Anticipatory anxiety and heightened responses to uncertainty are central features of anxiety disorders (ADs). We examined facial emotional responding in a sample of preadolescent girls with a range of anxiety symptoms: no/low anxiety (controls) to subthreshold anxiety (subthreshold-AD) to DSM-5 diagnoses of separation, social, and/or generalized ADs. Using a threat anticipation paradigm, we assessed how variations in image valence (negative vs. neutral) and image anticipation (uncertain vs. certain timing) impacted activity of the corrugator supercilii, a forehead muscle implicated in the ‘frown’ response that modulates to emotional stimuli (negative>neutral). Average corrugator magnitude and corrugator time-course were compared between groups. Findings demonstrate greater corrugator activity during anticipation and viewing of negative stimuli, with overall increased corrugator reactivity in subthreshold-AD and AD girls. Time-course analyses revealed anxiety-related sustained corrugator activity during uncertain anticipation of negative images. Results extend the physiological characterization of childhood pathological anxiety, highlighting the impact of subthreshold-AD symptoms.

OBJECTIVE:Anxiety disorders are among the most common psychiatric disorders in youths and emerge during childhood. This is also a period of rapid white matter (WM) development, which is critical for efficient neuronal communication. Previous work in preadolescent children with anxiety disorders demonstrated anxiety disorder-related reductions in WM microstructural integrity (fractional anisotropy [FA]) in the uncinate fasciculus (UF), the major WM tract facilitating prefrontal cortical-limbic structural connectivity. Importantly, this association was found only in boys with anxiety disorders. To confirm this finding and more comprehensively understand WM changes in childhood anxiety, this mega-analytic study characterizes WM alterations related to anxiety disorders and sex in the largest sample of preadolescent children to date.METHODS:Diffusion tensor imaging data from published studies of preadolescent children with anxiety disorders and healthy volunteers (ages 8-12) (N=198) were combined with a new data set (N=97) for a total sample of 165 children with anxiety disorders and 132 healthy volunteers. Children with anxiety disorders met DSM-5 criteria for current generalized, separation, and/or social anxiety disorder. Analyses of tractography and voxel-wise data assessed between-group differences (anxiety disorder vs. healthy volunteer), effects of sex, and their interaction.RESULTS:Tract-based and voxel-wise analyses confirmed a significant reduction in UF FA in boys but not girls with anxiety disorders. Results also demonstrated other significant widespread anxiety disorder-related WM alterations specifically in boys, including in multiple commissural, association, projection, and brainstem regions.CONCLUSIONS:In addition to confirming male-specific anxiety disorder-related reductions in UF FA, the results demonstrate that anxiety disorders in boys and not girls are associated with broadly distributed WM alterations across the brain. These findings support further studies focused on understanding the extent to which WM alterations in boys with anxiety disorders are involved in pathophysiological processes that mediate anxiety disorders. The findings also suggest the possibility that WM microarchitecture could serve as a novel treatment target for childhood anxiety disorders.

Pathological anxiety typically emerges during preadolescence and has been linked to alterations in white matter (WM) pathways. Because myelination is critical for efficient neuronal communication, characterizing associations between WM microstructure and symptoms may provide insights into pathophysiological mechanisms associated with childhood pathological anxiety. This longitudinal study examined 182 girls enrolled between the ages of 9–11 that were treatment-naïve at study entry: healthy controls ( n = 49), subthreshold-anxiety disorders (AD) ( n = 82), or meeting DSM-5 criteria for generalized, social, and/or separation ADs ( n = 51), as determined through structured clinical interview. Anxiety severity was assessed with the Clinical Global Impression Scale and Screen for Child Anxiety and Related Emotional Disorders (SCARED). Participants ( n = 182) underwent clinical, behavioral, and diffusion tensor imaging (DTI) assessments at study entry, and those with pathological anxiety (subthreshold-AD and AD, n = 133) were followed longitudinally for up to 3 additional years. Cross-sectional ANCOVAs (182 scans) examining control, subthreshold-AD, and AD participants found no significant relations between anxiety and DTI measurements. However, in longitudinal analyses of girls with pathological anxiety (343 scans), linear mixed-effects models demonstrated that increases in anxiety symptoms (SCARED scores) were associated with reductions in whole-brain fractional anisotropy, independent of age (Std. β (95% CI) = −0.06 (−0.09 to −0.03), F (1, 46.24) = 11.90, P = 0.001). Using a longitudinal approach, this study identified a dynamic, within-participant relation between whole-brain WM microstructural integrity and anxiety in girls with pathological anxiety. Given the importance of WM microstructure in modulating neural communication, this finding suggests the possibility that WM development could be a viable target in the treatment of anxiety-related psychopathology.

Objective: Anxiety disorders are common, can result in lifelong suffering, and frequently begin before adolescence. Evidence from adults suggests that altered prefrontal-limbic connectivity is a pathophysiological feature of anxiety disorders. More specifically, in adults with anxiety disorders, decreased fractional anisotropy (FA), a measure of white matter integrity, has been observed in the uncinate fasciculus, the major tract that connects limbic and prefrontal regions. Because of the early onset of anxiety disorders and the increased incidence in anxiety disorders in females during their reproductive years, it is important to understand whether the reduction in uncinate fasciculus FA exists in children with anxiety disorders and the extent to which this alteration is sex related. To address these issues, the authors assessed FA in the uncinate fasciculus in unmedicated boys and girls with anxiety disorders. Methods: FA measures were derived from diffusion tensor images that were acquired from 98 unmedicated children (ages 8-12); 52 met criteria for generalized anxiety disorder, separation anxiety disorder, social anxiety disorder, or anxiety disorder not otherwise specified, and 46 were matched control subjects. Results: Tract-based results demonstrated that children with anxiety disorders have significant reductions in uncinate fasciculus FA. A significant sex-by-group interaction and post hoc testing revealed that this effect was evident only in boys. No other main effects or sex-by-group interactions were found for other white matter tracts. Conclusions: These findings provide evidence of uncinate fasciculus white matter alterations in boys with anxiety disorders. The data demonstrate that anxiety disorder-related alterations in prefrontal-limbic structural connectivity are present early in life, are not related to psychotropic medication exposure, and are sex specific. Building on these findings, future research has the potential to provide insights into the genesis and sexual dimorphism of the pathophysiology that leads to anxiety disorders, as well as to identify sex-specific early-life treatment targets.

Anxiety disorders (ADs) are the most common childhood mental health diagnoses and confer increased risk for the development of later psychopathology. ADs are characterized by sustained anxiety and negative affect, manifesting as excessive and persistent worries and fears. Although the ability to anticipate threatening situations and their accompanying anxiety is critical for survival, prolonged vigilance and anticipatory anxiety are maladaptive. Understanding the biological basis underlying the development of childhood ADs will provide insights into furthering the development of novel interventions.

Recent cognitive, genetic, and histological studies have highlighted significant overlap between psychotic bipolar disorder and schizophrenia. Specifically, both bipolar disorder and schizophrenia are characterized by interneuron dysfunction within the hippocampus, an essential structure for relational memory. Relational memory impairments are a common feature of schizophrenia, but have yet to be investigated in psychotic bipolar disorder. Here, we tested the hypothesis that psychotic bipolar disorder is characterized by relational memory deficits. We used a transitive inference (TI) paradigm, previously employed to quantify relational memory deficits in schizophrenia, to assess relational memory performance in 17 patients with psychotic bipolar disorder and 22 demographically matched control participants. Functional magnetic resonance imaging was used to examine hippocampal activity during recognition memory in patients and controls. Hippocampal volumes were assessed by manual segmentation. In contrast to our hypothesis, we found similar TI performance, hippocampal volume, and hippocampal recruitment during recognition memory in both groups. Both psychotic bipolar disorder patients and controls exhibited a positive correlation between hippocampal volume and relational memory performance. These data indicate that relational memory impairments are not a shared feature of non-affective and affective psychosis.

Children with anxiety disorders (ADs) experience persistent fear and worries that are highly debilitating, conferring risk for lifelong psychopathology. Anticipatory anxiety is a core clinical feature of childhood ADs, often leading to avoidance of uncertain and novel situations. Extensive studies in non-human animals implicate amygdala dysfunction as a critical substrate for early life anxiety. To test specific amygdala-focused hypotheses in preadolescent children with ADs, we used fMRI to characterize amygdala activation during uncertain anticipation and in response to unexpected stimuli. Forty preadolescent (age 8-12 years) children, 20 unmedicated AD patients and 20 matched controls completed an anticipation task during an fMRI scan. In the task, symbolic cues preceded fear or neutral faces, such that 'certain' cues always predicted the presentation of fear or neutral faces, whereas 'uncertain' cues were equally likely to be followed by fear or neutral faces. Both AD children and controls showed robust amygdala response to faces. In response to the uncertain cues, AD children had increased amygdala activation relative to controls. Moreover, in the AD children, faces preceded by an 'uncertain' cue elicited increased amygdala activation, as compared with the same faces following a 'certain' cue. Children with ADs experience distress both in anticipation of and during novel and surprising events. Our findings suggest that increased amygdala activation may have an important role in the generation of uncertainty-related anxiety. These findings may guide the development of neuroscientifically informed treatments aimed at relieving the suffering and preventing the lifelong disability associated with pediatric ADs.

Background: Neural habituation, the decrease in brain response to repeated stimulation, is a basic form of learning. There is strong evidence for behavioral and physiological habituation deficits in schizophrenia, and one previous study found reduced neural habituation within the hippocampus. However, it is unknown whether neural habituation deficits are specific to faces and limited to the hippocampus. Here we studied habituation of several brain regions in schizophrenia, using both face and object stimuli. Post-scan memory measures were administered to test for a link between hippocampal habituation and memory performance.Methods: During an fMRI scan, 23 patients with schizophrenia and 21 control subjects viewed blocks of a repeated neutral face or neutral object, and blocks of different neutral faces and neutral objects. Habituation in the hippocampus, primary visual cortex and fusiform face area (FFA) was compared between groups. Memory for faces, words, and word pairs was assessed after the scan.Results: Patients showed reduced habituation to faces in the hippocampus and primary visual cortex, but not the FFA. Healthy control subjects exhibited a pattern of hippocampal discrimination that distinguished between repeated and different images for both faces and objects, and schizophrenia patients did not Hippocampal discrimination was positively correlated with memory for word pairs.Conclusion: Patients with schizophrenia showed reduced habituation of the hippocampus and visual cortex, and a lack of neural discrimination between old and new images in the hippocampus. Hippocampal discrimination correlated with memory performance, suggesting reduced habituation may contribute to the memory deficits commonly observed in schizophrenia. (C) 2013 Elsevier B.V. All rights reserved,

Background/Aims: Previous studies point to an association between childhood sexual abuse (CSA) and auditory hallucinations (AH). However, methodological issues limit the strength of these results. Here we compared childhood abuse between psychotic disorder patients and healthy control subjects using a reliable measure of abuse, and assessed the relationship between CSA and AR.Methods: 114 psychotic disorder patients and 81 healthy control subjects were administered the Structured Clinical Interview of the DSM-IV (SCID) and the Childhood Trauma Questionnaire (CTQ). We compared the severity of abuse between groups, and tested the relationship between different types of childhood abuse and specific psychotic symptoms.Results: Psychotic patients reported more childhood abuse than controls (p < .001). Psychotic patients with a history of AR reported significantly more sexual, emotional, and physical abuse than patients without a history of AR (p < .05). Emotional and physical abuse, in the absence of sexual abuse, did not lead to a higher rate of AR. Finally, reports of childhood abuse did not increase the risk of any form of hallucination other than AR or of any form of delusion.Conclusions: These results suggest that childhood abuse, especially childhood sexual abuse, shapes the phenotype of psychotic disorders by conferring a specific risk for AR. (C) 2013 Elsevier Inc. All rights reserved.

Childhood trauma is associated with smaller gray matter volume, similar to the pattern seen in psychotic disorders. We explored the relationship between childhood abuse, psychosis, and brain volume in a group of 60 individuals with a psychotic disorder and 26 healthy control subjects. We used voxel-based morphometry (VBM) to quantify gray and white matter volume and the Childhood Trauma Questionnaire (CTQ) to measure childhood abuse. Within the psychotic disorder group, total gray matter volume was inversely correlated with the severity of childhood sexual abuse (r=-.34, p=.008), but not the other types of abuse. When the 24 patients with sexual abuse were compared with demographically matched samples of 23 patients without sexual abuse and 26 control subjects, only patients with a history of sexual abuse had reduced total gray matter volume (t(48)=2.3, p=.03; Cohen's d=.63). Voxel-based analysis revealed a cluster in the prefrontal cortex where volume was negatively correlated with sexual abuse severity. Voxel based comparison of the three matched groups revealed a similar pattern of results, with widespread reductions in psychosis patients with sexual abuse relative to controls that were not found in psychosis patients without sexual abuse. These findings indicate that some of the variance of gray matter volume in psychotic disorders can be explained by a history of sexual abuse.

Background: Previous studies indicate that the transition to psychosis is associated with dynamic changes of hippocampal integrity. Here we explored hippocampal volume and neural activation during a relational memory task in patients who were in the early stage of a psychotic illness.Methods: Forty-one early psychosis patients and 34 healthy control subjects completed a transitive inference (TI) task used previously in chronic schizophrenia patients. Participants learned to select the "winner" of two sets of stimulus pairs drawn from an overlapping sequence (A > B > C > D > E) and a nonoverlapping set (a > b, c > d, e > f, g > h). During a functional magnetic resonance imaging scan, participants were tested on the trained pairs and made inferential judgments on novel pairings that could be solved based on training (e. g., B vs. D). Hippocampal volumes were manually segmented and compared between groups. Functional magnetic resonance imaging analyses included 27 early psychosis patients and 30 control subjects who met memory training criteria.Results: Groups did not differ on inference performance or hippocampal volume and exhibited similar activation of medial temporal regions when judging nonoverlapping pairs. However, patients who failed to meet memory training criteria had smaller hippocampal volumes. Neural activity during TI was less widespread in early psychosis patients, but between-group differences were not significant. Hippocampal activity during TI was positively correlated with inference performance only in control subjects.Conclusions: Our results provide evidence that relational memory impairment and hippocampal abnormalities, well established in chronic schizophrenia, are not fully present in early psychosis patients. This provides a rationale for early intervention, targeting the possible delay, reduction, or prevention of these deficits.

The ability to learn, store, and retrieve information about relationships is impaired in schizophrenia. Here, we tested 38 control and 61 schizophrenia subjects for their ability to identify the novel pairing of stimuli, based on associations learned during training. Subjects were trained on 3 sets of paired associates: 30 face-house pairs (H-F1), 30 face-house pairs (H-F2, same house with new face), and 30 face-face pairs (F3-F4). After training, participants were tested on the 3 explicitly trained pair types, as well as 30 new face-face pairs (F1-F2), which could only be linked together via the same house during the H-F1/H-F2 training blocks. Of 99 subjects tested, 37 patients with schizophrenia and 36 age-matched healthy control subjects learned the premise pairs and performed the relational memory test. Healthy control subjects were significantly more accurate in identifying the inferential (F1-F2) pairs than the noninferential (F3-F4) pairs. In contrast, schizophrenia patients were equally accurate on inferential and noninferential pairs, providing evidence for a relational memory deficit in schizophrenia. However, the current version of the associative inference paradigm, suggested by the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia initiative, has limited feasibility, calling into question the generalizability of the findings for the larger schizophrenia population.

OBJECTIVE Patients with schizophrenia have widespread cognitive impairments, with selective deficits in relational memory. We previously reported a differential relational memory deficit in schizophrenia using the Associative Inference Paradigm (AIP), a task suggested by the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative to examine relational memory. However, the AIP had limited feasibility for testing in schizophrenia because of high attrition of schizophrenia patients during training. Here we developed and tested a revised version of the AIP to improve feasibility. METHOD 30 healthy control and 37 schizophrenia subjects received 3 study-test sessions on 3 sets of paired associates: H-F1 (house paired with face), H-F2 (same house paired with new face), and F3-F4 (two novel faces). After training, subjects were tested on the trained, noninferential Face-Face pairs (F3-F4) and novel, inferential Face-Face pairs (F1-F2), constructed from the faces of the trained House-Face pairs. RESULTS Schizophrenia patients were significantly more impaired on the inferential F1-F2 pairs than the noninferential F3-F4 pairs, providing evidence for a differential relational memory deficit. Only 8% of schizophrenia patients were excluded from testing because of poor training performance. CONCLUSIONS The revised AIP confirmed the previous finding of a relational memory deficit in a larger and more representative sample of schizophrenia patients.

Synesthesia is an involuntary experience in which stimulation of one sensory modality triggers additional, atypical sensory experiences. Strong multisensory processes are present in the general population, but the relationship between these 'normal' sensory interactions and synesthesia is currently unknown. Neuroimaging research suggests that some forms of synesthesia are caused by enhanced cross-activation between brain areas specialized for the processing of different sensory attributes, and finds evidence of increased white matter connections among regions known to be involved in typical crossmodal processes. Using two classic crossmodal integration tasks we show that grapheme-color synesthetes exhibit enhanced crossmodal interactions between auditory and visual modalities, suggesting that the experience of synesthesia in one modality generalizes to enhanced crossmodal processes with other modalities. This finding supports our conjecture that the atypical sensory experiences of synesthetes represent a selective expression of a more diffuse propensity toward 'typical' crossmodality interactions.