Relationship between cortical brain atrophy, delirium, and long-term cognitive decline in older surgical patients.

In older patients, delirium after surgery is associated with long-term cognitive decline (LTCD). The neural substrates of this association are unclear. Neurodegenerative changes associated with dementia are possible contributors. We investigated the relationship between brain atrophy rates in Alzheimer's disease (AD) and cognitive aging signature regions from magnetic resonance imaging before and one year after surgery, LTCD assessed by the general cognitive performance (GCP) score over 6 years post-operatively, and delirium in 117 elective surgery patients without dementia (mean age = 76). The annual change in cortical thickness was 0.2(1.7) % (AD-signature p = 0.09) and 0.4(1.7) % (aging-signature p = 0.01). Greater atrophy was associated with LTCD (AD-signature: beta(CI) = 0.24(0.06-0.42) points of GCP/mm of cortical thickness; p < 0.01, aging-signature: beta(CI) = 0.55(0.07-1.03); p = 0.03). Atrophy rates were not significantly different between participants with and without delirium. We found an interaction with delirium severity in the association between atrophy and LTCD (AD-signature: beta(CI) = 0.04(0.00-0.08), p = 0.04; aging-signature: beta(CI) = 0.08(0.03-0.12), p < 0.01). The rate of cortical atrophy and severity of delirium are independent, synergistic factors determining postoperative cognitive decline in the elderly.

Default mode network tau predicts future clinical decline in atypical early Alzheimer's disease.

Identifying individuals with early stage Alzheimer's disease (AD) at greater risk of steeper clinical decline would allow professionals and loved ones to make better-informed medical, support, and life planning decisions. Despite accumulating evidence on the clinical prognostic value of tau PET in typical late-onset amnestic AD, its utility in predicting clinical decline in individuals with atypical forms of AD remains unclear. In this study, we examined the relationship between baseline tau PET signal and the rate of subsequent clinical decline in a sample of 48 A+/T+/N+ patients with mild cognitive impairment or mild dementia due to AD with atypical clinical phenotypes (Posterior Cortical Atrophy, logopenic variant Primary Progressive Aphasia, and amnestic syndrome with multi-domain impairment and age of onset < 65 years). All patients underwent structural magnetic resonance imaging (MRI), tau (18F-Flortaucipir) PET, and amyloid (either 18F-Florbetaben or 11C-Pittsburgh Compound B) PET scans at baseline. Each patient's longitudinal clinical decline was assessed by calculating the annualized change in the Clinical Dementia Rating Sum-of-Boxes (CDR-SB) scores from baseline to follow-up (mean time interval = 14.55 ± 3.97 months). Our sample of early atypical AD patients showed an increase in CDR-SB by 1.18 ± 1.25 points per year: t(47) = 6.56, p < .001, d = 0.95. These AD patients showed prominent baseline tau burden in posterior cortical regions including the major nodes of the default mode network, including the angular gyrus, posterior cingulate cortex/precuneus, and lateral temporal cortex. Greater baseline tau in the broader default mode network predicted faster clinical decline. Tau in the default mode network was the strongest predictor of clinical decline, outperforming baseline clinical impairment, tau in other functional networks, and the magnitude of cortical atrophy and amyloid burden in the default mode network. Overall, these findings point to the contribution of baseline tau burden within the default mode network of the cerebral cortex to predicting the magnitude of clinical decline in a sample of atypical early AD patients one year later. This simple measure based on a tau PET scan could aid the development of a personalized prognostic, monitoring, and treatment plan tailored to each individual patient, which would help clinicians not only predict the natural evolution of the disease but also estimate the effect of disease-modifying therapies on slowing subsequent clinical decline given the patient's tau burden while still early in the disease course.

The Sporadic Early-onset Alzheimer's Disease Signature Of Atrophy: Preliminary Findings From The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) Cohort.

INTRODUCTION: Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS: We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS: The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment. DISCUSSION: The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD. HIGHLIGHTS: We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.

Atrophy in behavioural variant frontotemporal dementia spans multiple large-scale prefrontal and temporal networks.

The identification of a neurodegenerative disorder's distributed pattern of atrophy-or atrophy 'signature'-can lend insights into the cortical networks that degenerate in individuals with specific constellations of symptoms. In addition, this signature can be used as a biomarker to support early diagnoses and to potentially reveal pathological changes associated with said disorder. Here, we characterized the cortical atrophy signature of behavioural variant frontotemporal dementia (bvFTD). We used a data-driven approach to estimate cortical thickness using surface-based analyses in two independent, sporadic bvFTD samples (n = 30 and n = 71, total n = 101), using age- and gender-matched cognitively and behaviourally normal individuals. We found highly similar patterns of cortical atrophy across the two independent samples, supporting the reliability of our bvFTD signature. Next, we investigated whether our bvFTD signature targets specific large-scale cortical networks, as is the case for other neurodegenerative disorders. We specifically asked whether the bvFTD signature topographically overlaps with the salience network, as previous reports have suggested. We hypothesized that because phenotypic presentations of bvFTD are diverse, this would not be the case, and that the signature would cross canonical network boundaries. Consistent with our hypothesis, the bvFTD signature spanned rostral portions of multiple networks, including the default mode, limbic, frontoparietal control and salience networks. We then tested whether the signature comprised multiple anatomical subtypes, which themselves overlapped with specific networks. To explore this, we performed a hierarchical clustering analysis. This yielded three clusters, only one of which extensively overlapped with a canonical network (the limbic network). Taken together, these findings argue against the hypothesis that the salience network is preferentially affected in bvFTD, but rather suggest that-at least in patients who meet diagnostic criteria for the full-blown syndrome-neurodegeneration in bvFTD encompasses a distributed set of prefrontal, insular and anterior temporal nodes of multiple large-scale brain networks, in keeping with the phenotypic diversity of this disorder.

Correspondence of functional connectivity gradients across human isocortex, cerebellum, and hippocampus.

Gradient mapping is an important technique to summarize high dimensional biological features as low dimensional manifold representations in exploring brain structure-function relationships at various levels of the cerebral cortex. While recent studies have characterized the major gradients of functional connectivity in several brain structures using this technique, very few have systematically examined the correspondence of such gradients across structures under a common systems-level framework. Using resting-state functional magnetic resonance imaging, here we show that the organizing principles of the isocortex, and those of the cerebellum and hippocampus in relation to the isocortex, can be described using two common functional gradients. We suggest that the similarity in functional connectivity gradients across these structures can be meaningfully interpreted within a common computational framework based on the principles of predictive processing. The present results, and the specific hypotheses that they suggest, represent an important step toward an integrative account of brain function.

Improving the study of brain-behavior relationships by revisiting basic assumptions.

Neuroimaging research has been at the forefront of concerns regarding the failure of experimental findings to replicate. In the study of brain-behavior relationships, past failures to find replicable and robust effects have been attributed to methodological shortcomings. Methodological rigor is important, but there are other overlooked possibilities: most published studies share three foundational assumptions, often implicitly, that may be faulty. In this paper, we consider the empirical evidence from human brain imaging and the study of non-human animals that calls each foundational assumption into question. We then consider the opportunities for a robust science of brain-behavior relationships that await if scientists ground their research efforts in revised assumptions supported by current empirical evidence.

Gray to white matter signal ratio as a novel biomarker of neurodegeneration in Alzheimer's disease.

Alzheimer's disease (AD) is characterized neuropathologically by ß-amyloid (Aß) plaques, hyperphosphorylated tau neurofibrillary tangles, and neurodegeneration, which lead to a phenotypically heterogeneous cognitive-behavioral dementia syndrome. Our understanding of how these neuropathological and neurodegeneration biomarkers relate to each other is still evolving. A relatively new approach to measuring structural brain change, gray matter to white matter signal intensity ratio (GWR), quantifies the signal contrast between these tissue compartments, and has emerged as a promising marker of AD-related neurodegeneration. We sought to validate GWR as a novel MRI biomarker of neurodegeneration in 29 biomarker positive individuals across the atypical syndromic spectrum of AD. Bivariate correlation analyses revealed that GWR was associated with cortical thickness, tau PET, and amyloid PET, with GWR showing a larger magnitude of abnormality than cortical thickness. We also found that combining GWR, cortical thickness, and amyloid PET better explained observed tau PET signal than using these modalities alone, suggesting that the three imaging biomarkers contribute independently and synergistically to explaining the variance in the distribution of tau pathology. We conclude that GWR is a uniquely sensitive in vivo marker of neurodegenerative change that reflects pathological mechanisms which may occur prior to cortical atrophy. By using all of these imaging biomarkers of AD together, we may be better able to capture, and possibly predict, AD neuropathologic changes in vivo. We hope that such an approach will ultimately contribute to better endpoints to evaluate the efficacy of therapeutic interventions as we move toward an era of disease-modifying treatments for this devastating disease.

Anterior dorsal attention network tau drives visual attention deficits in posterior cortical atrophy.

Posterior cortical atrophy (PCA), usually an atypical clinical syndrome of Alzheimer's disease, has well-characterized patterns of cortical atrophy and tau deposition that are distinct from typical amnestic presentations of Alzheimer's disease. However, the mechanisms underlying the cortical spread of tau in PCA remain unclear. Here, in a sample of 17 biomarker-confirmed (A+/T+/N+) individuals with PCA, we sought to identify functional networks with heightened vulnerability to tau pathology by examining the cortical distribution of elevated tau as measured by 18F-flortaucipir (FTP) PET. We then assessed the relationship between network-specific FTP uptake and visuospatial cognitive task performance. As predicted, we found consistent and prominent localization of tau pathology in the dorsal attention network and visual network of the cerebral cortex. Elevated FTP uptake within the dorsal attention network (particularly the ratio of FTP uptake between the anterior and posterior nodes) was associated with poorer visuospatial attention in PCA; associations were also identified in other functional networks, although to a weaker degree. Furthermore, using functional MRI data collected from each patient at wakeful rest, we found that a greater anterior-to-posterior ratio in FTP uptake was associated with stronger intrinsic functional connectivity between anterior and posterior nodes of the dorsal attention network. Taken together, we conclude that our cross-sectional marker of anterior-to-posterior FTP ratio could indicate tau propagation from posterior to anterior dorsal attention network nodes, and that this anterior progression occurs in relation to intrinsic functional connectivity within this network critical for visuospatial attention. Our findings help to clarify the spatiotemporal pattern of tau propagation in relation to visuospatial cognitive decline and highlight the key role of the dorsal attention network in the disease progression of PCA.

Association of Regional Cortical Network Atrophy With Progression to Dementia in Patients With Primary Progressive Aphasia.

BACKGROUND AND OBJECTIVES: Patients with primary progressive aphasia (PPA) have gradually progressive language deficits during the initial phase of the illness. As the underlying neurodegenerative disease progresses, patients with PPA start losing independent functioning due to the development of nonlanguage cognitive or behavioral symptoms. The timeline of this progression from the mild cognitive impairment stage to the dementia stage of PPA is variable across patients. In this study, in a sample of patients with PPA, we measured the magnitude of cortical atrophy within functional networks believed to subserve diverse cognitive and affective functions. The objective of the study was to evaluate the utility of this measure as a predictor of time to subsequent progression to dementia in PPA. METHODS: Patients with PPA with largely independent daily function were recruited through the Massachusetts General Hospital Frontotemporal Disorders Unit. All patients underwent an MRI scan at baseline. Cortical atrophy was then estimated relative to a group of amyloid-negative cognitively normal control participants. For each patient, we measured the time between the baseline visit and the subsequent visit at which dementia progression was documented or last observation. Simple and multivariable Cox regression models were used to examine the relationship between cortical atrophy and the likelihood of progression to dementia. RESULTS: Forty-nine patients with PPA (mean age = 66.39 ± 8.36 years, 59.2% females) and 25 controls (mean age = 67.43 ± 4.84 years, 48% females) were included in the data analysis. Greater baseline atrophy in not only the left language network (hazard ratio = 1.47, 95% CI = 1.17-1.84) but also in the frontoparietal control (1.75, 1.25-2.44), salience (1.63, 1.25-2.13), default mode (1.55, 1.19-2.01), and ventral frontotemporal (1.41, 1.16-1.71) networks was associated with a higher risk of progression to dementia. A multivariable model identified contributions of the left frontoparietal control (1.94, 1.09-3.48) and ventral frontotemporal (1.61, 1.09-2.39) networks in predicting dementia progression, with no additional variance explained by the language network (0.75, 0.43-1.31). DISCUSSION: These results suggest that baseline atrophy in cortical networks subserving nonlanguage cognitive and affective functions is an important predictor of progression to dementia in PPA. This measure should be included in precision medicine models of prognosis in PPA.

Structural integrity of the anterior mid-cingulate cortex contributes to resilience to delirium in SuperAging.

Despite its devastating clinical and societal impact, approaches to treat delirium in older adults remain elusive, making it important to identify factors that may confer resilience to this syndrome. Here, we investigated a cohort of 93 cognitively normal older patients undergoing elective surgery recruited as part of the Successful Aging after Elective Surgery study. Each participant was classified either as a SuperAger (n = 19) or typically aging older adult (n = 74) based on neuropsychological criteria, where the former was defined as those older adults whose memory function rivals that of young adults. We compared these subgroups to examine the role of preoperative memory function in the incidence and severity of postoperative delirium. We additionally investigated the association between indices of postoperative delirium symptoms and cortical thickness in functional networks implicated in SuperAging based on structural magnetic resonance imaging data that were collected preoperatively. We found that SuperAging confers the real-world benefit of resilience to delirium, as shown by lower (i.e. zero) incidence of postoperative delirium and decreased severity scores compared with typical older adults. Furthermore, greater baseline cortical thickness of the anterior mid-cingulate cortex-a key node of the brain's salience network that is also consistently implicated in SuperAging-predicted lower postoperative delirium severity scores in all patients. Taken together, these findings suggest that baseline memory function in older adults may be a useful predictor of postoperative delirium risk and severity and that superior memory function may contribute to resilience to delirium. In particular, the integrity of the anterior mid-cingulate cortex may be a potential biomarker of resilience to delirium, pointing to this region as a potential target for preventive or therapeutic interventions designed to mitigate the risk or consequences of developing this prevalent clinical syndrome.

Affective Enhancement of Episodic Memory Is Associated With Widespread Patterns of Intrinsic Functional Connectivity in the Brain Across the Adult Lifespan.

Subjectively arousing experiences tend to be better remembered than neutral ones. While numerous task-related neuroimaging studies have revealed the neural mechanisms associated with this phenomenon, it remains unclear how variability in the extent to which individuals show superior memory for subjectively arousing stimuli is associated with the intrinsic functional organization of their brains. Here, we addressed this issue using functional magnetic resonance imaging data collected at rest from a sample drawn from the Cambridge Centre for Ageing and Neuroscience cohort (N = 269, 18-86 years). Specifically, we performed multi-voxel pattern analysis of intrinsic functional connectivity, an unbiased, data-driven approach to examine whole-brain voxel-wise connectivity patterns. This technique allowed us to reveal the most important features from the high-dimensional, whole-brain connectivity structure without a priori hypotheses about the topography and direction of functional connectivity differences. Behaviorally, both item and associative memory accuracy were enhanced for trials with affectively arousing (positive or negative) stimuli than those with neutral ones. Whole-brain multi-voxel pattern analysis of functional connectivity revealed that the affective enhancement of memory was associated with intrinsic connectivity patterns of spatially distributed brain regions belonging to several functional networks in the cerebral cortex. Post hoc seed-based brain-behavior regression analysis and principal component analysis of the resulting correlation maps showed that these connectivity patterns were in turn primarily characterized by the involvement of heteromodal association and paralimbic (dorsal attention, salience, and default mode) networks of the cerebral cortex as well as select subcortical structures (striatum, thalamus, and cerebellum). Collectively, these findings suggest that the affective enhancement of episodic memory may be characterized as a whole-brain phenomenon, possibly supported by intrinsic functional interactions across several networks and structures in the brain.

Tau and the fractionated default mode network in atypical Alzheimer's disease.

Alzheimer's disease-related atrophy in the posterior cingulate cortex, a key node of the default mode network, is present in the early stages of disease progression across clinical phenotypic variants of the disease. In the typical amnestic variant, posterior cingulate cortex neuropathology has been linked with disrupted connectivity of the posterior default mode network, but it remains unclear if this relationship is observed across atypical variants of Alzheimer's disease. In the present study, we first sought to determine if tau pathology is consistently present in the posterior cingulate cortex and other posterior nodes of the default mode network across the atypical Alzheimer's disease syndromic spectrum. Second, we examined functional connectivity disruptions within the default mode network and sought to determine if tau pathology is related to functional disconnection within this network. We studied a sample of 25 amyloid-positive atypical Alzheimer's disease participants examined with high-resolution MRI, tau (18F-AV-1451) PET, and resting-state functional MRI. In these patients, high levels of tau pathology in the posteromedial cortex and hypoconnectivity between temporal and parietal nodes of the default mode network were observed relative to healthy older controls. Furthermore, higher tau signal and reduced grey matter density in the posterior cingulate cortex and angular gyrus were associated with reduced parietal functional connectivity across individual patients, related to poorer cognitive scores. Our findings converge with what has been reported in amnestic Alzheimer's disease, and together these observations offer a unifying mechanistic feature that relates posterior cingulate cortex tau deposition to aberrant default mode network connectivity across heterogeneous clinical phenotypes of Alzheimer's disease.

Allostasis as a core feature of hierarchical gradients in the human brain.

This paper integrates emerging evidence from two broad streams of scientific literature into one common framework: (a) hierarchical gradients of functional connectivity that reflect the brain's large-scale structural architecture (e.g., a lamination gradient in the cerebral cortex); and (b) approaches to predictive processing and one of its specific instantiations called allostasis (i.e., the predictive regulation of energetic resources in the service of coordinating the body's internal systems). This synthesis begins to sketch a coherent, neurobiologically inspired framework suggesting that predictive energy regulation is at the core of human brain function, and by extension, psychological and behavioral phenomena, providing a shared vocabulary for theory building and knowledge accumulation.

Allostasis refers to the process by which the brain anticipates the needs of the body and attempts to meet those needs before they arise, and is one specific instantiation of a broader predictive processing framework. In this perspective article, we propose that allostasis is a basic function of the human brain subserved by an intrinsic architecture composed of two hierarchical functional gradients. Our framework, based on a synthesis of multimodal and multiscale evidence across species, begins to sketch a coherent, neurobiologically inspired research program suggesting that predictive energy regulation is at the core of human brain function, and by extension, psychological and behavioral phenomena, providing a shared vocabulary for theory building and knowledge accumulation.

Electrophysiological Correlates of Social Decision-making: An EEG Investigation of a Modified Ultimatum Game.

Cooperation behaviors during social decision-making have been shown to be sensitive to manipulations of context. However, it remains unclear how aspects of context in dynamic social interactions, such as observed nonverbal behaviors, may modulate cooperation decisions and the associated neural mechanisms. In this study, participants responded to offers from proposers to split $10 in an Ultimatum Game following observation of proposer approach (friendly) or avoidance (nonfriendly) behaviors, displayed by dynamic whole-body animated avatars, or following a nonsocial interaction control condition. As expected, behavioral results showed that participants tended to have greater acceptance rates for unfair offers following observed nonverbal social interactions with proposers compared with control, suggesting an enhancing effect of social interactions on cooperative decisions. ERP results showed greater N1 and N2 responses at the beginning of social interaction conditions compared with control, and greater sustained and late positivity responses for observed approach and avoidance proposer behaviors compared with control. Event-related spectral perturbation (ERSP) results showed differential sensitivity within theta, alpha, and beta bands during observation of social interactions and offers that was associated with subsequent decision behaviors. Together, these results point to the impact of proposers' nonverbal behaviors on subsequent cooperation decisions at both behavioral and neural levels. The ERP and ERSP findings suggest modulated attention, monitoring, and processing of biological motion during the observed nonverbal social interactions, influencing the participants' responses to offers. These findings shed light on electrophysiological correlates of response to observed social interactions that predict subsequent social decisions.

Proof-of-concept evidence for trimodal simultaneous investigation of human brain function.

The link between spatial (where) and temporal (when) aspects of the neural correlates of most psychological phenomena is not clear. Elucidation of this relation, which is crucial to fully understand human brain function, requires integration across multiple brain imaging modalities and cognitive tasks that reliably modulate the engagement of the brain systems of interest. By overcoming the methodological challenges posed by simultaneous recordings, the present report provides proof-of-concept evidence for a novel approach using three complementary imaging modalities: functional magnetic resonance imaging (fMRI), event-related potentials (ERPs), and event-related optical signals (EROS). Using the emotional oddball task, a paradigm that taps into both cognitive and affective aspects of processing, we show the feasibility of capturing converging and complementary measures of brain function that are not currently attainable using traditional unimodal or other multimodal approaches. This opens up unprecedented possibilities to clarify spatiotemporal integration of brain function.

Greater Neural Differentiation in the Ventral Visual Cortex Is Associated with Youthful Memory in Superaging.

Superagers are older adults who maintain youthful memory despite advanced age. Previous studies showed that superagers exhibit greater structural and intrinsic functional brain integrity, which contribute to their youthful memory. However, no studies, to date, have examined brain activity as superagers learn and remember novel information. Here, we analyzed functional magnetic resonance imaging data collected from 41 young and 40 older adults while they performed a paired associate visual recognition memory task. Superaging was defined as youthful performance on the long delay free recall of the California Verbal Learning Test. We assessed the fidelity of neural representations as participants encoded and later retrieved a series of word stimuli paired with a face or a scene image. Superagers, like young adults, exhibited more distinct neural representations in the fusiform gyrus and parahippocampal gyrus while viewing visual stimuli belonging to different categories (greater neural differentiation) and more similar category representations between encoding and retrieval (greater neural reinstatement), compared with typical older adults. Greater neural differentiation and reinstatement were associated with superior memory performance in all older adults. Given that the fidelity of cortical sensory processing depends on neural plasticity and is trainable, these mechanisms may be potential biomarkers for future interventions to promote successful aging.

Intrinsic functional network contributions to the relationship between trait empathy and subjective happiness.

Subjective happiness (well-being) is a multi-dimensional construct indexing one's evaluations of everyday emotional experiences and life satisfaction, and has been associated with different aspects of trait empathy. Despite previous research identifying the neural substrates of subjective happiness and empathy, the mechanisms mediating the relationship between the two constructs remain largely unclear. Here, we performed a data-driven, multi-voxel pattern analysis of whole-brain intrinsic functional connectivity to reveal the neural mechanisms of subjective happiness and trait empathy in a sample of young females. Behaviorally, we found that subjective happiness was negatively associated with personal distress (i.e., self-referential experience of others' feelings). Consistent with this inverse relationship, subjective happiness was associated with the dorsolateral prefrontal cortex exhibiting decreased functional connectivity with regions important for the representation of unimodal sensorimotor information (e.g., primary sensory cortices) or multi-modal summaries of brain states (e.g., default mode network) and increased functional connectivity with regions important for the attentional modulation of these representations (e.g., frontoparietal, attention networks). Personal distress was associated with the medial prefrontal cortex exhibiting functional connectivity differences with similar networks--but in the opposite direction. Finally, intrinsic functional connectivity within and between these networks fully mediated the relationship between the two behavioral measures. These results identify an important contribution of the macroscale functional organization of the brain to human well-being, by demonstrating that lower levels of personal distress lead to higher subjective happiness through variation in intrinsic functional connectivity along a neural representation vs. modulation gradient.

The N400 indexes acquisition of novel emotion concepts via conceptual combination.

The ability to learn new emotion concepts is adaptive and socially valuable as it communicates culturally held understandings about values, goals, and experiences. Yet, little work has examined the underlying mechanisms that allow for new emotion concepts and words to be integrated into the conceptual system. One such mechanism may be conceptual combination, or the ability to form novel concepts by dynamically combining previously acquired conceptual knowledge. In this study, we used event-related potentials (ERPs) to investigate the electrophysiological correlates of novel emotion concept acquisition via conceptual combination. Participants were briefly trained on 30 novel emotion combinations, each consisting of two English emotion words (the components; e.g., "sadness + fatigue") and a pseudoword (the target; e.g., "despip"). Participants then completed a semantic congruency task while ERPs were recorded. On each trial, two components were presented serially, followed by a target; participants judged whether the target was a valid combination of the preceding components. Targets could be correct or incorrect trained pseudowords, or new untrained pseudowords. Furthermore, components could be presented in reversed order (e.g., "fatigue" then "sadness") or as synonyms (e.g., "exhaustion" for "fatigue"). Consistent with our main hypotheses, we found a main effect of target, such that the correct combinations showed reduced N400 amplitudes when compared to both incorrect and untrained pseudowords. Critically, this effect held regardless of how the preceding components were presented, suggesting deeper semantic learning. These results extend prior findings on conceptual combination and novel word learning, and are congruent with predictive processing accounts of brain function.