When making a decision, humans often have to ‘coordinate’—reach the same conclusion—as another individual without explicitly communicating. Relatively, little is known about the neural basis for coordination. Moreover, previous fMRI investigations have supported conflicting hypotheses. One account proposes that individuals coordinate using a ‘gut feeling’ and that this is supported by insula recruitment. Another account proposes that individuals recruit strategic decision-making mechanisms in prefrontal cortex in order to coordinate. We investigate the neural basis for coordination in individuals with behavioral-variant frontotemporal dementia (bvFTD) who have limitations in social decision-making associated with disease in prefrontal cortex. We demonstrate that bvFTD are impaired at establishing a focal point in a semantic task (e.g. ‘Tell me any boy's name’) that requires coordination relative to a similar, control semantic task that does not. Additionally, coordination limitations in bvFTD are related to cortical thinning in prefrontal cortex. These findings are consistent with behavioral economic models proposing that, beyond a ‘gut feeling’, strategic decision-making contributes to the coordination process, including a probabilistic mechanism that evaluates the salience of a response (e.g. is ‘John’ a frequent boy's name), a hierarchical mechanism that iteratively models an opponent's likely response and a mechanism involved in social perspective taking.
coordination; frontotemporal dementia; MRI; decision making; game theory
Frontotemporal lobar degeneration (FTLD) is most commonly associated with TAR-DNA binding protein (TDP-43) or tau pathology at autopsy, but there are no in vivo biomarkers reliably discriminating between sporadic cases. As disease-modifying treatments emerge, it is critical to accurately identify underlying pathology in living patients so that they can be entered into appropriate etiology-directed clinical trials. Patients with tau inclusions (FTLD-TAU) appear to have relatively greater white matter (WM) disease at autopsy than those patients with TDP-43 (FTLD-TDP). In this paper, we investigate the ability of white matter (WM) imaging to help discriminate between FTLD-TAU and FTLD-TDP during life using diffusion tensor imaging (DTI).
Patients with autopsy-confirmed disease or a genetic mutation consistent with FTLD-TDP or FTLD-TAU underwent multimodal T1 volumetric MRI and diffusion weighted imaging scans. We quantified cortical thickness in GM and fractional anisotropy (FA) in WM. We performed Eigenanatomy, a statistically robust dimensionality reduction algorithm, and used leave-one-out cross-validation to predict underlying pathology. Neuropathological assessment of GM and WM disease burden was performed in the autopsy-cases to confirm our findings of an ante-mortem GM and WM dissociation in the neuroimaging cohort.
ROC curve analyses evaluated classification accuracy in individual patients and revealed 96% sensitivity and 100% specificity for WM analyses. FTLD-TAU had significantly more WM degeneration and inclusion severity at autopsy relative to FTLD-TDP.
These neuroimaging and neuropathological investigations provide converging evidence for greater WM burden associated with FTLD-TAU, and emphasize the role of WM neuroimaging for in vivo discrimination between FTLD-TAU and FTLD-TDP.
To utilize values of cerebrospinal fluid (CSF) tau and ß-amyloid obtained from two different analytical immunoassays to differentiate Alzheimer’s disease (AD) from frontotemporal lobar degeneration (FTLD).
CSF values of total tau (t-tau) and ß-amyloid (Aß1-42) obtained using the INNOTEST® ELISA were transformed using a linear regression model to equivalent values obtained using the INNO-BIA AlzBio3™ (xMAP Luminex) assay. Cutoff values obtained from the xMAP assay were developed in a series of autopsy-confirmed cases and cross-validated in another series of autopsy-confirmed samples using transformed ELISA values to assess sensitivity and specificity for differentiating AD from FTLD.
Tertiary memory disorders clinics and neuropathological and biomarker core centers.
75 samples from patients with CSF data obtained from both assays were used for transformation of ELISA values. 40 autopsy-confirmed cases (30 AD, 10 FTLD) were used to establish diagnostic cutoff values, and then cross-validated in a second sample set of 21 autopsy-confirmed cases (11 AD, 10 FTLD) with transformed ELISA values.
Main outcome measure
Diagnostic accuracy using transformed biomarker values.
Data obtained from both assays were highly correlated. The t-tau:Aß1-42 ratio had the highest correlation between measures (r=0.928, p<0.001) and high reliability of transformation (ICC=0.89). A cutoff of 0.34 for the t-tau:Aß1-42 ratio had 90% and 100% sensitivity and 96.7% and 91% specificity to differentiate FTLD cases in the validation and cross-validation samples, respectively.
Values from two analytical platforms can be transformed into equivalent units, which can distinguish AD from FTLD more accurately than the clinical diagnosis.
Amyotrophic Lateral Sclerosis (ALS) is associated with impaired executive control. The aim of the current research was to test the hypothesis that concept formation deficits associated with an extra-motor neurocognitive network involving executive and semantic resources can be found in some ALS patients.
Forty-one patients with clinically-definite ALS were assessed with Delis Kaplan Executive Function System Sorting Test (D-KEFS), a measure of concept formation requiring patients to manipulate verbal and visual semantic information and neuropsychological tests measuring naming, semantic memory, and executive control. Using D-KEFS scale scores, a k-mean cluster analysis specifying a 3-group solution was able to classify ALS patients into groups presenting with mildly impaired, average, and above average sorting test performance. High resolution T1 structural MRI was used to examine cortical thickness in a subset of 16 ALS patients.
Step-wise regression analyses related free and recognition sorting test performance to measures of action naming, single word semantic knowledge, and mental search/working memory. MRI studies found widespread cortical thinning involving bilateral frontal, temporal and parietal regions. Regression analyses related recognition sorting performance to reduced MRI cortical thickness involving the left prefrontal and left parietal cortex.
An extra-motor cognitive network is associated with impaired concept formation in ALS.
Amyotrophic Lateral Sclerosis (ALS); executive control; prefrontal cortex; neuropsychology; Delis-Kaplan Executive Function System (D-KEFS) Sorting Test
We contribute a novel and interpretable dimensionality reduction strategy, eigenanatomy, that is tuned for neuroimaging data. The method approximates the eigendecomposition of an image set with basis functions (the eigenanatomy vectors) that are sparse, unsigned and are anatomically clustered. We employ the eigenanatomy vectors as anatomical predictors to improve detection power in morphometry. Standard voxel-based morphometry (VBM) analyzes imaging data voxel-by-voxel—and follows this with cluster-based or voxel-wise multiple comparisons correction methods to determine significance. Eigenanatomy reverses the standard order of operations by first clustering the voxel data and then using standard linear regression in this reduced dimensionality space. As with traditional region-of-interest (ROI) analysis, this strategy can greatly improve detection power. Our results show that eigenanatomy provides a principled objective function that leads to localized, data-driven regions of interest. These regions improve our ability to quantify biologically plausible rates of cortical change in two distinct forms of neurodegeneration. We detail the algorithm and show experimental evidence of its efficacy.
Traditional neuroanatomic models of language comprehension have emphasized a core language network situated in peri-Sylvian cortex. More recent evidence appears to extend the neuroanatomic network beyond peri-Sylvian cortex to encompass other aspects of sentence processing. In this study, we evaluate the neuroanatomic basis for processing the ambiguity in doubly-quantified sentences. For example, a sentence like “All the dogs jumped in a lake” can be interpreted with a collective interpretation (e.g., several dogs jumping into a single lake) or a distributive interpretation (e.g., several dogs each jumping into a different lake). In Experiment 1, we used BOLD fMRI to investigate neuroanatomic recruitment by young adults during the interpretation of ambiguous doubly-quantified sentences in a sentence-picture verification task. We observed that young adults exhibited a processing cost associated with interpreting ambiguous sentences and this was related to frontal and parietal cortex recruitment. In Experiment 2, we investigate ambiguous sentence processing with the identical materials in non-aphasic patients with behavioral variant frontotemporal dementia (bvFTD) who have frontal cortex disease and executive and decision-making limitations. bvFTD patients are insensitive to ambiguity associated with doubly-quantified sentences, and this is related to the magnitude of their frontal cortex disease. These studies provide converging evidence that cortical regions that extend beyond peri-Sylvian cortex help support the processing costs associated with the interpretation of ambiguous doubly-quantified sentences.
language; quantifiers; fMRI; volumetric MRI; frontotemporal dementia
Pronouns are extraordinarily common in daily language yet little is known about the neural mechanisms that support decisions about pronoun reference. We propose a large-scale neural network for resolving pronoun reference that consists of two components. First, a core language network in peri-Sylvian cortex supports syntactic and semantic resources for interpreting pronoun meaning in sentences. Second, a frontal-parietal network that supports strategic decision-making is recruited to support probabilistic and risk-related components of resolving a pronoun’s referent. In an fMRI study of healthy young adults, we observed activation of left inferior frontal and superior temporal cortex, consistent with a language network. We also observed activation of brain regions not associated with traditional language areas. By manipulating the context of the pronoun, we were able to demonstrate recruitment of dorsolateral prefrontal cortex during probabilistic evaluation of a pronoun’s reference, and orbital frontal activation when a pronoun must adopt a risky referent. Together, these findings are consistent with a two-component model for resolving a pronoun’s reference that includes neuroanatomic regions supporting core linguistic and decision-making mechanisms.
decision-making; language processing; pronouns; fMRI; lexical semantic
Prior work has related sentence processing to executive deficits in non-demented patients with Parkinson’s disease (PD). We extended this investigation to patients with dementia with Lewy bodies (DLB) and PD dementia (PDD) by examining grammatical and working memory components of sentence processing in the full range of patients with Lewy body spectrum disorder (LBSD). Thirty-three patients with LBSD were given a two-alternative, forced-choice sentence-picture matching task. Sentence type, working memory, and grammatical structure were systematically manipulated in the sentences. We found that patients with PDD and DLB were significantly impaired relative to non-demented PD patients and healthy controls. The deficit in PDD/DLB was most pronounced for sentences lengthened by the strategic placement of an additional prepositional phrase and for sentences with an additional proposition due to a center-embedded clause. However, there was no effect for subject-relative versus object-relative grammatical structure. An MRI voxel-based morphometry analysis in a subset of patients showed significant gray matter thinning in the frontal lobe bilaterally, and this extended to temporal, parietal and occipital regions. A regression analysis related sentence processing difficulty in LBSD to frontal neocortex, including inferiorprefrontal, premotor, and dorsolateral prefrontal regions, as well as right superior temporal cortex. These findings are consistent with the hypothesis that patients with PDD and DLB have difficulty processing sentences with increased working memory demands and that this deficit is related in part to their frontal disease.
Lewy body; Parkinson’s; sentence processing; working memory; MRI; prefrontal
Few studies have examined connected speech in demented and non-demented patients with Parkinson’s disease (PD). We assessed the speech production of 35 patients with Lewy body spectrum disorder (LBSD), including non-demented PD patients, patients with PD dementia (PDD), and patients with dementia with Lewy bodies (DLB), in a semi-structured narrative speech sample in order to characterize impairments of speech fluency and to determine the factors contributing to reduced speech fluency in these patients. Both demented and non-demented PD patients exhibited reduced speech fluency, characterized by reduced overall speech rate and long pauses between sentences. Reduced speech rate in LBSD correlated with measures of between-utterance pauses, executive functioning, and grammatical comprehension. Regression analyses related non-fluent speech, grammatical difficulty, and executive difficulty to atrophy in frontal brain regions. These findings indicate that multiple factors contribute to slowed speech in LBSD, and this is mediated in part by disease in frontal brain regions.
Parkinson’s disease; speech; language; fluency; dementia with Lewy bodies
Previous work investigating deficits in self-appraisal in behavioural-variant frontotemporal degeneration (bvFTD) has focused on a single domain: social/behavioural processes. We examined whether a domain-specific versus multi-domain model best explains degraded self-appraisal in bvFTD.
49 patients with bvFTD and 73 patients with Alzheimer’s disease (AD) were administered quantitative assessments of episodic memory, naming and grammatical comprehension. Self-appraisal of cognitive test performance was assessed by asking patients to rate their performance immediately after completing each neuropsychological test. A discrepancy score was created to reflect the difference between patient performance on neuropsychological tests and self-appraisal of their test performance. Self-appraisal for each neuropsychological measure was related to grey matter (GM) density in each group using voxel-based morphometry.
bvFTD patients were poor at evaluating their own performance on all cognitive tests, with no significant correlations between self-appraisal and actual performance. By contrast, poor self-appraisal in AD was restricted to episodic memory performance. Poor self-appraisal on each task in bvFTD and AD was related to reduced GM density in several ventral and rostral medial prefrontal regions. Crucially, poor self-appraisal for all domains in bvFTD was related to a specific area of reduced GM density in the subgenual cingulate (BA 25).
Poor self-appraisal in bvFTD affects multiple domains, and this multi-domain impairment pattern is associated with frontal disease in the subgenual cingulate.
While grammatical aspects of language are preserved, executive deficits are prominent in Lewy body spectrum disorder (LBSD), including Parkinson’s disease (PD), Parkinson’s dementia (PDD) and dementia with Lewy bodies (DLB). We examined executive control during sentence processing in LBSD by assessing temporary structural ambiguities. Using an on-line word detection procedure, patients heard sentences with a syntactic structure that has high-compatibility or low-compatibility with the main verb’s statistically preferred syntactic structure, and half of the sentences were lengthened strategically between the onset of the ambiguity and its resolution. We found selectively slowed processing of lengthened ambiguous sentences in the PDD/DLB subgroup. This correlated with impairments on measures of executive control. Regression analyses related the working memory deficit during ambiguous sentence processing to significant cortical thinning in frontal and parietal regions. These findings emphasize the role of prefrontal disease in the executive limitations that interfere with processing ambiguous sentences in LBSD.
Parkinson’s; Lewy body; syntactic ambiguity; working memory; frontal
Quantifiers are very common in everyday speech, but we know little about their cognitive basis or neural representation. The present study examined comprehension of three classes of quantifiers that depend on different cognitive components in patients with focal neurodegenerative diseases. Patients evaluated the truth-value of a sentence containing a quantifier relative to a picture illustrating a small number of familiar objects, and performance was related to MRI grey matter atrophy using voxel-based morphometry. We found that patients with corticobasal syndrome (CBS) and posterior cortical atrophy (PCA) are significantly impaired in their comprehension of Cardinal Quantifiers (e.g. “At least three birds are on the branch”), due in part to their deficit in quantity knowledge. MRI analyses related this deficit to temporal-parietal atrophy found in CBS/PCA. We also found that patients with behavioral variant frontotemporal dementia (bvFTD) are significantly impaired in their comprehension of Logical Quantifiers (e.g. “Some the birds are on the branch”), associated with a simple form of perceptual logic, and this correlated with their deficit on executive measures. This deficit was related to disease in rostral prefrontal cortex in bvFTD. These patients were also impaired in their comprehension of Majority Quantifiers (e.g. “At least half of the birds are on the branch”), and this too was correlated with their deficit on executive measures. This was related to disease in the basal ganglia interrupting a frontal-striatal loop critical for executive functioning. These findings suggest that a large-scale frontal-parietal neural network plays a crucial role in quantifier comprehension, and that comprehension of specific classes of quantifiers may be selectively impaired in patients with focal neurodegenerative conditions in these areas.
comprehension; quantifier; parietal; frontal; corticobasal; frontotemporal dementia
Narrative discourse is an essential component of day-to-day communication, but little is known about narrative in Lewy Body spectrum disorder (LBSD), including Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB). We performed a detailed analysis of a semi-structured speech sample in 32 non-aphasic patients with LBSD, and we related their narrative impairments to gray matter (GM) atrophy using voxel-based morphometry. We found that patients with PDD and DLB have significant difficulty organizing their narrative speech. This was correlated with deficits on measures of executive functioning and speech fluency. Regression analyses associated this deficit with reduced cortical volume in inferior frontal and anterior cingulate regions. These findings are consistent with a model of narrative discourse that includes executive as well as language components and with an impairment of the organizational component of narrative discourse in patients with PDD and DLB.
Parkinson's disease; discourse; speech; language; Dementia with Lewy bodies
To understand the scope of semantic impairment in semantic dementia.
Academic medical center.
A man with semantic dementia, as demonstrated by clinical, neuropsychological, and imaging studies.
Main Outcome Measures
Music performance and magnetic resonance imaging results.
Despite profoundly impaired semantic memory for words and objects due to left temporal lobe atrophy, this semiprofessional musician was creative and expressive in demonstrating preserved musical knowledge.
Long-term representations of words and objects in semantic memory may be dissociated from meaningful knowledge in other domains, such as music.
We investigated the cognitive and neural bases of impaired speech fluency, a central feature of primary progressive aphasia. Speech fluency was assessed in 35 patients with frontotemporal lobar degeneration (FTLD) who presented with progressive non-fluent aphasia (PNFA, n=11), semantic dementia (SemD, n=12), or a social and executive disorder without aphasia (SOC/EXEC, n=12). Fluency was quantified as the number of words per minute in an extended, semi-structured speech sample. This was related to language characteristics of the speech sample and to neuropsychological measures. PNFA patients were significantly less fluent than controls and other FTLD patients. Fluency correlated with grammatical expression but not with speech errors or executive difficulty. SemD and SOC/EXEC patients were also less fluent than controls. In SemD, fluency was associated with semantically limited content. In SOC/EXEC, fluency was associated with executive limitations. Voxel-based morphometry analyses of high-resolution MRI related fluency to gray matter volume in left inferior frontal, insula, and superior temporal regions for the entire cohort of FTLD patients. This region overlapped partially distinct atrophic areas in each FTLD subgroup. It thus appears to play a crucial role in speech fluency, which can be interrupted in different ways in different FTLD subgroups.
frontotemporal dementia; progressive aphasia; MRI; speech fluency
Recent investigations have supported the suggestion that phonological speech errors may reflect the simultaneous activation of more than one phonemic representation. This presents a challenge for speech error evidence which is based on the assumption of well-formedness, because we may continue to perceive well-formed errors, even when they are not produced. To address this issue, we present two tongue-twister experiments in which the articulation of onset consonants is quantified and compared to baseline measures from cases where there is no phonemic competition. We report three measure of articulatory variability: changes in tongue-to-palate contact using electropalatography (EPG, Experiment 1), changes in midsagittal spline of the tongue using ultrasound (Experiment 2), and acoustic changes manifested as voice-onset-time (VOT). These three sources provide converging evidence that articulatory variability increases when competing onsets differ by one phonological feature, but the increase is attenuated when onsets differ by two features. This finding provides clear evidence, based solely on production, that the articulation of phonemes is influenced by cascading activation from the speech plan.
The ventral medial prefrontal cortex (vmPFC) has been implicated in social and affectively influenced decision-making. Disease in this region may have clinical consequences for social judgments in patients with frontotemporal lobar degeneration (FTLD). To test this hypothesis, regional cortical activation was monitored with fMRI while healthy adults judged the acceptability of brief social scenarios such as cutting into a movie ticket line or going through a red light at 2 AM. The scenarios described: (i) a socially neutral condition, (ii) a variant of each scenario containing a negatively-valenced feature, and (iii) a variant containing a positively-valenced feature. Results revealed that healthy adults activated vmPFC during judgments of negatively-valenced scenarios relative to positive scenarios and neutral scenarios. In a comparative behavioral study, the same social decision-making paradigm was administered to patients with a social disorder due to FTLD. Patients differed significantly from healthy controls, specifically showing less sensitivity to negatively-valenced features. Comparative anatomical analysis revealed considerable overlap of vmPFC activation in healthy adults and vmPFC cortical atrophy in FTLD patients. These converging results support the role of vmPFC in social decision-making where potentially negative consequences must be considered.
ventromedial prefrontal cortex; social decision-making; frontotemporal dementia
The nature and frequency of speech production errors in neurodegenerative disease have not previously been precisely quantified. In the present study, 16 patients with a progressive form of nonfluent aphasia (PNFA) were asked to tell a story from a wordless children’s picture book. Errors in production were classified as either phonemic, involving language-based deformations that nevertheless result in possible sequences of English speech segments; or phonetic, involving a motor planning deficit and resulting in non-English speech segments. The distribution of cortical atrophy as revealed by structural MRI scans was examined quantitatively in a subset of PNFA patients (N=7). The few errors made by healthy seniors were only phonemic in type. PNFA patients made more than four times as many errors as controls. This included both phonemic and phonetic errors, with a preponderance of errors (82%) classified as phonemic. The majority of phonemic errors were substitutions that shared most distinctive features with the target phoneme. The systematic nature of these substitutions is not consistent with a motor planning deficit. Cortical atrophy was found in prefrontal regions bilaterally and peri-Sylvian regions of the left hemisphere. We conclude that the speech errors produced by PNFA patients are mainly errors at the phonemic level of language processing and are not caused by a motor planning impairment.
Progressive non-fluent aphasia; phonology; speech errors
To investigate the cognitive and neural correlates of discourse impairment in corticobasal syndrome (CBS).
Difficulty communicating is a frequent clinical manifestation in patients with CBS. However, the mechanisms underlying this disabling problem are not well understood.
Twenty patients with CBS and 8 healthy seniors narrated a picture story. Narratives were analyzed for maintenance of the narrative theme, identification of the overall point of the story (global connectedness), and connectedness between consecutive events (local connectedness). Discourse measures were correlated with performance on cognitive tasks and with cortical atrophy as determined by magnetic resonance imaging voxel-based morphometry.
Patients with CBS referred to the narrative theme significantly less frequently than controls. Global connectedness was intact in only 6 of 20 CBS patients (30%), but preserved in all controls. Local connectedness was significantly diminished in patients relative to controls. Discourse performance in CBS was related to tasks requiring higher-order integration of visual material, but not to basic visuospatial/visuoperceptual, language, or memory function. Discourse impairment was directly related to atrophy in the right parietal lobe and bilateral dorsolateral prefrontal cortex.
Our findings suggest that impaired information integration in CBS, related to parieto-frontal disease, interferes with patients’ ability to narrate a coherent story.
corticobasal syndrome; volumetric MRI; discourse; inferior parietal lobe; dorsolateral prefrontal cortex
To investigate the basis for impaired sentence comprehension in patients with frontotemporal dementia (FTD) we assessed grammatical comprehension and verbal working memory in 88 patients with three distinct presentations: progressive nonfluent aphasia (PNFA), semantic dementia (SD), and nonaphasic patients with a disorder of social comportment and executive processing (SOC/EXEC). We related sentence comprehension and working memory performance to regional cortical volume in a subgroup of 29 patients with structural MRI scans using voxel-based morphometry. PNFA patients exhibited the greatest difficulty with sentence comprehension and were especially impaired with grammatically complex sentences, which correlated with atrophy in left inferior frontal cortex. Working memory performance in these same patients correlated with a proximal but distinct left inferior frontal region. SD patients’ sentence comprehension scores correlated with left inferolateral temporal lobe damage, which we hypothesize and reflect impairments in lexical processing. We did not observe any consistent relationship between cortical atrophy and sentence comprehension impairment in SOC/EXEC patients, suggesting the deficits in this subgroup may be due to more variable declines in executive resources.
progressive aphasia; semantic dementia; sentence comprehension; MRI; VBM (voxel-based morphometry)