Overt social interaction and resting state in young adult males with autism: core and contextual neural features.

Conversation is an important and ubiquitous social behaviour. Individuals with autism spectrum disorder (autism) without intellectual disability often have normal structural language abilities but deficits in social aspects of communication like pragmatics, prosody, and eye contact. Previous studies of resting state activity suggest that intrinsic connections among neural circuits involved with social processing are disrupted in autism, but to date no neuroimaging study has examined neural activity during the most commonplace yet challenging social task: spontaneous conversation. Here we used functional MRI to scan autistic males (n = 19) without intellectual disability and age- and IQ-matched typically developing control subjects (n = 20) while they engaged in a total of 193 face-to-face interactions. Participants completed two kinds of tasks: conversation, which had high social demand, and repetition, which had low social demand. Autistic individuals showed abnormally increased task-driven interregional temporal correlation relative to controls, especially among social processing regions and during high social demand. Furthermore, these increased correlations were associated with parent ratings of participants' social impairments. These results were then compared with previously-acquired resting state data (56 autism, 62 control subjects). While some interregional correlation levels varied by task or rest context, others were strikingly similar across both task and rest, namely increased correlation among the thalamus, dorsal and ventral striatum, somatomotor, temporal and prefrontal cortex in the autistic individuals, relative to the control groups. These results suggest a basic distinction. Autistic cortico-cortical interactions vary by context, tending to increase relative to controls during task and decrease during test. In contrast, striato- and thalamocortical relationships with socially engaged brain regions are increased in both task and rest, and may be core to the condition of autism.

Rhythmic alternating patterns of brain activity distinguish rapid eye movement sleep from other states of consciousness.

Rapid eye movement (REM) sleep constitutes a distinct "third state" of consciousness, during which levels of brain activity are commensurate with wakefulness, but conscious awareness is radically transformed. To characterize the temporal and spatial features of this paradoxical state, we examined functional interactions between brain regions using fMRI resting-state connectivity methods. Supporting the view that the functional integrity of the default mode network (DMN) reflects "level of consciousness," we observed functional uncoupling of the DMN during deep sleep and recoupling during REM sleep (similar to wakefulness). However, unlike either deep sleep or wakefulness, REM was characterized by a more widespread, temporally dynamic interaction between two major brain systems: unimodal sensorimotor areas and the higher-order association cortices (including the DMN), which normally regulate their activity. During REM, these two systems become anticorrelated and fluctuate rhythmically, in reciprocally alternating multisecond epochs with a frequency ranging from 0.1 to 0.01 Hz. This unique spatiotemporal pattern suggests a model for REM sleep that may be consistent with its role in dream formation and memory consolidation.

Personal experience with narrated events modulates functional connectivity within visual and motor systems during story comprehension.

Past experience of everyday life activities, which forms the basis of our knowledge about the world, greatly affects how we understand stories. Yet, little is known about how this influence is instantiated in the human brain. Here, we used functional magnetic resonance imaging to investigate how past experience facilitates functional connectivity during the comprehension of stories rich in perceptual and motor details. We found that comprehenders' past experience with the scenes and actions described in the narratives selectively modulated functional connectivity between lower- and higher-level areas within the neural systems for visual and motor processing, respectively. These intramodal interactions may play an important role in integrating personal knowledge about a narrated situation with an evolving discourse representation. This study provides empirical evidence consistent with the idea that regions related to visual and motor processing are involved in the reenactment of experience as proposed by theories of embodied cognition.

Brain activity and connectivity during poetry composition: Toward a multidimensional model of the creative process.

Creativity, a multifaceted construct, can be studied in various ways, for example, investigating phases of the creative process, quality of the creative product, or the impact of expertise. Previous neuroimaging studies have assessed these individually. Believing that each of these interacting features must be examined simultaneously to develop a comprehensive understanding of creative behavior, we examined poetry composition, assessing process, product, and expertise in a single experiment. Distinct activation patterns were associated with generation and revision, two major phases of the creative process. Medial prefrontal cortex (MPFC) was active during both phases, yet responses in dorsolateral prefrontal and parietal executive systems (DLPFC/IPS) were phase-dependent, indicating that while motivation remains unchanged, cognitive control is attenuated during generation and re-engaged during revision. Experts showed significantly stronger deactivation of DLPFC/IPS during generation, suggesting that they may more effectively suspend cognitive control. Importantly however, similar overall patterns were observed in both groups, indicating the same cognitive resources are available to experts and novices alike. Quality of poetry, assessed by an independent panel, was associated with divergent connectivity patterns in experts and novices, centered upon MPFC (for technical facility) and DLPFC/IPS (for innovation), suggesting a mechanism by which experts produce higher quality poetry. Crucially, each of these three key features can be understood in the context of a single neurocognitive model characterized by dynamic interactions between medial prefrontal areas regulating motivation, dorsolateral prefrontal, and parietal areas regulating cognitive control and the association of these regions with language, sensorimotor, limbic, and subcortical areas distributed throughout the brain.

Embodied comprehension of stories: interactions between language regions and modality-specific neural systems.

The embodied view of language processing proposes that comprehension involves multimodal simulations, a process that retrieves a comprehender's perceptual, motor, and affective knowledge through reactivation of the neural systems responsible for perception, action, and emotion. Although evidence in support of this idea is growing, the contemporary neuroanatomical model of language suggests that comprehension largely emerges as a result of interactions between frontotemporal language areas in the left hemisphere. If modality-specific neural systems are involved in comprehension, they are not likely to operate in isolation but should interact with the brain regions critical to language processing. However, little is known about the ways in which language and modality-specific neural systems interact. To investigate this issue, we conducted a functional MRI study in which participants listened to stories that contained visually vivid, action-based, and emotionally charged content. Activity of neural systems associated with visual-spatial, motor, and affective processing were selectively modulated by the relevant story content. Importantly, when functional connectivity patterns associated with the left inferior frontal gyrus (LIFG), the left posterior middle temporal gyrus (pMTG), and the bilateral anterior temporal lobes (aTL) were compared, both LIFG and pMTG, but not the aTL, showed enhanced connectivity with the three modality-specific systems relevant to the story content. Taken together, our results suggest that language regions are engaged in perceptual, motor, and affective simulations of the described situation, which manifest through their interactions with modality-specific systems. On the basis of our results and past research, we propose that the LIFG and pMTG play unique roles in multimodal simulations during story comprehension.

Denoising the speaking brain: toward a robust technique for correcting artifact-contaminated fMRI data under severe motion.

A comprehensive set of methods based on spatial independent component analysis (sICA) is presented as a robust technique for artifact removal, applicable to a broad range of functional magnetic resonance imaging (fMRI) experiments that have been plagued by motion-related artifacts. Although the applications of sICA for fMRI denoising have been studied previously, three fundamental elements of this approach have not been established as follows: 1) a mechanistically-based ground truth for component classification; 2) a general framework for evaluating the performance and generalizability of automated classifiers; and 3) a reliable method for validating the effectiveness of denoising. Here we perform a thorough investigation of these issues and demonstrate the power of our technique by resolving the problem of severe imaging artifacts associated with continuous overt speech production. As a key methodological feature, a dual-mask sICA method is proposed to isolate a variety of imaging artifacts by directly revealing their extracerebral spatial origins. It also plays an important role for understanding the mechanistic properties of noise components in conjunction with temporal measures of physical or physiological motion. The potentials of a spatially-based machine learning classifier and the general criteria for feature selection have both been examined, in order to maximize the performance and generalizability of automated component classification. The effectiveness of denoising is quantitatively validated by comparing the activation maps of fMRI with those of positron emission tomography acquired under the same task conditions. The general applicability of this technique is further demonstrated by the successful reduction of distance-dependent effect of head motion on resting-state functional connectivity.

P600-like positivity and Left Anterior Negativity responses are elicited by semantic reversibility in nonanomalous sentences.

ERPs are commonly elicited by semantic and syntactic violations in sentences, leading to proposals that they reflect neural activity underlying ordinary language comprehension. We examined ERPs in an auditory sentence-picture-matching task, using nonanomalous sentences that were either semantically reversible, (boy pushes girl) or irreversible, (boy eats apple). Timelocked to the end of the critical clause, which occurred in the middle of a longer sentence, we observed an enhanced central-posterior positivity in response to the reversible sentences. The topography of this response is consistent with the P600 potential reported in studies of syntactic anomalies and other manipulations related to sentence structure. Following the end of the sentence, during a memory delay period prior to picture onset, reversible sentences also evoked a protracted anterior negativity, predominantly on the left. This negativity was stronger for sentences containing relative clauses compared to simple active sentences, but did not differ between object-embedded and the less complex subject-embedded clauses. The observation of a P600 occurring selectively in reversible sentences supports the interpretation of that potential as reflecting the syntactic processing of thematic relationships, as irreversible sentences contained alternative cues for thematic roles. The left anterior negativity likely reflects later processes of rehearsal and reanalysis of sentence content in working memory.

Symbolic gestures and spoken language are processed by a common neural system.

Symbolic gestures, such as pantomimes that signify actions (e.g., threading a needle) or emblems that facilitate social transactions (e.g., finger to lips indicating "be quiet"), play an important role in human communication. They are autonomous, can fully take the place of words, and function as complete utterances in their own right. The relationship between these gestures and spoken language remains unclear. We used functional MRI to investigate whether these two forms of communication are processed by the same system in the human brain. Responses to symbolic gestures, to their spoken glosses (expressing the gestures' meaning in English), and to visually and acoustically matched control stimuli were compared in a randomized block design. General Linear Models (GLM) contrasts identified shared and unique activations and functional connectivity analyses delineated regional interactions associated with each condition. Results support a model in which bilateral modality-specific areas in superior and inferior temporal cortices extract salient features from vocal-auditory and gestural-visual stimuli respectively. However, both classes of stimuli activate a common, left-lateralized network of inferior frontal and posterior temporal regions in which symbolic gestures and spoken words may be mapped onto common, corresponding conceptual representations. We suggest that these anterior and posterior perisylvian areas, identified since the mid-19th century as the core of the brain's language system, are not in fact committed to language processing, but may function as a modality-independent semiotic system that plays a broader role in human communication, linking meaning with symbols whether these are words, gestures, images, sounds, or objects.

Decoupling of the brain's default mode network during deep sleep.

The recent discovery of a circuit of brain regions that is highly active in the absence of overt behavior has led to a quest for revealing the possible function of this so-called default-mode network (DMN). A very recent study, finding similarities in awake humans and anesthetized primates, has suggested that DMN activity might not simply reflect ongoing conscious mentation but rather a more general form of network dynamics typical of complex systems. Here, by performing functional MRI in humans, it is shown that a natural, sleep-induced reduction of consciousness is reflected in altered correlation between DMN network components, most notably a reduced involvement of frontal cortex. This suggests that DMN may play an important role in the sustenance of conscious awareness.

Neural aspects of sentence comprehension: syntactic complexity, reversibility, and reanalysis.

Broca's area is preferentially activated by reversible sentences with complex syntax, but various linguistic factors may be responsible for this finding, including syntactic movement, working-memory demands, and post hoc reanalysis. To distinguish between these, we tested the interaction of syntactic complexity and semantic reversibility in a functional magnetic resonance imaging study of sentence-picture matching. During auditory comprehension, semantic reversibility induced selective activation throughout the left perisylvian language network. In contrast, syntactic complexity (object-embedded vs. subject-embedded relative clauses) within reversible sentences engaged only the left inferior frontal gyrus (LIFG) and left precentral gyrus. Within irreversible sentences, only the LIFG was sensitive to syntactic complexity, confirming a unique role for this region in syntactic processing. Nonetheless, larger effects of reversibility itself occurred in the same regions, suggesting that full syntactic parsing may be a nonautomatic process applied as needed. Complex reversible sentences also induced enhanced signals in LIFG and left precentral regions on subsequent picture selection, but with additional recruitment of the right hemisphere homolog area (right inferior frontal gyrus) as well, suggesting that post hoc reanalysis of sentence structure, compared with initial comprehension, engages an overlapping but larger network of brain regions. These dissociable effects may offer a basis for studying the reorganization of receptive language function after brain damage.

Single-trial fMRI shows contralesional activity linked to overt naming errors in chronic aphasic patients.

We used fMRI to investigate the roles played by perilesional and contralesional cortical regions during language production in stroke patients with chronic aphasia. We applied comprehensive psycholinguistic analyses based on well-established models of lexical access to overt picture-naming responses, which were evaluated using a single trial design that permitted distinction between correct and incorrect responses on a trial-by-trial basis. Although both correct and incorrect naming responses were associated with left-sided perilesional activation, incorrect responses were selectively associated with robust right-sided contralesional activity. Most notably, incorrect responses elicited overactivation in the right inferior frontal gyrus that was not observed in the contrasts for patients' correct responses or for responses of age-matched control subjects. Errors were produced at slightly later onsets than accurate responses and comprised predominantly semantic paraphasias and omissions. Both types of errors were induced by pictures with greater numbers of alternative names, and omissions were also induced by pictures with late acquired names. These two factors, number of alternative names per picture and age of acquisition, were positively correlated with activation in left and right inferior frontal gyri in patients as well as control subjects. These results support the hypothesis that some right frontal activation may normally be associated with increasing naming difficulty, but in patients with aphasia, right frontal overactivation may reflect ineffective effort when left hemisphere perilesional resources are insufficient. They also suggest that contralesional areas continue to play a role--dysfunctional rather than compensatory--in chronic aphasic patients who have experienced a significant degree of recovery.

Species-specific calls activate homologs of Broca's and Wernicke's areas in the macaque.

The origin of brain mechanisms that support human language-whether these originated de novo in humans or evolved from a neural substrate that existed in a common ancestor-remains a controversial issue. Although the answer is not provided by the fossil record, it is possible to make inferences by studying living species of nonhuman primates. Here we identified neural systems associated with perceiving species-specific vocalizations in rhesus macaques using H(2)(15)O positron emission tomography (PET). These vocalizations evoke distinct patterns of brain activity in homologs of the human perisylvian language areas. Rather than resulting from differences in elementary acoustic properties, this activity seems to reflect higher order auditory processing. Although parallel evolution within independent primate species is feasible, this finding suggests the possibility that the last common ancestor of macaques and humans, which lived 25-30 million years ago, possessed key neural mechanisms that were plausible candidates for exaptation during the evolution of language.

Strategies for longitudinal neuroimaging studies of overt language production.

Longitudinal fMRI studies of language production are of interest for evaluating recovery from post-stroke aphasia, but numerous methodological issues remain unresolved, particularly regarding strategies for evaluating single subjects at multiple timepoints. To address these issues, we studied overt picture naming in eleven healthy subjects, scanned four times each at one-month intervals. To evaluate the natural variability present across repeated sessions, repeated scans were directly contrasted in a unified statistical framework on a per-voxel basis. The effect of stimulus familiarity was evaluated using explicitly overtrained pictures, novel pictures, and untrained pictures that were repeated across sessions. For untrained pictures, we found that activation declined across multiple sessions, equally for both novel and repeated stimuli. Thus, no repetition priming for individual stimuli at one-month intervals was found, but rather a general effect of task habituation was present. Using a set of overtrained pictures identical in each session, no decline was found, but activation was minimized and produced less consistent patterns across participants, as measured by intra-class correlation coefficients. Subtraction of a baseline task, in which subjects produced a stereotyped utterance to scrambled pictures, resulted in specific activations in the left inferior frontal gyrus and other language areas for untrained items, while overlearned stimuli relative to pseudo pictures activated only the fusiform gyrus and supplementary motor area. These findings indicate that longitudinal fMRI is an effective means of detecting changes in neural activation magnitude over time, as long as the effect of task habituation is taken into account.

Positron emission tomography correlates of visually-scored electroencephalographic waveforms during non-Rapid Eye Movement sleep.

Visually-scored, non-Rapid Eye Movement (REM) sleep electroencephalographic (EEG) waveform activity for each 30-s sleep scored epoch-including the number of sleep spindles, the number of K-complexes, and the percentage of delta waves occupying the epoch-was correlated with H(2)(15)O positron emission tomography. Sleep spindle correlations included positive correlations in the thalamus and right hippocampus. K-complex correlations included positive correlations in the frontomedian prefrontal cortex and cerebellum. Delta wave correlations included negative correlations in the thalamus, frontomedian prefrontal cortex, dorsal pons, and primary visual cortex. Each pattern of correlations may suggest a functional significance for these waveforms that relates to a waking outcome.

Fronto-parietal mirror neuron system modeling: Visuospatial transformations support imitation learning independently of imitator perspective.

Although the human mirror neuron system (MNS) is critical for action observation and imitation, most MNS investigations overlook the visuospatial transformation processes that allow individuals to interpret and imitate actions observed from differing perspectives. This problem is not trivial since accurately reaching for and grasping an object requires a visuospatial transformation mechanism capable of precisely remapping fine motor skills where the observer's and imitator's arms and hands may have quite different orientations and sizes. Accordingly, here we describe a novel neural model to investigate the dynamics between the fronto-parietal MNS and visuospatial processes during observation and imitation of a reaching and grasping action. Our model encompasses i) the inferior frontal gyrus (IFG) and inferior parietal lobule (IPL), regions that are postulated to produce neural drive and sensory predictions, respectively; ii) the middle temporal (MT) and middle superior temporal (MST) regions that are postulated to process visual motion of a particular action; and iii) the superior parietal lobule (SPL) and intra-parietal sulcus (IPS) that are hypothesized to encode the visuospatial transformations enabling action observation/imitation based on different visuospatial viewpoints. The results reveal that when a demonstrator executes an action, an imitator can reproduce it with similar kinematics, independently of differences in anthropometry, distance, and viewpoint. As with prior empirical findings, similar model synaptic activity was observed during both action observation and execution along with the existence of both view-independent and view-dependent neural populations in the frontal MNS. Importantly, this work generates testable behavioral and neurophysiological predictions. Namely, the model predicts that i) during observation/imitation the response time increases linearly as the rotation angle of the observed action increases but remain similar when performing both clockwise and counterclockwise rotation and ii) IPL embeds essentially view-independent neurons while SPL/IPS includes both view-independent and view-dependent neurons. Overall, this work suggests that MT/MST visuomotion processes combined with the SPL/IPS allow the MNS to observe and imitate actions independently of demonstrator-imitator spatial relationships.

fMRI differences between early and late stage-1 sleep.

This study sought to test for differences in regional brain activity between stage-1 sleep immediately following wake and immediately preceding stage-2 sleep. Data were collected during daytime fMRI sessions with simultaneous EEG acquisition. A stage-1 interval was defined as follows: > or =30s of wake, immediately followed by > or =60s of continuous stage 1, immediately followed by > or =30s of stage 2. We compared brain activity between the first 30s of stage 1 (early stage 1), the last 30s of stage 1 (late stage 1), and isolated wake. A conjunction analysis sorted each voxel into one of a series of mutually exclusive categories that represented the various possible combinations of a significant increase, decrease, or no difference among these three states. The initial dataset consisted of 14 healthy volunteers. A total of 22 sessions in these participants yielded six stage-1 intervals (from four participants) that met criteria for inclusion in the analysis. There were multiple clusters of significant voxels. Examples include changes in default-mode network areas where activity increased compared to wake only in early stage 1 and a bilateral change in the hippocampus where activity increased compared to wake only in late stage 1. These results suggest that activity in anatomically identifiable, volumetric brain regions exhibit differences during stage-1 sleep that would not have been detected with the EEG. These differences may also have specific relevance to understanding the process of sleep onset as well as the neural mechanisms of performance lapses during sleep deprivation.

Neural mechanisms of auditory discrimination of long-duration tonal patterns: a neural modeling and fMRI study.

Language perception comprises mechanisms of perception and discrimination of auditory stimuli. An important component of auditory perception and discrimination concerns auditory objects. Many interesting auditory objects in our environment are of relatively long duration; however, the temporal window of integration of auditory cortex neurons processing these objects is very limited. Thus, it is necessary to make active use of short-term memory in order to construct and temporarily store long-duration objects. We sought to understand the mechanisms by which the brain manipulates long-duration tonal patterns, temporarily stores the segments of those patterns, and integrates them into an auditory object. We extended a previously constructed model of auditory recognition of short-duration tonal patterns by expanding the prefrontal cortically-based short-term memory module of the previous model into a memory buffer with multiple short-term memory submodules and by adding a gating module. The gating module distributes the segments of the input pattern to separate locations of the extended prefrontal cortex in an orderly fashion, allowing a subsequent comparison of the stored segments against the segments of a second pattern. In addition to simulating behavioral data and electrical activity of neurons, our model also produces simulations of the blood oxygen level dependent (BOLD) signal as obtained in fMRI studies. The results of these simulations provided us with predictions that we tested in an fMRI experiment with normal volunteers. This fMRI experiment used the same task and similar stimuli to that of the model. We compared simulated data with experimental values. We found that two brain areas, the right precentral gyrus and the left medial frontal gyrus, correlated well with our simulations of the memory gating module. Other fMRI studies of auditory perception and discrimination have also found correlation of fMRI activation of those areas with similar tasks and thus provide further support to our findings.

Left hemispheric lateralization of brain activity during passive rhythm perception in musicians.

The nature of hemispheric specialization of brain activity during rhythm processing remains poorly understood. The locus for rhythmic processing has been difficult to identify and there have been several contradictory findings. We therefore used functional magnetic resonance imaging to study passive rhythm perception to investigate the hypotheses that rhythm processing results in left hemispheric lateralization of brain activity and is affected by musical training. Twelve musicians and 12 nonmusicians listened to regular and random rhythmic patterns. Conjunction analysis revealed a shared network of neural structures (bilateral superior temporal areas, left inferior parietal lobule, and right frontal operculum) responsible for rhythm perception independent of musical background. In contrast, random-effects analysis showed greater left lateralization of brain activity in musicians compared to nonmusicians during regular rhythm perception, particularly within the perisylvian cortices (left frontal operculum, superior temporal gyrus, inferior parietal lobule). These results suggest that musical training leads to the employment of left-sided perisylvian brain areas, typically active during language comprehension, during passive rhythm perception.

Alterations in CNS activity induced by botulinum toxin treatment in spasmodic dysphonia: an H215O PET study.

Speech-related changes in regional cerebral blood flow (rCBF) were measured using H(2)(15)O positron-emission tomography in 9 adults with adductor spasmodic dysphonia (ADSD) before and after botulinum toxin (BTX) injection and 10 age- and gender-matched volunteers without neurological disorders. Scans were acquired at rest and during production of continuous narrative speech and whispered speech. Speech was recorded during scan acquisition for offline quantification of voice breaks, pitch breaks, and percentage aperiodicity to assess correlations between treatment-related changes in rCBF and clinical improvement. Results demonstrated that speech-related responses in heteromodal sensory areas were significantly reduced in persons with ADSD, compared with volunteers, before the administration of BTX. Three to 4 weeks after BTX injection, speech-related responses were significantly augmented in these regions and in left hemisphere motor areas commonly associated with oral-laryngeal motor control. This pattern of responses was most strongly correlated with the objective measures of clinical improvement (decreases in the frequency of voice breaks, pitch breaks, and percentage aperiodicity). These data suggest a pathophysiological model for ADSD in which BTX treatment results in more efficient cortical processing of sensory information, making this information available to motor areas that use it to more effectively regulate laryngeal movements.

Planum parietale of chimpanzees and orangutans: a comparative resonance of human-like planum temporale asymmetry.

We have previously demonstrated that leftward asymmetry of the planum temporale (PT), a brain language area, was not unique to humans since a similar condition is present in great apes. Here we report on a related area in great apes, the planum parietale (PP). PP in humans has a rightward asymmetry with no correlation to the L>R PT, which indicates functional independence. The roles of the PT in human language are well known while PP is implicated in dyslexia and communication disorders. Since posterior bifurcation of the sylvian fissure (SF) is unique to humans and great apes, we used it to determine characteristics of its posterior ascending ramus, an indicator of the PP, in chimpanzee and orangutan brains. Results showed a human-like pattern of R>L PP (P = 0.04) in chimpanzees with a nonsignificant negative correlation of L>R PT vs. R>L PP (CC = -0.3; P = 0.39). In orangutans, SF anatomy is more variable, although PP was nonsignificantly R>L in three of four brains (P = 0.17). We have now demonstrated human-like hemispheric asymmetry of a second language-related brain area in great apes. Our findings persuasively support an argument for addition of a new component to the comparative neuroanatomic complex that defines brain language or polymodal communication areas. PP strengthens the evolutionary links that living great apes may offer to better understand the origins of these progressive parts of the brain. Evidence mounts for the stable expression of a neural foundation for language in species that we recently shared a common ancestor with.