Human immunodeficiency virus infection of the human thymus and disruption of the thymic microenvironment in the SCID-hu mouse.

Infection with the human immunodeficiency virus (HIV) results in immunosuppression and depletion of circulating CD4+ T cells. Since the thymus is the primary organ in which T cells mature it is of interest to examine the effects of HIV infection in this tissue. HIV infection has been demonstrated in the thymuses of infected individuals and thymocytes have been previously demonstrated to be susceptible to HIV infection both in vivo, using the SCID-hu mouse, and in vitro. The present study sought to determine which subsets of thymocytes were infected in the SCID-hu mouse model and to evaluate HIV-related alterations in the thymic microenvironment. Using two different primary HIV isolates, infection was found in CD4+/CD8+ double positive thymocytes as well as in both the CD4+ and CD8+ single positive subsets of thymocytes. The kinetics of infection and resulting viral burden differed among the three thymocyte subsets and depended on which HIV isolate was used for infection. Thymic epithelial (TE) cells were also shown to endocytose virus and to often contain copious amounts of viral RNA in the cytoplasm by in situ hybridization, although productive infection of these cells could not be definitively shown. Furthermore, degenerating TE cells were observed even without detection of HIV in the degenerating cells. Two striking morphologic patterns of infection were seen, involving either predominantly thymocyte infection and depletion, or TE cell involvement with detectable cytoplasmic viral RNA and/or TE cell toxicity. Thus, a variety of cells in the human thymus is susceptible to HIV infection, and infection with HIV results in a marked disruption of the thymic microenvironment leading to depletion of thymocytes and degeneration of TE cells

Following the status of visual cortex over time in patients with macular degeneration reveals atrophy of visually deprived brain regions

Purpose: Previous research has shown atrophy of visual cortex can occur in retinotopic representations of retinal lesions resulting from eye disease. However, the time course of atrophy cannot be established from these cross-sectional studies, which included patients with long-standing disease of varying severity. Our aim therefore was to measure visual cortical structure over time in participants after onset of unilateral visual loss resulting from age-related macular degeneration (AMD). Methods: Inclusion criteria were onset of acute unilateral neovascular AMD with bilateral dry-AMD based on clinical examination. Therefore, substantial loss of unilateral visual input to cortex was relatively well-defined in time. Changes in cortical anatomy were assessed in the occipital lobe as a whole, and in cortical representations of the lesion and intact retina, the lesion and intact projection zones, respectively. Whole brain, T1-weighted MRI was taken at diagnosis (before anti-angiogenic treatment to stabilise the retina), during the 3-4-month initial treatment period, with a long-term follow-up ~5 (range 3.8 – 6.1 years) years later. Results: Significant cortical atrophy was detected at long-term follow-up only, with a reduction in mean cortical volume across the whole occipital lobe. Importantly, this reduction was explained by cortical thinning of the lesion projection zone, which suggests additional changes to those associated with normal ageing. Over the period of study, anti-angiogenic treatment stabilised visual acuity and central retinal thickness, suggesting that the atrophy detected was most likely governed by long-term decreased visual input. Conclusions: Our results indicate that consequences of eye disease on visual cortex are atrophic and retinotopic. Our work also raises the potential to follow the status of visual cortex in individuals over time to inform on how best to treat patients, particularly with restorative techniques

Population Receptive Field Dynamics in Human Visual Cortex

Seminal work in the early nineties revealed that the visual receptive field of neurons in cat primary visual cortex can change in location and size when artificial scotomas are applied. Recent work now suggests that these single neuron receptive field dynamics also pertain to the neuronal population receptive field (pRF) that can be measured in humans with functional magnetic resonance imaging (fMRI). To examine this further, we estimated the pRF in twelve healthy participants while masking the central portion of the visual field. We found that the pRF changes in location and size for two differently sized artificial scotomas, and that these pRF dynamics are most likely due to a combination of the neuronal receptive field position and size scatter as well as modulatory feedback signals from extrastriate visual areas

Contributions of feature shapes and surface cues to the recognition and neural representation of facial identity

A full understanding of face recognition will involve identifying the visual information that is used to discriminate different identities and how this is represented in the brain. The aim of this study was to explore the importance of shape and surface properties in the recognition and neural representation of familiar faces. We used image morphing techniques to generate hybrid faces that mixed shape properties (more specifically, second order spatial configural information as defined by feature positions in the 2D-image) from one identity and surface properties from a different identity. Behavioural responses showed that recognition and matching of these hybrid faces was primarily based on their surface properties. These behavioural findings contrasted with neural responses recorded using a block design fMRI adaptation paradigm to test the sensitivity of Haxby et al.'s (2000) core face-selective regions in the human brain to the shape or surface properties of the face. The fusiform face area (FFA) and occipital face area (OFA) showed a lower response (adaptation) to repeated images of the same face (same shape, same surface) compared to different faces (different shapes, different surfaces). From the behavioural data indicating the critical contribution of surface properties to the recognition of identity, we predicted that brain regions responsible for familiar face recognition should continue to adapt to faces that vary in shape but not surface properties, but show a release from adaptation to faces that vary in surface properties but not shape. However, we found that the FFA and OFA showed an equivalent release from adaptation to changes in both shape and surface properties. The dissociation between the neural and perceptual responses suggests that, although they may play a role in the process, these core face regions are not solely responsible for the recognition of facial identity

Structural changes to primary visual cortex in the congenital absence of cone input in achromatopsia

Autosomal recessive Achromatopsia (ACHM) is a rare inherited disorder associated with dysfunctional cone photoreceptors resulting in a congenital absence of cone input to visual cortex. This might lead to distinct changes in cortical architecture with a negative impact on the success of gene augmentation therapies. To investigate the status of the visual cortex in these patients, we performed a multi-centre study focusing on the cortical structure of regions that normally receive predominantly cone input. Using high-resolution T1-weighted MRI scans and surface-based morphometry, we compared cortical thickness, surface area and grey matter volume in foveal, parafoveal and paracentral representations of primary visual cortex in 15 individuals with ACHM and 42 normally sighted, healthy controls (HC). In ACHM, surface area was reduced in all tested representations, while thickening of the cortex was found highly localized to the most central representation. These results were comparable to more widespread changes in brain structure reported in congenitally blind individuals, suggesting similar developmental processes, i.e., irrespective of the underlying cause and extent of vision loss. The cortical differences we report here could limit the success of treatment of ACHM in adulthood. Interventions earlier in life when cortical structure is not different from normal would likely offer better visual outcomes for those with ACHM

Long-term and age-dependent restoration of visual function in a mouse model of CNGB3-associated achromatopsia following gene therapy

Mutations in the CNGB3 gene account for >50% of all known cases of achromatopsia. Although of early onset, its stationary character and the potential for rapid assessment of restoration of retinal function following therapy renders achromatopsia a very attractive candidate for gene therapy. Here we tested the efficacy of an rAAV2/8 vector containing a human cone arrestin promoter and a human CNGB3 cDNA in CNGB3 deficient mice. Following subretinal delivery of the vector, CNGB3 was detected in both M- and S-cones and resulted in increased levels of CNGA3, increased cone density and survival, improved cone outer segment structure and normal subcellular compartmentalization of cone opsins. Therapy also resulted in long-term improvement of retinal function, with restoration of cone ERG amplitudes of up to 90% of wild-type and a significant improvement in visual acuity. Remarkably, successful restoration of cone function was observed even when treatment was initiated at 6 months of age; however, restoration of normal visual acuity was only possible in younger animals (e.g. 2–4 weeks old). This study represents achievement of the most substantial restoration of visual function reported to date in an animal model of achromatopsia using a human gene construct, which has the potential to be utilized in clinical trials

Assessing functional reorganization in visual cortex with simulated retinal lesions

Macular degeneration (MD) causes central vision loss, removing input to corresponding representations in the primary visual cortex. There is disagreement concerning whether the cortical regions deprived of input can remain responsive, and the source of reported cortical responses is still debated. To simulate MD in controls, normally sighted participants viewed a bright central disk to adapt the retina, creating a transient 'retinal lesion' during a functional MRI experiment. Participants viewed blocks of faces, scrambled faces and uniform grey stimuli, either passively or whilst performing a one-back task. To assess the impact of the simulated lesion, participants repeated the paradigm using a more conventional mean luminance simulated scotoma without adaptation. Our results suggest our attempt to create a more realistic simulation of a lesion did not impact on responses in the representation of the simulated lesion. While most participants showed no evidence of stimulus-driven activation within the lesion representation, a few individuals (22%) exhibited responses similar to a participant with juvenile MD who completed the same paradigm (without adaptation). Reliability analysis showed that responses in the representation of the lesion were generally consistent irrespective of whether positive or negative. We provide some evidence that peripheral visual stimulation can also produce responses in central representations in controls while performing a task. This suggests that the 'signature of reorganization of visual processing', is not found solely in patients with retinal lesions, consistent with the idea that activity may be driven by unmasked top-down feedback

Modelling the perceptual similarity of facial expressions from image statistics and neural responses

The ability to perceive facial expressions of emotion is essential for effective social communication. We investigated how the perception of facial expression emerges from the image properties that convey this important social signal, and how neural responses in face-selective brain regions might track these properties. To do this, we measured the perceptual similarity between expressions of basic emotions, and investigated how this is reflected in image measures and in the neural response of different face-selective regions. We show that the perceptual similarity of different facial expressions (fear, anger, disgust, sadness, happiness) can be predicted by both surface and feature shape information in the image. Using block design fMRI, we found that the perceptual similarity of expressions could also be predicted from the patterns of neural response in the face-selective posterior superior temporal sulcus (STS), but not in the fusiform face area (FFA). These results show that the perception of facial expression is dependent on the shape and surface properties of the image and on the activity of specific face-selective regions