Amygdala abnormalities across disease stages in patients with sporadic amyotrophic lateral sclerosis.

To examine selective atrophy patterns and resting-state functional connectivity (FC) alterations in the amygdala at different stages of amyotrophic lateral sclerosis (ALS), and to explore any correlations between amygdala abnormalities and neuropsychiatric symptoms. We used the King's clinical staging system for ALS to divide 83 consecutive patients with ALS into comparable subgroups at different disease stages. We explored the pattern of selective amygdala subnucleus atrophy and amygdala-based whole-brain FC alteration in these patients and 94 healthy controls (HCs). Cognitive and emotional functions were also evaluated using a neuropsychological test battery. There were no significant differences between ALS patients at King's stage 1 and HCs for any amygdala subnucleus volumes. Compared with HCs, ALS patients at King's stage 2 had significantly lower left accessory basal nucleus and cortico-amygdaloid transition volumes. Furthermore, ALS patients at King's stage 3 demonstrated significant reductions in most amygdala subnucleus volumes and global amygdala volumes compared with HCs. Notably, amygdala-cuneus FC was increased in ALS patients at King's stage 3. Specific subnucleus volumes were significantly associated with Mini-Mental State Examination scores and Hamilton Anxiety Rating Scale scores in ALS patients. In conclusions, our study provides a comprehensive profile of amygdala abnormalities in ALS patients. The pattern of amygdala abnormalities in ALS patients differed greatly across King's clinical disease stages, and amygdala abnormalities are an important feature of patients with ALS at relatively advanced stages. Moreover, our findings suggest that amygdala volume may play an important role in anxiety and cognitive dysfunction in ALS patients.

Altered social behavior and neuronal development in mice lacking the Uba6-Use1 ubiquitin transfer system.

The Uba6 (E1)-Use1 (E2) ubiquitin transfer cascade is a poorly understood alternative arm of the ubiquitin proteasome system (UPS) and is required for mouse embryonic development, independent of the canonical Uba1-E2-E3 pathway. Loss of neuronal Uba6 during embryonic development results in altered patterning of neurons in the hippocampus and the amygdala, decreased dendritic spine density, and numerous behavioral disorders. The levels of the E3 ubiquitin ligase Ube3a (E6-AP) and Shank3, both linked with dendritic spine function, are elevated in the amygdala of Uba6-deficient mice, while levels of the Ube3a substrate Arc are reduced. Uba6 and Use1 promote proteasomal turnover of Ube3a in mouse embryo fibroblasts (MEFs) and catalyze Ube3a ubiquitylation in vitro. These activities occur in parallel with an independent pathway involving Uba1-UbcH7, but in a spatially distinct manner in MEFs. These data reveal an unanticipated role for Uba6 in neuronal development, spine architecture, mouse behavior, and turnover of Ube3a.

Maternal depressive symptoms during pregnancy are associated with amygdala hyperresponsivity in children.

Depression during pregnancy is highly prevalent and has a multitude of potential risks of the offspring. Among confirmed consequences is a higher risk of psychopathology. However, it is unknown how maternal depression may impact the child's brain to mediate this vulnerability. Here we studied amygdala functioning, using task-based functional MRI, in children aged 6-9 years as a function of prenatal maternal depressive symptoms selected from a prospective population-based sample (The Generation R Study). We show that children exposed to clinically relevant maternal depressive symptoms during pregnancy (N = 19) have increased amygdala responses to negative emotional faces compared to control children (N = 20) [F(1,36) 7.02, p = 0.022]. Strikingly, postnatal maternal depressive symptoms, obtained at 3 years after birth, did not explain this relation. Our findings are in line with a model in which prenatal depressive symptoms of the mother are associated with amygdala hyperresponsivity in her offspring, which may represent a risk factor for later-life psychopathology.

The perception of facial emotions--cues from the left amygdaloid complex.

The history and the behavioral profile of 2 patients with brain abnormalities in the region of the left amygdaloidal complex might suggest that the dysfunction of the neural pathways related to the left amygdala has to occur at an early developmental stage to result in impaired emotional judgments of facial expressions. This is in line with the hypothesis that emotional information processing is based on a distributed neural network which, during ontogenesis, gradually expands from the amygdala and the amygdaloidal complex to further components of the limbic system.

Impaired fear extinction learning and cortico-amygdala circuit abnormalities in a common genetic mouse strain.

Fear extinction is a form of new learning that results in the inhibition of conditioned fear. Trait deficits in fear extinction are a risk factor for anxiety disorders. There are few examples of naturally occurring animal models of impaired extinction. The present study compared fear extinction in a panel of inbred mouse strains. This strain survey revealed an impairment in fear extinction in 129/SvImJ (129S1). The phenotypic specificity of this deficit was evaluated by comparing 129S1 and C57BL/6J for one-trial and multitrial fear conditioning, nociception, and extinction of conditioned taste aversion and an appetitive instrumental response. 129S1 were tested for sensitivity to the extinction-facilitating effects of extended training, as well as d-cycloserine and yohimbine treatment. To elucidate the neural basis of impaired 129S1 fear extinction, c-Fos and Zif268 expression was mapped after extinction recall. Results showed that impaired fear extinction in 129S1 was unrelated to altered fear conditioning or nociception, and was dissociable from intact appetitive extinction. Yohimbine treatment facilitated extinction in 129S1, but neither extended extinction training nor d-cycloserine treatment improved 129S1 extinction. After extinction recall, 129S1 showed reduced c-Fos and Zif268 expression in the infralimbic cortex and basolateral amygdala, and elevated c-Fos or Zif268 expression in central nucleus of the amygdala and medial paracapsular intercalated cell mass, relative to C57BL/6J. Collectively, these data demonstrate a deficit in fear extinction in 129S1 associated with a failure to properly engage corticolimbic extinction circuitry. This common inbred strain provides a novel model for studying impaired fear extinction in anxiety disorders.

Amygdala volumes in childhood absence epilepsy.

Abnormal amygdala volumes in pediatric mood-anxiety disorders and attention deficit hyperactivity disorder (ADHD), as well as high rates of these diagnoses in childhood absence epilepsy (CAE), prompted this study of amygdala volume in CAE. Twenty-six children with CAE and 23 normal children, aged 6.6-15.8 years, underwent MRI at 1.5 T. The tissue imaged with MRI was segmented, and amygdala volumes were obtained by manual tracings. There were no significant amygdala volume differences between the CAE and normal groups. Within the CAE group, however, the children with ADHD had significantly smaller amygdala volumes than the subjects with CAE with no psychopathology and those with mood/anxiety diagnoses. There was also a significant relationship between higher seizure frequency and greater amygdala asymmetry in the epilepsy group. Given ongoing development of the amygdala during late childhood and adolescence, despite the lack of significant group differences in amygdala volumes, the association of amygdala volume abnormalities with ADHD and seizure frequency implies a possible impact of the disorder on amygdala development and CAE-associated comorbidities, such as ADHD.

The Amygdala in Schizophrenia and Bipolar Disorder: A Synthesis of Structural MRI, Diffusion Tensor Imaging, and Resting-State Functional Connectivity Findings.

Frequently implicated in psychotic spectrum disorders, the amygdala serves as an important hub for elucidating the convergent and divergent neural substrates in schizophrenia and bipolar disorder, the two most studied groups of psychotic spectrum conditions. A systematic search of electronic databases through December 2017 was conducted to identify neuroimaging studies of the amygdala in schizophrenia and bipolar disorder, focusing on structural MRI, diffusion tensor imaging (DTI), and resting-state functional connectivity studies, with an emphasis on cross-diagnostic studies. Ninety-four independent studies were selected for the present review (49 structural MRI, 27 DTI, and 18 resting-state functional MRI studies). Also selected, and analyzed in a separate meta-analysis, were 33 volumetric studies with the amygdala as the region-of-interest. Reduced left, right, and total amygdala volumes were found in schizophrenia, relative to both healthy controls and bipolar subjects, even when restricted to cohorts in the early stages of illness. No volume abnormalities were observed in bipolar subjects relative to healthy controls. Shape morphometry studies showed either amygdala deformity or no differences in schizophrenia, and no abnormalities in bipolar disorder. In contrast to the volumetric findings, DTI studies of the uncinate fasciculus tract (connecting the amygdala with the medial- and orbitofrontal cortices) largely showed reduced fractional anisotropy (a marker of white matter microstructure abnormality) in both schizophrenia and bipolar patients, with no cross-diagnostic differences. While decreased amygdalar-orbitofrontal functional connectivity was generally observed in schizophrenia, varying patterns of amygdalar-orbitofrontal connectivity in bipolar disorder were found. Future studies can consider adopting longitudinal approaches with multimodal imaging and more extensive clinical subtyping to probe amygdalar subregional changes and their relationship to the sequelae of psychotic disorders.

Association between absence of the adhesio interthalamica and amygdala volume in schizophrenia.

Abnormal neurodevelopment in midline structures such as the adhesio interthalamica (AI) has been reported in schizophrenia, but not consistently replicated. We investigated the prevalence and anterior-posterior length of the AI in 62 schizophrenia patients (32 males, 30 females) and 63 healthy controls (35 males, 28 females) using magnetic resonance imaging. We also explored the relation between the AI and volumetric measurements for the third ventricle, medial temporal structures (amygdala, hippocampus, and parahippocampal gyrus), superior temporal sub-regions, and frontal lobe regions (prefrontal area and anterior cingulate gyrus). The AI was absent in 24.2% (15/62) of the schizophrenia patients and in 9.5% (6/63) of the controls, showing a significant group difference. For the length of the AI, schizophrenia patients had a shorter AI than controls, and males had a shorter AI than females. The subjects without an AI had a significantly larger third ventricle and smaller parahippocampal gyrus than the subjects with an AI for both groups. We found a significant diagnosis-by-AI interaction for the amygdala. The schizophrenia patients without an AI had a smaller bilateral amygdala than those with an AI, whereas the AI was not associated with the volume of the amygdala in the control subjects. These findings suggest that the absence of AI in schizophrenia could be a marker of developmental abnormalities in the neural network including the thalamus and connected amygdaloid regions, which may play an important role in the pathogenesis of schizophrenia.

The mouse Engrailed genes: a window into autism.

The complex behavioral symptoms and neuroanatomical abnormalities observed in autistic individuals strongly suggest a multi-factorial basis for this perplexing disease. Although not the perfect model, we believe the Engrailed genes provide an invaluable "window" into the elusive etiology of autism spectrum disorder. The Engrailed-2 gene has been associated with autism in genetic linkage studies. The En2 knock-out mouse harbors cerebellar abnormalities that are similar to those found in autistic individuals and, as we report here, has a distinct anterior shift in the position of the amygdala in the cerebral cortex. Our initial analysis of background effects in the En1 mouse knock-out provides insight as to possible molecular mechanisms and gender differences associated with autism. These findings further the connection between Engrailed and autism and provide new avenues to explore in the ongoing study of the biological basis of this multifaceted disease.

Volume reduction of the left planum temporale gray matter associated with long duration of untreated psychosis in schizophrenia: a preliminary report.

A longer duration of untreated psychosis (DUP) in schizophrenia is reported to lead to a poorer clinical outcome, possibly reflecting a neurodegenerative process after the onset of overt psychosis. However, the effect of DUP on brain morphology in schizophrenia is still poorly understood. In this study, we used magnetic resonance imaging to investigate the relation between DUP and volumetric measurements for the superior temporal sub-regions (Heschl's gyrus, planum temporale, and caudal superior temporal gyrus), the medial temporal lobe structures (hippocampus and amygdala), and the frontal lobe regions (prefrontal area and anterior cingulate gyrus) in a sample of 38 schizophrenia patients (20 males and 18 females) whose illness duration was less than five years. We found a significant negative correlation between DUP and the volume of gray matter in the left planum temporale even after controlling for age, age at illness onset, and duration and dosage of neuroleptic medication. There was no such correlation for the other brain regions including each sub-region of the prefrontal cortex (the superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus, ventral medial prefrontal cortex, orbitofrontal cortex, and straight gyrus). When subjects were divided into two groups around the median DUP, the long-DUP group had a significantly smaller planum temporale gray matter than the short-DUP group. These findings may reflect a progressive pathological process in the gray matter of the left planum temporale during the initial untreated phase of schizophrenia, whereas abnormalities in the medial temporal regions might be, as has been suggested from previous longitudinal findings, relatively static at least during the early course of the illness.

Early life adversity during the infant sensitive period for attachment: Programming of behavioral neurobiology of threat processing and social behavior.

Animals, including humans, require a highly coordinated and flexible system of social behavior and threat evaluation. However, trauma can disrupt this system, with the amygdala implicated as a mediator of these impairments in behavior. Recent evidence has further highlighted the context of infant trauma as a critical variable in determining its immediate and enduring consequences, with trauma experienced from an attachment figure, such as occurs in cases of caregiver-child maltreatment, as particularly detrimental. This review focuses on the unique role of caregiver presence during early-life trauma in programming deficits in social behavior and threat processing. Using data primarily from rodent models, we describe the interaction between trauma and attachment during a sensitive period in early life, which highlights the role of the caregiver's presence in engagement of attachment brain circuitry and suppressing threat processing by the amygdala. These data suggest that trauma experienced directly from an abusive caregiver and trauma experienced in the presence of caregiver cues produce similar neurobehavioral deficits, which are unique from those resulting from trauma alone. We go on to integrate this information into social experience throughout the lifespan, including consequences for complex scenarios, such as dominance hierarchy formation and maintenance.

Brain morphology in first-episode schizophrenia: a meta-analysis of quantitative magnetic resonance imaging studies.

BACKGROUND: A number of meta-analytic reviews of structural brain imaging studies have shown that multiple subtle brain abnormalities are consistently found in schizophrenia. However, quantitative reviews till now published have included mainly studies performed on chronic schizophrenic patients but have failed to provide clear information on specific, possibly different, findings in first-episode schizophrenia. METHODS: We performed a systematic search for MRI studies that reported quantitative measurements of volumes of brain regions in first-episode schizophrenic patients and in healthy controls. Twelve meta-analyses were performed for 6 cerebral regions. RESULTS: Twenty-one studies were identified as suitable for analysis. Significant overall effect sizes were demonstrated for lateral and third ventricular volume increase, and for volume reduction of whole brain and hippocampus, but not for temporal lobe, amygdala and total intracranial volumes. CONCLUSIONS: The available literature data strongly indicate that some brain abnormalities are already present in first-episode schizophrenic patients. However, unlike the results of published meta-analyses conducted primarily on samples of chronic schizophrenic patients, the present study did not confirm a significant reduction of temporal lobe or amygdala volumes in first-episode schizophrenia. These findings support the hypothesis of different patterns of involvement of various cerebral areas over the time course of schizophrenia.

[Childhood maltreatment and its impact on the mental health]. / Zhestokoe obrashchenie s det'mi i ego vliianie na psikhicheskoe zdorov'e.

This review covers the literature of the last 25 years on the impact of childhood maltreatment on the mental health throughout the individual's life. Child abuse increases the risk of many mental disorders including depression, suicidal ideation and suicidal behavior, anxiety-related disorders, psychoses as well as alcohol and other drug abuse. The impact of child trauma on the mental health is largely due to structural and functional changes in the hippocampus, amygdala and prefrontal cortex. Early preventive interventions play a great role in the prevention of mental disorders associated with childhood adversities.

Structural and Functional Brain Abnormalities in Attention-Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder: A Comparative Meta-analysis.

IMPORTANCE: Patients with attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) share impaired inhibitory control. However, it is unknown whether impairments are mediated by shared or disorder-specific neurostructural and neurofunctional abnormalities. OBJECTIVE: To establish shared and disorder-specific structural, functional, and overlapping multimodal abnormalities in these 2 disorders through a voxel-based meta-analytic comparison of whole-brain gray matter volume (GMV) and functional magnetic resonance imaging (fMRI) studies of inhibition in patients with ADHD and OCD. DATA SOURCES: Literature search using PubMed, ScienceDirect, Web of Knowledge, and Scopus up to September 30, 2015. STUDY SELECTION: Whole-brain voxel-based morphometry (VBM) or fMRI studies during inhibitory control comparing children and adults with ADHD or OCD with controls. DATA EXTRACTION AND SYNTHESIS: Voxel-wise meta-analyses of GMV or fMRI differences were performed using Seed-based d-Mapping. Regional structure and function abnormalities were assessed within each patient group and then a quantitative comparison was performed of abnormalities (relative to controls) between ADHD and OCD. MAIN OUTCOMES AND MEASURES: Meta-analytic disorder-specific and shared abnormalities in GMV, in inhibitory fMRI, and in multimodal functional and structural measures. RESULTS: The search revealed 27 ADHD VBM data sets (including 931 patients with ADHD and 822 controls), 30 OCD VBM data sets (928 patients with OCD and 942 controls), 33 ADHD fMRI data sets (489 patients with ADHD and 591 controls), and 18 OCD fMRI data sets (287 patients with OCD and 284 controls). Patients with ADHD showed disorder-contrasting multimodal structural (left z = 1.904, P < .001; right z = 1.738, P < .001) and functional (left z = 1.447, P < .001; right z = 1.229, P < .001) abnormalities in bilateral basal ganglia/insula, which were decreased in GMV and function in patients with ADHD relative to those with OCD (and controls). In OCD patients, they were enhanced relative to controls. Patients with OCD showed disorder-specific reduced function and structure in rostral and dorsal anterior cingulate/medial prefrontal cortex (fMRI z = 2.113, P < .001; VBM z = 1.622, P < .001), whereas patients with ADHD showed disorder-specific underactivation predominantly in the right ventrolateral prefrontal cortex (z = 1.229, P < .001). Ventromedial prefrontal GMV reduction was shared in both disorders relative to controls. CONCLUSIONS AND RELEVANCE: Shared impairments in inhibitory control, rather than representing a transdiagnostic endophenotype in ADHD and OCD, were associated with disorder-differential functional and structural abnormalities. Patients with ADHD showed smaller and underfunctioning ventrolateral prefrontal/insular-striatal regions whereas patients with OCD showed larger and hyperfunctioning insular-striatal regions that may be poorly controlled by smaller and underfunctioning rostro/dorsal medial prefrontal regions.

Neurobiology of emotion and high risk for schizophrenia: role of the amygdala and the X-chromosome.

Abnormalities in emotion processing and in structure of the amygdala have consistently been documented in schizophrenia. A major question is whether amygdala abnormalities reflect a genetic vulnerability for the disease. In the present paper, we reviewed Magnetic Resonance Imaging (MRI) studies that reported amygdala measures in several high-risk populations: subjects from the general population with subclinical schizophrenia symptoms and relatives of schizophrenia patients. In addition, we reviewed the evidence regarding Klinefelter syndrome (characterised by an additional X-chromosome), which has also been related to an increased risk for schizophrenia. Overall, the evidence points to structural abnormalities of the amygdala in individuals at increased risk for schizophrenia. Although the genetic basis of amygdala deficits remains unclear, abnormalities (of genes) on the X-chromosome might play a role as suggested by the evidence from individuals with sex chromosome aneuploidies. We propose that amygdala abnormalities are an endophenotype in schizophrenia and may account for subtle emotional processing deficits that have been described in these high-risk groups.

Hippocampus and amygdala volumes in schizophrenia and other psychoses in the Northern Finland 1966 birth cohort.

Structural brain differences have been reported in many studies with schizophrenia, but few have involved a general population birth cohort. We investigated differences in volume, shape and laterality of hippocampus and amygdala in patients with schizophrenia, all psychoses and comparison subjects within a large general birth cohort sample, and explored effects of family history of psychosis, perinatal risk and age-at-onset of illness. All subjects with psychosis from the Northern Finland 1966 birth cohort were invited to a survey including MRI scan of the brain, conducted in 1999-2001. Comparison subjects not known to have psychosis were randomly selected from the same cohort. Volumes of hippocampus and amygdala were measured in 56 subjects with DSM-III-R schizophrenia, 26 patients with other psychoses and 104 comparison subjects. Small hippocampal volume reductions in schizophrenia (2%) and all psychoses (3%) were not significant when adjusted for total brain volume. The shape of hippocampus in schizophrenia did not differ significantly from comparison subjects. Right hippocampus and amygdala were significantly larger than the left in all groups. Mean amygdala volume in schizophrenia or all psychoses did not differ from comparison subjects. Patients with family history of psychosis had larger hippocampus than patients without. Neither perinatal risk nor age-at-onset of illness had any effect on hippocampal or amygdala volumes. Small hippocampal volume reduction in schizophrenia and all psychoses was not disproportionate to reduced whole brain volume in this population-based sample. Perinatal events that have been suggested as of etiological importance in structural pathology of psychosis had no effect.

Olfactory functions and volumetric measures of orbitofrontal and limbic regions in schizophrenia.

OBJECTIVE: Olfactory deficits in schizophrenia patients have been suggested to reflect medial temporal and/or prefrontal brain abnormalities. In this study, we examined the relationship between different olfactory functions and volumes of the hippocampus-amygdala complex (HAC) and the orbitofrontal brain region using magnetic resonance imaging (MRI). METHODS: Thirty-three young men with schizophrenia (DSM-IV) and 40 healthy controls performed unirhinal olfactory assessment including the main olfactory functions (threshold, discrimination, and identification), and odor judgements (intensity, edibility, familiarity, and pleasantness). Volumes of regions in the medial temporal lobe (hippocampus and amygdala) and the prefrontal region (orbitofrontal gray and white matter) were measured on MRI scans. RESULTS: Compared with controls, patients showed bilaterally impaired thresholds, quality discrimination and identification, as well as edibility judgements. Olfactory deficits were not attributable to smoking, premorbid intelligence, or impaired thresholds. Relative to controls, patients had bilateral reduced hippocampus and amygdala volumes. In patients, smaller hippocampus volumes were associated with poorer olfactory discrimination ability. CONCLUSIONS: Olfactory deficits in schizophrenia appear to be associated with morphometric abnormalities in the medial temporal rather than the orbitofrontal region (OFR). These results indicate that olfactory quality discrimination deficits are related to structural hippocampus abnormalities. Future studies of genetic and behavioral high-risk samples seem warranted.

Amygdala response to fearful faces in anxious and depressed children.

BACKGROUND: Alterations in amygdala function have been implicated in the pathophysiological characteristics of adult anxiety and depressive disorders. Studies with healthy adults and children, as well as with adults who have amygdala lesions, have found facial expressions of emotion to be useful probes of amygdala activity. Our study examined the amygdala response to fearful and neutral facial expressions in healthy, anxious, and depressed children. We hypothesized that children with anxiety and depression may show atypical amygdala responses to emotional stimuli. METHODS: Twelve children (8-16 years of age) with generalized anxiety or panic disorder and 12 healthy comparison children underwent noninvasive functional magnetic resonance imaging while viewing photographs of fearful and neutral facial expressions. In a second comparison, 5 girls with major depressive disorder were compared with 5 anxious and 5 healthy girls from the previous sample. RESULTS: Children with anxiety disorders showed an exaggerated amygdala response to fearful faces compared with healthy children, whereas depressed children showed a blunted amygdala response to these faces. In addition, the magnitude of the amygdala's signal change between fearful and neutral faces was positively correlated with the severity of everyday anxiety symptoms. CONCLUSIONS: Our results suggest that amygdala function is affected in both anxiety and depression during childhood and adolescence. Moreover, this disruption appears to be specific to the child's own rating of everyday anxiety.

Lipoid proteinosis.

Lipoid proteinosis is a rare autosomal recessive disorder caused by mutations in ECM1, encoding extracellular matrix protein 1, a glycoprotein expressed in many organs and which has important protein-protein interactions in tissue homeostasis. Although the disease usually presents clinically with warty infiltration of the skin and mucous membranes and a hoarse voice, neuropsychological and neuropsychiatric abnormalities are often prominent features. There may be bean- or comma-shaped intracranial calcifications, often selectively affecting the amygdala. Patients with lipoid proteinosis therefore have been used as models for demonstrating physiologic and pathologic abnormalities of the amygdala with respect to fear processing, affect and cognition, anxiety and memory. Clinically, patients may also have epilepsy, especially involving the temporal lobes. Less common or rare disease associations are headache (including migraine), ataxia, dizziness, schizophrenia, generalized dystonia, transient brachiofacial paralysis, and intracerebral hemorrhage. Beyond the foci of calcification, the cause of the neurologic abnormalities in lipoid proteinosis is unknown, although the ECM1 protein can normally bind to various extracellular matrix proteins and glycosaminoglycans as well as certain enzymes, including matrix metalloproteinase 9. Loss of key protein-protein interactions may underscore some of the disease pathophysiology. There is currently no effective treatment for lipoid proteinosis and clinical care is largely supportive.

Functional neuroimaging abnormalities in youth with psychosis spectrum symptoms.

IMPORTANCE: The continuum view of the psychosis spectrum (PS) implies that, in population-based samples, PS symptoms should be associated with neural abnormalities similar to those found in help-seeking clinical risk individuals and in schizophrenia. To our knowledge, functional neuroimaging has not previously been applied in large population-based PS samples and can help us understand the neural architecture of psychosis more broadly and identify brain phenotypes beyond symptoms that are associated with the extended psychosis phenotype. OBJECTIVE: To examine the categorical and dimensional relationships of PS symptoms to prefrontal hypoactivation during working memory and to amygdala hyperactivation during threat emotion processing. DESIGN, SETTING, AND PARTICIPANTS: The Philadelphia Neurodevelopmental Cohort is a genotyped, prospectively accrued, population-based sample of almost 10,000 youths who received a structured psychiatric evaluation and a computerized neurocognitive battery. The study was conducted at an academic and children's hospital health care network, between November 1, 2009 to November 30, 2011. A subsample of 1445 youths underwent neuroimaging, including functional magnetic resonance imaging tasks examined herein. Participants were youth aged 11 to 22 years old identified through structured interview as having PS features (PS group) (n = 260) and typically developing (TD) comparison youth without significant psychopathology (TD group) (n = 220). MAIN OUTCOMES AND MEASURES: Two functional magnetic resonance imaging paradigms were used: a fractal n-back working memory task probing executive system function and an emotion identification task probing amygdala responses to threatening faces. RESULTS: In the n-back task, working memory evoked lower activation in the PS group than the TD group throughout the executive control circuitry, including dorsolateral prefrontal cortex (cluster-corrected P < .05). Within the PS group, dorsolateral prefrontal cortex activation correlated with cognitive deficits (r = .32, P < .001), but no correlation was found with positive symptom severity. During emotion identification, PS demonstrated elevated responses to threatening facial expressions in amygdala, as well as left fusiform cortex and right middle frontal gyrus (cluster-corrected P < .05). The response in the amygdala correlated with positive symptom severity (r = .16, P = .01) but not with cognitive deficits. CONCLUSIONS AND RELEVANCE: The pattern of functional abnormalities observed in the PS group is similar to that previously found in schizophrenia and help-seeking risk samples. Specific circuit dysfunction during cognitive and emotion-processing tasks is present early in the development of psychopathology and herein could not be attributed to chronic illness or medication confounds. Hypoactivation in executive circuitry and limbic hyperactivation to threat could reflect partly independent risk factors for PS symptoms, with the former relating to cognitive deficits that increase the risk for developing psychotic symptoms and the latter contributing directly to positive psychotic symptoms.