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Resting-state network research is extremely influential, yet the functions of many networks remain unknown. In part, this is due to typical (e.g., univariate) analyses testing the function of individual regions and not the full set of co-activated regions that form a network. Connectivity is dynamic and the function of a region may change based on its current connections. Therefore, determining the function of a network requires assessment at the network-level. Yet popular theories implicating the default mode network (DMN) in episodic memory and social cognition, rest principally upon analyses performed at the level of individual brain regions. Here we use independent component analysis to formally test the role of the DMN in episodic and social processing at the network level. As well as an episodic retrieval task, two independent datasets were employed to assess DMN function across the breadth of social cognition; a person knowledge judgement and a theory of mind task. Each task dataset was separated into networks of co-activated regions. In each, the co-activated DMN, was identified through comparison to an a priori template and its relation to the task model assessed. This co-activated DMN did not show greater activity in episodic or social tasks than high-level baseline conditions. Thus, no evidence was found to support hypotheses that the co-activated DMN is involved in explicit episodic or social processing tasks at a network-level. The networks associated with these processes are described. Implications for prior univariate findings and the functional significance of the co-activated DMN are considered.

Impaired social cognition is a core deficit of frontotemporal dementia (FTD). It is most commonly associated with the behavioural-variant of FTD, with atrophy of the orbitofrontal and ventromedial prefrontal cortex. However, social cognitive changes are also common in semantic dementia, with atrophy centred on the anterior temporal lobes. The impairment of social behaviour in FTD has typically been attributed to damage to the orbitofrontal cortex and/or temporal poles and/or the uncinate fasciculus that connects them. However, the relative contribution of each region is unresolved. In this review, we present a unified neurocognitive model of controlled social behaviour that not only explains the observed impairment of social behaviours in FTD, but also assimilates findings from other patient groups, comparative neurology, and normative cognitive neuroscience. We propose that impaired social behaviour results from damage to two cognitively- and anatomically-distinct components. The first component is social-semantic knowledge, supported by the anterior temporal lobes bilaterally. The second component is social control, supported by the orbitofrontal cortex, medial frontal cortex and ventrolateral frontal cortex, which interact with social-semantic knowledge to guide and shape social behaviour.

A key challenge for neurobiological models of social cognition is to elucidate whether brain regions are specialised for that domain. In recent years, discussion surrounding the role of anterior temporal regions epitomises such debates; some argue the anterior temporal lobe (ATL) is part of a domain-specific network for social processing, while others claim it comprises a domain-general hub for semantic representation. In the present study, we used ATL-optimised fMRI to map the contribution of different ATL structures to a variety of paradigms frequently used to probe a crucial social ability, namely ‘theory of mind’ (ToM). Using multiple tasks enables a clearer attribution of activation to ToM as opposed to idiosyncratic features of stimuli. Further, we directly explored whether these same structures are also activated by a non-social task probing semantic representations. We revealed that common to all of the tasks was activation of a key ventrolateral ATL region that is often invisible to standard fMRI. This constitutes novel evidence in support of the view that the ventrolateral ATL contributes to social cognition via a domain-general role in semantic processing, and against claims of a specialised social function.

Aesthetic judgements dominate much of daily life by guiding how we evaluate objects, people, and experiences in our environment. One key question that remains unanswered is the extent to which more specialised or largely general cognitive resources support aesthetic judgements. To investigate this question in the context of working memory, we examined the extent to which a working memory load produces similar or different response time interference on aesthetic compared with non-aesthetic judgements. Across three pre-registered experiments that used Bayesian multi-level modelling approaches ( N > 100 per experiment), we found clear evidence that a working memory load produces similar response time interference on aesthetic judgements relative to non-aesthetic (motion) judgements. We also showed that this similarity in processing across aesthetic versus non-aesthetic judgements holds across variations in the form of art (people vs. landscape; Experiments 1–3), medium type (artwork vs. photographs; Experiment 2), and load content (art images vs. letters; Experiments 1–3). These findings suggest that across a range of experimental contexts, as well as different processing streams in working memory (e.g., visual vs. verbal), aesthetic and motion judgements commonly rely on a domain-general cognitive system, rather than a system that is more specifically tied to aesthetic judgements. In doing so, these findings shine new light on the working memory resources that support aesthetic judgements, as well as on how domain-general cognitive systems operate more generally in cognition.

Aesthetic judgments dominate much of daily life by guiding how we evaluate objects, people, and experiences in our environment. One key question that remains unanswered is the extent to which more specialised or largely general cognitive resources support aesthetic judgments. To investigate this question in the context of executive resources, we examined the extent to which a central working memory load produces similar or different reaction time interference on aesthetic compared to non-aesthetic judgments. Across three pre-registered experiments that used Bayesian multi-level modelling approaches (N>100 per experiment), we found clear evidence that a central working memory load produces similar reaction time interference on aesthetic judgments relative to non-aesthetic (motion) judgments. We also showed that this similarity in processing across aesthetic versus non-aesthetic judgments holds across variations in the form of art (people vs landscape; Exps. 1-3), medium type (artwork vs photographs; Exp. 2) and load content (art images vs letters; Exps. 1-3). These findings suggest that across a range of experimental contexts, as well as different processing streams in working memory (e.g., visual vs verbal), aesthetic and motion judgments commonly rely on a domain-general executive system, rather than a system that is more specifically tied to aesthetic judgments. In doing so, these findings shine new light on the cognitive architecture that supports aesthetic judgments, as well as how domain-general executive systems operate more generally in cognition.

Given that aesthetic experiences typically involve extracting meaning from environment, we believe that semantic cognition research has much to offer the field of neuroaesthetics. In the current paper, we propose a generalised framework that is inspired by the semantic cognition literature and that treats aesthetic experience as just one example of how meaning accumulates. According to our framework, aesthetic experiences are underpinned by the same cognitive and brain systems that are involved in deriving meaning from the environment in general, such as modality-specific conceptual representations and controlled processes for retrieving the appropriate type of information. Our generalised semantic cognition view of aesthetic experience has substantial implications for theory development: it leads to novel, falsifiable predictions and it reconfigures foundational assumptions regarding the structure of the cognitive and brain systems that may be involved in aesthetic experiences.

Background: Patients with nonfluent/agrammatic variant primary progressive aphasia (nfvPPA) have more difficulty producing verbs than nouns, but the reason for this discrepancy remains unclear. One...

Processing a famous face involves a cascade of steps including detecting the presence of a face, recognizing it as familiar, accessing semantic/biographical information about the person, and finally, if required, production of the proper name. Decades of neuropsychological and neuroimaging studies have identified a network of occipital and temporal brain regions ostensibly comprising the 'core' system for face processing. Recent research has also begun to elucidate upon an 'extended' network, including anterior temporal and frontal regions. However, there is disagreement about which brain areas are involved in each step, as many aspects of face processing occur automatically in healthy individuals and rarely dissociate in patients. Moreover, some common phenomena are not easily induced in an experimental setting, such as having a sense of familiarity without being able to recall who the person is. Patients with the semantic variant of Primary Progressive Aphasia (svPPA) often recognize a famous face as familiar, even when they cannot specifically recall the proper name or biographical details. In this study, we analyzed data from a large sample of 105 patients with neurodegenerative disorders, including 43 svPPA, to identify the neuroanatomical substrates of three different steps of famous face processing. Using voxel-based morphometry, we correlated whole-brain grey matter volumes with scores on three experimental tasks that targeted familiarity judgment, semantic/biographical information retrieval, and naming. Performance in naming and semantic association significantly correlates with grey matter volume in the left anterior temporal lobe, whereas familiarity judgment with integrity of the right anterior middle temporal gyrus. These findings shed light on the neuroanatomical substrates of key components of overt face processing, addressing issues of functional lateralization, and deepening our understanding of neural substrates of semantic knowledge.

Semantic variant primary progressive aphasia (svPPA) typically presents with left-hemisphere predominant rostral temporal lobe (rTL) atrophy and the most significant complaints within the language domain. Less frequently, patients present with right-hemisphere predominant temporal atrophy coupled with marked impairments in processing of famous faces and emotions. Few studies have objectively compared these patient groups in both domains and therefore it is unclear to what extent the syndromes overlap. Clinically diagnosed svPPA patients were characterized as left- (n=21) or right-predominant (n=12) using imaging and compared along with 14 healthy controls. Regarding language, our primary focus was upon two hallmark features of svPPA; confrontation naming and surface dyslexia. Both groups exhibited naming deficits and surface dyslexia although the impairments were more severe in the left-predominant group. Familiarity judgments on famous faces and affect processing were more profoundly impaired in the right-predominant group. Our findings suggest that the two syndromes overlap significantly but that early cases at the tail ends of the continuum constitute a challenge for current clinical criteria. Correlational neuroimaging analyses implicated a mid portion of the left lateral temporal lobe in exception word reading impairments in line with proposals that this region is an interface between phonology and semantic knowledge.

Neurodegeneration is hypothesized to follow large-scale networks through the trans-synaptic spread of toxic proteins from a syndrome-specific epicentre. Mandelli et al. report that the pattern of atrophy progression in the non-fluent variant of primary progressive aphasia reflects the strength of connectivity in the speech production network of the healthy brain.Neurodegeneration is hypothesized to follow large-scale networks through the trans-synaptic spread of toxic proteins from a syndrome-specific epicentre. Mandelli et al. report that the pattern of atrophy progression in the non-fluent variant of primary progressive aphasia reflects the strength of connectivity in the speech production network of the healthy brain.Neurodegeneration has been hypothesized to follow predetermined large-scale networks through the trans-synaptic spread of toxic proteins from a syndrome-specific epicentre. To date, no longitudinal neuroimaging study has tested this hypothesis in vivo in frontotemporal dementia spectrum disorders. The aim of this study was to demonstrate that longitudinal progression of atrophy in non-fluent/agrammatic variant primary progressive aphasia spreads over time from a syndrome-specific epicentre to additional regions, based on their connectivity to the epicentre in healthy control subjects. The syndrome-specific epicentre of the non-fluent/agrammatic variant of primary progressive aphasia was derived in a group of 10 mildly affected patients (clinical dementia rating equal to 0) using voxel-based morphometry. From this region, the inferior frontal gyrus (pars opercularis), we derived functional and structural connectivity maps in healthy controls (n = 30) using functional magnetic resonance imaging at rest and diffusion-weighted imaging tractography. Graph theory analysis was applied to derive functional network features. Atrophy progression was calculated using voxel-based morphometry longitudinal analysis on 34 non-fluent/agrammatic patients. Correlation analyses were performed to compare volume changes in patients with connectivity measures of the healthy functional and structural speech/language network. The default mode network was used as a control network. From the epicentre, the healthy functional connectivity network included the left supplementary motor area and the prefrontal, inferior parietal and temporal regions, which were connected through the aslant, superior longitudinal and arcuate fasciculi. Longitudinal grey and white matter changes were found in the left language-related regions and in the right inferior frontal gyrus. Functional connectivity strength in the healthy speech/language network, but not in the default network, correlated with longitudinal grey matter changes in the non-fluent/agrammatic variant of primary progressive aphasia. Graph theoretical analysis of the speech/language network showed that regions with shorter functional paths to the epicentre exhibited greater longitudinal atrophy. The network contained three modules, including a left inferior frontal gyrus/supplementary motor area, which was most strongly connected with the epicentre. The aslant tract was the white matter pathway connecting these two regions and showed the most significant correlation between fractional anisotropy and white matter longitudinal atrophy changes. This study showed that the pattern of longitudinal atrophy progression in the non-fluent/agrammatic variant of primary progressive aphasia relates to the strength of connectivity in pre-determined functional and structural large-scale speech production networks. These findings support the hypothesis that the spread of neurodegeneration occurs by following specific anatomical and functional neuronal network architectures.

Research in social neuroscience has primarily focused on carving up cognition into distinct pieces, as a function of mental process, neural network or social behaviour, while the need for unifying models that span multiple social phenomena has been relatively neglected. Here we present a novel framework that treats social cognition as a case of semantic cognition, and which is neurobiologically constrained and generalizable, with clear, testable predictions regarding sociocognitive processing in the context of both health and disease. According to this framework, social cognition relies on two principal systems of representation and control. These systems are neuroanatomically and functionally distinct, but interact to (1) enable development of foundational, conceptual-level knowledge and (2) regulate access to this information in order to generate flexible and context-appropriate social behaviour. The Social Semantics framework shines new light on the mechanisms of social information processing by maintaining as much explanatory power as prior models of social cognition, whilst remaining simpler, by virtue of relying on fewer components that are "tuned" towards social interactions.

The anterior temporal lobes (ATLs) play a key role in conceptual knowledge representation. The hub-and-spoke theory suggests that the contribution of the ATLs to semantic representation is (a) transmodal, i.e. integrating information from multiple sensorimotor and verbal modalities, and (b) pan-categorical, representing concepts from all categories. Another literature, however, suggests that this region's responses are modality- and category-selective; prominent examples include category selectivity for socially relevant concepts and face recognition. The predictions of each approach have never been directly compared. We used data from three studies to compare category-selective responses within the ATLs. Study 1 compared ATL responses to famous people versus another conceptual category (landmarks) from visual versus auditory inputs. Study 2 compared ATL responses to famous people from pictorial and written word inputs. Study 3 compared ATL responses to a different kind of socially relevant stimuli, namely abstract non-person-related words, in order to ascertain whether ATL subregions are engaged for social concepts more generally or only for person-related knowledge. Across all three studies a dominant bilateral ventral ATL cluster responded to all categories in all modalities. Anterior to this ‘pan-category’ transmodal region, a second cluster responded more weakly overall yet selectively for people, but did so equally for spoken names and faces (Study 1). A third region in the anterior superior temporal gyrus responded selectively to abstract socially relevant words (Study 3), but did not respond to concrete socially relevant words (i.e. written names; Study 2). These findings can be accommodated by the graded hub-and-spoke model of concept representation. On this view, the ventral ATL is the centre point of a bilateral ATL hub, which contributes to conceptual representation through transmodal distillation of information arising from multiple modality-specific association cortices. Partial specialization occurs across the graded ATL hub as a consequence of gradedly differential connectivity across the region. This article is part of the theme issue ‘Varieties of abstract concepts: development, use and representation in the brain’.

In a verbal fluency task, a person is required to produce as many exemplars of a given category (e.g., 'animals', or words starting with 'f') as possible within a fixed duration. Successful verbal fluency performance relies both on the depth of search within semantic/phonological neighborhoods ('clustering') and the ability to flexibly disengage between exhausted clusters ('switching'). Convergent evidence from functional imaging and neuropsychology suggests that cluster-switch behaviors engage dissociable brain regions. Switching has been linked to a frontoparietal network dedicated to executive functioning and controlled lexical retrieval, whereas clustering is more commonly associated with temporal lobe regions dedicated to semantic and phonological processing. Here we attempted to modulate cluster-switch dynamics among neurotypical adults (N = 24) using transcranial direct current stimulation (tDCS) delivered at three sites: a) anterior temporal cortex; b) frontal cortex; and c) temporoparietal cortex. Participants completed letter-guided and semantic category verbal fluency tasks pre/post stimulation. Cathodal stimulation of anterior temporal cortex facilitated the total number of words generated and the number of words generated within clusters during semantic category verbal fluency. These neuromodulatory effects were specific to stimulation of the one anatomical site. Our findings highlight the role of the anterior temporal lobes in representing semantic category structure and support the claim that clustering and switching behaviors have distinct substrates. We discuss implications both for theory and application to neurorehabilitation.

Numerous neuroimaging studies have identified various brain networks using task-free analyses. While these networks undoubtedly support higher cognition, their precise functional characteristics are rarely probed directly. The frontal, temporal, and parietal lobes contain the majority of the tertiary association cortex, which are key substrates for higher cognition including executive function, language, memory, and attention. Accordingly, we established the cognitive signature of a set of contrastive brain networks on the main tertiary association cortices, identified in two task-independent datasets. Using graph-theory analysis, we revealed multiple networks across the frontal, temporal, and parietal cortex, derived from structural and functional connectivity. The patterns of network activity were then investigated using three task-active fMRI datasets to generate the functional profiles of the identified networks. We employed representational dissimilarity analysis on these functional data to quantify and compare the representational characteristics of the networks. Our results demonstrated that the topology of the task-independent networks was strongly associated with the patterns of network activity in the task-active fMRI. Our findings establish a direct relationship between the brain networks identified from task-free datasets and higher cognitive functions including cognitive control, language, memory, visuospatial function, and perception. Not only does this study support the widely held view that higher cognitive functions are supported by widespread, distributed cortical networks, but also it elucidates a methodological approach for formally establishing their relationship. Electronic supplementary material The online version of this article (10.1007/s00429-018-1734-x) contains supplementary material, which is available to authorized users.

Human higher cognition arises from the main tertiary association cortices including the frontal, temporal and parietal lobes. Many studies have suggested that cortical functions must be shaped or emerge from the pattern of underlying physical (white matter) connectivity. Despite the importance of this hypothesis, there has not been a large-scale analysis of the white-matter connectivity within and between these associative cortices. Thus, we explored the pattern of intra- and inter-lobe white matter connectivity between multiple areas defined in each lobe. We defined 43 regions of interest on the lateral associative cortex cytoarchitectonically (6 regions of interest – ROIs in the frontal lobe and 17 ROIs in the parietal lobe) and anatomically (20 ROIs in the temporal lobe) on individuals' native space. The results demonstrated that intra-region connectivity for all 3 lobes was dense and graded generally. In contrary, the inter-lobe connectivity was relatively discrete and regionally specific such that only small sub-regions exhibited long-range connections to another lobe. The long-range connectivity was mediated by 6 major associative white matter tracts, consistent with the notion that these higher cognitive functions arises from brain-wide distributed connectivity. Using graph-theory network analysis we revealed five physically-connected sub-networks, which correspond directly to five known functional networks. This study provides strong and direct evidence that core functional brain networks mirror the brain's structural connectivity.

Author(s): Binney, Richard J; Pankov, Aleksandr; Marx, Gabriel; He, Xuanzie; McKenna, Faye; Staffaroni, Adam M; Kornak, John; Attygalle, Suneth; Boxer, Adam L; Schuff, Norbert; Gorno-Tempini, Maria-Luisa; Weiner, Michael W; Kramer, Joel H; Miller, Bruce L; Rosen, Howard J | Abstract: IntroductionLongitudinal imaging of neurodegenerative disorders is a potentially powerful biomarker for use in clinical trials. In Alzheimer's disease, studies have demonstrated that empirically derived regions of interest (ROIs) can provide more reliable measurement of disease progression compared with anatomically defined ROIs.MethodsWe set out to derive ROIs with optimal effect size for quantifying longitudinal change in a hypothetical clinical trial by comparing atrophy rates in 44 patients with behavioral variant of frontotemporal dementia (bvFTD), 30 with the semantic variant primary progressive aphasia (svPPA), and 26 with the nonfluent variant PPA (nfvPPA) to atrophy in 97 cognitively healthy controls.ResultsThe regions identified for each variant were generally what would be expected from prior studies of frontotemporal lobar degeneration (FTLD). Sample size estimates for detecting a 40% reduction in annual rate of ROI atrophy varied substantially across groups, being 103 per arm in bvFTD, 31 in nfvPPA, and 10 in svPPA, but in all groups were less than those estimated for a priori ROIs and clinical measures. The variability in location of peak regions of atrophy across individuals was highest in bvFTD and lowest in svPPA, likely relating to the differences in effect size.ConclusionsThese findings suggest that, while cross-validated maps of change can improve sensitivity to change in FTLD compared with a priori regions, the reliability of these maps differs considerably across syndromes. Future studies can utilize these maps to design clinical trials, and should try to identify factors accounting for the variability in patterns of atrophy across individuals, particularly those with bvFTD.

In primary progressive aphasia (PPA), speech and language difficulties are caused by neurodegeneration of specific brain networks. In the nonfluent/agrammatic variant (nfvPPA), motor speech and grammatical deficits are associated with atrophy in a left fronto-insular-striatal network previously implicated in speech production. In vivo dissection of the crossing white matter (WM) tracts within this "speech production network" is complex and has rarely been performed in health or in PPA. We hypothesized that damage to these tracts would be specific to nfvPPA and would correlate with differential aspects of the patients' fluency abilities. We prospectively studied 25 PPA and 21 healthy individuals who underwent extensive cognitive testing and 3 T MRI. Using residual bootstrap Q-ball probabilistic tractography on high angular resolution diffusion-weighted imaging (HARDI), we reconstructed pathways connecting posterior inferior frontal, inferior premotor, insula, supplementary motor area (SMA) complex, striatum, and standard ventral and dorsal language pathways. We extracted tract-specific diffusion tensor imaging (DTI) metrics to assess changes across PPA variants and perform brain-behavioral correlations. Significant WM changes in the left intrafrontal and frontostriatal pathways were found in nfvPPA, but not in the semantic or logopenic variants. Correlations between tract-specific DTI metrics with cognitive scores confirmed the specific involvement of this anterior-dorsal network in fluency and suggested a preferential role of a posterior premotor-SMA pathway in motor speech. This study shows that left WM pathways connecting the speech production network are selectively damaged in nfvPPA and suggests that different tracts within this system are involved in subcomponents of fluency. These findings emphasize the emerging role of diffusion imaging in the differential diagnosis of neurodegenerative diseases.

Objective: To examine the utility and reliability of volumetric MRI in measuring disease progression in the 4 repeat tauopathies, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), to support clinical development of new tau-directed therapeutic agents. Methods: Six- and 12-month changes in regional MRI volumes and PSP Rating Scale scores were examined in 55 patients with PSP and 33 patients with CBS (78% amyloid PET negative) compared to 30 normal controls from a multicenter natural history study. Longitudinal voxel-based morphometric analyses identified patterns of volume loss, and region-of-interest analyses examined rates of volume loss in brainstem (midbrain, pons, superior cerebellar peduncle), cortical, and subcortical regions based on previously validated atlases. Results were compared to those in a replication cohort of 226 patients with PSP with MRI data from the AL-108-231 clinical trial. Results: Patients with CBS exhibited greater baseline atrophy and greater longitudinal atrophy rates in cortical and basal ganglia regions than patients with PSP; however, midbrain and pontine atrophy rates were similar. Voxel-wise analyses showed distinct patterns of regional longitudinal atrophy in each group as compared to normal controls. The midbrain/pons volumetric ratio differed between diagnoses but remained stable over time. In both patient groups, brainstem atrophy rates were correlated with disease progression measured using the PSP Rating Scale. Conclusions: Volume loss is quantifiable over a period of 6 months in CBS and PSP. Future clinical trials may be able to combine CBS and PSP to measure therapeutic effects.

Natural languages are rife with words that describe feelings, introspective states, and social constructs (e.g., liberty, persuasion) that cannot be directly observed through the senses. Effective communication demands linguistic competence with such abstract words. In clinical neurological settings, abstract words are especially vulnerable to the effects of stroke and neurodegenerative conditions such as Alzheimer’s disease. A parallel literature in cognitive neuroscience suggests that abstract and concrete words are at least partially neuroanatomically dissociable. Much remains to be learned about the nature of lexical-semantic deficits of abstract words and how best to promote their recovery. Here, we review contemporary theoretical approaches to abstract-concrete word representation with an aim toward contextualizing patient-based dissociations for abstract words. We then describe a burgeoning treatment approach for targeting abstract words and suggest a number of potential strategies for future interventions. We argue that a deeper understanding of is essential for informing language rehabilitation.

A growing body of recent convergent evidence indicates that the anterior temporal lobe (ATL) has connectivity-derived graded differences in semantic function: the ventrolateral region appears to be the transmodal, omni-category center-point of the hub whilst secondary contributions come from the peripheries of the hub in a manner that reflects their differential connectivity to different input/output modalities. One of the key challenges for this neurocognitive theory is how different types of concept, especially those with less reliance upon external sensory experience (such as abstract and social concepts), are coded across the graded ATL hub. We were able to answer this key question by using distortion-corrected fMRI to detect functional activations across the entire ATL region and thus to map the neural basis of social and psycholinguistically-matched abstract concepts. Both types of concept engaged a core left-hemisphere semantic network, including the ventrolateral ATL, prefrontal regions and posterior MTG. Additionally, we replicated previous findings of weaker differential activation of the superior and polar ATL for the processing of social stimuli, in addition to the stronger, omni-category activation observed in the vATL. These results are compatible with the view of the ATL as a graded transmodal substrate for the representation of coherent concepts.

Much remains to be learned about the neural architecture underlying word meaning. Fully distributed models of semantic memory predict that the sound of a barking dog will conjointly engage a network of distributed sensorimotor spokes. An alternative framework holds that modality-specific features additionally converge within transmodal hubs. Participants underwent functional MRI while covertly naming familiar objects versus newly learned novel objects from only one of their constituent semantic features (visual form, characteristic sound, or point-light motion representation). Relative to the novel object baseline, familiar concepts elicited greater activation within association regions specific to that presentation modality. Furthermore, visual form elicited activation within high-level auditory association cortex. Conversely, environmental sounds elicited activation in regions proximal to visual association cortex. Both conditions commonly engaged a putative hub region within lateral anterior temporal cortex. These results support hybrid semantic models in which local hubs and distributed spokes are dually engaged in service of semantic memory.

Current research is investigating the potential utility of longitudinal measurement of brain structure as a marker of drug effect in clinical trials for neurodegenerative disease. Recent studies in Alzheimer's disease (AD) have shown that measurement of change in empirically derived regions of interest (ROIs) allows more reliable measurement of change over time compared with regions chosen a-priori based on known effects of AD on brain anatomy. Frontotemporal lobar degeneration (FTLD) is a devastating neurodegenerative disorder for which there are no approved treatments. The goal of this study was to identify an empirical ROI that maximizes the effect size for the annual rate of brain atrophy in FTLD compared with healthy age matched controls, and to estimate the effect size and associated power estimates for a theoretical study that would use change within this ROI as an outcome measure. Eighty six patients with FTLD were studied, including 43 who were imaged twice at 1.5 T and 43 at 3 T, along with 105 controls (37 imaged at 1.5 T and 67 at 3 T). Empirically-derived maps of change were generated separately for each field strength and included the bilateral insula, dorsolateral, medial and orbital frontal, basal ganglia and lateral and inferior temporal regions. The extent of regions included in the 3 T map was larger than that in the 1.5 T map. At both field strengths, the effect sizes for imaging were larger than for any clinical measures. At 3 T, the effect size for longitudinal change measured within the empirically derived ROI was larger than the effect sizes derived from frontal lobe, temporal lobe or whole brain ROIs. The effect size derived from the data-driven 1.5 T map was smaller than at 3 T, and was not larger than the effect size derived from a-priori ROIs. It was estimated that measurement of longitudinal change using 1.5 T MR systems requires approximately a 3-fold increase in sample size to obtain effect sizes equivalent to those seen at 3 T. While the results should be confirmed in additional datasets, these results indicate that empirically derived ROIs can reduce the number of subjects needed for a longitudinal study of drug effects in FTLD compared with a-priori ROIs. Field strength may have a significant impact on the utility of imaging for measuring longitudinal change., Highlights • Identified regions of increased change in a longitudinal cohort of FTLD patients • Data-driven ROIs outperform anatomically predefined regions. • Effect size derived from data-driven 1.5 T map was smaller and less robust than 3 T.

The default mode network (DMN) and semantic network (SN) are two of the most extensively studied systems, and both are increasingly used as clinical biomarkers in neurological studies. There are strong theoretical reasons to assume a relationship between the networks, as well as anatomical evidence that they might rely on overlapping cortical regions, such as the anterior temporal lobe (ATL) or angular gyrus (AG). Despite these strong motivations, the relationship between the two systems has received minimal attention. We directly compared the SN and DMN using a large (n = 69) distortion-corrected functional MRI (fMRI) dataset, spanning a range of semantic and nonsemantic tasks that varied input modality. The results showed that both networks fractionate depending on the semantic nature of the task, stimulus type, modality, and task difficulty. Furthermore, despite recent claims that both AG and ATL are semantic hubs, the two areas responded very differently, with results supporting the role of ATL, but not AG, in semantic representation. Specifically, the left ATL was positively activated for all semantic tasks, but deactivated during nonsemantic task performance. In contrast, the left AG was deactivated for all tasks, with the level of deactivation related to task difficulty. Thus, ATL and AG do not share a common interest in semantic tasks, but, rather, a common "disinterest" in nonsemantic tasks. The implications for the variability in the DMN, its cognitive coherence, and interpretation of resting-state fMRI data are discussed.

Semantic cognition is underpinned by regions involved in representing conceptual knowledge and executive control areas that provide regulation of this information according to current task requirements. Using distortion-corrected fMRI, we investigated the contributions of these two systems to abstract and concrete word comprehension. We contrasted semantic decisions made either with coherent contextual support, which encouraged retrieval of a rich conceptual representation, or with irrelevant contextual information, which instead maximised demands on control processes. Inferior prefrontal cortex was activated more when decisions were made in the presence of irrelevant context, suggesting that this region is crucial for the semantic control functions required to select appropriate aspects of meaning in the face of competing information. It also exhibited greater activation for abstract words, which reflects the fact that abstract words tend to have variable, context-dependent meanings that place higher demands on control processes. In contrast, anterior temporal regions (ATL) were most active when decisions were made with the benefit of a coherent context, suggesting a representational role. There was a graded shift in concreteness effects in this region, with dorsolateral areas particularly active for abstract words and ventromedial areas preferentially activated by concrete words. This supports the idea that concrete concepts are closely associated with visual experience and abstract concepts with auditory-verbal information; and that sub-regions of the ATL display graded specialisation for these two types of knowledge. Between these two extremes, we identified significant activations for both word types in ventrolateral ATL. This area is known to be involved in representing knowledge for concrete concepts; here we established that it is also activated by abstract concepts. These results converge with data from rTMS and neuropsychological investigations in demonstrating that representational content and task demands influence recruitment of different areas in the semantic network.

Robson et al. use fMRI to investigate preserved written word and picture comprehension in Wernicke’s aphasia (impaired verbal comprehension following left temporoparietal damage). Bilaterally enhanced activation in the ventral and anterior temporal lobes as patients semantically process visually presented material emphasizes the importance of these regions for multimodal comprehension., Wernicke’s aphasia occurs after a stroke to classical language comprehension regions in the left temporoparietal cortex. Consequently, auditory–verbal comprehension is significantly impaired in Wernicke’s aphasia but the capacity to comprehend visually presented materials (written words and pictures) is partially spared. This study used functional magnetic resonance imaging to investigate the neural basis of written word and picture semantic processing in Wernicke’s aphasia, with the wider aim of examining how the semantic system is altered after damage to the classical comprehension regions. Twelve participants with chronic Wernicke’s aphasia and 12 control participants performed semantic animate–inanimate judgements and a visual height judgement baseline task. Whole brain and region of interest analysis in Wernicke’s aphasia and control participants found that semantic judgements were underpinned by activation in the ventral and anterior temporal lobes bilaterally. The Wernicke’s aphasia group displayed an ‘over-activation’ in comparison with control participants, indicating that anterior temporal lobe regions become increasingly influential following reduction in posterior semantic resources. Semantic processing of written words in Wernicke’s aphasia was additionally supported by recruitment of the right anterior superior temporal lobe, a region previously associated with recovery from auditory-verbal comprehension impairments. Overall, the results provide support for models in which the anterior temporal lobes are crucial for multimodal semantic processing and that these regions may be accessed without support from classic posterior comprehension regions.

Highlights • The dorsal stream has been postulated to constitute multiple pathways. • Tractography was used to map the connectivity of regions within the left SMG. • The arcuate fasciculus was subdivided into dorso-dorsal/ventro-dorsal pathways. • The parallel pathways appear to underlie functional heterogeneity within the SMG., Primate studies have recently identified the dorsal stream as constituting multiple dissociable pathways associated with a range of specialized cognitive functions. To elucidate the nature and number of dorsal pathways in the human brain, the current study utilized in vivo probabilistic tractography to map the structural connectivity associated with subdivisions of the left supramarginal gyrus (SMG). The left SMG is a prominent region within the dorsal stream, which has recently been parcellated into five structurally-distinct regions which possess a dorsal–ventral (and rostral-caudal) organisation, postulated to reflect areas of functional specialisation. The connectivity patterns reveal a dissociation of the arcuate fasciculus into at least two segregated pathways connecting frontal-parietal-temporal regions. Specifically, the connectivity of the inferior SMG, implicated as an acoustic-motor speech interface, is carried by an inner/ventro-dorsal arc of fibres, whilst the pathways of the posterior superior SMG, implicated in object use and cognitive control, forms a parallel outer/dorso-dorsal crescent.

Importance We provide novel evidence of specific clinical and neuroimaging features that may help for the in vivo prediction of underlying pathology in patients with nonfluent/agrammatic primary progressive aphasia (nfvPPA) and progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) proved by autopsy. Objective To characterize the neurological, cognitive, and neuroimaging features of patients with nfvPPA—in whom either PSP or CBD was eventually confirmed at autopsy—at initial presentation and at 1-year follow-up. Design, Setting, and Participants A prospective longitudinal clinical-pathological study was conducted in a tertiary research clinic that specialized in cognitive disorders. Fourteen patients were evaluated between January 2002 and December 2014. Inclusion criteria for the study were a clinical diagnosis of nfvPPA; the availability of speech, language, and cognitive testing for at least 1 evaluation; magnetic resonance imaging within 6 months of initial evaluation; and a postmortem pathological diagnosis of PSP or CBD. Ten matched healthy control participants were also included. Main Outcomes and Measures Clinical, cognitive, and neuroimaging longitudinal data were analyzed to characterize the whole nfvPPA–4-repeat–tau group and identify differences between nfvPPA-PSP and nfvPPA-CBD both at presentation and longitudinally. Results Patient groups did not differ significantly in age, sex, or handedness (nfvPPA-PSP group: median [interquartile range (IQR)] age, 74 [67-76] years; 1 of 5 male [20%]; 1 of 5 left-handed [20%]; and nfvPPA-CBD group: mean [IQR] age, 65 [54-81] years; 3 of 9 male [33%]; 0 left-handed). Motor speech impairment and left frontal white matter atrophy were the most prominent common features. At presentation, dysarthria (Motor Speech Examination median [IQR] score: nfvPPA-PSP, 4 [2-7]; nfvPPA-CBD, 0 [0-4]; P = .02), depression (Geriatric Depression Scale median [IQR] score: nfvPPA-PSP, 19 [3-28]; nfvPPA-CBD, 4 [0-16]; P = .04), and relatively selective white matter atrophy were typical of the nfvPPA-PSP group, while greater gray matter atrophy and a trend toward greater sentence comprehension deficits (median [IQR] sentence comprehension correct: nfvPPA-PSP, 98% [80-100]; nfvPPA-CBD, 81% [65-98]; P = .08) were found in the nfvPPA-CBD group. At follow-up after 1 year, we observed no significant differences in any speech or language measures. Furthermore, atrophy in patients with PSP progressed within the subcortical/brainstem motor system generating greater oculomotors deficits and swallowing difficulty; atrophy in patients with CBD spread anteriorly in prefrontal regions consistent with their greater working memory impairment and development of behavioral symptoms. Conclusions and Relevance In patients presenting with nfvPPA, presence of early severe dysarthria, relatively selective white matter atrophy at presentation, and a greater rate of change in the brainstem measured by longitudinal imaging may be useful for differentiating underlying PSP from CBD pathology during life.

Although there is an emerging consensus that the anterior temporal lobes (ATLs) are involved in semantic memory, it is currently unclear which specific parts of this region are implicated in semantic representation. Answers to this question are difficult to glean from the existing literature for 3 reasons: 1) lesions of relevant patient groups tend to encompass the whole ATL region; 2) while local effects of repetitive transcranial magnetic stimulation (rTMS) are spatially more specific, only the lateral aspects of the ATL are available to stimulation; and 3) until recently, functional magnetic resonance imaging (fMRI) studies were hindered by technical limitations such as signal distortion and dropout due to magnetic inhomogeneities and also, in some cases, by methodological factors, including a restricted field of view and the choice of baseline contrast for subtraction analysis. By utilizing the same semantic task across semantic dementia, rTMS, and distortion-corrected fMRI in normal participants, we directly compared the results across the 3 methods for the first time. The findings were highly convergent and indicated that crucial regions within the ATL for semantic representation include the anterior inferior temporal gyrus, anterior fusiform gyrus, and the anterior superior temporal sulcus. © The Author 2010. Published by Oxford University Press. All rights reserved.

By developing and applying a method which combines fMRI and rTMS to explore semantic cognition, we identified both intrinsic (related to automatic changes in task/stimulus-related processing) and induced (i.e., associated with the effect of TMS) activation changes in the core, functionally-coupled network elements. Low-frequency rTMS applied to the human anterior temporal lobe (ATL) induced: (a) a local suppression at the site of stimulation; (b) remote suppression in three other ipsilateral semantic regions; and (c) a compensatory up-regulation in the contralateral ATL. Further examination of activity over time revealed that the compensatory changes appear to be a modulation of intrinsic variations that occur within the unperturbed network. As well as providing insights into the dynamic collaboration between core regions, the ability to observe intrinsic and induced changes in vivo may provide an important opportunity to understand the key mechanisms that underpin recovery of function in neurological patient groups., Highlights • First use of combined fMRI and rTMS to explore semantic cognition. • Intrinsic-automatic and TMS-induced activation changes were identified. • rTMS induced local suppression and up-regulation in the contralateral ATL. • Compensatory changes relate to intrinsic variations in the unperturbed network. • These key mechanisms may underpin recovery of function in neurological patients.