The effect of misophonia on cognitive and social judgments.

Misophonia, a heightened aversion to certain sounds, turns common cognitive and social exercises (e.g., paying attention during a lecture near a pen-clicking classmate, coexisting at the dinner table with a food-chomping relative) into challenging endeavors. How does exposure to triggering sounds impact cognitive and social judgments? We investigated this question in a sample of 65 participants (26 misophonia, 39 control) from the general population. In Phase 1, participants saw faces paired with auditory stimuli while completing a gender judgment task, then reported sound discomfort and identification. In Phase 2, participants saw these same faces with novel ones and reported face likeability and memory. For both oral and non-oral triggers, misophonic participants gave higher discomfort ratings than controls did-especially when identification was correct-and performed slower on the gender judgment. Misophonic participants rated lower likeability than controls did for faces they remembered with high discomfort sounds, and face memory was worse overall for faces originally paired with high discomfort sounds. Altogether, these results suggest that misophonic individuals show impairments on social and cognitive judgments if they must endure discomforting sounds. This experiment helps us better understand the day-to-day impact of misophonia and encourages usage of individualized triggers in future studies.

Predicting high-level visual areas in the absence of task fMRI.

The ventral visual stream is organized into units, or functional regions of interest (fROIs), specialized for processing high-level visual categories. Task-based fMRI scans ("localizers") are typically used to identify each individual's nuanced set of fROIs. The unique landscape of an individual's functional activation may rely in large part on their specialized connectivity patterns; recent studies corroborate this by showing that connectivity can predict individual differences in neural responses. We focus on the ventral visual stream and ask: how well can an individual's resting state functional connectivity localize their fROIs for face, body, scene, and object perception? And are the neural processors for any particular visual category better predicted by connectivity than others, suggesting a tighter mechanistic relationship between connectivity and function? We found, among 18 fROIs predicted from connectivity for each subject, all but one were selective for their preferred visual category. Defining an individual's fROIs based on their connectivity patterns yielded regions that were more selective than regions identified from previous studies or atlases in nearly all cases. Overall, we found that in the absence of a domain-specific localizer task, a 10-min resting state scan can be reliably used for defining these fROIs.

Effect of Extremely Preterm Birth on Adolescent Brain Network Organization.

Introduction: Extremely preterm (EPT) birth, defined as birth at a gestational age (GA) <28 weeks, can have a lasting impact on cognition throughout the life span. Previous investigations reveal differences in brain structure and connectivity between infants born preterm and full-term (FT), but how does preterm birth impact the adolescent connectome? Methods: In this study, we investigate how EPT birth can alter broadscale network organization later in life by comparing resting-state functional magnetic resonance imaging connectome-based parcellations of the entire cortex in adolescents born EPT (N = 22) to age-matched adolescents born FT (GA ≥37 weeks, N = 28). We compare these parcellations to adult parcellations from previous studies and explore the relationship between an individual's network organization and behavior. Results: Primary (occipital and sensorimotor) and frontoparietal networks were observed in both groups. However, there existed notable differences in the limbic and insular networks. Surprisingly, the connectivity profile of the limbic network of EPT adolescents was more adultlike than the same network in FT adolescents. Finally, we found a relationship between adolescents' overall cognition score and their limbic network maturity. Discussion: Overall, preterm birth may contribute to the atypical development of broadscale network organization in adolescence and may partially explain the observed cognitive deficits.

Individual Variability in Performance Reflects Selectivity of the Multiple Demand Network among Children and Adults.

Executive function (EF) is essential for humans to effectively engage in cognitively demanding tasks. In adults, EF is subserved by frontoparietal regions in the multiple demand (MD) network, which respond to various cognitively demanding tasks. However, children initially show poor EF and prolonged development. Do children recruit the same network as adults? Is it functionally and connectionally distinct from adjacent language cortex, as in adults? And is this activation or connectivity dependent on age or ability? We examine task-dependent (spatial working memory and passive language tasks) and resting state functional data in 44 adults (18-38 years, 68% female) and 37 children (4-12 years, 35% female). Subject-specific functional ROIs (ss-fROIs) show bilateral MD network activation in children. In both children and adults, these MD ss-fROIs are not recruited for linguistic processing and are connectionally distinct from language ss-fROIs. While MD activation was lower in children than in adults (even in motion- and performance-matched groups), both showed increasing MD activation with better performance, especially in right hemisphere ss-fROIs. We observe this relationship even when controlling for age, cross-sectionally and in a small longitudinal sample of children. These data suggest that the MD network is selective to cognitive demand in children, is distinct from adjacent language cortex, and increases in selectivity as performance improves. These findings show that neural structures subserving domain-general EF emerge early and are sensitive to ability even in children. This research advances understanding of how high-level human cognition emerges and could inform interventions targeting cognitive control.SIGNIFICANCE STATEMENT This study provides evidence that young children already show differentiated brain network organization between regions that process cognitive demand and language. These data support the hypothesis that children recruit a similar network as adults to process cognitive demand; and despite immature characteristics, children's selectivity looks more adult-like as their executive function ability increases. Mapping early stages of network organization furthers our understanding of the functional architecture underlying domain-general executive function. Determining typical variability underlying cognitive processing across developmental periods helps establish a threshold for executive dysfunction. Early markers of dysfunction are necessary for effective early identification, prevention, and intervention efforts for individuals struggling with deficits in processing cognitive demand.

Neural evidence for non-orofacial triggers in mild misophonia.

Misophonia, an extreme aversion to certain environmental sounds, is a highly prevalent yet understudied condition plaguing roughly 20% of the general population. Although neuroimaging research on misophonia is scant, recent work showing higher resting-state functional connectivity (rs-fMRI) between auditory cortex and orofacial motor cortex in misophonia vs. controls has led researchers to speculate that misophonia is caused by orofacial mirror neurons. Since orofacial motor cortex was defined using rs-fMRI, we attempted to theoretically replicate these findings using orofacial cortex defined by task-based fMRI instead. Further, given our recent work showing that a wide variety of sounds can be triggering (i.e., not just oral/nasal sounds), we investigated whether there is any neural evidence for misophonic aversion to non-orofacial stimuli. Sampling 19 adults with varying misophonia from the community, we collected resting state data and an fMRI task involving phoneme articulation and finger-tapping. We first defined "orofacial" cortex in each participant using rs-fMRI as done previously, producing what we call resting-state regions of interest (rsROIs). Additionally, we functionally defined regions (fROIs) representing "orofacial" or "finger" cortex using phoneme or finger-tapping activation from the fMRI task, respectively. To investigate the motor specificity of connectivity differences, we subdivided the rsROIs and fROIs into separate sensorimotor areas based on their overlap with two common atlases. We then calculated rs-fMRI between each rsROI/fROI and a priori non-sensorimotor ROIs. We found increased connectivity in mild misophonia between rsROIs and both auditory cortex and insula, theoretically replicating previous results, with differences extending across multiple sensorimotor regions. However, the orofacial task-based fROIs did not show this pattern, suggesting the "orofacial" cortex described previously was not capturing true orofacial cortex; in fact, using task-based fMRI evidence, we find no selectivity to orofacial action in these previously described "orofacial" regions. Instead, we observed higher connectivity between finger fROIs and insula in mild misophonia, demonstrating neural evidence for non-orofacial triggers. These results provide support for a neural representation of misophonia beyond merely an orofacial/motor origin, leading to important implications for the conceptualization and treatment of misophonia.

Individual variability in functional organization of the neonatal brain.

The adult brain is organized into distinct functional networks, forming the basis of information processing and determining individual differences in behavior. Is this network organization genetically determined and present at birth? And what is the individual variability in this organization in neonates? Here, we use unsupervised learning to uncover intrinsic functional brain organization using resting-state connectivity from a large cohort of neonates (Developing Human Connectome Project). We identified a set of symmetric, hierarchical, and replicable networks: sensorimotor, visual, default mode, ventral attention, and high-level vision. We quantified individual variability across neonates, and found the most individual variability in the ventral attention networks. Crucially, the variability of these networks was not driven by SNR differences or differences from adult networks (Yeo et al., 2011). Finally, differential gene expression provided a potential explanation for the emergence of these distinct networks and identified potential genes of interest for future developmental and individual variability research. Overall, we found neonatal connectomes (even at the voxel-level) can reveal broad individual-specific information processing units. The presence of individual differences in neonates and the framework for personalized parcellations demonstrated here has the potential to improve prediction of behavior and future outcomes from neonatal and infant brain data.

Atypical age-related changes in the structure of the mentalizing network in children with refractory focal epilepsy.

Refractory focal epilepsy (rFE) is commonly comorbid with impaired social functioning, which significantly reduces quality of life. Previous research has identified a mentalizing network in the brain-composed of the anterior temporal cortex, medial prefrontal cortex (mPFC), posterior temporal sulcus (pSTS), and temporoparietal junction-that is thought to play a critical role in social cognition. In typically-developing (TD) youth, this network undergoes a protracted developmental process with cortical thinning and white matter expansion occurring across adolescence. Because epilepsy is associated with both social dysfunction and irregular neural development, we investigated whether gray and white matter in the mentalizing network differed between youth with rFE (n = 22) and TD youth (n = 41) aged 8-21 years. Older age was associated with reduced cortical thickness in the bilateral mPFC in TD youth, but not in rFE youth. Compared to TD youth, rFE youth had greater white matter density in the right pSTS. Our findings suggest that rFE youth show atypical patterns of cortical thickness and white matter density in regions of the brain that are typically associated with social information processing, potentially as a result of ongoing seizures, comorbid conditions, or other illness-related factors. These results encourage future research to examine whether such variations in neural structure are predictive of specific social deficits in rFE youth.

What sound sources trigger misophonia? Not just chewing and breathing.

OBJECTIVES: Misophonia is a highly prevalent yet understudied condition characterized by aversion toward particular environmental sounds. Oral/nasal sounds (e.g., chewing, breathing) have been the focus of research, but variable experiences warrant an objective investigation. Experiment 1 asked whether human-produced oral/nasal sounds were more aversive than human-produced nonoral/nasal sounds and non-human/nature sounds. Experiment 2 additionally asked whether machine-learning algorithms could predict the presence and severity of misophonia. METHOD: Sounds were presented to individuals with misophonia (Exp.1: N = 48, Exp.2: N = 45) and members of the general population (Exp.1: N = 39, Exp.2: N = 61). Aversiveness ratings to each sound were self-reported. RESULTS: Sounds from all three source categories-not just oral/nasal sounds-were rated as significantly more aversive to individuals with misophonia than controls. Further, modeling all sources classified misophonia with 89% accuracy and significantly predicted misophonia severity (r = 0.75). CONCLUSIONS: Misophonia should be conceptualized as more than an aversion to oral/nasal sounds, which has implications for future diagnostics and experimental consistency moving forward.

Adults vs. neonates: Differentiation of functional connectivity between the basolateral amygdala and occipitotemporal cortex.

The amygdala, a subcortical structure known for social and emotional processing, consists of multiple subnuclei with unique functions and connectivity patterns. Tracer studies in adult macaques have shown that the basolateral subnuclei differentially connect to parts of visual cortex, with stronger connections to anterior regions and weaker connections to posterior regions; infant macaques show robust connectivity even with posterior visual regions. Do these developmental differences also exist in the human amygdala, and are there specific functional regions that undergo the most pronounced developmental changes in their connections with the amygdala? To address these questions, we explored the functional connectivity (from resting-state fMRI data) of the basolateral amygdala to occipitotemporal cortex in human neonates scanned within one week of life and compared the connectivity patterns to those observed in young adults. Specifically, we calculated amygdala connectivity to anterior-posterior gradients of the anatomically-defined occipitotemporal cortex, and also to putative occipitotemporal functional parcels, including primary and high-level visual and auditory cortices (V1, A1, face, scene, object, body, high-level auditory regions). Results showed a decreasing gradient of functional connectivity to the occipitotemporal cortex in adults-similar to the gradient seen in macaque tracer studies-but no such gradient was observed in neonates. Further, adults had stronger connections to high-level functional regions associated with face, body, and object processing, and weaker connections to primary sensory regions (i.e., A1, V1), whereas neonates showed the same amount of connectivity to primary and high-level sensory regions. Overall, these results show that functional connectivity between the amygdala and occipitotemporal cortex is not yet differentiated in neonates, suggesting a role of maturation and experience in shaping these connections later in life.

Innate connectivity patterns drive the development of the visual word form area.

What determines the functional organization of cortex? One hypothesis is that innate connectivity patterns, either structural or functional connectivity, set up a scaffold upon which functional specialization can later take place. We tested this hypothesis by asking whether the visual word form area (VWFA), an experience-driven region, was already functionally connected to proto language networks in neonates scanned within one week of birth. Using the data from the Human Connectone Project (HCP) and the Developing Human Connectome Project (dHCP), we calculated intrinsic functional connectivity during resting-state functional magnetic resonance imaging (fMRI), and found that neonates showed similar functional connectivity patterns to adults. We observed that (1) language regions connected more strongly with the putative VWFA than other adjacent ventral visual regions that also show foveal bias, and (2) the VWFA connected more strongly with frontotemporal language regions than with regions adjacent to these language regions. These data suggest that the location of the VWFA is earmarked at birth due to its connectivity with the language network, providing evidence that innate connectivity instructs the later refinement of cortex.

The intrinsic neonatal hippocampal network: rsfMRI findings.

Many adults cannot voluntarily recall memories before the ages of 3-5, a phenomenon referred to as "infantile amnesia." The development of the hippocampal network likely plays a significant part in the emergence of the ability to form long-lasting memories. In adults, the hippocampus has specialized and privileged connections with certain cortical networks, which presumably facilitate its involvement in memory encoding, consolidation, and retrieval. Is the hippocampus already specialized in these cortical connections at birth? And are the topographical principles of connectivity (e.g., long-axis specialization) present at birth? We analyzed resting-state hippocampal connectivity in neonates scanned within 1 wk of birth (Developmental Human Connectome Project) and compared it with that of adults (Human Connectome Project). We explored the connections of the whole hippocampus and its long-axis specialization to seven canonical cortical networks. We found that the neonatal hippocampal networks show clear immaturity at birth: adults showed hippocampal connectivity that was unique for each cortical network, whereas neonates showed no differentiation in hippocampal connectivity across these networks. Furthermore, neonates lacked long-axis specialization (i.e., along the anterior-posterior axis) of the hippocampus in its differential connectivity patterns to the cortical networks. This immaturity in connectivity may contribute to immaturity in memory formation in the first years of life.NEW & NOTEWORTHY Although both animal data and human data suggest that the hippocampus is immature at birth, to date, there are no direct assessments of human hippocampal functional connectivity (FC) very early in life. Our study explores the FC of the hippocampus to the cortex at birth, allowing insight into the development of human memory systems. In particular, we find that adults and neonates exhibit vastly different hippocampal connectivity profiles-a finding that likely has large developmental implications.

Facephenes and rainbows: Causal evidence for functional and anatomical specificity of face and color processing in the human brain.

Neuroscientists have long debated whether some regions of the human brain are exclusively engaged in a single specific mental process. Consistent with this view, fMRI has revealed cortical regions that respond selectively to certain stimulus classes such as faces. However, results from multivoxel pattern analyses (MVPA) challenge this view by demonstrating that category-selective regions often contain information about "nonpreferred" stimulus dimensions. But is this nonpreferred information causally relevant to behavior? Here we report a rare opportunity to test this question in a neurosurgical patient implanted for clinical reasons with strips of electrodes along his fusiform gyri. Broadband gamma electrocorticographic responses in multiple adjacent electrodes showed strong selectivity for faces in a region corresponding to the fusiform face area (FFA), and preferential responses to color in a nearby site, replicating earlier reports. To test the causal role of these regions in the perception of nonpreferred dimensions, we then electrically stimulated individual sites while the patient viewed various objects. When stimulated in the FFA, the patient reported seeing an illusory face (or "facephene"), independent of the object viewed. Similarly, stimulation of color-preferring sites produced illusory "rainbows." Crucially, the patient reported no change in the object viewed, apart from the facephenes and rainbows apparently superimposed on them. The functional and anatomical specificity of these effects indicate that some cortical regions are exclusively causally engaged in a single specific mental process, and prompt caution about the widespread assumption that any information scientists can decode from the brain is causally relevant to behavior.

Integration and Segregation of Default Mode Network Resting-State Functional Connectivity in Transition-Age Males with High-Functioning Autism Spectrum Disorder: A Proof-of-Concept Study.

The aim of this study is to assess the resting-state functional connectivity (RsFc) profile of the default mode network (DMN) in transition-age males with autism spectrum disorder (ASD). Resting-state blood oxygen level-dependent functional magnetic resonance imaging data were acquired from adolescent and young adult males with high-functioning ASD (n = 15) and from age-, sex-, and intelligence quotient-matched healthy controls (HCs; n = 16). The DMN was examined by assessing the positive and negative RsFc correlations of an average of the literature-based conceptualized major DMN nodes (medial prefrontal cortex [mPFC], posterior cingulate cortex, bilateral angular, and inferior temporal gyrus regions). RsFc data analysis was performed using a seed-driven approach. ASD was characterized by an altered pattern of RsFc in the DMN. The ASD group exhibited a weaker pattern of intra- and extra-DMN-positive and -negative RsFc correlations, respectively. In ASD, the strength of intra-DMN coupling was significantly reduced with the mPFC and the bilateral angular gyrus regions. In addition, the polarity of the extra-DMN correlation with the right hemispheric task-positive regions of fusiform gyrus and supramarginal gyrus was reversed from typically negative to positive in the ASD group. A wide variability was observed in the presentation of the RsFc profile of the DMN in both HC and ASD groups that revealed a distinct pattern of subgrouping using pattern recognition analyses. These findings imply that the functional architecture profile of the DMN is altered in ASD with weaker than expected integration and segregation of DMN RsFc. Future studies with larger sample sizes are warranted.

Impaired Frontal-Limbic White Matter Maturation in Children at Risk for Major Depression.

Depression is among the most common neuropsychiatric disorders. It remains unclear whether brain abnormalities associated with depression reflect the pathological state of the disease or neurobiological traits predisposing individuals to depression. Parental history of depression is a risk factor that more than triples the risk of depression. We compared white matter (WM) microstructure cross-sectionally in 40 children ages 8-14 with versus without parental history of depression (At-Risk vs. Control). There were significant differences in age-related changes of fractional anisotropy (FA) between the groups, localized in the anterior fronto-limbic WM pathways, including the anterior cingulum and the genu of the corpus callosum. Control children exhibited typical increasing FA with age, whereas At-Risk children exhibited atypical decreasing FA with age in these fronto-limbic regions. Furthermore, dorsal cingulate FA significantly correlated with depressive symptoms for At-Risk children. The results suggest maturational WM microstructure differences in mood-regulatory neurocircuitry that may contribute to neurodevelopmental risk for depression. The study provides new insights into neurodevelopmental susceptibility to depression and related disabilities that may promote early preventive intervention approaches.

Connectivity precedes function in the development of the visual word form area.

What determines the cortical location at which a given functionally specific region will arise in development? We tested the hypothesis that functionally specific regions develop in their characteristic locations because of pre-existing differences in the extrinsic connectivity of that region to the rest of the brain. We exploited the visual word form area (VWFA) as a test case, scanning children with diffusion and functional imaging at age 5, before they learned to read, and at age 8, after they learned to read. We found the VWFA developed functionally in this interval and that its location in a particular child at age 8 could be predicted from that child's connectivity fingerprints (but not functional responses) at age 5. These results suggest that early connectivity instructs the functional development of the VWFA, possibly reflecting a general mechanism of cortical development.

Structural Connectivity Fingerprints Predict Cortical Selectivity for Multiple Visual Categories across Cortex.

A fundamental and largely unanswered question in neuroscience is whether extrinsic connectivity and function are closely related at a fine spatial grain across the human brain. Using a novel approach, we found that the anatomical connectivity of individual gray-matter voxels (determined via diffusion-weighted imaging) alone can predict functional magnetic resonance imaging (fMRI) responses to 4 visual categories (faces, objects, scenes, and bodies) in individual subjects, thus accounting for both functional differentiation across the cortex and individual variation therein. Furthermore, this approach identified the particular anatomical links between voxels that most strongly predict, and therefore plausibly define, the neural networks underlying specific functions. These results provide the strongest evidence to date for a precise and fine-grained relationship between connectivity and function in the human brain, raise the possibility that early-developing connectivity patterns may determine later functional organization, and offer a method for predicting fine-grained functional organization in populations who cannot be functionally scanned.

Altered resting-state functional connectivity of the frontal-striatal reward system in social anxiety disorder.

We investigated differences in the intrinsic functional brain organization (functional connectivity) of the human reward system between healthy control participants and patients with social anxiety disorder. Functional connectivity was measured in the resting-state via functional magnetic resonance imaging (fMRI). 53 patients with social anxiety disorder and 33 healthy control participants underwent a 6-minute resting-state fMRI scan. Functional connectivity of the reward system was analyzed by calculating whole-brain temporal correlations with a bilateral nucleus accumbens seed and a ventromedial prefrontal cortex seed. Patients with social anxiety disorder, relative to the control group, had (1) decreased functional connectivity between the nucleus accumbens seed and other regions associated with reward, including ventromedial prefrontal cortex; (2) decreased functional connectivity between the ventromedial prefrontal cortex seed and lateral prefrontal regions, including the anterior and dorsolateral prefrontal cortices; and (3) increased functional connectivity between both the nucleus accumbens seed and the ventromedial prefrontal cortex seed with more posterior brain regions, including anterior cingulate cortex. Social anxiety disorder appears to be associated with widespread differences in the functional connectivity of the reward system, including markedly decreased functional connectivity between reward regions and between reward regions and lateral prefrontal cortices, and markedly increased functional connectivity between reward regions and posterior brain regions.

Structural connectivity of the developing human amygdala.

A large corpus of research suggests that there are changes in the manner and degree to which the amygdala supports cognitive and emotional function across development. One possible basis for these developmental differences could be the maturation of amygdalar connections with the rest of the brain. Recent functional connectivity studies support this conclusion, but the structural connectivity of the developing amygdala and its different nuclei remains largely unstudied. We examined age related changes in the DWI connectivity fingerprints of the amygdala to the rest of the brain in 166 individuals of ages 5-30. We also developed a model to predict age based on individual-subject amygdala connectivity, and identified the connections that were most predictive of age. Finally, we segmented the amygdala into its four main nucleus groups, and examined the developmental changes in connectivity for each nucleus. We observed that with age, amygdalar connectivity becomes increasingly sparse and localized. Age related changes were largely localized to the subregions of the amygdala that are implicated in social inference and contextual memory (the basal and lateral nuclei). The central nucleus' connectivity also showed differences with age but these differences affected fewer target regions than the basal and lateral nuclei. The medial nucleus did not exhibit any age related changes. These findings demonstrate increasing specificity in the connectivity patterns of amygdalar nuclei across age.

Tracking the roots of reading ability: white matter volume and integrity correlate with phonological awareness in prereading and early-reading kindergarten children.

Developmental dyslexia, an unexplained difficulty in learning to read, has been associated with alterations in white matter organization as measured by diffusion-weighted imaging. It is unknown, however, whether these differences in structural connectivity are related to the cause of dyslexia or if they are consequences of reading difficulty (e.g., less reading experience or compensatory brain organization). Here, in 40 kindergartners who had received little or no reading instruction, we examined the relation between behavioral predictors of dyslexia and white matter organization in left arcuate fasciculus, inferior longitudinal fasciculus, and the parietal portion of the superior longitudinal fasciculus using probabilistic tractography. Higher composite phonological awareness scores were significantly and positively correlated with the volume of the arcuate fasciculus, but not with other tracts. Two other behavioral predictors of dyslexia, rapid naming and letter knowledge, did not correlate with volumes or diffusion values in these tracts. The volume and fractional anisotropy of the left arcuate showed a particularly strong positive correlation with a phoneme blending test. Whole-brain regressions of behavioral scores with diffusion measures confirmed the unique relation between phonological awareness and the left arcuate. These findings indicate that the left arcuate fasciculus, which connects anterior and posterior language regions of the human brain and which has been previously associated with reading ability in older individuals, is already smaller and has less integrity in kindergartners who are at risk for dyslexia because of poor phonological awareness. These findings suggest a structural basis of behavioral risk for dyslexia that predates reading instruction.

Predicting treatment response in social anxiety disorder from functional magnetic resonance imaging.

CONTEXT: Current behavioral measures poorly predict treatment outcome in social anxiety disorder (SAD). To our knowledge, this is the first study to examine neuroimaging-based treatment prediction in SAD. OBJECTIVE: To measure brain activation in patients with SAD as a biomarker to predict subsequent response to cognitive behavioral therapy (CBT). DESIGN: Functional magnetic resonance imaging (fMRI) data were collected prior to CBT intervention. Changes in clinical status were regressed on brain responses and tested for selectivity for social stimuli. SETTING: Patients were treated with protocol-based CBT at anxiety disorder programs at Boston University or Massachusetts General Hospital and underwent neuroimaging data collection at Massachusetts Institute of Technology. PATIENTS: Thirty-nine medication-free patients meeting DSM-IV criteria for the generalized subtype of SAD. INTERVENTIONS: Brain responses to angry vs neutral faces or emotional vs neutral scenes were examined with fMRI prior to initiation of CBT. MAIN OUTCOME MEASURES: Whole-brain regression analyses with differential fMRI responses for angry vs neutral faces and changes in Liebowitz Social Anxiety Scale score as the treatment outcome measure. RESULTS: Pretreatment responses significantly predicted subsequent treatment outcome of patients selectively for social stimuli and particularly in regions of higher-order visual cortex. Combining the brain measures with information on clinical severity accounted for more than 40% of the variance in treatment response and substantially exceeded predictions based on clinical measures at baseline. Prediction success was unaffected by testing for potential confounding factors such as depression severity at baseline. CONCLUSIONS: The results suggest that brain imaging can provide biomarkers that substantially improve predictions for the success of cognitive behavioral interventions and more generally suggest that such biomarkers may offer evidence-based, personalized medicine approaches for optimally selecting among treatment options for a patient.