Theory of mind performance and prefrontal connectivity in adolescents at clinical high risk for psychosis

Theory of mind(ToM) impairment is a key feature of psychotic disorders and has been documented in individuals at clinical high-risk for psychosis (CHR), suggesting that it may predate illness onset. However, no study to date has examined brain functional correlates of ToM in individuals at CHR during adolescence. The “Reading-the-Mind-in-the-Eyes” test was used to measure ToM performance in 50 CHR youth, 15 of whom transitioned to psychosis (CHR-t) at follow-up (12 ± 6 months) and 36 healthy volunteers. Resting-state functional MRI was acquired to evaluate functional connectivity within the default mode network. Group by age interaction revealed an age-positive association in ToM performance in healthy volunteers, which was not present in adolescents at CHR-t. Intrinsic functional connectivity in the medial prefrontal cortex was reduced in adolescents at CHR-t relative to those who did not transition and to healthy volunteers. Survival analyses revealed that participants at CHR with lower medial prefrontal cortex connectivity were at greatest risk of developing psychosis at follow-up. We demonstrate that lack of age-related maturation of ToM and reduced medial prefrontal cortex connectivity both precede the onset of psychosis during adolescence. Medial prefrontal cortex connectivity holds potential as a brain-based marker for the early identification of transition to psychosis.     

Altered Amygdala Connectivity Within the Social Brain in Schizophrenia

Background: Impairments in social cognition have been described in schizophrenia and relate to core symptoms of the disorder. Social cognition is subserved by a network of brain regions, many of which have been implicated in schizophrenia. We hypothesized that deficits in connectivity between components of this social brain network may underlie the social cognition impairments seen in the disorder. Methods: We investigated brain activation and connectivity in a group of individuals with schizophrenia making social judgments of approachability from faces (n = 20), compared with a group of matched healthy volunteers (n = 24), using functional magnetic resonance imaging. Effective connectivity from the amygdala was estimated using the psychophysiological interaction approach. Results: While making approachability judgments, healthy participants recruited a network of social brain regions including amygdala, fusiform gyrus, cerebellum, and inferior frontal gyrus bilaterally and left medial prefrontal cortex. During the approachability task, healthy participants showed increased connectivity from the amygdala to the fusiform gyri, cerebellum, and left superior frontal cortex. In comparison to controls, individuals with schizophrenia overactivated the right middle frontal gyrus, superior frontal gyrus, and precuneus and had reduced connectivity between the amygdala and the insula cortex. Discussion: We report increased activation of frontal and medial parietal regions during social judgment in patients with schizophrenia, accompanied by decreased connectivity between the amygdala and insula. We suggest that the increased activation of frontal control systems and association cortex may reflect a compensatory mechanism for impaired connectivity of the amygdala with other parts of the social brain networks in schizophrenia.Key words: fMRI, social cognition, approachability, psychosis, neural, psychophysiological interaction     

Differences in resting corticolimbic functional connectivity in bipolar I euthymia

Objective: We examined resting state functional connectivity in the brain between key emotion regulation regions in bipolar I disorder to delineate differences in coupling from healthy subjects. Methods: Euthymic subjects with bipolar I disorder (n = 20) and matched healthy subjects (n = 20) participated in a resting state functional magnetic resonance imaging scan. Low‐frequency fluctuations in blood oxygen level‐dependent (BOLD) signal were correlated in the six connections between four anatomically defined nodes: left and right amygdala and left and right ventrolateral prefrontal cortex (vlPFC). Seed‐to‐voxel connectivity results were probed for commonly coupled regions. Following this, an identified region was included in a mediation analysis to determine the potential of mediation. Results: The bipolar I disorder group exhibited significant hyperconnectivity between right amygdala and right vlPFC relative to healthy subjects. The connectivity between these regions in the bipolar I disorder group was partially mediated by activity in the anterior cingulate cortex (ACC). Conclusions: Greater coupling between right amygdala and right vlPFC and their partial mediation by the ACC were found in bipolar I disorder subjects in remission and in the absence of a psychological task. These findings have implications for a trait‐related and clinically important imaging biomarker.     

Reduced structural connectivity of a major frontolimbic pathway in generalized anxiety disorder

CONTEXT Emotion regulation deficits figure prominently in generalized anxiety disorder (GAD) and in other anxiety and mood disorders. Research examining emotion regulation and top-down modulation has implicated reduced coupling of the amygdala with prefrontal cortex and anterior cingulate cortex, suggesting altered frontolimbic white matter connectivity in GAD. OBJECTIVES To investigate structural connectivity between ventral prefrontal cortex or anterior cingulate cortex areas and the amygdala in GAD and to assess associations with functional connectivity between those areas. DESIGN Participants underwent diffusion-tensor imaging and functional magnetic resonance imaging. SETTING University magnetic resonance imaging facility. PARTICIPANTS Forty-nine patients with GAD and 39 healthy volunteer control subjects, including a matched subset of 21 patients having GAD without comorbid Axis I diagnoses and 21 healthy volunteers matched for age, sex, and education. MAIN OUTCOME MEASURES The mean fractional anisotropy values in the left and right uncinate fasciculus, as measured by tract-based analysis for diffusion-tensor imaging data. RESULTS Lower mean fractional anisotropy values in the bilateral uncinate fasciculus indicated reduced frontolimbic structural connectivity in patients with GAD. This reduction in uncinate fasciculus integrity was most pronounced for patients without comorbidity and was not observed in other white matter tracts. Across all participants, higher fractional anisotropy values were associated with more negative functional coupling between the pregenual anterior cingulate cortex and the amygdala during the anticipation of aversion. CONCLUSIONS Reduced structural connectivity of a major frontolimbic pathway suggests a neural basis for emotion regulation deficits in GAD. The functional significance of these structural differences is underscored by decreased functional connectivity between the anterior cingulate cortex and the amygdala in individuals with reduced structural integrity of the uncinate fasciculus.     

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.     

Ventral medial prefrontal functional connectivity and emotion regulation in chronic schizophrenia: A pilot study

People with schizophrenia exhibit impaired social cognitive functions, particularly emotion regulation. Abnormal activations of the ventral medial prefrontal cortex (vMPFC) during emotional tasks have been demonstrated in schizophrenia, suggesting its important role in emotion processing in patients. We used the resting-state functional connectivity approach, setting a functionally relevant region, the vMPFC, as a seed region to examine the intrinsic functional interactions and communication between the vMPFC and other brain regions in schizophrenic patients. We found hypo-connectivity between the vMPFC and the medial frontal cortex, right middle temporal lobe (MTL), right hippocampus, parahippocampal cortex (PHC) and amygdala. Further, there was a decreased strength of the negative connectivity (or anticorrelation) between the vMPFC and the bilateral dorsal lateral prefrontal cortex (DLPFC) and pre-supplementary motor areas. Among these connectivity alterations, reduced vMPFC-DLPFC connectivity was positively correlated with positive symptoms on the Positive and Negative Syndrome Scale, while vMPFC-right MTL/PHC/amygdala functional connectivity was positively correlated with the performance of emotional regulation in patients. These findings imply that communication and coordination throughout the brain networks are disrupted in schizophrenia. The emotional correlates of vMPFC connectivity suggest a role of the hypo-connectivity between these regions in the neuropathology of abnormal social cognition in chronic schizophrenia.     

Amygdala Connectivity Differs Among Chronic,Early Course,and Individuals at Risk for Developing Schizophrenia

Alterations in circuits involving the amygdala have been repeatedly implicated in schizophrenia neuropathology, given their role in stress, affective salience processing, and psychosis onset. Disturbances in amygdala whole-brain functional connectivity associated with schizophrenia have yet to be fully characterized despite their importance in psychosis. Moreover, it remains unknown if there are functional alterations in amygdala circuits across illness phases. To evaluate this possibility, we compared whole-brain amygdala connectivity in healthy comparison subjects (HCS), individuals at high risk (HR) for schizophrenia, individuals in the early course of schizophrenia (EC-SCZ), and patients with chronic schizophrenia (C-SCZ). We computed whole-brain resting-state connectivity using functional magnetic resonance imaging at 3T via anatomically defined individual-specific amygdala seeds. We identified significant alterations in amygdala connectivity with orbitofrontal cortex (OFC), driven by reductions in EC-SCZ and C-SCZ (effect sizes of 1.0 and 0.97, respectively), but not in HR for schizophrenia, relative to HCS. Reduced amygdala-OFC coupling was associated with schizophrenia symptom severity (r = .32, P < .015). Conversely, we identified a robust increase in amygdala connectivity with a brainstem region around noradrenergic arousal nuclei, particularly for HR individuals relative to HCS (effect size = 1.54), but not as prominently for other clinical groups. These results suggest that deficits in amygdala-OFC coupling could emerge during the initial episode of schizophrenia (EC-SCZ) and may present as an enduring feature of the illness (C-SCZ) in association with symptom severity but are not present in individuals with elevated risk for developing schizophrenia. Instead, in HR individuals, there appears to be increased connectivity in a circuit implicated in stress response.Key words: schizophrenia, prefrontal cortex, amygdala, connectivity, first episode, risk for schizophrenia     

An fMRI study of cognitive reappraisal in major depressive disorder and borderline personality disorder

BackgroundOne common denominator to the clinical phenotypes of borderline personality disorder (BPD) and major depressive disorder (MDD) is emotion regulation impairment. Although these two conditions have been extensively studied separately, it remains unclear whether their emotion regulation impairments are underpinned by shared or distinct neurobiological alterations.MethodsWe contrasted the neural correlates of negative emotion regulation across an adult sample of BPD patients (n = 19), MDD patients (n = 20), and healthy controls (HCs; n = 19). Emotion regulation was assessed using an established functional magnetic resonance imaging cognitive reappraisal paradigm. We assessed both task-related activations and modulations of interregional connectivity.ResultsWhen compared to HCs, patients with BPD and MDD displayed homologous decreased activation in the right ventrolateral prefrontal cortex (vlPFC) during cognitive reappraisal. In addition, the MDD group presented decreased activations in other prefrontal areas (i.e., left dorsolateral and bilateral orbitofrontal cortices), while the BPD group was characterized by a more extended pattern of alteration in the connectivity between the vlPFC and cortices of the visual ventral stream during reappraisal.ConclusionsThis study identified, for the first time, a shared neurobiological contributor to emotion regulation deficits in MDD and BPD characterized by decreased vlPFC activity, although we also observed disorder-specific alterations. In MDD, results suggest a primary deficit in the strength of prefrontal activations, while BPD is better defined by connectivity disruptions between the vlPFC and temporal emotion processing regions. These findings substantiate, in neurobiological terms, the different profiles of emotion regulation alterations observed in these disorders.     

Impaired context processing as a potential marker of psychosis risk state

While structural abnormalities of the dorsolateral prefrontal cortex (DLPFC) may pre-date and predict psychosis onset, the relationships between functional deficits, cognitive and psychosocial impairments has yet to be explored in the at-risk period. An established measure of cognitive control (AXCPT) was administered to demographically matched clinical-high-risk (CHR; n=25), first-episode schizophrenia (FE; n=35), and healthy control (HC; n=35) participants during functional magnetic resonance imaging (fMRI) to investigate these relationships. CHR and FE individuals demonstrated impaired context processing and reduced DLPFC activation relative to HC individuals during increased cognitive control demands. FE and CHR individuals' ability to increase DLPFC activity in response to cognitive control demands was associated with better task performance. Task performance was also associated with severity of disorganization and poverty symptoms in FE participants. These findings support more extensive studies using fMRI to examine the clinical significance of prefrontal cortical functioning in the earliest stages of psychosis.     

Threat-related amygdala functional connectivity is associated with 5-HTTLPR genotype and neuroticism

Communication between the amygdala and other brain regions critically regulates sensitivity to threat, which has been associated with risk for mood and affective disorders. The extent to which these neural pathways are genetically determined or correlate with risk-related personality measures is not fully understood. Using functional magnetic resonance imaging, we evaluated independent and interactive effects of the 5-HTTLPR genotype and neuroticism on amygdala functional connectivity during an emotional faces paradigm in 76 healthy individuals. Functional connectivity between left amygdala and medial prefrontal cortex (mPFC) and between both amygdalae and a cluster including posterior cingulate cortex, precuneus and visual cortex was significantly increased in 5-HTTLPR S′ allele carriers relative to L_AL_A individuals. Neuroticism was negatively correlated with functional connectivity between right amygdala and mPFC and visual cortex, and between both amygdalae and left lateral orbitofrontal (lOFC) and ventrolateral prefrontal cortex (vlPFC). Notably, 5-HTTLPR moderated the association between neuroticism and functional connectivity between both amygdalae and left lOFC/vlPFC, such that S′ carriers exhibited a more negative association relative to L_AL_A individuals. These findings provide novel evidence for both independent and interactive effects of 5-HTTLPR genotype and neuroticism on amygdala communication, which may mediate effects on risk for mood and affective disorders.     

Functional disconnections in the direct and indirect amygdala pathways for fear processing in schizophrenia

BACKGROUND: Schizophrenia patients show reduced neural activity, relative to controls, in the amygdala and its projection to the medial prefrontal cortex (MPFC) in response to fear perception. In this study we tested the hypothesis that schizophrenia is characterized by abnormal functional connectivity in the amygdala network underlying fear perception. METHODS: Functional MRI images were acquired from 14 schizophrenia patients and 14 matched healthy control subjects during an emotion perception task, in which fearful and neutral facial expression stimuli were presented pseudorandomly under nonconscious (using masking) and conscious conditions. Both subtraction and functional connectivity analyses were undertaken using a region of interest approach. RESULTS: In response to fearful facial expressions, schizophrenia patients displayed reduced amygdala activity, compared to controls, in both the conscious and nonconscious conditions. The amygdala displayed a reversal of the normal pattern of connectivity with the brainstem, visual cortex, and also with the dorsal and ventral divisions of the MPFC in the schizophrenia patients. CONCLUSIONS: The presence of functional disconnections in amygdala pathways suggests that schizophrenia patients have a failure in coordinating their automatic orienting to salient signals and the associated prefrontal monitoring of these signals.     

Altered relationships between age and functional brain activation in adolescents at clinical high risk for psychosis

Schizophrenia is considered a neurodevelopmental disorder, but whether the adolescent period, proximal to onset, is associated with aberrant development in individuals at clinical high risk (CHR) for psychosis is incompletely understood. While abnormal gray and white matter development has been observed, alterations in functional neuroimaging (fMRI) parameters during adolescence as related to conversion to psychosis have not yet been investigated. Twenty CHR individuals and 19 typically developing controls (TDC), (ages 14–21), were recruited from the Center for Assessment and Prevention of Prodromal States (CAPPS) at UCLA. Participants performed a Sternberg-style verbal working memory (WMem) task during fMRI and data were analyzed using a cross-sectional design to test the hypothesis that there is a deviant developmental trajectory in WMem associated neural circuitry in those at risk for psychosis. Eight of the CHR adolescents converted to psychosis within 2 years of initial assessment. A voxel-wise regression examining the relationship between age and activation revealed a significant group-by-age interaction. TDC showed a negative association between age and functional activation in the WMem circuitry while CHR adolescents showed a positive association. Moreover, CHR patients who later converted to overt psychosis showed a distinct pattern of abnormal age-associated activation in the frontal cortex relative to controls, while non-converters showed a more diffuse posterior pattern. Finding that age related variation in baseline patterns of neural activity differentiate individuals who subsequently convert to psychosis from healthy subjects suggests that these differences are likely to be clinically relevant.     

Alterations of fronto-temporal connectivity during word encoding in schizophrenia

Cognitive deficits, including impaired verbal memory, are prominent in schizophrenia and lead to increased disability. Functional neuroimaging of patients with schizophrenia performing memory tasks has revealed abnormal activation patterns in prefrontal cortex and temporo-limbic regions. Aberrant fronto-temporal interactions thus represent a potential pathophysiological mechanism underlying verbal memory deficits, yet this hypothesis of disturbed connectivity is not tested directly with standard activation studies. We performed within-subject correlations of frontal and temporal timeseries to measure functional connectivity during verbal encoding. Our results confirm earlier findings of aberrant fronto-temporal connectivity in schizophrenia, and extend them by identifying distinct alterations within dorsal and ventral prefrontal cortex. Relative to healthy controls, patients with schizophrenia had reduced connectivity between the dorsolateral prefrontal cortex (DLPFC) and temporal lobe areas including parahippocampus and superior temporal gyrus. In contrast, patients showed increased connectivity between a region of ventrolateral prefrontal cortex (VLPFC) and these same temporal lobe regions. Higher temporal-DLPFC connectivity during encoding was associated with better subsequent recognition accuracy in controls, but not patients. Temporal-VLPFC connectivity was uncorrelated with recognition accuracy in either group. The results suggest that reduced temporal-DLPFC connectivity in schizophrenia could underlie encoding deficits, and increased temporal-VLPFC connectivity may represent an ineffective compensatory effort.     

Distinct and opposite profiles of connectivity during self‐reference task and rest in youth at clinical high risk for psychosis

Self‐reference is impaired in psychotic disorders such as schizophrenia, associated with disability, and closely related to characteristic patterns of aberrant brain connectivity. However, at present, it is unclear whether self‐reference is impacted in pathogenesis of the disorder. Alterations in connectivity during a self‐reference task or resting‐state in the psychosis risk (i.e., prodromal) period may yield important clues for biomarker development, as well as for novel treatment targets. This study examined a task‐based and resting‐state functional magnetic resonance imaging in individuals at clinical high risk (CHR) for psychosis (n = 22) and healthy control unaffected peers (n = 20). The self‐reference task comprised three task conditions where subjects were asked if an adjective was relevant to themselves (self), a designated other individual (other), or to evaluate the word's spelling (letter). Connectivity analyses examined medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC), regions commonly found in conjunction analyses of self‐reference, during both the self‐reference task and rest. In task connectivity analyses, CHR individuals exhibited decreased mPFC–PCC connectivity when compared to controls. In resting‐state analyses, CHR participants showed greater mPFC–PCC connectivity. Taken together, results suggest that psychosis‐like alterations in mPFC–PCC connectivity is present prior to psychosis onset across both task and rest.     

Disrupted neural processing of emotional faces in psychopathy

Psychopaths show a reduced ability to recognize emotion facial expressions, which may disturb the interpersonal relationship development and successful social adaptation. Behavioral hypotheses point toward an association between emotion recognition deficits in psychopathy and amygdala dysfunction. Our prediction was that amygdala dysfunction would combine deficient activation with disturbances in functional connectivity with cortical regions of the face-processing network. Twenty-two psychopaths and 22 control subjects were assessed and functional magnetic resonance maps were generated to identify both brain activation and task-induced functional connectivity using psychophysiological interaction analysis during an emotional face-matching task. Results showed significant amygdala activation in control subjects only, but differences between study groups did not reach statistical significance. In contrast, psychopaths showed significantly increased activation in visual and prefrontal areas, with this latest activation being associated with psychopaths’ affective–interpersonal disturbances. Psychophysiological interaction analyses revealed a reciprocal reduction in functional connectivity between the left amygdala and visual and prefrontal cortices. Our results suggest that emotional stimulation may evoke a relevant cortical response in psychopaths, but a disruption in the processing of emotional faces exists involving the reciprocal functional interaction between the amygdala and neocortex, consistent with the notion of a failure to integrate emotion into cognition in psychopathic individuals.     

An Event-Related Potential Investigation of Early Visual Processing Deficits During Face Perception in Youth at Clinical High Risk for Psychosis

Impairments in early visual face perception are well documented in patients with schizophrenia. Specifically, event-related potential (ERP) research in patients with schizophrenia has demonstrated deficits in early sensory processing of stimulus properties (P1 component) and the structural encoding of faces (N170 component). However, it is not well understood if similar impairments are present in individuals at clinical high risk (CHR) for psychosis (ie, those in the putative prodromal stage of the illness). Thus, it is unknown if face perception deficits are the result of illness onset or are present in the high-risk period for the illness. The present study used the ERP technique to examine neural activation when viewing facial emotion expressions and objects in 44 CHR and 47 control adolescents and young adults (N = 91). P1 amplitude was similar across groups, indicating that early sensory processing impairments did not substantially contribute to face perception deficits in CHR youth. CHR youth exhibited reduced N170 amplitude compared to controls when viewing faces but not objects, implicating a specific deficit in the structural encoding of faces rather than a general perceptual deficit. Further, whereas controls demonstrated the expected face-selective N170 effect (ie, larger amplitude for faces than objects), CHR youth did not, which suggests that facial emotion expressions do not elicit the expected preferential perceptual processing for critical social information in individuals at CHR for psychosis. Together, these findings provide valuable information regarding the specific impairments contributing to face perception deficits in the high-risk period where treatment stands to aid in preventing illness progression.     

Age-Normative Pathways of Striatal Connectivity Related to Clinical Symptoms in the General Population

BackgroundAltered striatal development contributes to core deficits in motor and inhibitory control, impulsivity, and inattention associated with attention-deficit/hyperactivity disorder and may likewise play a role in deficient reward processing and emotion regulation in psychosis and depression. The maturation of striatal connectivity has not been well characterized, particularly as it relates to clinical symptomatology.MethodsResting-state functional connectivity with striatal subdivisions was examined for 926 participants (8–22 years of age, 44% male) from the general population who had participated in two large cross-sectional studies. Developing circuits were identified and growth charting of age-related connections was performed to obtain individual scores reflecting relative neurodevelopmental attainment. Associations of clinical symptom scales (attention-deficit/hyperactivity disorder, psychosis, depression, and general psychopathology) with the resulting striatal connectivity age-deviation scores were then tested using elastic net regression.ResultsLinear and nonlinear developmental patterns occurred across 231 striatal age-related connections. Both unique and overlapping striatal age-related connections were associated with the four symptom domains. Attention-deficit/hyperactivity disorder severity was related to age-advanced connectivity across several insula subregions, but to age-delayed connectivity with the nearby inferior frontal gyrus. Psychosis was associated with advanced connectivity with the medial prefrontal cortex and superior temporal gyrus, while aberrant limbic connectivity predicted depression. The dorsal posterior insula, a region involved in pain processing, emerged as a strong contributor to general psychopathology as well as to each individual symptom domain.ConclusionsDevelopmental striatal pathophysiology in the general population is consistent with dysfunctional circuitry commonly found in clinical populations. Atypical age-normative connectivity may thereby reflect aberrant neurodevelopmental processes that contribute to clinical risk.     

Age‐related effect of serotonin transporter genotype on amygdala and prefrontal cortex function in adolescence

The S and L_G alleles of the serotonin transporter‐linked polymorphic region (5‐HTTLPR) lower serotonin transporter expression. These low‐expressing alleles are linked to increased risk for depression and brain activation patterns found in depression (increased amygdala activation and decreased amygdala–prefrontal cortex connectivity). Paradoxically, serotonin transporter blockade relieves depression symptoms. Rodent models suggest that decreased serotonin transporter in early life produces depression that emerges in adolescence, whereas decreased serotonin transporter that occurs later in development ameliorates depression. However, no brain imaging research has yet investigated the moderating influence of human development on the link between 5‐HTTLPR and effect‐related brain function. We investigated the age‐related effect of 5‐HTTLPR on amygdala activation and amygdala–prefrontal cortex connectivity using a well‐replicated probe, an emotional face task, in children and adolescents aged 9–19 years. A significant genotype‐by‐age interaction predicted amygdala activation, such that the low‐expressing genotype (S/S and S/L_G) group showed a greater increase in amygdala activation with age compared to the higher expressing (L_A/L_A and S/L_A) group. Additionally, compared to the higher expressing group, the low‐expressing genotype group exhibited decreased connectivity between the right amygdala and ventromedial prefrontal cortex with age. Findings indicate that low‐expressing genotypes may not result in the corticolimbic profile associated with depression risk until later adolescence. Hum Brain Mapp 35:646–658, 2014. © 2012 Wiley‐Periodicals, Inc.     

The relationship between performance in a theory of mind task and intrinsic functional connectivity in youth with early onset psychosis

Psychotic disorders are characterized by theory of mind (ToM) impairment. Although ToM undergoes maturational changes throughout adolescence, there is a lack of studies examining ToM performance and its brain functional correlates in individuals with an early onset of psychosis (EOP; onset prior to age 18), and its relationship with age. Twenty-seven individuals with EOP were compared with 41 healthy volunteers using the “Reading-the-Mind-in-the-Eyes” Test, as a measure of ToM performance. A resting-state functional MRI scan was also acquired, in which the default mode network was used to identify areas relevant to ToM processing employing independent component analysis. Group effects revealed worse ToM performance and less intrinsic functional connectivity in the medial prefrontal cortex in EOP relative to healthy volunteers. Group by age interaction revealed age-positive associations in ToM task performance and in intrinsic connectivity in the medial prefrontal cortex in healthy volunteers, which were not present in EOP. Differences in ToM performance were partially mediated by intrinsic functional connectivity in the medial prefrontal cortex. Poorer ToM performance in EOP, coupled with less medial prefrontal cortex connectivity, could be associated with the impact of psychosis during a critical period of development of the social brain, limiting normative age-related maturation.     

Fatty acid amide hydrolase binding is inversely correlated with amygdalar functional connectivity: a combined positron emission tomography and magnetic resonance imaging study in healthy individuals

BackgroundUpregulation of the endocannabinoid enzyme fatty acid amide hydrolase (FAAH) has been linked to abnormal activity in frontoamygdalar circuits, a hallmark of posttraumatic stress disorder. We tested the hypothesis that FAAH levels in the amygdala were negatively correlated with functional connectivity between the amygdala and prefrontal cortex, subserving stress and affect control.MethodsThirty-one healthy participants completed positron emission tomography (PET) imaging with the FAAH probe [C-11]CURB, and resting-state functional MRI scans. Participants were genotyped for the FAAH polymorphism rs324420, and trait neuroticism was assessed. We calculated amygdala functional connectivity using pre-determined regions of interest (including the subgenual ventromedial prefrontal cortex [sgvmPFC] and the dorsal anterior cingulate cortex [dACC]) and a seed-to-voxel approach. We conducted correlation analyses on functional connectivity, with amygdala [C-11]CURB binding as a variable of interest.ResultsThe strength of amygdala functional connectivity with the sgvmPFC and dACC was negatively correlated with [C-11]CURB binding in the amygdala (sgvmPFC: r = −0.38, q = 0.04; dACC: r = −0.44; q = 0.03). Findings were partly replicated using the seed-to-voxel approach, which showed a cluster in the ventromedial prefrontal cortex, including voxels in the dACC but not the sgvmPFC (cluster-level, family-wise error rate corrected p < 0.05).LimitationsWe did not replicate earlier findings of a relationship between an FAAH polymorphism (rs324420) and amygdala functional connectivity.ConclusionOur data provide preliminary evidence that lower levels of FAAH in the amygdala relate to increased frontoamygdalar functional coupling. Our findings were consistent with the role of FAAH in regulating brain circuits that underlie fear and emotion processing in humans.