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1.  Music Recognition in Frontotemporal Lobar Degeneration and Alzheimer Disease 
To compare music recognition in patients with frontotemporal dementia, semantic dementia, Alzheimer disease, and controls and to evaluate the relationship between music recognition and brain volume.
Recognition of familiar music depends on several levels of processing. There are few studies about how patients with dementia recognize familiar music.
Subjects were administered tasks that assess pitch and melody discrimination, detection of pitch errors in familiar melodies, and naming of familiar melodies.
There were no group differences on pitch and melody discrimination tasks. However, patients with semantic dementia had considerable difficulty naming familiar melodies and also scored the lowest when asked to identify pitch errors in the same melodies. Naming familiar melodies, but not other music tasks, was strongly related to measures of semantic memory. Voxel-based morphometry analysis of brain MRI showed that difficulty in naming songs was associated with the bilateral temporal lobes and inferior frontal gyrus, whereas difficulty in identifying pitch errors in familiar melodies correlated with primarily the right temporal lobe.
The results support a view that the anterior temporal lobes play a role in familiar melody recognition, and that musical functions are affected differentially across forms of dementia.
PMCID: PMC3691095  PMID: 21617528
Pitch; Melody; temporal lobe; auditory perception
2.  Sound Naming in Neurodegenerative Disease 
Brain and cognition  2010;72(3):423-429.
Modern cognitive neuroscientific theories and empirical evidence suggest that brain structures involved in movement may be related to action-related semantic knowledge. To test this hypothesis, we examined the naming of environmental sounds in patients with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), two neurodegenerative diseases associated with cognitive and motor deficits. Subjects were presented with 56 environmental sounds: 28 of objects that required manipulation when producing the sound, and 28 that required no manipulation. Subjects were asked to provide the name of the object that produced the sound and also complete a sound-picture matching condition. Subjects included 33 individuals from four groups: CBD/PSP, Alzheimer disease, frontotemporal dementia, and normal controls. We hypothesized that CBD/PSP patients would exhibit impaired naming performance compared with controls, but the impairment would be most apparent when naming sounds associated with actions. We also explored neural correlates of naming environmental sounds using voxel-based morphometry (VBM) of brain MRI. As expected, CBD/PSP patients scored lower on environmental sounds naming (p<0.007) compared with the controls. In particular, the CBD/PSP patients scored the lowest when naming sounds of manipulable objects (p<0.05), but did not show deficits in naming sounds of non-manipulable objects. VBM analysis across all groups showed that performance in naming sounds of manipulable objects correlated with atrophy in the left premotor region, extending from area 6 to the middle and superior frontal gyrus. These results indicate an association between impairment in the retrieval of action-related names and the motor system, and suggest that difficulty in naming manipulable sounds may be related to atrophy in the premotor cortex. Our results support the hypothesis that retrieval of action-related semantic knowledge involves motor regions in the brain.
PMCID: PMC2832081  PMID: 20089342
3.  Language networks in semantic dementia 
Brain  2009;133(1):286-299.
Cognitive deficits in semantic dementia have been attributed to anterior temporal lobe grey matter damage; however, key aspects of the syndrome could be due to altered anatomical connectivity between language pathways involving the temporal lobe. The aim of this study was to investigate the left language-related cerebral pathways in semantic dementia using diffusion tensor imaging-based tractography and to combine the findings with cortical anatomical and functional magnetic resonance imaging data obtained during a reading activation task. The left inferior longitudinal fasciculus, arcuate fasciculus and fronto-parietal superior longitudinal fasciculus were tracked in five semantic dementia patients and eight healthy controls. The left uncinate fasciculus and the genu and splenium of the corpus callosum were also obtained for comparison with previous studies. From each tract, mean diffusivity, fractional anisotropy, as well as parallel and transverse diffusivities were obtained. Diffusion tensor imaging results were related to grey and white matter atrophy volume assessed by voxel-based morphometry and functional magnetic resonance imaging activations during a reading task. Semantic dementia patients had significantly higher mean diffusivity, parallel and transverse in the inferior longitudinal fasciculus. The arcuate and uncinate fasciculi demonstrated significantly higher mean diffusivity, parallel and transverse and significantly lower fractional anisotropy. The fronto-parietal superior longitudinal fasciculus was relatively spared, with a significant difference observed for transverse diffusivity and fractional anisotropy, only. In the corpus callosum, the genu showed lower fractional anisotropy compared with controls, while no difference was found in the splenium. The left parietal cortex did not show significant volume changes on voxel-based morphometry and demonstrated normal functional magnetic resonance imaging activation in response to reading items that stress sublexical phonological processing. This study shows that semantic dementia is associated with anatomical damage to the major superior and inferior temporal white matter connections of the left hemisphere likely involved in semantic and lexical processes, with relative sparing of the fronto-parietal superior longitudinal fasciculus. Fronto-parietal regions connected by this tract were activated normally in the same patients during sublexical reading. These findings contribute to our understanding of the anatomical changes that occur in semantic dementia, and may further help to explain the dissociation between marked single-word and object knowledge deficits, but sparing of phonology and fluency in semantic dementia.
PMCID: PMC2801321  PMID: 19759202
semantic dementia; semantic knowledge; diffusion tensor-based tractography; functional MRI; voxel-based morphometry
4.  The neural correlates of verbal and non-verbal semantic processing deficits in neurodegenerative disease 
To investigate the neural correlates of verbal and non-verbal semantic processing in neurodegenerative disease.
Semantic memory is often impaired in neurodegenerative disease. Neuropsychological and functional neuroimaging studies suggest that the semantic processing of verbal and non-verbal stimuli may depend on partially distinct brain networks.
We examined this possibility using voxel-based morphometry to correlate performance on verbal and non-verbal versions of a semantic association task with regional gray matter atrophy in 144 individuals with a variety of neurodegenerative diseases.
Results showed that, regardless of stimulus type, semantic processing correlated with atrophy in both temporal lobes. In addition, material-specific correlations were found in left temporal regions for verbal stimuli and the right fusiform gyrus for non-verbal stimuli.
These results provide evidence for a differential role of the left and right hemispheres in the extraction of semantic information from verbal and pictorial representations. Areas in the right inferior temporal lobe may be necessary to access structural descriptions of visually presented objects.
PMCID: PMC2754058  PMID: 19506422
5.  Rule Violation Errors are Associated With Right Lateral Prefrontal Cortex Atrophy in Neurodegenerative Disease 
Good cognitive performance requires adherence to rules specific to the task at hand. Patients with neurological disease often make rule violation errors, but the anatomical basis for rule violation during cognitive testing remains debated. The current study examined the neuroanatomical correlates of rule violation (RV) errors made on tests of executive functioning in 166 subjects diagnosed with neurodegenerative disease or as neurologically healthy. Specifically, RV errors were voxel-wisely correlated with gray matter volume derived from high-definition MR images using voxel-based morphometry implemented in SPM2. Latent variable analysis showed that rule violation errors tapped a unitary construct separate from repetition errors. This analysis was used to generate factor scores to represent what is common among rule violation errors across tests. The extracted rule violation factor scores correlated with tissue loss in the lateral middle and inferior frontal gyri and the caudate nucleus bilaterally. When a more stringent control for global cognitive functioning was applied using Mini Mental State Exam scores, only the correlations with the right lateral prefrontal cortex remained significant. These data underscore the importance of right lateral prefrontal cortex in behavioral monitoring and highlight the potential of rule violation error assessment for identifying patients with damage to this region.
PMCID: PMC2748220  PMID: 19402921
cognitive control; neuropsychological assessment; executive functioning; voxel-based morphometry; inhibition; frontal lobe
6.  The neural basis of surface dyslexia in semantic dementia 
Brain  2008;132(1):71-86.
Semantic dementia (SD) is a neurodegenerative disease characterized by atrophy of anterior temporal regions and progressive loss of semantic memory. SD patients often present with surface dyslexia, a relatively selective impairment in reading low-frequency words with exceptional or atypical spelling-to-sound correspondences. Exception words are typically ‘over-regularized’ in SD and pronounced as they are spelled (e.g. ‘sew’ is pronounced as ‘sue’). This suggests that in the absence of sufficient item-specific knowledge, exception words are read by relying mainly on subword processes for regular mapping of orthography to phonology. In this study, we investigated the functional anatomy of surface dyslexia in SD using functional magnetic resonance imaging (fMRI) and studied its relationship to structural damage with voxel-based morphometry (VBM). Five SD patients and nine healthy age-matched controls were scanned while they read regular words, exception words and pseudowords in an event-related design. Vocal responses were recorded and revealed that all patients were impaired in reading low-frequency exception words, and made frequent over-regularization errors. Consistent with prior studies, fMRI data revealed that both groups activated a similar basic network of bilateral occipital, motor and premotor regions for reading single words. VBM showed that these regions were not significantly atrophied in SD. In control subjects, a region in the left intraparietal sulcus was activated for reading pseudowords and low-frequency regular words but not exception words, suggesting a role for this area in subword mapping from orthographic to phonological representations. In SD patients only, this inferior parietal region, which was not atrophied, was also activated by reading low-frequency exception words, especially on trials where over-regularization errors occurred. These results suggest that the left intraparietal sulcus is involved in subword reading processes that are differentially recruited in SD when word-specific information is lost. This loss is likely related to degeneration of the anterior temporal lobe, which was severely atrophied in SD. Consistent with this, left mid-fusiform and superior temporal regions that showed reading-related activations in controls were not activated in SD. Taken together, these results suggest that the left inferior parietal region subserves subword orthographic-to-phonological processes that are recruited for exception word reading when retrieval of exceptional, item-specific word forms is impaired by degeneration of the anterior temporal lobe.
PMCID: PMC2638692  PMID: 19022856
semantic dementia; dyslexia; parietal lobe; voxel-based morphometry; functional MRI
7.  Regional Brain Stem Atrophy in Idiopathic Parkinson's Disease Detected by Anatomical MRI 
PLoS ONE  2009;4(12):e8247.
Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder characterized by the dysfunction of dopaminergic dependent cortico-basal ganglia loops and diagnosed on the basis of motor symptoms (tremors and/or rigidity and bradykinesia). Post-mortem studies tend to show that the destruction of dopaminergic neurons in the substantia nigra constitutes an intermediate step in a broader neurodegenerative process rather than a unique feature of Parkinson's disease, as a consistent pattern of progression would exist, originating from the medulla oblongata/pontine tegmentum. To date, neuroimaging techniques have been unable to characterize the pre-symptomatic stages of PD. However, if such a regular neurodegenerative pattern were to exist, consistent damages would be found in the brain stem, even at early stages of the disease. We recruited 23 PD patients at Hoenn and Yahr stages I to II of the disease and 18 healthy controls (HC) matched for age. T1-weighted anatomical scans were acquired (MPRAGE, 1 mm3 resolution) and analyzed using an optimized VBM protocol to detect white and grey matter volume reduction without spatial a priori. When the HC group was compared to the PD group, a single cluster exhibited statistical difference (p<0.05 corrected for false detection rate, 4287 mm3) in the brain stem, between the pons and the medulla oblongata. The present study provides in-vivo evidence that brain stem damage may be the first identifiable stage of PD neuropathology, and that the identification of this consistent damage along with other factors could help with earlier diagnosis in the future. This damage could also explain some non-motor symptoms in PD that often precede diagnosis, such as autonomic dysfunction and sleep disorders.
PMCID: PMC2784293  PMID: 20011063
8.  A tensor based morphometry study of longitudinal gray matter contraction in FTD 
NeuroImage  2007;35(3):998-1003.
Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by progressive behavioural abnormalities and frontotemporal atrophy. Here we used tensor based morphometry (TBM) to identify regions of longitudinal progression of gray matter atrophy in FTD compared to controls. T1-weighted MRI images were acquired at presentation and 1-year follow-up from 12 patients with mild to moderate FTD and 12 healthy controls. Using TBM as implemented in SPM2, a voxel-wise estimation of regional tissue volume change was derived from the deformation field required to warp a subject’s late to early anatomical images. A whole brain analysis was performed, in which a level of significance of p<0.05 corrected for multiple comparisons (family wise error-FWE) was accepted. Based on prior studies, a region of interest (ROI) analysis was also performed, including in the search area bilateral medial and orbital frontal regions, anterior cingulate gyrus, insula, amygdala and hippocampus. Within this ROI a level of significance of p<0.001 uncorrected was accepted. In the whole brain analysis, the anterior cingulate/paracingulate gyri were the only regions that showed significant atrophy change over 1 year. In the ROI analysis, the left ventro-medial frontal cortex, right medial superior frontal gyrus, anterior insulae and left amygdala/hippocampus showed significant longitudinal changes. In conclusion, limbic and paralimbic regions showed detectable gray matter contraction over 1 year in FTD, confirming the susceptibility of these regions to the disease and the consistency with their putative role in causing typical presenting behaviours. These results suggest that TBM might be useful in tracking progression of regional atrophy in FTD.
PMCID: PMC2443736  PMID: 17350290

Results 1-8 (8)