Divergent Associations of Slow-Wave Sleep versus Rapid Eye Movement Sleep with Plasma Amyloid-Beta.

OBJECTIVE: Recent evidence shows that during slow-wave sleep (SWS), the brain is cleared from potentially toxic metabolites, such as the amyloid-beta protein. Poor sleep or elevated cortisol levels can worsen amyloid-beta clearance, potentially leading to the formation of amyloid plaques, a neuropathological hallmark of Alzheimer disease. Here, we explored how nocturnal neural and endocrine activity affects amyloid-beta fluctuations in the peripheral blood. METHODS: We acquired simultaneous polysomnography and all-night blood sampling in 60 healthy volunteers aged 20-68 years. Nocturnal plasma concentrations of amyloid-beta-40, amyloid-beta-42, cortisol, and growth hormone were assessed every 20 minutes. Amyloid-beta fluctuations were modeled with sleep stages, (non)oscillatory power, and hormones as predictors while controlling for age and participant-specific random effects. RESULTS: Amyloid-beta-40 and amyloid-beta-42 levels correlated positively with growth hormone concentrations, SWS proportion, and slow-wave (0.3-4Hz) oscillatory and high-band (30-48Hz) nonoscillatory power, but negatively with cortisol concentrations and rapid eye movement sleep (REM) proportion measured 40-100 minutes previously (all t values > |3|, p values < 0.003). Older participants showed higher amyloid-beta-40 levels. INTERPRETATION: Slow-wave oscillations are associated with higher plasma amyloid-beta levels, whereas REM sleep is related to decreased amyloid-beta plasma levels, possibly representing changes in central amyloid-beta production or clearance. Strong associations between cortisol, growth hormone, and amyloid-beta presumably reflect the sleep-regulating role of the corresponding releasing hormones. A positive association between age and amyloid-beta-40 may indicate that peripheral clearance becomes less efficient with age. ANN NEUROL 2024;96:46-60.

Learning and Representation of Hierarchical Concepts in Hippocampus and Prefrontal Cortex.

A key aspect of conceptual knowledge is that it can be flexibly applied at different levels of abstraction, implying a hierarchical organization. It is yet unclear how this hierarchical structure is acquired and represented in the brain. Here we investigate the computations underlying the acquisition and representation of the hierarchical structure of conceptual knowledge in the hippocampal-prefrontal system of 32 human participants (22 females). We assessed the hierarchical nature of learning during a novel tree-like categorization task via computational model comparisons. The winning model allowed to extract and quantify estimates for accumulation and updating of hierarchical compared with single-feature-based concepts from behavior. We find that mPFC tracks accumulation of hierarchical conceptual knowledge over time, and mPFC and hippocampus both support trial-to-trial updating. As a function of those learning parameters, mPFC and hippocampus further show connectivity changes to rostro-lateral PFC, which ultimately represented the hierarchical structure of the concept in the final stages of learning. Our results suggest that mPFC and hippocampus support the integration of accumulated evidence and instantaneous updates into hierarchical concept representations in rostro-lateral PFC.SIGNIFICANCE STATEMENT A hallmark of human cognition is the flexible use of conceptual knowledge at different levels of abstraction, ranging from a coarse category level to a fine-grained subcategory level. While previous work probed the representational geometry of long-term category knowledge, it is unclear how this hierarchical structure inherent to conceptual knowledge is acquired and represented. By combining a novel hierarchical concept learning task with computational modeling of categorization behavior and concurrent fMRI, we differentiate the roles of key concept learning regions in hippocampus and PFC in learning computations and the representation of a hierarchical category structure.

Recursive hierarchical embedding in vision is impaired by posterior middle temporal gyrus lesions.

The generation of hierarchical structures is central to language, music and complex action. Understanding this capacity and its potential impairments requires mapping its underlying cognitive processes to the respective neuronal underpinnings. In language, left inferior frontal gyrus and left posterior temporal cortex (superior temporal sulcus/middle temporal gyrus) are considered hubs for syntactic processing. However, it is unclear whether these regions support computations specific to language or more generally support analyses of hierarchical structure. Here, we address this issue by investigating hierarchical processing in a non-linguistic task. We test the ability to represent recursive hierarchical embedding in the visual domain by contrasting a recursion task with an iteration task. The recursion task requires participants to correctly identify continuations of a hierarchy generating procedure, while the iteration task applies a serial procedure that does not generate new hierarchical levels. In a lesion-based approach, we asked 44 patients with left hemispheric chronic brain lesion to perform recursion and iteration tasks. We modelled accuracies and response times with a drift diffusion model and for each participant obtained parametric estimates for the velocity of information accumulation (drift rates) and for the amount of information accumulated before a decision (boundary separation). We then used these estimates in lesion-behaviour analyses to investigate how brain lesions affect specific aspects of recursive hierarchical embedding. We found that lesions in the posterior temporal cortex decreased drift rate in recursive hierarchical embedding, suggesting an impaired process of rule extraction from recursive structures. Moreover, lesions in inferior temporal gyrus decreased boundary separation. The latter finding does not survive conservative correction but suggests a shift in the decision criterion. As patients also participated in a grammar comprehension experiment, we performed explorative correlation-analyses and found that visual and linguistic recursive hierarchical embedding accuracies are correlated when the latter is instantiated as sentences with two nested embedding levels. While the roles of the inferior temporal gyrus and posterior temporal cortex in linguistic processes are well established, here we show that posterior temporal cortex lesions slow information accumulation (drift rate) in the visual domain. This suggests that posterior temporal cortex is essential to acquire the (knowledge) representations necessary to parse recursive hierarchical embedding in visual structures, a finding mimicking language acquisition in young children. On the contrary, inferior frontal gyrus lesions seem to affect recursive hierarchical embedding processing by interfering with more general cognitive control (boundary separation). This interesting separation of roles, rooted on a domain-general taxonomy, raises the question of whether such cognitive framing is also applicable to other domains.

Eye-Movement Intervention Enhances Extinction via Amygdala Deactivation.

Improving extinction learning is essential to optimize psychotherapy for persistent fear-related disorders. In two independent studies (both n = 24), we found that goal-directed eye movements activate a dorsal frontoparietal network and transiently deactivate the amygdala (η p2 = 0.17). Connectivity analyses revealed that this downregulation potentially engages a ventromedial prefrontal pathway known to be involved in cognitive regulation of emotion. Critically, when eye movements followed memory reactivation during extinction learning, it reduced spontaneous fear recovery 24 h later (η p2 = 0.21). Stronger amygdala deactivation furthermore predicted a stronger reduction in subsequent fear recovery after reinstatement (r = 0.39). In conclusion, we show that extinction learning can be improved with a noninvasive eye-movement intervention that triggers a transient suppression of the amygdala. Our finding that another task which taxes working memory leads to a similar amygdala suppression furthermore indicates that this effect is likely not specific to eye movements, which is in line with a large body of behavioral studies. This study contributes to the understanding of a widely used treatment for traumatic symptoms by providing a parsimonious account for how working-memory tasks and goal-directed eye movements can enhance extinction-based psychotherapy, namely through neural circuits (e.g., amygdala deactivation) similar to those that support cognitive control of emotion.SIGNIFICANCE STATEMENT Fear-related disorders represent a significant burden on individual sufferers and society. There is a high need to optimize treatment, in particular via noninvasive means. One potentially effective intervention is execution of eye movements following trauma recall. However, a neurobiological understanding of how eye movements reduce traumatic symptoms is lacking. We demonstrate that goal-directed eye-movements, like working-memory tasks, deactivate the amygdala, the core neural substrate of fear learning. Effective connectivity analyses revealed amygdala deactivation potentially engaged dorsolateral and ventromedial prefrontal pathways. When applied during safety learning, this deactivation predicts a reduction in later fear recovery. These findings provide a parsimonious and mechanistic account of how behavioral manipulations taxing working memory and suppressing amygdala activity can alter retention of emotional memories.

Split brain: divided perception but undivided consciousness.

In extensive studies with two split-brain patients we replicate the standard finding that stimuli cannot be compared across visual half-fields, indicating that each hemisphere processes information independently of the other. Yet, crucially, we show that the canonical textbook findings that a split-brain patient can only respond to stimuli in the left visual half-field with the left hand, and to stimuli in the right visual half-field with the right hand and verbally, are not universally true. Across a wide variety of tasks, split-brain patients with a complete and radiologically confirmed transection of the corpus callosum showed full awareness of presence, and well above chance-level recognition of location, orientation and identity of stimuli throughout the entire visual field, irrespective of response type (left hand, right hand, or verbally). Crucially, we used confidence ratings to assess conscious awareness. This revealed that also on high confidence trials, indicative of conscious perception, response type did not affect performance. These findings suggest that severing the cortical connections between hemispheres splits visual perception, but does not create two independent conscious perceivers within one brain.

Associative and Identity Words Promote the Speed of Visual Categorization: A Hierarchical Drift Diffusion Account.

Words can either boost or hinder the processing of visual information, which can lead to facilitation or interference of the behavioral response. We investigated the stage (response execution or target processing) of verbal interference/facilitation in the response priming paradigm with a gender categorization task. Participants in our study were asked to judge whether the presented stimulus was a female or male face that was briefly preceded by a gender word either congruent (prime: "man," target: "man"), incongruent (prime: "woman," target: "man") or neutral (prime: "day," target: "man") with respect to the face stimulus. We investigated whether related word-picture pairs resulted in faster reaction times in comparison to the neutral word-picture pairs (facilitation) and whether unrelated word-picture pairs resulted in slower reaction times in comparison to neutral word-picture pairs (interference). We further examined whether these effects (if any) map onto response conflict or aspects of target processing. In addition, identity ("man," "woman") and associative ("tie," "dress") primes were introduced to investigate the cognitive mechanisms of semantic and Stroop-like effects in response priming (introduced respectively by associations and identity words). We analyzed responses and reaction times using the drift diffusion model to examine the effect of facilitation and/or interference as a function of the prime type. We found that regardless of prime type words introduce a facilitatory effect, which maps to the processes of visual attention and response execution.

Lexical-semantic and executive deficits revealed by computational modelling: A drift diffusion model perspective.

Flexible language use requires coordinated functioning of two systems: conceptual representations and control. The interaction between the two systems can be observed when people are asked to match a word to a picture. Participants are slower and less accurate for related word-picture pairs (word: banana, picture: apple) relative to unrelated pairs (word: banjo, picture: apple). The mechanism underlying interference however is still unclear. We analyzed word-picture matching (WPM) performance of patients with stroke-induced lesions to the left-temporal (N = 5) or left-frontal cortex (N = 5) and matched controls (N = 12) using the drift diffusion model (DDM). In DDM, the process of making a decision is described as the stochastic accumulation of evidence towards a response. The parameters of the DDM model that characterize this process are decision threshold, drift rate, starting point and non-decision time, each of which bears cognitive interpretability. We compared the estimated model parameters from controls and patients to investigate the mechanisms of WPM interference. WPM performance in controls was explained by the amount of information needed to make a decision (decision threshold): a higher threshold was associated with related word-picture pairs relative to unrelated ones. No difference was found in the quality of the evidence (drift rate). This suggests an executive rather than semantic mechanism underlying WPM interference. Both patients with temporal and frontal lesions exhibited both increased drift rate and decision threshold for unrelated pairs relative to related ones. Left-frontal and temporal damage affected the computations required by WPM similarly, resulting in systematic deficits across lexical-semantic memory and executive functions. These results support a diverse but interactive role of lexical-semantic memory and semantic control mechanisms.

Peer-Influence on Risk-Taking in Male Adolescents with Mild to Borderline Intellectual Disabilities and/or Behavior Disorders.

This study aimed to disentangle the effects of Mild-to-Borderline Intellectual Disability (MBID) and Behavior Disorders (BD)on risk taking in circumstances where peer influence was absent or present. We studied 319 adolescents in four groups: MBID-only, MBID+BD, BD-only, and typically developing controls. The Balloon Analogue Risk-Task (BART), in a solo or peer condition, was used as a proxy of real-life risk-taking. Results show a significant main effect of BART condition. Post-hoc tests indicated higher risk-taking in the peer compared to the solo condition in all groups except BD-only. Moreover, risk taking was increased in adolescents with MBID compared to adolescents without MBID, but only under peer-influence. No main or interaction effects with BD were observed. Model based decomposition of BART performance in underlying processes showed that the MBID related increase in risk-taking under peer-influence was mainly related to increased risk-taking propensity, and in the MBID-only group also to increased safety estimates and increased confidence in these safety estimates. The present study shows that risk-taking in MBID may be better explained by low intellectual functioning than by comorbid BD, and may not originate in increased risk taking per se, but may rather be related to risk-taking under peer-influence, which is a complex, multifaceted risk-taking context. Therefore, interventions to decrease risk-taking by adolescents with MBID that specifically target peer-influence may be successful.

Words affect visual perception by activating object shape representations.

Linguistic labels are known to facilitate object recognition, yet the mechanism of this facilitation is not well understood. Previous psychophysical studies have suggested that words guide visual perception by activating information about visual object shape. Here we aimed to test this hypothesis at the neural level, and to tease apart the visual and semantic contribution of words to visual object recognition. We created a set of object pictures from two semantic categories with varying shapes, and obtained subjective ratings of their shape and category similarity. We then conducted a word-picture matching experiment, while recording participants' EEG, and tested if the shape or the category similarity between the word's referent and target picture explained the spatiotemporal pattern of the picture-evoked responses. The results show that hearing a word activates representations of its referent's shape, which interacts with the visual processing of a subsequent picture within 100 ms from its onset. Furthermore, non-visual categorical information, carried by the word, affects the visual processing at later stages. These findings advance our understanding of the interaction between language and visual perception and provide insights into how the meanings of words are represented in the brain.