[Show abstract][Hide abstract] ABSTRACT: The information contained in a sensory signal plays a critical role in determining what neural processes are engaged. Here we used interleaved silent steady-state (ISSS) functional magnetic resonance imaging (fMRI) to explore how human listeners cope with different degrees of acoustic richness during auditory sentence comprehension. Twenty-six healthy young adults underwent scanning while hearing sentences that varied in acoustic richness (high vs. low spectral detail) and syntactic complexity (subject-relative vs. object-relative center-embedded clause structures). We manipulated acoustic richness by presenting the stimuli as unprocessed full-spectrum speech, or noise-vocoded with 24 channels. Importantly, although the vocoded sentences were spectrally impoverished, all sentences were highly intelligible. These manipulations allowed us to test how intelligible speech processing was affected by orthogonal linguistic and acoustic demands. Acoustically rich speech showed stronger activation than acoustically less-detailed speech in a bilateral temporoparietal network with more pronounced activity in the right hemisphere. By contrast, listening to sentences with greater syntactic complexity resulted in increased activation of a left-lateralized network including left posterior lateral temporal cortex, left inferior frontal gyrus, and left dorsolateral prefrontal cortex. Significant interactions between acoustic richness and syntactic complexity occurred in left supramarginal gyrus, right superior temporal gyrus, and right inferior frontal gyrus, indicating that the regions recruited for syntactic challenge differed as a function of acoustic properties of the speech. Our findings suggest that the neural systems involved in speech perception are finely tuned to the type of information available, and that reducing the richness of the acoustic signal dramatically alters the brain's response to spoken language, even when intelligibility is high.
No preview · Article · Jan 2016 · Hearing research
[Show abstract][Hide abstract] ABSTRACT: Background/Study Context: In a variety of collaborative circumstances, participants must adopt the perspective of a partner and establish a shared mental representation that helps mediate common understanding. This process is referred to as social coordination. Here, the authors investigate the effect of aging on social coordination and consider separately the component processes related to perspective-taking and working memory.Methods: Twelve young adults and 14 older adults completed an experimental, language-based coordination task. Subjects were asked to describe a scene with sufficient detail so that a conversational partner could identify a target object in the context of other, competing objects that shared a variable number of features. Trials varied in the information available to the partner (perspective-taking demand) and in the number of competing objects present in the scene (working memory demand). Responses were scored according to adjective use.Results: Results indicated that social coordination performance decreases with age. Whereas young adults performed close to ceiling, older adults were only precise in 49.70% of trials. In analyses examining perspective-taking conditions with no competitors, older adults were consistently impaired relative to young adults; in analyses examining the number of competitors during the simplest perspective-taking condition, both older and younger adults became more impaired with increasing numbers of competitors.Conclusion: The experimental data suggest that social coordination decreases with age, which may affect communicative efficacy. Older adults’ tendency to provide insufficient responses suggests a limitation in perspective-taking, and the pattern of decline in common ground performance with increasing competitors suggests that this is independent of working memory decline. In sum, our results suggest that social coordination deficits in aging may be multifactorial.
No preview · Article · Jan 2016 · Experimental Aging Research
[Show abstract][Hide abstract] ABSTRACT: This review article summarizes our current understanding of a specific type of human memory known as semantic memory. Semantic memory is our basic world knowledge of words, objects, people, and places. The first section of this article describes semantic memory within a broader context by discussing the major division between episodic memory and semantic memory. We next review cognitive and neuroanatomical perspectives of the semantic memory system, including how sensory, motor, and heteromodal regions play a role in representing modality-specific and modality-invariant semantic knowledge of the world.
[Show abstract][Hide abstract] ABSTRACT: We investigated the distribution patterns of Lewy body-related pathology (LRP) and the effect of coincident Alzheimer disease (AD) pathology using a data-driven clustering approach that identified groups with different LRP pathology distributions without any diagnostic or researcher's input in two cohorts including: Parkinson disease patients without (PD, n = 141) and with AD (PD-AD, n = 80), dementia with Lewy bodies subjects without AD (DLB, n = 13) and demented subjects with AD and LRP pathology (Dem-AD-LB, n = 308). The Dem-AD-LB group presented two LRP patterns, olfactory-amygdala and limbic LRP with negligible brainstem pathology, that were absent in the PD groups, which are not currently included in the DLB staging system and lacked extracranial LRP as opposed to the PD group. The Dem-AD-LB individuals showed relative preservation of substantia nigra cells and dopamine active transporter in putamen. PD cases with AD pathology showed increased LRP. The cluster with occipital LRP was associated with non-AD type dementia clinical diagnosis in the Dem-AD-LB group and a faster progression to dementia in the PD groups. We found that (1) LRP pathology in Dem-AD-LB shows a distribution that differs from PD, without significant brainstem or extracranial LRP in initial phases; (2) coincident AD pathology is associated with increased LRP in PD indicating an interaction; (3) LRP and coincident AD pathology independently predict progression to dementia in PD, and (4) evaluation of LRP needs to acknowledge different LRP spreading patterns and evaluate substantia nigra integrity in the neuropathological assessment and consider the implications of neuropathological heterogeneity for clinical and biomarker characterization.
No preview · Article · Dec 2015 · Acta Neuropathologica
[Show abstract][Hide abstract] ABSTRACT: Semantic representations capture the statistics of experience and store this information in memory. A fundamental component of this memory system is knowledge of the visual environment, including knowledge of objects and their associations. Visual semantic information underlies a range of behaviors, from perceptual categorization to cognitive processes such as language and reasoning. Here we examine the neuroanatomic system that encodes visual semantics. Across three experiments, we found converging evidence indicating that knowledge of verbally mediated visual concepts relies on information encoded in a region of the ventral-medial temporal lobe centered on parahippocampal cortex. In an fMRI study, this region was strongly engaged by the processing of concepts relying on visual knowledge but not by concepts relying on other sensory modalities. In a study of patients with the semantic variant of primary progressive aphasia (semantic dementia), atrophy that encompassed this region was associated with a specific impairment in verbally mediated visual semantic knowledge. Finally, in a structural study of healthy adults from the fMRI experiment, gray matter density in this region related to individual variability in the processing of visual concepts. The anatomic location of these findings aligns with recent work linking the ventral-medial temporal lobe with high-level visual representation, contextual associations, and reasoning through imagination. Together, this work suggests a critical role for parahippocampal cortex in linking the visual environment with knowledge systems in the human brain.
No preview · Article · Dec 2015 · Journal of Cognitive Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Objective:
To characterize sequential patterns of regional neuropathology and clinical symptoms in a well-characterized cohort of 21 patients with autopsy-confirmed Pick's disease.
Detailed neuropathological examination using 70 µm and traditional 6 µm sections was performed using Thioflavin-S staining and immunohistochemistry for phosphorylated-tau, 3R and 4R tau isoforms, ubiquitin, and C-terminally truncated tau. Patterns of regional tau deposition were correlated with clinical data. In a subset of cases (n=5) converging evidence was obtained using antemortem neuroimaging measures of grey and white matter integrity.
Four sequential patterns of pathological tau deposition were identified starting in frontotemporal limbic/paralimbic and neocortical regions (Phase I). Sequential involvement was seen in subcortical structures, including basal ganglia, locus coeruleus and raphe nuclei (Phase II), followed by primary motor cortex and pre-cerebellar nuclei (Phase III) and finally visual cortex in the most severe (Phase IV) cases. Behavioral variant frontotemporal dementia was the predominant clinical phenotype (18/21) but all patients eventually developed a social comportment disorder. Pathological tau phases reflected the evolution of clinical symptoms and degeneration on serial antemortem neuroimaging, directly correlated with disease-duration and inversely correlated with brain-weight at autopsy. The majority of neuronal and glial tau inclusions were 3R tau-positive and 4R tau-negative in sporadic cases. There was a relative abundance of mature tau pathology markers in frontotemporal limbic/paralimbic regions compared to neocortical regions.
Pick's disease tau neuropathology may originate in limbic/paralimbic cortices. The patterns of tau pathology observed here provide novel insights into the natural history and biology of tau-mediated neurodegeneration. This article is protected by copyright. All rights reserved.
No preview · Article · Nov 2015 · Annals of Neurology
[Show abstract][Hide abstract] ABSTRACT: Background: Apathy, the major manifestation of impaired goal-directed behavior (GDB), is the most common neuropsychiatric syndrome associated with behavioral variant frontotemporal degeneration (bvFTD). The behavioral and biological mechanisms of apathy, however, are not well understood. We hypothesized that GDB has multiple components—including at least initiation, planning and motivation—and that GDB is supported by a network of multiple frontal brain regions. In this study, we examined this hypothesis by evaluating the selective breakdown of GDB in bvFTD, and relating these deficits to gray matter (GM) atrophy and white matter (WM) integrity.
Methods: Eighteen apathetic bvFTD participants and 17 healthy controls completed the Philadelphia Apathy Computerized Test (PACT). This test quantifies each of three components of GDB hypothesized to contribute to apathy. We then used regression analyses to relate PACT scores to GM atrophy and reduced white matter (WM) fractional anisotropy (FA) in bvFTD.
Results: Compared to controls, bvFTD participants demonstrated significant impairments in each of the three hypothesized components of GDB that contribute to apathy. Regression analyses related each component to disease in specific GM structures and associated WM tracts. Poor initiation thus was related to GM atrophy in anterior cingulate and reduced FA in the cingulum. Planning impairment was related to GM atrophy in dorsolateral prefrontal cortex and reduced FA in superior longitudinal fasciculus. Poor motivation was related to GM atrophy in orbitofrontal cortex (OFC) and reduced FA in uncinate fasciculus (UNC).
Conclusions: bvFTD patients have difficulty with initiation, planning and motivation components of GDB. These findings are consistent with the hypotheses that GDB encompasses at least three processes, that these are supported by a large-scale neural network within specific portions of the frontal lobe, and that degradation of any one of these prefrontal regions in bvFTD may contribute to apathy.
Full-text · Article · Nov 2015 · Frontiers in Human Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Digital image analysis of histology sections provides reliable, high-throughput methods for neuropathological studies but data is scant in frontotemporal lobar degeneration (FTLD), which has an added challenge of study due to morphologically diverse pathologies. Here, we describe a novel method of semi-automated digital image analysis in FTLD subtypes including: Pick's disease (PiD, n=11) with tau-positive intracellular inclusions and neuropil threads, and TDP-43 pathology type C (FTLD-TDPC, n=10), defined by TDP-43-positive aggregates predominantly in large dystrophic neurites. To do this, we examined three FTLD-associated cortical regions: mid-frontal gyrus (MFG), superior temporal gyrus (STG) and anterior cingulate gyrus (ACG) by immunohistochemistry. We used a color deconvolution process to isolate signal from the chromogen and applied both object detection and intensity thresholding algorithms to quantify pathological burden. We found object-detection algorithms had good agreement with gold-standard manual quantification of tau- and TDP-43-positive inclusions. Our sampling method was reliable across three separate investigators and we obtained similar results in a pilot analysis using open-source software. Regional comparisons using these algorithms finds differences in regional anatomic disease burden between PiD and FTLD-TDP not detected using traditional ordinal scale data, suggesting digital image analysis is a powerful tool for clinicopathological studies in morphologically diverse FTLD syndromes.
No preview · Article · Nov 2015 · Journal of Histochemistry and Cytochemistry
[Show abstract][Hide abstract] ABSTRACT: Some extent of ambiguity is ubiquitous in everyday conversations. For example, words have multiple meaning and very common pronouns, like “he” and “she” (anaphoric pronouns), have little meaning on their own and refer to a noun that has been previously introduced in the discourse. Ambiguity triggers a decision process that is not a subroutine of language processing but rather a more general domain resource. Therefore non-aphasic patients with limited decision-making capability can encounter severe limitation in language processing due to extra linguistic limitations. In the present study, we test patients with behavioral variant frontotemporal degeneration (bvFTD), focusing on anaphora as a paradigmatic example of ambiguity resolution in the linguistic domain. bvFTD is characterized by gray matter (GM) atrophy in prefrontal cortex, but relative sparing of peri-Sylvian cortex. A group of patients with parietal disease due to corticobasal syndrome (CBS) was also tested here in order to investigate the specific role of prefrontal cortex in the task employed in the current study. Participants were presented with a pair of sentences in which the first sentence contained two nouns while the second contained a pronoun. In the experimental (ambiguous) condition, both nouns are plausible referents of the pronoun, thus requiring decision-making resources. The results revealed that bvFTD patients are significantly less accurate than healthy seniors in identifying the correct referent of a pronoun in the ambiguous condition, although CBS patients were as accurate as healthy seniors. Imaging analyses related bvFTD patients’ performance to GM atrophy in ventromedial prefrontal cortex (vmPFC). These results suggest that bvFTD patients have difficulties in decision processes that involve the resolution of an ambiguity.
Preview · Article · Oct 2015 · Frontiers in Human Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Previous work has shown that the meaning of a quantifier such as "many" or "few" depends in part on quantity. However, the meaning of a quantifier may vary depending on the context, e.g. in the case of common entities such as "many ants" (perhaps several thousands) compared to endangered species such as "many pandas" (perhaps a dozen). In a recent study (Heim et al., 2015 Front. Psychol.) we demonstrated that the relative meaning of "many" and "few" may be changed experimentally. In a truth value judgment task, displays with 40% of circles in a named color initially had a low probability of being labeled "many". After a training phase, the likelihood of acceptance 40% as "many" increased. Moreover, the semantic learning effect also generalized to the related quantifier "few" which had not been mentioned in the training phase. Thus, fewer 40% arrays were considered "few." In the present study, we tested the hypothesis that this semantic adaptation effect was supported by cytoarchitectonic Brodmann area (BA) 45 in Broca's region which may contribute to semantic evaluation in the context of language and quantification. In an event-related fMRI study, 17 healthy volunteers performed the same paradigm as in the previous behavioral study. We found a relative signal increase when comparing the critical, trained proportion to untrained proportions. This specific effect was found in left BA 45 for the trained quantifier "many", and in left BA 44 for both quantifiers, reflecting the semantic adjustment for the untrained but related quantifier "few." These findings demonstrate the neural basis for processing the flexible meaning of a quantifier, and illustrate the neuroanatomical structures that contribute to variable meanings that can be associated with a word when used in different contexts.
[Show abstract][Hide abstract] ABSTRACT: Our knowledge of objects reflects the statistics of the visual environment. From our experiences in the world, we store information about categories of objects and the features that define them. One important statistical property of objects is the co-occurrence of their constituent features. For example, the round shape of an apple co-occurs frequently with the color red, but not the color blue. Here we examine the neural mechanisms that encode such feature co-occurrence statistics at the interface of perception and memory. In an fMRI experiment, subjects viewed images of colored objects while performing an unrelated scrambled-object detection task. The stimuli included exemplars from three different categories: apples, leaves, and roses. To create stimuli that sampled a range of co-occurrence statistics, each exemplar image had its color systematically manipulated to be red, pink, yellow, green, or blue (Fig.1A). We quantified co-occurrence frequencies of color-object combinations (e.g., "yellow apple") in a large lexical corpus. A separate norming study demonstrated that this metric was strongly correlated with subjective ratings of color-object typicality. Importantly, the co-occurrence of object and color information is independent of the frequencies of each feature alone. We tested the hypothesis that feature co-occurrence information is encoded in semantic memory regions and automatically retrieved during object perception. Using representational similarity analysis, we identified regions where response patterns were similar for category exemplars with similar co-occurrence statistics (Fig.2B). We expected that the angular gyrus would encode combinatorial information given its proposed role in semantic integration. Indeed, we found that this region and the anterior fusiform cortex encode high-level feature co-occurrence statistics, while early visual cortex, lateral-occipital complex, and inferior-temporal cortex did not. These results suggest that regions at the interface of vision and semantic memory encode combinatorial information that underlies real-world knowledge of objects and is independent of coding for individual features. Meeting abstract presented at VSS 2015.
No preview · Article · Sep 2015 · Journal of Vision
[Show abstract][Hide abstract] ABSTRACT: Introduction:
The dynamic range of cerebrospinal fluid (CSF) amyloid β (Aβ1-42) measurement does not parallel to cognitive changes in Alzheimer's disease (AD) and cognitively normal (CN) subjects across different studies. Therefore, identifying novel proteins to characterize symptomatic AD samples is important.
Proteins were profiled using a multianalyte platform by Rules Based Medicine (MAP-RBM). Due to underlying heterogeneity and unbalanced sample size, we combined subjects (344 AD and 325 CN) from three cohorts: Alzheimer's Disease Neuroimaging Initiative, Penn Center for Neurodegenerative Disease Research of the University of Pennsylvania, and Knight Alzheimer's Disease Research Center at Washington University in St. Louis. We focused on samples whose cognitive and amyloid status was consistent. We performed linear regression (accounted for age, gender, number of APOE e4 alleles, and cohort variable) to identify amyloid-related proteins for symptomatic AD subjects in this largest ever CSF-based MAP-RBM study. ANOVA and Tukey's test were used to evaluate if these proteins were related to cognitive impairment changes as measured by mini-mental state examination (MMSE).
Seven proteins were significantly associated with Aβ1-42 levels in the combined cohort (false discovery rate adjusted P < .05), of which lipoprotein a (Lp(a)), prolactin (PRL), resistin, and vascular endothelial growth factor (VEGF) have consistent direction of associations across every individual cohort. VEGF was strongly associated with MMSE scores, followed by pancreatic polypeptide and immunoglobulin A (IgA), suggesting they may be related to staging of AD.
Lp(a), PRL, IgA, and tissue factor/thromboplastin have never been reported for AD diagnosis in previous individual CSF-based MAP-RBM studies. Although some of our reported analytes are related to AD pathophysiology, others' roles in symptomatic AD samples worth further explorations.