Mapping access to meaning in adolescents with autism: Atypical lateralization and spatiotemporal patterns as a function of language ability.

Individuals with autism spectrum disorders (ASD) vary in their language abilities, associated with atypical patterns of brain activity. However, few studies have examined the spatiotemporal profiles of lexico-semantic processing in ASD, particularly as a function of language heterogeneity. Thirty-nine high-functioning adolescents with ASD and 21 typically developing (TD) peers took part in a lexical decision task that combined semantic access with demands on cognitive control. Spatiotemporal characteristics of the processing stages were examined with a multimodal anatomically-constrained magnetoencephalography (aMEG) approach, which integrates MEG with structural MRI. Additional EEG data were acquired from a limited montage simultaneously with MEG. TD adolescents showed the canonical left-dominant activity in frontotemporal regions during both early (N250m) and late (N400m) stages of lexical access and semantic integration. In contrast, the ASD participants showed bilateral engagement of the frontotemporal language network, indicative of compensatory recruitment of the right hemisphere. The left temporal N400m was prominent in both groups, confirming preserved attempts to access meaning. In contrast, the left prefrontal N400m was reduced in ASD participants, consistent with impaired semantic/contextual integration and inhibitory control. To further investigate the impact of language proficiency, the ASD sample was stratified into high- and low-performing (H-ASD and L-ASD) subgroups based on their task accuracy. The H-ASD subgroup performed on par with the TD group and showed greater activity in the right prefrontal and bilateral temporal cortices relative to the L-ASD subgroup, suggesting compensatory engagement. The L-ASD subgroup additionally showed reduced and delayed left prefrontal N400m, consistent with more profound semantic and executive impairments in this subgroup. These distinct spatiotemporal activity profiles reveal the neural underpinnings of the ASD-specific access to meaning and provide insight into the phenotypic heterogeneity of language in ASD, which may be a result of different neurodevelopmental trajectories and adoption of compensatory strategies.

Pattern differentiation and tuning shift in human sensory cortex underlie long-term threat memory.

The amygdala-prefrontal-cortex circuit has long occupied the center of the threat system,1 but new evidence has rapidly amassed to implicate threat processing outside this canonical circuit.2-4 Through nonhuman research, the sensory cortex has emerged as a critical substrate for long-term threat memory,5-9 underpinned by sensory cortical pattern separation/completion10,11 and tuning shift.12,13 In humans, research has begun to associate the human sensory cortex with long-term threat memory,14,15 but the lack of mechanistic insights obscures a direct linkage. Toward that end, we assessed human olfactory threat conditioning and long-term (9 days) threat memory, combining affective appraisal, olfactory psychophysics, and functional magnetic resonance imaging (fMRI) over a linear odor-morphing continuum (five levels of binary mixtures of the conditioned stimuli/CS+ and CS- odors). Affective ratings and olfactory perceptual discrimination confirmed (explicit) affective and perceptual learning and memory via conditioning. fMRI representational similarity analysis (RSA) and voxel-based tuning analysis further revealed associative plasticity in the human olfactory (piriform) cortex, including immediate and lasting pattern differentiation between CS and neighboring non-CS and a late onset, lasting tuning shift toward the CS. The two plastic processes were especially salient and lasting in anxious individuals, among whom they were further correlated. These findings thus support an evolutionarily conserved sensory cortical system of long-term threat representation, which can underpin threat perception and memory. Importantly, hyperfunctioning of this sensory mnemonic system of threat in anxiety further implicates a hitherto underappreciated sensory mechanism of anxiety.

Transcranial stimulation of alpha oscillations up-regulates the default mode network.

The default mode network (DMN) is the most-prominent intrinsic connectivity network, serving as a key architecture of the brain's functional organization. Conversely, dysregulated DMN is characteristic of major neuropsychiatric disorders. However, the field still lacks mechanistic insights into the regulation of the DMN and effective interventions for DMN dysregulation. The current study approached this problem by manipulating neural synchrony, particularly alpha (8 to 12 Hz) oscillations, a dominant intrinsic oscillatory activity that has been increasingly associated with the DMN in both function and physiology. Using high-definition alpha-frequency transcranial alternating current stimulation (α-tACS) to stimulate the cortical source of alpha oscillations, in combination with simultaneous electroencephalography and functional MRI (EEG-fMRI), we demonstrated that α-tACS (versus Sham control) not only augmented EEG alpha oscillations but also strengthened fMRI and (source-level) alpha connectivity within the core of the DMN. Importantly, increase in alpha oscillations mediated the DMN connectivity enhancement. These findings thus identify a mechanistic link between alpha oscillations and DMN functioning. That transcranial alpha modulation can up-regulate the DMN further highlights an effective noninvasive intervention to normalize DMN functioning in various disorders.

Human Sensory Cortex Contributes to the Long-Term Storage of Aversive Conditioning.

Growing animal data evince a critical role of the sensory cortex in the long-term storage of aversive conditioning, following acquisition and consolidation in the amygdala. Whether and how this function is conserved in the human sensory cortex is nonetheless unclear. We interrogated this question in a human aversive conditioning study using multidimensional assessments of conditioning and long-term (15 d) retention. Conditioned stimuli (CSs; Gabor patches) were calibrated to differentially activate the parvocellular (P) and magnocellular (M) visual pathways, further elucidating cortical versus subcortical mechanisms. Full-blown conditioning and long-term retention emerged for M-biased CS (vs limited effects for P-biased CS), especially among anxious individuals, in all four dimensions assessed: threat appraisal (threat ratings), physiological arousal (skin conductance response), perceptual learning [discrimination sensitivity (d') and response speed], and cortical plasticity [visual evoked potentials (VEPs) and cortical current density]. Interestingly, while behavioral, physiological, and VEP effects were comparable at immediate and delayed assessments, the cortical substrates evolved markedly over time, transferring from high-order cortices [inferotemporal/fusiform cortex and orbitofrontal cortex (OFC)] immediately to the primary and secondary visual cortex after the delay. In sum, the contrast between P- and M-biased conditioning confirms privileged conditioning acquisition via the subcortical pathway while the immediate cortical plasticity lends credence to the triadic amygdala-OFC-fusiform network thought to underlie threat processing. Importantly, long-term retention of conditioning in the basic sensory cortices supports the conserved role of the human sensory cortex in the long-term storage of aversive conditioning.SIGNIFICANCE STATEMENT A growing network of neural substrates has been identified in threat learning and memory. The sensory cortex plays a key role in long-term threat memory in animals, but such a function in humans remains unclear. To explore this problem, we conducted multidimensional assessments of immediate and delayed (15 d) effects of human aversive conditioning. Behavioral, physiological, and scalp electrophysiological data demonstrated conditioning effects and long-term retention. High-density EEG intracranial source analysis further revealed the cortical underpinnings, implicating high-order cortices immediately and primary and secondary visual cortices after the long delay. Therefore, while high-order cortices support aversive conditioning acquisition (i.e., threat learning), the human sensory cortex (akin to the animal homolog) underpins long-term storage of conditioning (i.e., long-term threat memory).

MEG Theta during Lexico-Semantic and Executive Processing Is Altered in High-Functioning Adolescents with Autism.

Neuroimaging studies have revealed atypical activation during language and executive tasks in individuals with autism spectrum disorders (ASD). However, the spatiotemporal stages of processing associated with these dysfunctions remain poorly understood. Using an anatomically constrained magnetoencephalography approach, we examined event-related theta oscillations during a double-duty lexical decision task that combined demands on lexico-semantic processing and executive functions. Relative to typically developing peers, high-functioning adolescents with ASD had lower performance accuracy on trials engaging selective semantic retrieval and cognitive control. They showed an early overall theta increase in the left fusiform cortex followed by greater activity in the left-lateralized temporal (starting at ~250 ms) and frontal cortical areas (after ~450 ms) known to contribute to language processing. During response preparation and execution, the ASD group exhibited elevated theta in the anterior cingulate cortex, indicative of greater engagement of cognitive control. Simultaneously increased activity in the ipsilateral motor cortex may reflect a less lateralized and suboptimally organized motor circuitry. Spanning early sensory-specific and late response selection stages, the higher event-related theta responsivity in ASD may indicate compensatory recruitment to offset inefficient lexico-semantic retrieval under cognitively demanding conditions. Together, these findings provide further support for atypical language and executive functions in high-functioning ASD.

Functional Connectome Analyses Reveal the Human Olfactory Network Organization.

The olfactory system is uniquely heterogeneous, performing multifaceted functions (beyond basic sensory processing) across diverse, widely distributed neural substrates. While knowledge of human olfaction continues to grow, it remains unclear how the olfactory network is organized to serve this unique set of functions. Leveraging a large and high-quality resting-state functional magnetic resonance imaging (rs-fMRI) dataset of nearly 900 participants from the Human Connectome Project (HCP), we identified a human olfactory network encompassing cortical and subcortical regions across the temporal and frontal lobes. Highlighting its reliability and generalizability, the connectivity matrix of this olfactory network mapped closely onto that extracted from an independent rs-fMRI dataset. Graph theoretical analysis further explicated the organizational principles of the network. The olfactory network exhibits a modular composition of three (i.e., the sensory, limbic, and frontal) subnetworks and demonstrates strong small-world properties, high in both global integration and local segregation (i.e., circuit specialization). This network organization thus ensures the segregation of local circuits, which are nonetheless integrated via connecting hubs [i.e., amygdala (AMY) and anterior insula (INSa)], thereby enabling the specialized, yet integrative, functions of olfaction. In particular, the degree of local segregation positively predicted olfactory discrimination performance in the independent sample, which we infer as a functional advantage of the network organization. In sum, an olfactory functional network has been identified through the large HCP dataset, affording a representative template of the human olfactory functional neuroanatomy. Importantly, the topological analysis of the olfactory network provides network-level insights into the remarkable functional specialization and spatial segregation of the olfactory system.

Human chemosignals of disgust facilitate food judgment.

Choosing food is not a trivial decision that people need to make daily, which is often subject to social influences. Here, we studied a human homolog of social transmission of food preference (STFP) as observed in rodents and other animals via chemosignals of body secretions. Human social chemosignals (sweat) produced during a disgust or neutral state among a group of donors were presented to participants undergoing a 2-alternative-forced-choice food healthiness judgment task during functional magnetic resonance imaging (fMRI). Response speed and two key signal detection indices-d' (discrimination sensitivity) and ß (response bias)-converged to indicate that social chemosignals of disgust facilitated food healthiness decisions, in contrast to primary disgust elicitors (disgust odors) that impaired the judgment. fMRI analyses (disgust vs. neutral sweat) revealed that the fusiform face area (FFA), amygdala, and orbitofrontal cortex (OFC) were engaged in processing social chemosignals of disgust during food judgment. Importantly, a double contrast of social signaling across modalities (olfactory vs. visual-facial expressions) indicated that the FFA and OFC exhibited preferential response to social chemosignals of disgust. Together, our findings provide initial evidence for human STFP, where social chemosignals are incorporated into food decisions by engaging social and emotional areas of the brain.

Parallel processing of general and specific threat during early stages of perception.

Differential processing of threat can consummate as early as 100 ms post-stimulus. Moreover, early perception not only differentiates threat from non-threat stimuli but also distinguishes among discrete threat subtypes (e.g. fear, disgust and anger). Combining spatial-frequency-filtered images of fear, disgust and neutral scenes with high-density event-related potentials and intracranial source estimation, we investigated the neural underpinnings of general and specific threat processing in early stages of perception. Conveyed in low spatial frequencies, fear and disgust images evoked convergent visual responses with similarly enhanced N1 potentials and dorsal visual (middle temporal gyrus) cortical activity (relative to neutral cues; peaking at 156 ms). Nevertheless, conveyed in high spatial frequencies, fear and disgust elicited divergent visual responses, with fear enhancing and disgust suppressing P1 potentials and ventral visual (occipital fusiform) cortical activity (peaking at 121 ms). Therefore, general and specific threat processing operates in parallel in early perception, with the ventral visual pathway engaged in specific processing of discrete threats and the dorsal visual pathway in general threat processing. Furthermore, selectively tuned to distinctive spatial-frequency channels and visual pathways, these parallel processes underpin dimensional and categorical threat characterization, promoting efficient threat response. These findings thus lend support to hybrid models of emotion.

Emotion impairs extrinsic source memory--An ERP study.

Substantial advancements in understanding emotional modulation of item memory notwithstanding, controversies remain as to how emotion influences source memory. Using an emotional extrinsic source memory paradigm combined with remember/know judgments and two key event-related potentials (ERPs)-the FN400 (a frontal potential at 300-500 ms related to familiarity) and the LPC (a later parietal potential at 500-700 ms related to recollection), our research investigated the impact of emotion on extrinsic source memory and the underlying processes. We varied a semantic prompt (either "people" or "scene") preceding a study item to manipulate the extrinsic source. Behavioral data indicated a significant effect of emotion on "remember" responses to extrinsic source details, suggesting impaired recollection-based source memory in emotional (both positive and negative) relative to neutral conditions. In parallel, differential FN400 and LPC amplitudes (correctly remembered - incorrectly remembered sources) revealed emotion-related interference, suggesting impaired familiarity and recollection memory of extrinsic sources associated with positive or negative items. These findings thus lend support to the notion of emotion-induced memory trade off: while enhancing memory of central items and intrinsic/integral source details, emotion nevertheless disrupts memory of peripheral contextual details, potentially impairing both familiarity and recollection. Importantly, that positive and negative items result in comparable memory impairment suggests that arousal (vs. affective valence) plays a critical role in modulating dynamic interactions among automatic and elaborate processes involved in memory.

Voxel-based analysis of postnatal white matter microstructure in mice exposed to immune challenge in early or late pregnancy.

Maternal infection during prenatal life is a risk factor for neurodevelopmental disorders, including schizophrenia and autism, in the offspring. We and others have reported white mater microstructure abnormalities in prefrontal-striato-temporal networks in these disorders. In addition we have shown that early rather than late maternal immune challenge in the mouse model precipitates ventricular volume change and impairs sensorimotor gating similar to that found in schizophrenia. However, it is not known whether the timing of maternal infection has a differential impact upon white matter microstructural indices. Therefore this study directly tested the effect of early or late gestation maternal immune activation on post-natal white matter microstructure in the mouse. The viral mimic PolyI:C was administered on day 9 or day 17 of gestation. In-vivo diffusion tensor imaging (DTI) was carried out when the offspring reached adulthood. We describe a novel application of voxel-based analysis to evaluate fractional anisotrophy (FA). In addition we conducted a preliminary immunohistochemical exploration of the oligodendrocyte marker, 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), to determine whether differences in myelination might contribute to any changes in FA observed. Our results provide experimental evidence that prenatal exposure to inflammation elicits widespread differences in FA throughout fronto-striatal-limbic circuits compared to control saline exposure. Moreover, FA changes were more extensive in the group exposed earliest in gestation.