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1.  Prominent effects and neural correlates of visual crowding in a neurodegenerative disease population 
Brain  2014;137(12):3284-3299.
Visual crowding is a perceptual phenomenon whereby recognition of a stimulus is disrupted by the presence of flanker stimuli. Yong et al. observe excessive crowding in individuals with a neurodegenerative condition (posterior cortical atrophy) and identify associations between prominent crowding and lower grey matter volume in the right collateral sulcus.
Crowding is a breakdown in the ability to identify objects in clutter, and is a major constraint on object recognition. Crowding particularly impairs object perception in peripheral, amblyopic and possibly developing vision. Here we argue that crowding is also a critical factor limiting object perception in central vision of individuals with neurodegeneration of the occipital cortices. In the current study, individuals with posterior cortical atrophy (n = 26), typical Alzheimer’s disease (n = 17) and healthy control subjects (n = 14) completed centrally-presented tests of letter identification under six different flanking conditions (unflanked, and with letter, shape, number, same polarity and reverse polarity flankers) with two different target-flanker spacings (condensed, spaced). Patients with posterior cortical atrophy were significantly less accurate and slower to identify targets in the condensed than spaced condition even when the target letters were surrounded by flankers of a different category. Importantly, this spacing effect was observed for same, but not reverse, polarity flankers. The difference in accuracy between spaced and condensed stimuli was significantly associated with lower grey matter volume in the right collateral sulcus, in a region lying between the fusiform and lingual gyri. Detailed error analysis also revealed that similarity between the error response and the averaged target and flanker stimuli (but not individual target or flanker stimuli) was a significant predictor of error rate, more consistent with averaging than substitution accounts of crowding. Our findings suggest that crowding in posterior cortical atrophy can be regarded as a pre-attentive process that uses averaging to regularize the pathologically noisy representation of letter feature position in central vision. These results also help to clarify the cortical localization of feature integration components of crowding. More broadly, we suggest that posterior cortical atrophy provides a neurodegenerative disease model for exploring the basis of crowding. These data have significant implications for patients with, or who will go on to develop, dementia-related visual impairment, in whom acquired excessive crowding likely contributes to deficits in word, object, face and scene perception.
doi:10.1093/brain/awu293
PMCID: PMC4240300  PMID: 25351740
crowding; lateral masking; Alzheimer’s disease; posterior cortical atrophy; acquired dyslexia
2.  Magnetic resonance imaging evidence for presymptomatic change in thalamus and caudate in familial Alzheimer’s disease 
Brain  2013;136(5):1399-1414.
Amyloid imaging studies of presymptomatic familial Alzheimer’s disease have revealed the striatum and thalamus to be the earliest sites of amyloid deposition. This study aimed to investigate whether there are associated volume and diffusivity changes in these subcortical structures during the presymptomatic and symptomatic stages of familial Alzheimer’s disease. As the thalamus and striatum are involved in neural networks subserving complex cognitive and behavioural functions, we also examined the diffusion characteristics in connecting white matter tracts. A cohort of 20 presenilin 1 mutation carriers underwent volumetric and diffusion tensor magnetic resonance imaging, neuropsychological and clinical assessments; 10 were symptomatic, 10 were presymptomatic and on average 5.6 years younger than their expected age at onset; 20 healthy control subjects were also studied. We conducted region of interest analyses of volume and diffusivity changes in the thalamus, caudate, putamen and hippocampus and examined diffusion behaviour in the white matter tracts of interest (fornix, cingulum and corpus callosum). Voxel-based morphometry and tract-based spatial statistics were also used to provide unbiased whole-brain analyses of group differences in volume and diffusion indices, respectively. We found that reduced volumes of the left thalamus and bilateral caudate were evident at a presymptomatic stage, together with increased fractional anisotropy of bilateral thalamus and left caudate. Although no significant hippocampal volume loss was evident presymptomatically, reduced mean diffusivity was observed in the right hippocampus and reduced mean and axial diffusivity in the right cingulum. In contrast, symptomatic mutation carriers showed increased mean, axial and in particular radial diffusivity, with reduced fractional anisotropy, in all of the white matter tracts of interest. The symptomatic group also showed atrophy and increased mean diffusivity in all of the subcortical grey matter regions of interest, with increased fractional anisotropy in bilateral putamen. We propose that axonal injury may be an early event in presymptomatic Alzheimer’s disease, causing an initial fall in axial and mean diffusivity, which then increases with loss of axonal density. The selective degeneration of long-coursing white matter tracts, with relative preservation of short interneurons, may account for the increase in fractional anisotropy that is seen in the thalamus and caudate presymptomatically. It may be owing to their dense connectivity that imaging changes are seen first in the thalamus and striatum, which then progress to involve other regions in a vulnerable neuronal network.
doi:10.1093/brain/awt065
PMCID: PMC3634199  PMID: 23539189
familial Alzheimer’s disease; presenilin 1 (PSEN1, PS1); presymptomatic; diffusion tensor imaging; subcortical atrophy
3.  Impairments of auditory scene analysis in Alzheimer's disease 
Brain  2011;135(1):190-200.
Parsing of sound sources in the auditory environment or ‘auditory scene analysis’ is a computationally demanding cognitive operation that is likely to be vulnerable to the neurodegenerative process in Alzheimer’s disease. However, little information is available concerning auditory scene analysis in Alzheimer's disease. Here we undertook a detailed neuropsychological and neuroanatomical characterization of auditory scene analysis in a cohort of 21 patients with clinically typical Alzheimer's disease versus age-matched healthy control subjects. We designed a novel auditory dual stream paradigm based on synthetic sound sequences to assess two key generic operations in auditory scene analysis (object segregation and grouping) in relation to simpler auditory perceptual, task and general neuropsychological factors. In order to assess neuroanatomical associations of performance on auditory scene analysis tasks, structural brain magnetic resonance imaging data from the patient cohort were analysed using voxel-based morphometry. Compared with healthy controls, patients with Alzheimer's disease had impairments of auditory scene analysis, and segregation and grouping operations were comparably affected. Auditory scene analysis impairments in Alzheimer's disease were not wholly attributable to simple auditory perceptual or task factors; however, the between-group difference relative to healthy controls was attenuated after accounting for non-verbal (visuospatial) working memory capacity. These findings demonstrate that clinically typical Alzheimer's disease is associated with a generic deficit of auditory scene analysis. Neuroanatomical associations of auditory scene analysis performance were identified in posterior cortical areas including the posterior superior temporal lobes and posterior cingulate. This work suggests a basis for understanding a class of clinical symptoms in Alzheimer's disease and for delineating cognitive mechanisms that mediate auditory scene analysis both in health and in neurodegenerative disease.
doi:10.1093/brain/awr260
PMCID: PMC3267978  PMID: 22036957
Alzheimer's disease; auditory scene analysis; auditory processing; voxel-based morphometry
4.  Voice processing in dementia: a neuropsychological and neuroanatomical analysis 
Brain  2011;134(9):2535-2547.
Voice processing in neurodegenerative disease is poorly understood. Here we undertook a systematic investigation of voice processing in a cohort of patients with clinical diagnoses representing two canonical dementia syndromes: temporal variant frontotemporal lobar degeneration (n = 14) and Alzheimer’s disease (n = 22). Patient performance was compared with a healthy matched control group (n = 35). All subjects had a comprehensive neuropsychological assessment including measures of voice perception (vocal size, gender, speaker discrimination) and voice recognition (familiarity, identification, naming and cross-modal matching) and equivalent measures of face and name processing. Neuroanatomical associations of voice processing performance were assessed using voxel-based morphometry. Both disease groups showed deficits on all aspects of voice recognition and impairment was more severe in the temporal variant frontotemporal lobar degeneration group than the Alzheimer’s disease group. Face and name recognition were also impaired in both disease groups and name recognition was significantly more impaired than other modalities in the temporal variant frontotemporal lobar degeneration group. The Alzheimer’s disease group showed additional deficits of vocal gender perception and voice discrimination. The neuroanatomical analysis across both disease groups revealed common grey matter associations of familiarity, identification and cross-modal recognition in all modalities in the right temporal pole and anterior fusiform gyrus; while in the Alzheimer’s disease group, voice discrimination was associated with grey matter in the right inferior parietal lobe. The findings suggest that impairments of voice recognition are significant in both these canonical dementia syndromes but particularly severe in temporal variant frontotemporal lobar degeneration, whereas impairments of voice perception may show relative specificity for Alzheimer’s disease. The right anterior temporal lobe is likely to have a critical role in the recognition of voices and other modalities of person knowledge.
doi:10.1093/brain/awr205
PMCID: PMC3170540  PMID: 21908871
voice; face; phonagnosia; frontotemporal dementia; Alzheimer’s disease
5.  The cognitive organization of music knowledge: a clinical analysis 
Brain  2010;133(4):1200-1213.
Despite much recent interest in the clinical neuroscience of music processing, the cognitive organization of music as a domain of non-verbal knowledge has been little studied. Here we addressed this issue systematically in two expert musicians with clinical diagnoses of semantic dementia and Alzheimer’s disease, in comparison with a control group of healthy expert musicians. In a series of neuropsychological experiments, we investigated associative knowledge of musical compositions (musical objects), musical emotions, musical instruments (musical sources) and music notation (musical symbols). These aspects of music knowledge were assessed in relation to musical perceptual abilities and extra-musical neuropsychological functions. The patient with semantic dementia showed relatively preserved recognition of musical compositions and musical symbols despite severely impaired recognition of musical emotions and musical instruments from sound. In contrast, the patient with Alzheimer’s disease showed impaired recognition of compositions, with somewhat better recognition of composer and musical era, and impaired comprehension of musical symbols, but normal recognition of musical emotions and musical instruments from sound. The findings suggest that music knowledge is fractionated, and superordinate musical knowledge is relatively more robust than knowledge of particular music. We propose that music constitutes a distinct domain of non-verbal knowledge but shares certain cognitive organizational features with other brain knowledge systems. Within the domain of music knowledge, dissociable cognitive mechanisms process knowledge derived from physical sources and the knowledge of abstract musical entities.
doi:10.1093/brain/awp345
PMCID: PMC2850578  PMID: 20142334
music; semantic memory; dementia; semantic dementia; Alzheimer’s disease
6.  Non-verbal sound processing in the primary progressive aphasias 
Brain  2009;133(1):272-285.
Little is known about the processing of non-verbal sounds in the primary progressive aphasias. Here, we investigated the processing of complex non-verbal sounds in detail, in a consecutive series of 20 patients with primary progressive aphasia [12 with progressive non-fluent aphasia; eight with semantic dementia]. We designed a novel experimental neuropsychological battery to probe complex sound processing at early perceptual, apperceptive and semantic levels, using within-modality response procedures that minimized other cognitive demands and matching tests in the visual modality. Patients with primary progressive aphasia had deficits of non-verbal sound analysis compared with healthy age-matched individuals. Deficits of auditory early perceptual analysis were more common in progressive non-fluent aphasia, deficits of apperceptive processing occurred in both progressive non-fluent aphasia and semantic dementia, and deficits of semantic processing also occurred in both syndromes, but were relatively modality specific in progressive non-fluent aphasia and part of a more severe generic semantic deficit in semantic dementia. Patients with progressive non-fluent aphasia were more likely to show severe auditory than visual deficits as compared to patients with semantic dementia. These findings argue for the existence of core disorders of complex non-verbal sound perception and recognition in primary progressive aphasia and specific disorders at perceptual and semantic levels of cortical auditory processing in progressive non-fluent aphasia and semantic dementia, respectively.
doi:10.1093/brain/awp235
PMCID: PMC2801322  PMID: 19797352
auditory perception; non-verbal sound; agnosia; dementia; environmental sounds

Results 1-6 (6)