, suggesting that it involves an automatic process triggered by the upcoming execution of a saccade (e.g., an efference copy signal).

Hands in motion: an upper-limb-selective area in the occipitotemporal cortex shows sensitivity to viewed hand kinematics.

Regions in the occipitotemporal cortex (OTC) show clear selectivity to static images of human body parts, and upper limbs in particular, with respect to other object categories. Such selectivity was previously attributed to shape aspects, which presumably vary across categories. Alternatively, it has been proposed that functional selectivity for upper limbs is driven by processing of their distinctive motion features. In the present study we show that selectivity to static upper-limb images and motion processing go hand in hand. Using resting-state and task-based functional MRI, we demonstrate that OTC voxels showing greater preference to static images of arms and hands also show stronger functional connectivity with motion coding regions within the human middle temporal complex (hMT+), but not with shape-selective midtier areas, such as hV4 or LO-1, suggesting a tight link between upper-limb selectivity and motion processing. To test this directly, we created a set of natural arm-movement videos where kinematic patterns were parametrically manipulated, while keeping shape information constant. Using multivariate pattern analysis, we show that the degree of (dis)similarity in arm-velocity profiles across the video set predicts, to a significant extent, the degree of (dis)similarity in multivoxel activation patterns in both upper-limb-selective OTC regions and the hMT+. Together, these results suggest that the functional specificity of upper-limb-selective regions may be partially determined by their involvement in the processing of upper-limb dynamics. We propose that the selectivity to static upper-limb images in the OTC may be a result of experience-dependent association between shape elements, which characterize upper limbs, and upper-limb-specific motion patterns.

Viewed actions are mapped in retinotopic coordinates in the human visual pathways.

Viewed object-oriented actions elicit widespread fMRI activation in the dorsal and ventral visual pathways. This activation is typically stronger in the hemisphere contralateral to the visual field in which action is seen. However, since in previous studies participants kept fixation at the same screen position throughout the scan, it was impossible to infer if the viewed actions are represented in retina-based coordinates or in a more elaborated coordinate system. Here, participants changed their gaze between experimental conditions, such that some conditions shared the same retinotopic coordinates (but differed in their screen position), while other pairs of conditions shared the opposite trait. The degree of similarity between the patterns of activation elicited by the various conditions was assessed using multivoxel pattern analysis methods. Regions of interest, showing robust overall activation, included the intraparietal sulcus (IPS) and the occipitotemporal cortex. In these areas, the correlation between activation patterns for conditions sharing the same retinotopic coordinates was significantly higher than that of those having different retinotopic coordinates. In contrast, the correlations between activation patterns for conditions with the same spatiotopic coordinates were not significantly greater than for non-spatiotopic conditions. These results suggest that viewed object-oriented actions are likely to be maintained in retinotopic-framed coordinates.

Modality-specific and modality-independent components of the human imagery system.

Imagery research typically deals with the commonalities and differences between imagery and perception. As such, it is usually confined to one specific modality. Yet, it is likely that some of the underlying processes are shared between different sensory modalities while others are modality-specific. In this fMRI study, we used a balanced design that allowed for a direct comparison between imagery and perception in visual and auditory modalities, and also for a link between subjective imagery experience and brain activation. Results indicated a selective role for the "default mode network" as a modality-independent "core" imagery network. In addition, results identified areas in the visual and auditory association cortices that contributed to mental imagery in a modality-specific fashion. Interestingly during mental imagery, primary visual and auditory cortices showed modality-specific suppression of activity. This is the first fMRI study to characterize both modality-specific and modality-independent components of the human imagery system.