Dynamic Alterations in Neural Networks Supporting Aversive Learning in Children Exposed to Trauma: Neural Mechanisms Underlying Psychopathology.

BACKGROUND: Altered aversive learning represents a potential mechanism through which childhood trauma (CT) might influence risk for psychopathology. This study examines the temporal dynamics of neural activation and patterns of functional connectivity during aversive learning in children with and without exposure to CT involving interpersonal violence and evaluates whether these neural patterns mediate the association of CT with psychopathology in a longitudinal design. METHODS: A total of 147 children (aged 8-16 years, 77 with CT) completed a fear conditioning procedure during a functional magnetic resonance imaging scan. Dynamic patterns of neural activation were examined, and functional connectivity was assessed with generalized psychophysiological interaction analyses. We evaluated whether the associations between CT and psychopathology symptoms at baseline and 2-year follow-up were mediated by neural activation and connectivity during aversive learning. RESULTS: Children exposed to trauma displayed blunted patterns of neural activation over time to the conditioned threat versus safety stimuli (CS+>CS-) in the right amygdala. In addition, trauma was associated with reduced functional connectivity of right amygdala with the hippocampus, posterior parahippocampal gyrus, and posterior cingulate cortex and with elevated connectivity with the anterior cingulate cortex to CS+>CS-. The longitudinal association between CT and later externalizing symptoms was mediated by blunted activation in the right amygdala. Reduced amygdala-hippocampal connectivity mediated the association of CT with transdiagnostic anxiety symptoms, and elevated amygdala-anterior cingulate cortex connectivity mediated the association of CT with generalized anxiety symptoms. CONCLUSIONS: CT is associated with poor threat-safety discrimination and altered functional coupling between salience and default mode network regions during aversive learning. These altered dynamics may be key mechanisms linking CT with distinct forms of psychopathology.

Neural Abnormalities in Fear Generalization in Schizophrenia and Associations With Negative Symptoms.

BACKGROUND: Associative learning and memory processes, including the generalization of previously learned associations, may be altered in schizophrenia. Deficits in schizophrenia in stimulus generalization, one of the simplest forms of memory, could interfere with the ability to efficiently categorize related, similar information, potentially leading to impairments in daily functioning. METHODS: To measure generalization in schizophrenia, 37 individuals with a nonaffective psychotic disorder and 32 demographically matched healthy control subjects underwent a Pavlovian fear conditioning and generalization procedure, which accounted for variation in perceptual ability across participants, while undergoing functional magnetic resonance imaging. Skin conductance and neural responses to conditioned (CS+), neutral (CS-), and generalization stimuli were measured. Explicit memory ratings reflecting successful generalization were also collected after the scanning, as well as measures of symptom severity. RESULTS: Compared with healthy control subjects, individuals with nonaffective psychotic disorders showed significant deficits in fear generalization across multiple measurements, with impairments in memory ratings and reductions in activation and deactivation of the salience and default networks, respectively, during fear generalization. Moreover, in the psychotic disorder group, greater behavioral and neural abnormalities in generalization were associated with higher levels of negative symptoms. CONCLUSIONS: Fear generalization is impaired in psychotic illness. Given that successful generalization relies on a dynamic balance between excitatory and inhibitory neurotransmission, these results reveal a potentially quantifiable mechanism linked to negative symptoms that can be investigated further in future human and experimental animal studies.

Elevated Amygdala Activity in Young Adults With Familial Risk for Depression: A Potential Marker of Low Resilience.

BACKGROUND: Amygdala overactivity has been frequently observed in patients with depression, as well as in nondepressed relatives of patients with depression. A remaining unanswered question is whether elevated amygdala activity in those with familial risk for depression is related to the presence of subthreshold symptoms or to a trait-level vulnerability for illness. METHODS: To examine this question, functional magnetic resonance imaging data were collected in nondepressed young adults with (family history [FH+]) (n = 27) or without (FH-) (n = 45) a first-degree relative with a history of depression while they viewed images of "looming" or withdrawing stimuli (faces and cars) that varied in salience by virtue of their apparent proximity to the subject. Activation of the amygdala and 2 other regions known to exhibit responses to looming stimuli, the dorsal intraparietal sulcus (DIPS) and ventral premotor cortex (PMv), were measured, as well as levels of resilience, anxiety, and psychotic and depressive symptoms. RESULTS: Compared with the FH- group, the FH+ group exhibited significantly greater responses of the amygdala, but not the dorsal intraparietal sulcus or ventral premotor cortex, to looming face stimuli. Moreover, amygdala responses in the FH+ group were negatively correlated with levels of resilience and unrelated to levels of subthreshold symptoms of psychopathology. CONCLUSIONS: These findings indicate that elevated amygdala activity in nondepressed young adults with a familial history of depression is more closely linked to poor resilience than to current symptom state.

Increased amygdala-visual cortex connectivity in youth with persecutory ideation.

BACKGROUND: Subclinical delusional ideas, including persecutory beliefs, in otherwise healthy individuals are heritable symptoms associated with increased risk for psychotic illness, possibly representing an expression of one end of a continuum of psychosis severity. The identification of variation in brain function associated with these symptoms may provide insights about the neurobiology of delusions in clinical psychosis. METHODS: A resting-state functional magnetic resonance imaging scan was collected from 131 young adults with a wide range of severity of subclinical delusional beliefs, including persecutory ideas. Because of evidence for a key role of the amygdala in fear and paranoia, resting-state functional connectivity of the amygdala was measured. RESULTS: Connectivity between the amygdala and early visual cortical areas, including striate cortex (V1), was found to be significantly greater in participants with high (n = 43) v. low (n = 44) numbers of delusional beliefs, particularly in those who showed persistence of those beliefs. Similarly, across the full sample, the number of and distress associated with delusional beliefs were positively correlated with the strength of amygdala-visual cortex connectivity. Moreover, further analyses revealed that these effects were driven by those who endorsed persecutory beliefs. CONCLUSIONS: These findings are consistent with the hypothesis that aberrant assignments of threat to sensory stimuli may lead to the downstream development of delusional ideas. Taken together with prior findings of disrupted sensory-limbic coupling in psychosis, these results suggest that altered amygdala-visual cortex connectivity could represent a marker of psychosis-related pathophysiology across a continuum of symptom severity.

Mechanisms linking childhood adversity with psychopathology: Learning as an intervention target.

Exposure to childhood adversity is common and a powerful risk factor for many forms of psychopathology. In this opinion piece, we argue for greater translation of knowledge about the developmental processes that are influenced by childhood adversity into targeted interventions to prevent the onset of psychopathology. Existing evidence has consistently identified several neurodevelopmental pathways that serve as mechanisms linking adversity with psychopathology. We highlight three domains in which these mechanisms are well-established and point to clear targets for intervention: 1) threat-related social information processing biases; 2) heightened emotional reactivity and difficulties with emotion regulation; and 3) disruptions in reward processing. In contrast to these established pathways, knowledge of how childhood adversity influences emotional learning mechanisms, including fear and reward learning, is remarkably limited. We see the investigation of these mechanisms as a critical next step for the field that will not only advance understanding of developmental pathways linking childhood adversity with psychopathology, but also provide clear targets for behavioral interventions. Knowledge of the mechanisms linking childhood adversity with psychopathology has advanced rapidly, and the time has come to translate that knowledge into clinical interventions to prevent the onset of mental health problems in children who have experienced adversity.

Understanding the effects of emotional reactivity on depression and suicidal thoughts and behaviors: Moderating effects of childhood adversity and resilience.

BACKGROUND: Early adulthood is a period of increased risk for depression and suicide. Emotional reactivity (a tendency to react to stress with increases in negative affect and maladaptive interpretations of events) is an important risk factor for these outcomes that has been under-studied. We hypothesized that elevated emotional reactivity would be associated with higher levels of depressive symptoms and suicidal thoughts and behaviors. Further, we hypothesized that experiences of childhood maltreatment would amplify this relationship, whereas the presence of resilience would act as a buffer. METHODS: 1703 young adults (Mean Age = 19.56 years), 71% female) completed well-validated self-report questionnaires at a single time point. RESULTS: Higher emotional reactivity was directly associated with higher levels of depressive symptoms and suicidal thoughts and behaviors. Further, resilience levels significantly moderated the relationships between emotional reactivity and depressive symptoms and suicidal thoughts and behaviors. Finally, childhood trauma significantly moderated the relationship between emotional reactivity and suicidal thoughts and behaviors only. LIMITATIONS: This study was cross-sectional in design and relied upon self-report measures only. CONCLUSIONS: The current study demonstrates an association between emotional reactivity, depressive symptoms, and suicidal thoughts and behaviors during emerging adulthood. Whereas a history of childhood maltreatment may amplify the relationship between emotional reactivity, depression, and suicidal thoughts and behaviors, certain qualities associated with resilience may buffer against the effects of emotional reactivity. Future studies can identify the resilience-promoting factors that are most protective and develop and test interventions that can potentially augment those factors.

The relationship of perceptual discrimination to neural mechanisms of fear generalization.

The generalization of conditioned fear responses has been shown to decrease as a function of perceptual similarity. However, generalization may also extend beyond the perceptual discrimination threshold, ostensibly due to contributions from processes other than perception. Currently the neural mechanisms that mediate perceptual and non-perceptual aspects of fear generalization are unclear. To investigate this question, we conducted a Pavlovian fear conditioning and generalization experiment, collecting functional magnetic resonance imaging (fMRI), skin conductance and explicit shock likelihood ratings, in 37 healthy subjects. Face stimuli were initially paired (CS+) or not paired (CS) with an electrical shock. During the generalization phase, responses were measured to the CS+, CS and a range of CS + -toCS morphs (generalization stimuli), selected for each participant based on that participant's discrimination ability. Across multiple measurements, we found that fear generalization responses were limited to stimuli that could not be distinguished from the CS + stimulus, thus following a gradient closely linked to perceptual discriminability. These measurements, which were correlated with one another, included skin conductance responses, behavioral ratings, and fMRI responses of anterior insula and superior frontal gyrus. In contrast, responses in areas of the default network, including the posterior cingulate gyrus, angular gyrus and hippocampus, showed a negative generalization function extending to stimuli that were more likely to be distinguished from the CS+. In addition, the generalization gradients of the anterior insula and the behavioral ratings showed some evidence for extension beyond perceptual limits. Taken together, these results suggest that distinct brain areas are involved in perceptual and non-perceptual components of fear generalization.

Correlation Between Levels of Delusional Beliefs and Perfusion of the Hippocampus and an Associated Network in a Non-Help-Seeking Population.

BACKGROUND: Delusions are a defining and common symptom of psychotic disorders. Recent evidence suggests that subclinical and clinical delusions may represent distinct stages on a phenomenological and biological continuum. However, few studies have tested whether subclinical psychotic experiences are associated with neural changes that are similar to those observed in clinical psychosis. For example, it is unclear if overactivity of the hippocampus, a replicated finding of neuroimaging studies of schizophrenia, is also present in individuals with subclinical psychotic symptoms. METHODS: To investigate this question, structural and pulsed arterial spin labeling scans were collected in 77 adult participants with no psychiatric history. An anatomical region of interest approach was used to extract resting perfusion of the hippocampus, and 15 other regions, from each individual. A self-report measure of delusional ideation was collected on the day of scanning. RESULTS: The level of delusional thinking (number of beliefs [r = .27, p = .02]), as well as the associated level of distress (r = .29, p = .02), was significantly correlated with hippocampal perfusion (averaged over right and left hemispheres). The correlations remained significant after controlling for age, hippocampal volume, symptoms of depression and anxiety, and image signal-to-noise ratio, and they were confirmed in a voxelwise regression analysis. The same association was observed in the thalamus and parahippocampal, lateral temporal, and cingulate cortices. CONCLUSIONS: Similar to patients with schizophrenia, non-help-seeking individuals show elevated perfusion of a network of limbic regions in association with delusional beliefs.

Abnormalities in personal space and parietal-frontal function in schizophrenia.

Schizophrenia is associated with subtle abnormalities in day-to-day social behaviors, including a tendency in some patients to "keep their distance" from others in physical space. The neural basis of this abnormality, and related changes in social functioning, is unknown. Here we examined, in schizophrenic patients and healthy control subjects, the functioning of a parietal-frontal network involved in monitoring the space immediately surrounding the body ("personal space"). Using fMRI, we found that one region of this network, the dorsal intraparietal sulcus (DIPS), was hyper-responsive in schizophrenic patients to face stimuli appearing to move towards the subjects, intruding into personal space. This hyper-responsivity was predicted both by the size of personal space (which was abnormally elevated in the schizophrenia group) and the severity of negative symptoms. In contrast, in a second study, the activity of two lower-level visual areas that send information to DIPS (the fusiform face area and middle temporal area) was normal in schizophrenia. Together, these findings suggest that changes in parietal-frontal networks that support the sensory-guided initiation of behavior, including actions occurring in the space surrounding the body, contribute to social dysfunction and negative symptoms in schizophrenia.