Older adults with slow sit to stand times show reduced temporal precision of audio-visual integration.

Sustained integration of sensory inputs over increased temporal delays is associated with reduced cognitive and physical functioning in older adults and adverse outcomes such as falls. Here, we explored the relationship between multisensory integration and a clinically relevant measure of balance/postural control; Sit-to-Stand Time, the efficiency with which an older adult can transition between a seated and a standing posture. We investigated whether temporal multisensory integration was associated with performance on the Five-Times Sit-to-Stand Test (FTSST) in a large sample of 2556 older adults (mean age = 63.62 years, SD = 7.50; 55% female) drawn from The Irish Longitudinal Study on Ageing (TILDA). K-means clustering was applied to FTSST data, yielding three clusters characterised by fast (mean = 10.88 s; n = 1122), medium (mean = 14.34 s; n = 1133) and slow (mean = 18.97 s; n = 301) sit-to-stand times. At wave 3 of TILDA, older adults participated in the Sound Induced Flash Illusion (SIFI), a measure of the precision of temporal audio-visual integration, which included three audio-visual stimulus onset asynchronies (SOAs): 70, 150 and 230 ms. Older adults with the slowest sit-to-stand times were more susceptible to the SIFI at the longest SOA (230 ms) compared to the shortest SOA (70 ms) relative to those with the fastest times (p = 0.02). Older adults who take longer to repeatedly transition from a seated to a standing posture exhibit an expanded temporal binding window for audio-visual events, supporting a link between multisensory perception and balance/postural control in ageing.

Self-reported vividness of tactile imagery for object properties and body regions: An exploratory study.

Mental imagery ability has been examined principally in the visual domain. Despite evidence for tactile mental representations in the absence of direct stimulation, this ability is poorly understood. We investigated tactile imagery for both active and passive tasks in a large sample (N = 118). Vividness of imagery was tested across two different tasks: somatosensory imagery (of body sensitivity) and tactile imagery (of object properties) in all participants. Evidence for vivid imagery across tactile and somatosensory dimensions was found with a positive, albeit weak, correlation in imagery strength between dimensions. Imagery ratings varied across objects and object properties in the tactile imagery task and across body sites in the somatosensory imagery task. These findings shed light on the capacity for, and characteristics of, tactile mental imagery in the general population and suggest that the ability to experience vivid tactile mental images may mediate performance across a number of perceptual tasks.

Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers.

BACKGROUND: Whole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer. PATIENTS AND METHODS: We carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n = 26) or BRCA2 (n = 22) or from non-carriers (non-BRCA1/2; n = 30). RESULTS: Matched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2. CONCLUSIONS: Our study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases.

Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism.

BACKGROUND: To assess the utility of whole-exome sequencing (WES) for mutation detection in maturity-onset diabetes of the young (MODY) and congenital hyperinsulinism (CHI). MODY and CHI are the two commonest monogenic disorders of glucose-regulated insulin secretion in childhood, with 13 causative genes known for MODY and 10 causative genes identified for CHI. The large number of potential genes makes comprehensive screening using traditional methods expensive and time-consuming. METHODS: Ten subjects with MODY and five with CHI with known mutations underwent WES using two different exome capture kits (Nimblegen SeqCap EZ Human v3.0 Exome Enrichment Kit, Nextera Rapid Capture Exome Kit). Analysis was blinded to previously identified mutations, and included assessment for large deletions. The target capture of five exome capture technologies was also analyzed using sequencing data from >2800 unrelated samples. RESULTS: Four of five MODY mutations were identified using Nimblegen (including a large deletion in HNF1B). Although targeted, one mutation (in INS) had insufficient coverage for detection. Eleven of eleven mutations (six MODY, five CHI) were identified using Nextera Rapid (including the previously missed mutation). On reconciliation, all mutations concorded with previous data and no additional variants in MODY genes were detected. There were marked differences in the performance of the capture technologies. CONCLUSIONS: WES can be useful for screening for MODY/CHI mutations, detecting both point mutations and large deletions. However, capture technologies require careful selection.

Longitudinal grip strength is associated with susceptibility to the Sound Induced Flash Illusion in older adults.

The precision of temporal multisensory integration is associated with specific aspects of physical functioning in ageing, including gait speed and incidents of falling. However, it is unknown if such an association exists between multisensory integration and grip strength, an important index of frailty and brain health and predictor of disease and mortality in older adults. Here, we investigated whether temporal multisensory integration is associated with longitudinal (eight-year) grip strength trajectories in a large sample of 2,061 older adults (mean age = 64.42 years, SD = 7.20; 52% female) drawn from The Irish Longitudinal Study on Ageing (TILDA). Grip strength (kg) for the dominant hand was assessed with a hand-held dynamometer across four testing waves. Longitudinal k-means clustering was applied to these data separately for sex (male, female) and age group (50-64, 65-74, 75+ years). At wave 3, older adults participated in the Sound Induced Flash Illusion (SIFI), a measure of the precision of temporal audio-visual integration, which included three audio-visual stimulus onset asynchronies (SOAs): 70, 150 and 230 ms. Results showed that older adults with a relatively lower (i.e., weaker) grip strength were more susceptible to the SIFI at the longer SOAs compared to those with a relatively higher (i.e., stronger) grip strength (p <.001). These novel findings suggest that older adults with relatively weaker grip strength exhibit an expanded temporal binding window for audio-visual events, possibly reflecting a reduction in the integrity of the central nervous system.

Multisensory perception constrains the formation of object categories: a review of evidence from sensory-driven and predictive processes on categorical decisions.

Although object categorization is a fundamental cognitive ability, it is also a complex process going beyond the perception and organization of sensory stimulation. Here we review existing evidence about how the human brain acquires and organizes multisensory inputs into object representations that may lead to conceptual knowledge in memory. We first focus on evidence for two processes on object perception, multisensory integration of redundant information (e.g. seeing and feeling a shape) and crossmodal, statistical learning of complementary information (e.g. the 'moo' sound of a cow and its visual shape). For both processes, the importance attributed to each sensory input in constructing a multisensory representation of an object depends on the working range of the specific sensory modality, the relative reliability or distinctiveness of the encoded information and top-down predictions. Moreover, apart from sensory-driven influences on perception, the acquisition of featural information across modalities can affect semantic memory and, in turn, influence category decisions. In sum, we argue that both multisensory processes independently constrain the formation of object categories across the lifespan, possibly through early and late integration mechanisms, respectively, to allow us to efficiently achieve the everyday, but remarkable, ability of recognizing objects. This article is part of the theme issue 'Decision and control processes in multisensory perception'.

Comparison of actionable events detected in cancer genomes by whole-genome sequencing, in silico whole-exome and mutation panels.

BACKGROUND: Next-generation sequencing is used in cancer research to identify somatic and germline mutations, which can predict sensitivity or resistance to therapies, and may be a useful tool to reveal drug repurposing opportunities between tumour types. Multigene panels are used in clinical practice for detecting targetable mutations. However, the value of clinical whole-exome sequencing (WES) and whole-genome sequencing (WGS) for cancer care is less defined, specifically as the majority of variants found using these technologies are of uncertain significance. PATIENTS AND METHODS: We used the Cancer Genome Interpreter and WGS in 726 tumours spanning 10 cancer types to identify drug repurposing opportunities. We compare the ability of WGS to detect actionable variants, tumour mutation burden (TMB) and microsatellite instability (MSI) by using in silico down-sampled data to mimic WES, a comprehensive sequencing panel and a hotspot mutation panel. RESULTS: We reveal drug repurposing opportunities as numerous biomarkers are shared across many solid tumour types. Comprehensive panels identify the majority of approved actionable mutations, with WGS detecting more candidate actionable mutations for biomarkers currently in clinical trials. Moreover, estimated values for TMB and MSI vary when calculated from WGS, WES and panel data, and are dependent on whether all mutations or only non-synonymous mutations were used. Our results suggest that TMB and MSI thresholds should not only be tumour-dependent, but also be sequencing platform-dependent. CONCLUSIONS: There is a large opportunity to repurpose cancer drugs, and these data suggest that comprehensive sequencing is an invaluable source of information to guide clinical decisions by facilitating precision medicine and may provide a wealth of information for future studies. Furthermore, the sequencing and analysis approach used to estimate TMB may have clinical implications if a hard threshold is used to indicate which patients may respond to immunotherapy.

The rubber hand illusion is influenced by self-recognition.

Susceptibility to the Rubber Hand Illusion (RHI) demonstrates that body ownership can be modulated by visuotactile inputs. In contrast to body-like images, other objects cannot be embodied suggesting that crossmodal interactions on body ownership are based on a 'goodness-of-fit' mechanism relative to one's own body. However, it is not clear whether visual self-recognition influences susceptibility to the RHI, although evidence for individual differences in the perceptual body image on the RHI suggests that this may be the case. We investigated the role of self-recognition on the subjective experience of the RHI and measured proprioceptive drift and onset time of the RHI between two groups, one with the ability to identify an image of their own hand and the other without this ability. A typical RHI response was found overall with no group difference in the subjective experience of the RHI. However, a larger proprioceptive drift and an earlier onset time for the RHI was found for the non-recognisers than the self-recognition group. Our findings provide evidence for a link between a visual representation of one's own body in long-term memory and plasticity of the body representation.

A neural basis for general intelligence.

Universal positive correlations between different cognitive tests motivate the concept of "general intelligence" or Spearman's g. Here the neural basis for g is investigated by means of positron emission tomography. Spatial, verbal, and perceptuo-motor tasks with high-g involvement are compared with matched low-g control tasks. In contrast to the common view that g reflects a broad sample of major cognitive functions, high-g tasks do not show diffuse recruitment of multiple brain regions. Instead they are associated with selective recruitment of lateral frontal cortex in one or both hemispheres. Despite very different task content in the three high-g-low-g contrasts, lateral frontal recruitment is markedly similar in each case. Many previous experiments have shown these same frontal regions to be recruited by a broad range of different cognitive demands. The results suggest that "general intelligence" derives from a specific frontal system important in the control of diverse forms of behavior.

Distinctive voices enhance the visual recognition of unfamiliar faces.

Several studies have provided evidence in favour of a norm-based representation of faces in memory. However, such models have hitherto failed to take account of how other person-relevant information affects face recognition performance. Here we investigated whether distinctive or typical auditory stimuli affect the subsequent recognition of previously unfamiliar faces and whether the type of auditory stimulus matters. In this study participants learned to associate either unfamiliar distinctive and typical voices or unfamiliar distinctive and typical sounds to unfamiliar faces. The results indicated that recognition performance was better to faces previously paired with distinctive than with typical voices but we failed to find any benefit on face recognition when the faces were previously associated with distinctive sounds. These findings possibly point to an expertise effect, as faces are usually associated to voices. More importantly, it suggests that the memory for visual faces can be modified by the perceptual quality of related vocal information and more specifically that facial distinctiveness can be of a multi-sensory nature. These results have important implications for our understanding of the structure of memory for person identification.

Electro-oculography in infants.

To record the electro-oculogram in infants without using general anesthesia and passive globe rotation, we used the static vestibular reflex in which compensatory eye movements occur in response to angular rotation of the semicircular canal. To produce these eye movements, we placed the infant in a supine position in his mother's arms in a rocking chair and, while he nursed from a bottle, directed his attention to a distracting stimulus. We recorded the electro-oculogram during rocking under conditions of light and dark adaptation. We used the electro-oculograms to calculate the conventional light-to-dark amplitude ratio.

Transscleral electroretinography.

We studied the electroretinogram in normal patients, patients with opacities of the anterior segment, and patients with vitreous hemorrage, using a high-intensity light stimulus delivered either through the sclera or through the pupil. We found the response obtained with transscleral stimulation a consistent indicator of gross retinal function. Since the stimulus entered the eye through the sclera, it provided a method for studying the retinal responses independent of opaque or translucent media.

Autosomal recessive incomplete achromatopsia with deutan luminosity.

Four patients in three different families had a form of autosomal recessive incomplete achromatopsia not previously described. The visual acuity was 6/18 to 6/60 (20/60 to 20/200) with minimal ophthalmoscopic abnormality and normal fluorescein angiogram. The photopic electroretinographic responses were present in all four patients; the fusion rate of 60 Hz was only slightly subnormal. The high-intensity scotopic response was subnormal. The patients failed color screening plates and accumulated over 400 errors with scotopic axis on the Farnsworth-Munsell 100-hue test. The Rayleigh match was abnormal, displaced toward the red primary, but with normal luminance. The photopic luminous efficiency function was similar to that of the deuteranope. Color matching revealed a trichromatic form of color vision mediated by long wavelength and short wavelength cones, and a rhodopsin receptor.

A new mucolipidosis with psychomotor retardation, corneal clouding, and retinal degeneration.

A 23-year-old man had slow psychomotor development at 6 months of age and developed intermittent corneal clouding at about 18 months. He developed a truncal ataxia and hypotonia of the limbs combined with spasticity and active deep reflexes that did not progress. His skeleton and facies were normal. Between 1 and 13 years of age, he developed severe optic atrophy, absence of retinal blood vessels, and an extinguished electroretinogram. Biochemical analysis of cultured fibroblasts indicated no lysosomal hydrolase deficiency; cellular metachromasia was absent and there was no mucopolysaccharidoses. Ultrastructural studies indicated single-membrane-limited vacuoles containing lamellated membranes and a polymorphous substance in tissue-cultured cells and conjunctiva.

Pigmentary degeneration of the retina in the Hallervorden-Spatz syndrome.

Dizygotic twins developed a progressive neurologic disorder at age 6 months. When examined at age 7 1/2 years each had spastic quadriparesis and dystonia. Neither had ever spoken a complete sentence. The fundi showed bone spicule formation, a conspicuous choroidal circulation, and a striking accumulation of yellowish-white globular masses of varying sizes and shapes. Because our patients developed both the pigmentary degeneration and clinical signs of Hallervorden-Spatz syndrome at a much younger age than patients without retinopathy, we believe this case demonstrated a distinct nosologic entity.

Fundus changes in persistent and recurrent choroidal folds.

Linear bead-like pigmentation in choroidal folds and diffuse nonspecific retinal pigment epithelial proliferation are seen in long-study choroidal folds. In addition there may be linear streaks of scleral staining.

A new mucolipidosis with psychomotor retardation, corneal clouding, and retinal degeneration.

A man now 22 years of age had slow psychomotor development about 6 months after birth and developed intermittent corneal clouding at about 18 months. He developed truncal ataxia, hypotonia of the limbs combined with spasticity, and active deep reflexes. These have not progressed. His skeleton and facies are normal. Between his first and thriteenth year he developed sev ere optic atrophy, absence of retinal blood vessels, and an extinguished electroretinogram. Biochemical analysis of cultured fibroblasts indicated no lysosomal hydrolase deficiency; cellular metachromasia was absent and there was no mucopolysaccharidoses. Ultrastructural studies indicated single membrane vacuoles containing lamellated membranes and a polymorphous substance in tissue cultured cells and conjunctiva.