Neural Basis Research Articles

Profiles of brain topology for dual-functional stability in old age.

Dual-functional stability (DFS) in cognitive and physical abilities is important for successful aging. This study examines the brain topology profiles that underpin high DFS in older adults by testing two hypotheses: (1) older adults with high DFS would exhibit a unique brain organization that preserves their physical and cognitive functions across various tasks, and (2) any individuals with this distinct brain topology would consistently show high DFS. We analyzed two cohorts of cognitively and physically healthy older adults from the UK (Cam-CAN, n = 79) and the US (CF, n = 48) using neuroimaging data and a combination of cognitive and physical tasks. Variability in DFS was characterized using k-mean clustering for intra-individual variability (IIV) in cognitive and physical tasks. Graph theory analyses of diffusion tensor imaging connectomes were used to assess brain network segregation and integration through clustering coefficients (CCs) and shortest path lengths (PLs). Using support vector machine and regression, brain topology features, derived from PLs + CCs, differentiated the high DFS subgroup from low and mix DFS subgroups with accuracies of 65.82% and 84.78% in Cam-CAN and CF samples, respectively, which predicted cross-task DFS score in CF samples at 58.06% and 70.53% for cognitive and physical stability, respectively. Results showed distinctive neural correlates associated with high DFS, notably varying regional brain segregation and integration within critical areas such as the insula, frontal pole, and temporal pole. The identified brain topology profiles suggest a distinctive neural basis for DFS, a trait indicative of successful aging. These insights offer a foundation for future research to explore targeted interventions that could enhance cognitive and physical resilience in older adults, promoting a healthier and more functional lifespan.

Socially induced plasticity of the posterior tuberculum and motor behavior in zebrafish (Danio rerio).

Social dominance is prevalent throughout the animal kingdom. It facilitates the stabilization of social relationships and allows animals to divide resources according to social rank. Zebrafish form stable dominance relationships that consist of dominants and subordinates. Although social-status-dependent differences in behavior must arise due to neural plasticity, mechanisms of how neural circuits are reconfigured to cope with social dominance are poorly described. Here, we describe how the posterior tuberculum nucleus (PT), which integrates sensory social information to modulate spinal motor circuits, is morphologically and functionally influenced by social status. We combined non-invasive behavioral monitoring of motor activity (startle escape and swim) and histological approaches to investigate how social dominance affects the morphological structure, axosomatic synaptic connectivity, and functional activity of the PT in relation to changes in motor behavior. We show that dopaminergic cell number significantly increases in dominants compared to subordinates, while PT synaptic interconnectivity, demonstrated with PSD-95 expression, is higher in subordinates compared to dominants. Secondly, these socially induced morphological differences emerge after one week of dominance formation and correlate with differences in cellular activities illustrated with higher phosphor-S6 ribosomal protein expression in dominants compared to subordinates. Thirdly, these morphological differences are reversible as the social environment evolves and correlates with adaptations in startle escape and swim behaviors. Our results provide new insights of the neural bases of social behavior that may be applicable to other social species with similar structural and functional organization.

Freezing of movements and its correspondence with MLG1 neurons response to looming stimuli in the crab Neohelice.

Upon visually detecting a moving predator animals often freeze, i.e. stop moving, to minimize being uncovered and to gather detailed information of the object's movements and properties. In certain conditions the freezing behavior can be enough to avoid a predatory menace but, when the risk is high or increases to a higher level, animals switch strategy and engage in an escape response. The neural bases underlying escape responses to visual stimuli are extensively investigated both in vertebrates and arthropods. However, those involved in freezing behaviors are much less studied. Here, we investigated the freezing behavior displayed by the crab Neohelice granulata when confronted with a variety of looming stimuli simulating objects of distinct sizes approaching on a collision course at different speeds. The experiments were performed in a treadmill-like device. Animals engaged in exploratory walks respond to the looming stimulus with freezing followed by escaping. The analysis of the stimulus optical variables shows that regardless of the looming dynamic, the freezing decision is made when the angular size of the object increases by 1.4°. In vivo intracellular recording responses of Monostratified Lobula Giant Neurons (MLG1) to the same looming stimuli show that the freezing times correlate with the times predicted by a hypothetical spike counter of this neuron.

Understanding the neural basis of natural intelligence

Understanding the neural basis of natural intelligence necessitates a paradigm shift: from strict reductionism toward embracing complexity and diversity. New tools and theories enable us to tackle this challenge, providing unprecedented access to neural dynamics and behavior across time, contexts, and species. Principles for intelligent behavior and learning in the natural world are now, more than ever, within reach.

On role models and Joe LeDoux.

Joseph LeDoux is a pioneering neuroscientist who has made profound discoveries that continue to impact our understanding of the neural basis of emotion and memory, particularly the role of the amygdala in threat conditioning. LeDoux's trailblazing and elegant studies were some of the first to examine the circuit basis of behavior. His work combined techniques to trace pathways into and out of the amygdala important for threat conditioning and related behaviors. Since that time, these types of circuit tracing studies have exploded in popularity across neuroscience, and I would argue, we all owe a debt to LeDoux for this. LeDoux has made numerous additional contributions to neuroscience and, by bringing emotion back to neuroscience, has helped unite neuroscience with psychology. A gifted writer with a knack for communicating complicated scientific ideas in an accessible manner, LeDoux has become an ambassador of science who uses his love of music to help educate and inspire. Perhaps more important than these laudable scientific achievements, LeDoux is also a true "gentleman" of science, showing that science need not be a contact sport. Here, I give a personal account on why Joseph LeDoux is one of my scientific role models.

Scale matters: Large language models with billions (rather than millions) of parameters better match neural representations of natural language.

Recent research has used large language models (LLMs) to study the neural basis of naturalistic language processing in the human brain. LLMs have rapidly grown in complexity, leading to improved language processing capabilities. However, neuroscience researchers haven't kept up with the quick progress in LLM development. Here, we utilized several families of transformer-based LLMs to investigate the relationship between model size and their ability to capture linguistic information in the human brain. Crucially, a subset of LLMs were trained on a fixed training set, enabling us to dissociate model size from architecture and training set size. We used electrocorticography (ECoG) to measure neural activity in epilepsy patients while they listened to a 30-minute naturalistic audio story. We fit electrode-wise encoding models using contextual embeddings extracted from each hidden layer of the LLMs to predict word-level neural signals. In line with prior work, we found that larger LLMs better capture the structure of natural language and better predict neural activity. We also found a log-linear relationship where the encoding performance peaks in relatively earlier layers as model size increases. We also observed variations in the best-performing layer across different brain regions, corresponding to an organized language processing hierarchy.

Deciphering the neural responses to a naturalistic persuasive message

Effective health promotion may benefit from understanding how persuasion emerges. While earlier research has identified brain regions implicated in persuasion, these studies often relied on event-related analyses and frequently simplified persuasive communications. The present study investigates the neural basis of valuation change induced by a persuasive healthy eating call, employing naturalistic stimuli. Fifty healthy participants performed two blocks of a bidding task, in which they had to bid on sugar-containing, sugar-free, and nonedible products during functional MRI. In between the two blocks, they listened to a persuasive healthy eating call that influenced their bidding behavior. Intriguingly, participants who resisted persuasion exhibited increased synchronization of brain activity during listening in several regions, including default mode network structures. Additionally, intersubject functional connectivity among these brain regions was found to be weaker in persuaded individuals. These results emphasize the individualized nature of processing persuasive messages, challenging conventional interpretations of synchronized neural activity. Our findings support the emerging practice of tailoring persuasive messages in health promotion campaigns.

The hippocampal CA2 region discriminates social threat from social safety.

The dorsal cornu ammonis 2 (dCA2) region of the hippocampus enables the discrimination of novel from familiar conspecifics. However, the neural bases for more complex social-spatial episodic memories are unknown. Here we report that the spatial and social contents of an aversive social experience require distinct hippocampal regions. While dorsal CA1 (dCA1) pyramidal neurons mediate the memory of an aversive location, dCA2 pyramidal neurons enable the discrimination of threat-associated (CS+) from safety-associated (CS-) conspecifics in both female and male mice. Silencing dCA2 during encoding or recall trials disrupted social fear discrimination memory, resulting in fear responses toward both the CS+ and CS- mice. Calcium imaging revealed that the aversive experience strengthened and stabilized dCA2 representations of both the CS+ and CS- mice, with the incorporation of an abstract representation of social valence into representations of social identity. Thus, dCA2 contributes to both social novelty detection and the adaptive discrimination of threat-associated from safety-associated individuals during an aversive social episodic experience.

A meta-analysis of letter-sound integration: Assimilation and accommodation in the superior temporal gyrus.

Despite being a relatively new cultural phenomenon, the ability to perform letter-sound integration is readily acquired even though it has not had time to evolve in the brain. Leading theories of how the brain accommodates literacy acquisition include the neural recycling hypothesis and the assimilation-accommodation hypothesis. The neural recycling hypothesis proposes that a new cultural skill is developed by "invading" preexisting neural structures to support a similar cognitive function, while the assimilation-accommodation hypothesis holds that a new cognitive skill relies on direct invocation of preexisting systems (assimilation) and adds brain areas based on task requirements (accommodation). Both theories agree that letter-sound integration may be achieved by reusing pre-existing functionally similar neural bases, but differ in their proposals of how this occurs. We examined the evidence for each hypothesis by systematically comparing the similarities and differences between letter-sound integration and two other types of preexisting and functionally similar audiovisual (AV) processes, namely object-sound and speech-sound integration, by performing an activation likelihood estimation (ALE) meta-analysis. All three types of AV integration recruited the left posterior superior temporal gyrus (STG), while speech-sound integration additionally activated the bilateral middle STG and letter-sound integration directly invoked the AV areas involved in speech-sound integration. These findings suggest that letter-sound integration may reuse the STG for speech-sound and object-sound integration through an assimilation-accommodation mechanism.

The bidirectional role of music effect in epilepsy: Friend or foe?

Epilepsy is a prevalent neurological disease that impacts around 70 million individuals globally. Anti-seizure medications (ASMs) are the first choice for clinicians to control unprovoked epileptic seizures. Although more than 30 ASMs are available in the market, patients with epilepsy (PWEs) still show poor responses to adequate drug treatment. Meanwhile, long-term medications not only bring heavy financial burdens but also lead to undesirable side effects. Music, a ubiquitous art form throughout human history, has been confirmed as therapeutically effective in various neurological conditions, including epilepsy. This alternative therapy offers convenience and a relatively safe approach to alleviating epileptic symptoms. Paradoxically, besides anti-convulsant effect, some particular music would cause seizures inversely, indicating the pro-convulsant effect of it. Considering that investigating the impact of music on epilepsy emerges as a compelling subject. In this review, we tried to present the following sections of content on this topic. Initially, we overviewed the impact of music on the brain and the significant progress of music therapy in central neurological disorders. Afterward, we classified the anti-convulsant and pro-convulsant effects of music in epilepsy, relying on both clinical and laboratory evidences. Finally, possible mechanisms and neural basis of the music effect were concluded, and the translational potentials and some future outlooks about the music effect in epilepsy were proposed. PLAIN LANGUAGE SUMMARY: Epilepsy is an extremely severe neurological disorder. Although anti-seizure medications are preferred choice to control seizures, the efficacy is not satisfied due to the tolerance. Anecdotal music effect had been deemed functional diversity but not clarified on epilepsy, pro-convulsive, or anti-convulsive. Here, we reviewed this interesting but puzzling topic, as well as illustrating the potential mechanisms and its translational potential.

Neural Transformation from Retinotopic to Background-Centric Coordinates in the Macaque Precuneus.

Visual information is initially represented in retinotopic coordinates and later in craniotopic coordinates. Psychophysical evidence suggests that visual information is further represented in more general coordinates related to the external world; however, the neural basis of non-egocentric coordinates remains elusive. This study investigates the automatic transformation from egocentric to non-egocentric coordinates in the macaque precuneus (two males, one female), identified by a functional imaging study as a key area for non-egocentric representation. We found that 6.2% of neurons in the precuneus have receptive fields anchored to the background rather than to the retina or the head, while 16% had traditional retinotopic receptive fields. Notably, these two types were not exclusive: many background-centric neurons initially encode a stimulus's position in retinotopic coordinates (up to ∼90 ms from stimulus onset) but later shift to background coordinates, peaking at ∼150 ms. Regarding retinotopic information, the stimulus dominated the initial period, whereas the background dominated the later period. In the absence of a background, there is a dramatic surge in retinotopic information about the stimulus during the later phase, clearly delineating two distinct periods of retinotopic encoding: one focusing on the figure to be attended and another on the background. These findings suggest that the initial retinotopic information of the stimulus is combined with the background retinotopic information in a subsequent stage, yielding a more stable representation of the stimulus relative to the background through time-division multiplexing.Significance Statement According to psychological literature, the location of visual stimuli is automatically positioned against the background of a scene. This representation relative to the background, not being influenced by eye movements, should be important for stabilizing the visual world. A human functional imaging study suggested that the precuneus in the medial cerebral cortex is a strong candidate. This study recorded neural activity from the precuneus of monkeys and demonstrated the existence of background-centered cells with receptive fields fixed relative to the background.

Neural Mechanisms of Social Interaction Perception: Observing Interpersonal Synchrony Modulates Action Observation Network Activation and Is Spared in Autism.

How the temporal dynamics of social interactions are perceived arguably plays an important role in how one engages in social interactions and how difficulties in establishing smooth social interactions may occur. One aspect of temporal dynamics in social interactions is the mutual coordination of individuals' behaviors during social interaction, otherwise known as behavioral interpersonal synchrony (IPS). Behavioral IPS has been studied increasingly in various contexts, such as a feature of the social interaction difficulties inherent to autism. To fully understand the temporal dynamics of social interactions, or reductions thereof in autism, the neural basis of IPS perception needs to be established. Thus, the current study's aim was twofold: to establish the basic neuro-perceptual processing of IPS in social interactions for typical observers and to test whether it might differ for autistic individuals. In a task-based fMRI paradigm, participants viewed short, silent video vignettes of humans during social interactions featuring a variation of behavioral IPS. The results show that observing behavioral IPS modulates the Action Observation Network (AON). Interestingly, autistic participants showed similar neural activation patterns as non-autistic participants which were modulated by the behavioral IPS they observed in the videos, suggesting that the perception oftemporal dynamics of social interactions is spared and may not underly reduced behavioral IPS often observed in autism. Nevertheless, a general difference in processing social interactions was found in autistic observers, characterized by decreased neural activation in the right middle frontal gyrus, angular gyrus, and superior temporal areas. These findings demonstrate that although the autistic and non-autistic groups indeed differed in the neural processing of social interaction perception, the temporal dynamics of these social interactions were not the reason for these differences in social interaction perception in autism. Hence, spared recruitment of the AON for processing temporal dynamics of social interactions in autism does not account for the widely reported attenuation of IPS in autism and for the widely reported and presently observed differences in social interaction perception in autism.

Gateway to the study of the amygdala and emotion.

The study of the amygdala and its role in the processing of emotions has become a common focus in neuroscience. The modern expansion of research in this area is partly due to the discovery of a subcortical pathway for the transmission of emotional information and the experimental paradigm that was developed to study it. Groundbreaking experiments during the 90s utilized anatomical, neurophysiological, and behavioral lesion studies in a rodent animal model to uncover the neural circuitry of a simple emotional memory. These studies demonstrated the essential role of a specific monosynaptic pathway in emotional memory, using traditional tools and behavioral methods. The development of an animal model with a simple and appropriate classical conditioning paradigm made experimental investigations into the neural basis of emotion tenable and available to a generation of neuroscientists. These tools and a focus on the amygdala's neural connections and their essential role in emotional memory were a driving force in the explosion of research regarding the amygdala and emotion.

Attentional guidance through object associations in visual cortex

Efficient behavior requires the rapid attentional selection of task-relevant objects. Preparatory activity of target-selective neurons in visual cortex is thought to support attentional selection, guiding spatial attention and favoring processing of target-matching input. However, naturalistic searches are often guided by nontargets, including target-associated “anchor” objects. For instance, when looking for a pen, we may direct our attention to the office desk on which we expect to find it. Here, using fMRI and eye tracking in a context-guided search task, we tested whether preparatory activity in visual cortex reflected the target, the guiding anchor object, or both. Participants learned associations between targets and anchors, reversing across two scene contexts, before searching for these targets. Participants’ first fixations were reliably guided by the associated anchor. Preparatory activity in lateral occipital cortex (LOC) and right intraparietal sulcus (IPS) represented the target-associated anchor rather than the target. These results shed light on the neural basis of context-guided search in structured environments.

Comparison of resting-state brain activity between insomnia and generalized anxiety disorder: A coordinate-based meta-analysis.

Patients with insomnia disorder (ID) usually experience a greater burden of comorbid anxiety symptoms. However, the neural mechanism under the mutual relationship between ID and anxiety remains largely unclear. The meta-analysis aimed to explore the concordance and distinction of regional brain functional activity in patients with ID and those with generalized anxiety disorder (GAD) using coordinate-based activation likelihood estimation approach. Studies using resting-state regional homogeneity, amplitude of low-frequency fluctuations (ALFF), or fractional ALFF in patients with ID or GAD were included by searching multiple databases up to May 24, 2024. Using meta-analytic approach, 21 studies of ID vs. healthy controls (HC) and 16 studies of GAD vs. HC were included to illuminate the common and distinct patterns between the two disorders. Results showed that ID and GAD shared increased brain activities in the left posterior cingulate cortex and left precuneus, as well as decreased brain activity in the left medial prefrontal cortex. Additionally, compared with ID, GAD showed greater increased activities in the left superior frontal gyrus. Our study reveals both common and different activation patterns between ID and GAD, which may provide novel insights for understanding the neural basis of the two disorders and enlighten the possibility of the development of more targeted treatment strategies for ID and GAD.

Thalamic Roles in Conscious Perception Revealed by Low-Intensity Focused Ultrasound Neuromodulation.

The neural basis of conscious perception remains incompletely understood. While cortical mechanisms of conscious content have been extensively investigated, the role of subcortical structures, including the thalamus, remains less explored. We aim to elucidate the causal contributions of different thalamic regions to conscious perception using transcranial low-intensity focused ultrasound (LIFU) neuromodulation. We hypothesize that modulating different thalamic regions would result in distinct perceptual outcomes. We apply LIFU in human volunteers to investigate region-specific and sonication parameter-dependent effects. We target anterior (transmodal-dominant) and posterior (unimodal-dominant) thalamic regions, further divided into ventral and dorsal regions, while participants perform a near-threshold visual perception task. Task performance is evaluated using Signal Detection Theory metrics. We find that the high duty cycle stimulation of the ventral anterior thalamus enhanced object recognition sensitivity. We also observe a general (i.e., region-independent) effect of LIFU on decision bias (i.e., a tendency toward a particular response) and object categorization accuracy. Specifically, high duty cycle stimulation decreases categorization accuracy, whereas low duty cycle shifts decision bias towards a more conservative stance. In conclusion, our results provide causal insight into the functional organization of the thalamus in shaping human visual experience and highlight the unique role of the transmodal-dominant ventral anterior thalamus.

6953 Bridging the Gender Gap: Sexually Dimorphic Brain Responses in Distressing Low Sexual Desire

Abstract Disclosure: J. Tsoutsouki: None. N. Ertl: None. E.G. Mills: None. M.B. Wall: None. L. Thurston: None. L. Yang: None. S. Suladze: None. T. Hunjan: None. M. Phylactou: None. B. Patel: None. J. Howard: None. A. Abbara: None. D. Golmeier: None. A.N. Comninos: None. W.S. Dhillo: None. Background: Distressing low sexual desire, termed Hypoactive Sexual Desire Disorder (HSDD), affects 10% of women and 8% of men. The established ‘top-down’ neurofunctional model of HSDD in women suggests that in response to erotic cues, excessive activation of higher-level cognitive brain regions (involved in introspection/self-monitoring) suppresses lower-level sexual brain centres, thereby impeding normal sexual function. By contrast, the neurodysfunction in men with HSDD remains to be fully characterised and crucially unlike in women, there are currently no licensed therapies. Herein, we report the first direct comparison of the neural bases of HSDD in women and men. Methods: 32 premenopausal women with HSDD [mean age±SD (y) 29.2±6.7] and 32 men with HSDD [age 37.9±8.6] underwent a task-based functional MRI (fMRI) measuring sexual brain activity during erotic versus control (exercise) videos. Participants completed psychometric questionnaires before and after the fMRI scan, providing functional relevance for the brain activity changes. Results: Women displayed significantly greater activation in higher-level cortical regions (e.g. inferior frontal gyrus, superior frontal gyrus) and lower-level limbic brain regions (e.g. amygdala, striatum, thalamus) in response to erotic videos, compared to the men. Lower activation in lower-limbic sexual regions in women correlated with more severe HSDD, which along with a hyperactivation in the inferior-frontal gyrus relative to the men, supports the ‘top-down’ mechanism underlying HSDD in women. By contrast, men exhibited lower activation in both higher-cortical and lower-limbic regions, but greater activation than the women in the visual cortex in response to erotic videos. Hence, a heightened sensitivity to visual erotic cues in men might not be effectively relayed to the limbic system. In women only, hypothalamic hyperactivation in response to erotic videos correlated with ‘increased heartbeat’ (r=0.5, P=0.001), and ‘tingling all over’ (r=0.6, P<0.001), while higher striatal activation correlated with feeling more ‘stimulated’ (r=0.4, P=0.001) and ‘genital tingling’ (r=0.6, P<0.001) on the psychometric questionnaires. Crucially, these findings were specific to erotic stimuli as no differences were identified in the control comparison (exercise>baseline contrast). Discussion: This is the first study to directly compare the neural bases of distressing low sexual desire in women and men. While supporting the ‘top-down’ mechanism of HSDD in women, it suggests a different neurodysfunctional process in men with HSDD, highlighting a potential functional disconnection between sensory/attention and sexual centres. Our findings have key clinical implications as they identify a sexual dimorphism in the neural bases of low sexual desire relevant to the escalating development of therapeutics for patients with HSDD. Presentation: 6/3/2024

GABALAGEN Facilitates Pentobarbital-Induced Sleep by Modulating the Serotonergic System in Rats.

Gamma-aminobutyric acid (GABA) is one of the inhibitory neurotransmitters with beneficial effects including sedative properties. However, despite various clinical trials, scientific evidence regarding the impact on sleep of orally ingested GABA, whether natural or synthesized through biological pathways, is not clear. GABALAGEN (GBL) is the product of fermented collagen by Lactobacillus brevis BJ20 (L. brevis BJ20) and Lactobacillus plantarum BJ21 (L. plantarum BJ21), enriched with GABA and characterized by low molecular weight. The aim of this study was to investigate the effect of GBL on sleep improvement via a receptor binding assay in a pentobarbital-induced sleep-related rat model. We utilized a pentobarbital-induced sleep-related rat model to conduct this research. The present study investigated the sedative effects of GBL through electroencephalography (EEG) analysis in the pentobarbital-induced sleep animal model. Exploration of the neural basis of these positive effects involved evaluating orexin in the brain via immunohistochemical methods and 5-HT in the serum using an enzyme-linked immunosorbent assay (ELISA). Furthermore, we conducted a binding assay for 5-HT2C receptors, as these are considered pivotal targets in the mechanism of action for sleep aids. Diazepam (DZP) was used as a positive control to compare the efficacy of GBL. Results: In the binding assay, GBL displayed binding affinity to the 5-HT2C receptor (IC50 value, 5.911 µg/mL). Administration of a low dose of GBL (GBL_L; 100 mg/kg) increased non-rapid eye movement sleep time and decreased wake time based on EEG data in pentobarbital-induced rats. Administration of a high dose of GBL (GBL_H; 250 mg/kg) increased non-rapid eye movement sleep time. Additionally, GBL groups significantly increased concentration of the 5-HT level in the serum. GBL_H decreased orexin expression in the lateral hypothalamus. Conclusion: Overall, the sedative effect of GBL may be linked to the activation of serotonergic systems, as indicated by the heightened affinity of the 5-HT2C receptor binding and elevated levels of 5-HT observed in the serum. This suggests that GBL holds promise as a novel compound for inducing sleep in natural products.

11C-UCB-J PET imaging is consistent with lower synaptic density in autistic adults.

The neural bases of autism are poorly understood at the molecular level, but evidence from animal models, genetics, post-mortem studies, and single-gene disorders implicate synaptopathology. Here, we use positron emission tomography (PET) to assess the density of synapses with synaptic vesicle glycoprotein 2A (SV2A) in autistic adults using 11C-UCB-J. Twelve autistic (mean (SD)age 25 (4)years; six males), and twenty demographically matched non-autistic individuals (26 (3)years; eleven males) participated in a 11C-UCB-J PET scan. Binding potential, BPND, was the primary outcome measure and computed with the centrum semiovale as the reference region. Partial volume correction with Iterative Yang was applied to control for possible volumetric differences. Mixed-model statistics were calculated for between-group differences. Relationships to clinical characteristics were evaluated based on clinician ratings of autistic features. Whole cortex synaptic density was 17% lower in the autism group (p = 0.01). All brain regions in autism had lower 11C-UCB-J BPND compared to non-autistic participants. This effect was evident in all brain regions implicated in autism. Significant differences were observed across multiple individual regions, including the prefrontal cortex (-15%, p = 0.02), with differences most pronounced in gray matter (p < 0.0001). Synaptic density was significantly associated with clinical measures across the whole cortex (r = 0.67, p = 0.02) and multiple regions (rs = -0.58 to -0.82, ps = 0.05 to <0.01). The first in vivo investigation of synaptic density in autism with PET reveals pervasive and large-scale lower density in the cortex and across multiple brain areas. Synaptic density also correlated with clinical features, such that a greater number of autistic features were associated with lower synaptic density. These results indicate that brain-wide synaptic density may represent an as-yet-undiscovered molecular basis for the clinical phenotype of autism and associated pervasive alterations across a diversity of neural processes.

Aberrant individual large-scale functional network connectivity and topology in chronic insomnia disorder with and without depression

Insomnia is increasingly prevalent with significant associations with depression. Delineating specific neural circuits for chronic insomnia disorder (CID) with and without depressive symptoms is fundamental to develop precision diagnosis and treatment. In this study, we examine static, dynamic and network topology changes of individual large-scale functional network for CID with (CID-D) and without depression to reveal their specific neural underpinnings. Seventeen individual-specific functional brain networks are obtained using a regularized nonnegative matrix factorization technique. Disorders-shared and -specific differences in static and dynamic large-scale functional network connectivities within or between the cognitive control network, dorsal attention network, visual network, limbic network, and default mode network are found for CID and CID-D. Additionally, CID and CID-D groups showed compromised network topological architecture including reduced small-world properties, clustering coefficients and modularity indicating decreased network efficiency and impaired functional segregation. Moreover, the altered neuroimaging indices show significant associations with clinical manifestations and could serve as effective neuromarkers to distinguish among healthy controls, CID and CID-D. Taken together, these findings provide novel insights into the neural basis of CID and CID-D, which may facilitate developing new diagnostic and therapeutic approaches.