Erratum: "Causal Contributions of the Domain-General (Multiple Demand) and the Language-Selective Brain Networks to Perceptual and Semantic Challenges in Speech Comprehension".

[This corrects the article DOI: 10.1162/nol_a_00081.].

Causal Contributions of the Domain-General (Multiple Demand) and the Language-Selective Brain Networks to Perceptual and Semantic Challenges in Speech Comprehension.

Listening to spoken language engages domain-general multiple demand (MD; frontoparietal) regions of the human brain, in addition to domain-selective (frontotemporal) language regions, particularly when comprehension is challenging. However, there is limited evidence that the MD network makes a functional contribution to core aspects of understanding language. In a behavioural study of volunteers (n = 19) with chronic brain lesions, but without aphasia, we assessed the causal role of these networks in perceiving, comprehending, and adapting to spoken sentences made more challenging by acoustic-degradation or lexico-semantic ambiguity. We measured perception of and adaptation to acoustically degraded (noise-vocoded) sentences with a word report task before and after training. Participants with greater damage to MD but not language regions required more vocoder channels to achieve 50% word report, indicating impaired perception. Perception improved following training, reflecting adaptation to acoustic degradation, but adaptation was unrelated to lesion location or extent. Comprehension of spoken sentences with semantically ambiguous words was measured with a sentence coherence judgement task. Accuracy was high and unaffected by lesion location or extent. Adaptation to semantic ambiguity was measured in a subsequent word association task, which showed that availability of lower-frequency meanings of ambiguous words increased following their comprehension (word-meaning priming). Word-meaning priming was reduced for participants with greater damage to language but not MD regions. Language and MD networks make dissociable contributions to challenging speech comprehension: Using recent experience to update word meaning preferences depends on language-selective regions, whereas the domain-general MD network plays a causal role in reporting words from degraded speech.

Cognitive Diversity in a Healthy Aging Cohort: Cross-Domain Cognition in the Cam-CAN Project.

Objective: Studies of "healthy" cognitive aging often focus on a limited set of measures that decline with age. The current study argues that defining and supporting healthy cognition requires understanding diverse cognitive performance across the lifespan. Method: Data from the Cambridge Centre for Aging and Neuroscience (Cam-CAN) cohort was examined across a range of cognitive domains. Performance was related to lifestyle including education, social engagement, and enrichment activities. Results: Results indicate variable relationships between cognition and age (positive, negative, or no relationship). Principal components analysis indicated maintained cognitive diversity across the adult lifespan, and that cognition-lifestyle relationships differed by age and domain. Discussion: Our findings support a view of normal cognitive aging as a lifelong developmental process with diverse relationships between cognition, lifestyle, and age. This reinforces the need for large-scale studies of cognitive aging to include a wider range of both ages and cognitive tasks.

Huntington's disease patients display progressive deficits in hippocampal-dependent cognition during a task of spatial memory.

BACKGROUND: Cognitive disturbances occur early in Huntington's disease (HD) and place a significant burden on the lives of patients and family members. Whilst these impairments are typically attributed to deterioration of the frontal-striatal pathways, accumulating evidence suggests that hippocampal dysfunction may also contribute to such impairments. Here, we employ a novel spatial memory task that has previously been shown to elicit impairments in individuals with focal hippocampal lesions, as a means to further investigate the role of hippocampal dysfunction in HD. METHOD: Sixty-four individuals participated in the study, including 32 healthy controls, 11 patients with diagnosed HD and 16 premanifest HD gene carriers. We also included an additional control group of 5 individuals with focal unilateral basal ganglia lesions. Participants undertook a task that measured perception and short-term spatial memory using computer-generated visual scenes. RESULTS: HD patients experienced significant impairments in spatial perception and memory, which strongly correlated with disease burden score (DBS). Premanifest gene carriers performed at a similar level to healthy controls throughout all aspects of the task indicating that the effects seen in the HD patients represent a deterioration in function. Interestingly, basal ganglia lesion patients were not impaired in any aspects of the task. CONCLUSION: There is evidence of significant deficits in hippocampal-dependent spatial cognition in HD that cannot be explained as a function of degeneration to the basal ganglia. The impairments were greatest in individuals with higher DBSs, suggesting that deficits relate to the disease process in HD.

No effect of hippocampal lesions on stimulus-response bindings.

The hippocampus is believed to be important for rapid learning of arbitrary stimulus-response contingencies, or S-R bindings. In support of this, Schnyer et al. (2006) (Experiment 2) measured priming of reaction times (RTs) to categorise visual objects, and found that patients with medial temporal lobe damage, unlike healthy controls, failed to show evidence of reduced priming when response contingencies were reversed between initial and repeated categorisation of objects (a signature of S-R bindings). We ran a similar though extended object classification task on 6 patients who appear to have selective hippocampal lesions, together with 24 age-matched controls. Unlike Schnyer et al. (2006), we found that reversing response contingencies abolished priming in both controls and patients. Bayes Factors provided no reason to believe that response reversal had less effect on patients than controls. We therefore conclude that it is unlikely that the hippocampus is needed for S-R bindings.

Multiple determinants of lifespan memory differences.

Memory problems are among the most common complaints as people grow older. Using structural equation modeling of commensurate scores of anterograde memory from a large (N = 315), population-derived sample (www.cam-can.org), we provide evidence for three memory factors that are supported by distinct brain regions and show differential sensitivity to age. Associative memory and item memory are dramatically affected by age, even after adjusting for education level and fluid intelligence, whereas visual priming is not. Associative memory and item memory are differentially affected by emotional valence, and the age-related decline in associative memory is faster for negative than for positive or neutral stimuli. Gray-matter volume in the hippocampus, parahippocampus and fusiform cortex, and a white-matter index for the fornix, uncinate fasciculus and inferior longitudinal fasciculus, show differential contributions to the three memory factors. Together, these data demonstrate the extent to which differential ageing of the brain leads to differential patterns of memory loss.

The effects of hippocampal lesions on MRI measures of structural and functional connectivity.

Focal lesions can affect connectivity between distal brain regions (connectional diaschisis) and impact the graph-theoretic properties of major brain networks (connectomic diaschisis). Given its unique anatomy and diverse range of functions, the hippocampus has been claimed to be a critical "hub" in brain networks. We investigated the effects of hippocampal lesions on structural and functional connectivity in six patients with amnesia, using a range of magnetic resonance imaging (MRI) analyses. Neuropsychological assessment revealed marked episodic memory impairment and generally intact performance across other cognitive domains. The hippocampus was the only brain structure exhibiting reduced grey-matter volume that was consistent across patients, and the fornix was the only major white-matter tract to show altered structural connectivity according to both diffusion metrics. Nonetheless, functional MRI revealed both increases and decreases in functional connectivity. Analysis at the level of regions within the default-mode network revealed reduced functional connectivity, including between nonhippocampal regions (connectional diaschisis). Analysis at the level of functional networks revealed reduced connectivity between thalamic and precuneus networks, but increased connectivity between the default-mode network and frontal executive network. The overall functional connectome showed evidence of increased functional segregation in patients (connectomic diaschisis). Together, these results point to dynamic reorganization following hippocampal lesions, with both decreased and increased functional connectivity involving limbic-diencephalic structures and larger-scale networks. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.

Stress, distress and mucosal immunity in carers of a partner with fronto-temporal dementia.

OBJECTIVES: This study investigates the psychological and physiological impact of caring for a partner with fronto-temporal dementia (FTD). Carers were expected to exhibit greater stress and poorer psychological well-being in comparison with non-carers, and suppressed mucosal immunity. METHOD: Twenty-five carers and 36 non-carers completed standardised psychological assessments of perceived stress, psychological well-being, coping and social support. Levels of mucosal immunity were assessed in saliva samples collected over the 3 days of the study, alongside daily assessments of stress, arousal and mood. RESULTS: Informal carers as a group reported greater stress and poorer psychological well-being, but there was considerable variation, with some carers reporting better psychological functioning than non-carers. Immune levels were not suppressed in carers compared with non-carers; counter to hypothesis, there was a positive correlation between immunity and poorer psychological well-being. CONCLUSIONS: This research suggests that caring for a partner with FTD increases distress and carers might benefit from psychological intervention. However, the variation in psychological well-being requires explanation. Furthermore, this first examination of mucosal immunity employing participants experiencing enduring stress suggests that, in contrast to previous research, enduring stress does not lead to suppression of mucosal immunity and may actually enhance it.

Differentiation of semantic dementia and Alzheimer's disease using the Addenbrooke's Cognitive Examination (ACE).

BACKGROUND: The Addenbrooke's Cognitive Examination (ACE) is a simple diagnostic tool bridging the gap between the very brief Mini Mental State Exam (MMSE) and much longer test batteries used by neuropsychologists which has proven extremely popular internationally. OBJECTIVE: We aimed to assess the ability of the ACE to differentiate semantic dementia (SD) from Alzheimer's disease (AD). METHODS: The ACE was administered to three groups: SD patients (n = 40) and two separate groups of AD patients (n = 40 in each), matched for overall ACE or MMSE score. RESULTS: Significant differences were found between SD and both AD groups for the ACE sub-scores of naming, reading and orientation in time. Discriminant analysis (SD versus AD) led to the formulation of a 'semantic index' (naming plus reading minus scores for serial-7s, orientation in time and drawing). Application of the semantic index to the patient data found values of less than zero to be predictive of SD rather than AD with 88% sensitivity and 90% specificity. Validation analysis in an independent sample of 24 SD and AD patients proved even more favourable. CONCLUSIONS: The overall ACE score is known to be a sensitive, and specific, indicator of early neurodegenerative dementia; this study shows that the ACE can also be used to detect SD through application of the semantic index.

Patterns of frontal lobe atrophy in frontotemporal dementia: a volumetric MRI study.

OBJECTIVES: Frontotemporal dementia (FTD), the second commonest degenerative cause of dementia under the age of 65, often presents with striking changes in behaviour and personality in association with frontal lobe atrophy. Based on the behavioural changes observed in FTD, it is commonly assumed that the orbitofrontal cortex is the earliest and most severely affected frontal sub-region. However, evidence to support this assumption has to date been largely lacking. METHODS: Using a novel volumetric MRI method, we performed a detailed volumetric analysis of six frontal regions in 12 subjects with the frontal or behavioural variant of FTD (fvFTD) and 12 age-, education- and sex-matched normal controls. The regions studied were: the orbitofrontal and insula regions (representing the orbitobasal cortex); the inferior and middle frontal regions (representing the dorsolateral prefrontal areas); and the superior frontal and anterior cingulate regions (representing the medial prefrontal areas). RESULTS: As a group, the fvFTD patients showed atrophy involving all six regions. We then segregated the 12 patients into three sub-groups according to their overall degree of atrophy. In the mildest group (n = 3) all regions fell within 2 standard deviations of normal. In the intermediate group (n = 6) only the orbitofrontal region (bilaterally) fell clearly outside the control range (>2 z scores below the control mean); the next most atrophic region in this group was the right insular region. The severe group (n = 3) had generalized atrophy throughout the frontal regions measured. CONCLUSIONS: In conclusion, patients with the earliest stages of fvFTD show no significant loss of volume in any frontal lobe area as measured by a novel MRI volumetric technique. When volume loss does occur, changes are initially seen in the orbitofrontal cortex before atrophy becomes more widespread. These results provide some partial support for the often-quoted assumption that the orbitofrontal cortex is the locus of earliest pathology in fvFTD, although these findings must be regarded as preliminary in view of the small numbers of patients involved.

Evolution of cognitive deficits and conversion to dementia in patients with mild cognitive impairment: a very-long-term follow-up study.

Ten patients with mild cognitive impairment (MCI) underwent extensive neuropsychological evaluation at 12-monthly intervals for a minimum of 6 years. All 10 patients declined and 5 have now died. The onset of dementia, as defined by a fall in global cognitive function (MMSE <24) or activities of daily living (Clinical Dementia Rating Scale; CDR) ranged from 1 to 8 years with generally good concordance between these measures. The rate of decline on the MMSE was highly variable ranging from 0.86 to 2.83 points per year. Other than a consistent impairment on tests of episodic memory and category fluency (8 out of 10), other early cognitive deficits were difficult to define and tended to be unstable in the early stages. Impairment of semantic memory, visuo-spatial and attentional abilities eventually developed but the sequence of deficit acquisition was heterogeneous. These findings are discussed in the light of current views of MCI. Amnestic MCI may not be an accurate concept unless semantic memory impairment is also considered as an integral core deficit. Full-blown dementia may take many years to develop in patients with MCI but was a universal feature in this study.

A comparison of the Addenbrooke's Cognitive Examination (ACE), conventional neuropsychological assessment, and simple MRI-based medial temporal lobe evaluation in the early diagnosis of Alzheimer's disease.

OBJECTIVE: To examine the contribution of the Addenbrooke's Cognitive Examination (ACE), neuropsychological assessment, and a magnetic resonance imaging (MRI)-based temporal lobe rating scale to the prediction of which patients with questionable dementia will progress to Alzheimer's disease (AD). METHODS: Fifty subjects (19 early AD, 31 questionable dementia [QD]) underwent the ACE, a neuropsychological evaluation, and a volumetric MRI. The degree of atrophy of hippocampal, parahippocampal, and other temporal lobe structures was assessed using a validated visual rating scale. Subjects were followed 8 monthly for an average of 19.1 months. RESULTS: Of the 31 QD subjects, 11 converted to AD within 24 months of follow-up (another 2 developed dementia with Lewy bodies) and 18 were nonconverters. Converters were impaired relative to nonconverters at baseline on measures of episodic and semantic memory (category fluency and naming) and the ACE. Converters also had a greater degree of hippocampal and parahippocampal atrophy. Discriminant analysis demonstrated that the best single test for distinguishing converters was the ACE. In combination, the hippocampal rating and category fluency were also contributory. CONCLUSIONS: Progression to AD in patients with QD is best predicted by neuropsychological measures, particularly those that assess episodic and semantic memory, although simple rating methods based on MRI may have an adjunctive role.

Theory of mind in patients with frontal variant frontotemporal dementia and Alzheimer's disease: theoretical and practical implications.

A key aspect of social cognition is the ability to infer other people's mental states, thoughts and feelings; referred to as 'theory of mind' (ToM). We tested the hypothesis that the changes in personality and behaviour seen in frontal variant frontotemporal dementia (fvFTD) may reflect impairment in this cognitive domain. Tests of ToM, executive and general neuropsychological ability were given to 19 fvFTD patients, a comparison group of Alzheimer's disease patients (n = 12) and matched healthy controls (n = 16). Neuropsychiatric assessment was undertaken using the Neuropsychiatric Inventory (NPI). Patients with fvFTD were impaired on all tests of ToM (first-order false belief; second-order false belief; faux pas detection; and Reading the Mind in the Eyes), but had no difficulty with control questions designed to test general comprehension and memory. By contrast, the Alzheimer's disease group failed only one ToM task (second-order false belief), which places heavy demands on working memory. Performance on the faux pas test revealed a double dissociation, with the fvFTD group showing deficits on ToM-based questions and the Alzheimer's disease group failing memory-based questions only. Rank order of the fvFTD patients according to the magnitude of impairment on tests of ToM and their degree of frontal atrophy showed a striking concordance between ToM performances and ventromedial frontal damage. There was a significant correlation between the NPI score and more sophisticated tests of ToM in the fvFTD group. This study supports the hypothesis that patients with fvFTD, but not those with Alzheimer's disease, are impaired on tests of ToM, and may explain some of the abnormalities in interpersonal behaviour that characterize fvFTD.