Neural systems for cognitive reappraisal in children and adolescents with autism spectrum disorder.

Despite substantial clinical and anecdotal evidence for emotion dysregulation in individuals with autism spectrum disorder (ASD), little is known about the neural substrates underlying this phenomenon. We sought to explore neural mechanisms for cognitive reappraisal in children and adolescents with ASD using functional magnetic resonance imaging (fMRI). We studied 16 youth with ASD and 15 age- and IQ-matched typically developing (TD) comparison youth. Participants were instructed in the use of cognitive reappraisal strategies to increase and decrease their emotional responses to disgusting images. Participants in both groups displayed distinct patterns of brain activity for increasing versus decreasing their emotions. TD participants showed downregulation of bilateral insula and left amygdala on decrease trials, whereas ASD participants showed no modulation of insula and upregulation of left amygdala. Furthermore, TD youth exhibited increased functional connectivity between amygdala and ventrolateral prefrontal cortex compared to ASD participants when downregulating disgust, as well as decreased functional connectivity between amygdala and orbitofrontal cortex. These findings have important implications for our understanding of emotion dysregulation and its treatment in ASD. In particular, the relative lack of prefrontal-amygdala connectivity provides a potential target for treatment-related outcome measurements.

Impact of brain tissue filtering on neurostimulation fields: a modeling study.

Electrical neurostimulation techniques, such as deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS), are increasingly used in the neurosciences, e.g., for studying brain function, and for neurotherapeutics, e.g., for treating depression, epilepsy, and Parkinson's disease. The characterization of electrical properties of brain tissue has guided our fundamental understanding and application of these methods, from electrophysiologic theory to clinical dosing-metrics. Nonetheless, prior computational models have primarily relied on ex-vivo impedance measurements. We recorded the in-vivo impedances of brain tissues during neurosurgical procedures and used these results to construct MRI guided computational models of TMS and DBS neurostimulatory fields and conductance-based models of neurons exposed to stimulation. We demonstrated that tissues carry neurostimulation currents through frequency dependent resistive and capacitive properties not typically accounted for by past neurostimulation modeling work. We show that these fundamental brain tissue properties can have significant effects on the neurostimulatory-fields (capacitive and resistive current composition and spatial/temporal dynamics) and neural responses (stimulation threshold, ionic currents, and membrane dynamics). These findings highlight the importance of tissue impedance properties on neurostimulation and impact our understanding of the biological mechanisms and technological potential of neurostimulatory methods.

Development of neural systems for processing social exclusion from childhood to adolescence.

Adolescence is a period of development in which peer relationships become especially important. A computer-based game (Cyberball) has been used to explore the effects of social exclusion in adolescents and adults. The current functional magnetic resonance imaging (fMRI) study used Cyberball to extend prior work to the cross-sectional study of younger children and adolescents (7 to 17 years), identifying age-related changes in the neural correlates of social exclusion across the important transition from middle childhood into adolescence. Additionally, a control task illustrated the specificity of these age-related changes for social exclusion as distinct from expectancy violation more generally. During exclusion, activation in and functional connectivity between ventrolateral prefrontal cortex and ventral anterior cingulate cortex increased with age. These effects were specific to social exclusion and did not exist for expectancy violation. Our results illustrate developmental changes from middle childhood through adolescence in both affective and regulatory brain regions during social exclusion.

Enhanced neural responses to rule violation in children with autism: a comparison to social exclusion.

The present study aimed to explore the neural correlates of two characteristic deficits in autism spectrum disorders (ASD); social impairment and restricted, repetitive behavior patterns. To this end, we used comparable experiences of social exclusion and rule violation to probe potentially atypical neural networks in ASD. In children and adolescents with and without ASD, we used the interactive ball-toss game (Cyberball) to elicit social exclusion and a comparable game (Cybershape) to elicit a non-exclusive rule violation. Using functional magnetic resonance imaging (fMRI), we identified group differences in brain responses to social exclusion and rule violation. Though both groups reported equal distress following exclusion, the right insula and ventral anterior cingulate cortex were hypoactive during exclusion in children with ASD. In rule violation, right insula and dorsal prefrontal cortex were hyperactive in ASD. Right insula showed a dissociation in activation; it was hypoactive to social exclusion and hyperactive to rule violation in the ASD group. Further probed, different regions of right insula were modulated in each game, highlighting differences in regional specificity for which subsequent analyses revealed differences in patterns of functional connectivity. These results demonstrate neurobiological differences in processing social exclusion and rule violation in children with ASD.

How grossed out are you? The neural bases of emotion regulation from childhood to adolescence.

The ability to regulate one's emotions is critical to mental health and well-being, and is impaired in a wide range of psychopathologies, some of which initially manifest in childhood or adolescence. Cognitive reappraisal is a particular approach to emotion regulation frequently utilized in behavioral psychotherapies. Despite a wealth of research on cognitive reappraisal in adults, little is known about the developmental trajectory of brain mechanisms subserving this form of emotion regulation in children. In this functional magnetic resonance imaging study, we asked children and adolescents to up-and down-regulate their response to disgusting images, as the experience of disgust has been linked to anxiety disorders. We demonstrate distinct patterns of brain activation during successful up- and down-regulation of emotion, as well as an inverse correlation between activity in ventromedial prefrontal cortex (vmPFC) and limbic structures during down-regulation, suggestive of a potential regulatory role for vmPFC. Further, we show age-related effects on activity in PFC and amygdala. These findings have important clinical implications for the understanding of cognitive-based therapies in anxiety disorders in childhood and adolescence.

Brain mechanisms for processing direct and averted gaze in individuals with autism.

Prior studies have indicated brain abnormalities underlying social processing in autism, but no fMRI study has specifically addressed the differential processing of direct and averted gaze, a critical social cue. Fifteen adolescents and adults with autism and 14 typically developing comparison participants viewed dynamic virtual-reality videos depicting a simple but realistic social scenario, in which an approaching male figure maintained either direct or averted gaze. Significant group by condition interactions reflecting differential responses to direct versus averted gaze in people with autism relative to typically developing individuals were identified in the right temporoparietal junction, right anterior insula, left lateral occipital cortex, and left dorsolateral prefrontal cortex. Our results provide initial evidence regarding brain mechanisms underlying the processing of gaze direction during simple social encounters, providing new insight into the social deficits in individuals with autism.

Dissociable brain mechanisms for processing social exclusion and rule violation.

Social exclusion inherently involves an element of expectancy violation, in that we expect other people to follow the unwritten rule to include us in social interactions. In this functional magnetic resonance imaging (fMRI) study, we employed a unique modification of an interactive virtual ball-tossing game called "Cyberball" (Williams et al., 2000) and a novel paradigm called "Cybershape," in which rules are broken in the absence of social exclusion, to dissociate brain regions that process social exclusion from rule violations more generally. Our Cyberball game employed an alternating block design and removed evoked responses to events when the participant was throwing the ball in inclusion to make this condition comparable to exclusion, where participants did not throw. With these modifications, we replicated prior findings of ventral anterior cingulate cortex (vACC), insula, and posterior cingulate cortex activity evoked by social exclusion relative to inclusion. We also identified exclusion-evoked activity in the hippocampi, left ventrolateral prefrontal cortex, and left middle temporal gyrus. Comparing social exclusion and rule violation revealed a functional dissociation in the active neural systems as well as differential functional connectivity with vACC. Some overlap was observed in regions differentially modulated by social exclusion and rule violation, including the vACC and lateral parietal cortex. These overlapping brain regions showed different activation during social exclusion compared to rule violation, each relative to fair play. Comparing activation patterns to social exclusion and rule violation allowed for the dissociation of brain regions involved in the experience of exclusion versus expectancy violation.

Three systems of insular functional connectivity identified with cluster analysis.

Despite much research on the function of the insular cortex, few studies have investigated functional subdivisions of the insula in humans. The present study used resting-state functional connectivity magnetic resonance imaging (MRI) to parcellate the human insular lobe based on clustering of functional connectivity patterns. Connectivity maps were computed for each voxel in the insula based on resting-state functional MRI (fMRI) data and segregated using cluster analysis. We identified 3 insular subregions with distinct patterns of connectivity: a posterior region, functionally connected with primary and secondary somatomotor cortices; a dorsal anterior to middle region, connected with dorsal anterior cingulate cortex, along with other regions of a previously described control network; and a ventral anterior region, primarily connected with pregenual anterior cingulate cortex. Applying these regions to a separate task data set, we found that dorsal and ventral anterior insula responded selectively to disgusting images, while posterior insula did not. These results demonstrate that clustering of connectivity patterns can be used to subdivide cerebral cortex into anatomically and functionally meaningful subregions; the insular regions identified here should be useful in future investigations on the function of the insula.

Neural signatures of autism.

Functional magnetic resonance imaging of brain responses to biological motion in children with autism spectrum disorder (ASD), unaffected siblings (US) of children with ASD, and typically developing (TD) children has revealed three types of neural signatures: (i) state activity, related to the state of having ASD that characterizes the nature of disruption in brain circuitry; (ii) trait activity, reflecting shared areas of dysfunction in US and children with ASD, thereby providing a promising neuroendophenotype to facilitate efforts to bridge genomic complexity and disorder heterogeneity; and (iii) compensatory activity, unique to US, suggesting a neural system-level mechanism by which US might compensate for an increased genetic risk for developing ASD. The distinct brain responses to biological motion exhibited by TD children and US are striking given the identical behavioral profile of these two groups. These findings offer far-reaching implications for our understanding of the neural systems underlying autism.

Rapid and reversible recruitment of early visual cortex for touch.

BACKGROUND: The loss of vision has been associated with enhanced performance in non-visual tasks such as tactile discrimination and sound localization. Current evidence suggests that these functional gains are linked to the recruitment of the occipital visual cortex for non-visual processing, but the neurophysiological mechanisms underlying these crossmodal changes remain uncertain. One possible explanation is that visual deprivation is associated with an unmasking of non-visual input into visual cortex. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the effect of sudden, complete and prolonged visual deprivation (five days) in normally sighted adult individuals while they were immersed in an intensive tactile training program. Following the five-day period, blindfolded subjects performed better on a Braille character discrimination task. In the blindfold group, serial fMRI scans revealed an increase in BOLD signal within the occipital cortex in response to tactile stimulation after five days of complete visual deprivation. This increase in signal was no longer present 24 hours after blindfold removal. Finally, reversible disruption of occipital cortex function on the fifth day (by repetitive transcranial magnetic stimulation; rTMS) impaired Braille character recognition ability in the blindfold group but not in non-blindfolded controls. This disruptive effect was no longer evident once the blindfold had been removed for 24 hours. CONCLUSIONS/SIGNIFICANCE: Overall, our findings suggest that sudden and complete visual deprivation in normally sighted individuals can lead to profound, but rapidly reversible, neuroplastic changes by which the occipital cortex becomes engaged in processing of non-visual information. The speed and dynamic nature of the observed changes suggests that normally inhibited or masked functions in the sighted are revealed by visual loss. The unmasking of pre-existing connections and shifts in connectivity represent rapid, early plastic changes, which presumably can lead, if sustained and reinforced, to slower developing, but more permanent structural changes, such as the establishment of new neural connections in the blind.

Time-dependent changes in cortical excitability after prolonged visual deprivation.

Transcranial magnetic stimulation applied to the occipital cortex can elicit phosphenes. Changes in the phosphene threshold provide a measure of visual cortex excitability. Phosphene threshold was measured in participants blindfolded for five consecutive days to assess the effects of prolonged visual deprivation on visual cortical excitability. After 48 h of blindfolding, an acute decrease in phosphene threshold was observed, followed by a significant increase by day 5. Phosphene threshold returned to preblindfold levels within 2 h of light re-exposure. Thus, light deprivation is characterized by a transient increase in visual cortical excitability, followed by a sustained decrease in visual cortex excitability that quickly returns to baseline levels after re-exposure to light.