Jiook Cha

Circuit-Wide Structural and Functional Measures Predict Ventromedial Prefrontal Cortex Fear Generalization: Implications for Generalized Anxiety Disorder

The ventromedial prefrontal cortex (vmPFC) plays a critical role in a number of evaluative processes, including risk assessment. Impaired discrimination between threat and safety is considered a hallmark of clinical anxiety. Here, we investigated the circuit-wide structural and functional mechanisms underlying vmPFC threat–safety assessment in humans. We tested patients with generalized anxiety disorder (GAD; n = 32, female) and healthy controls (n = 25, age-matched female) on a task that assessed the generalization of conditioned threat during fMRI scanning. The task consisted of seven rectangles of graded widths presented on a screen; only the midsize one was paired with mild electric shock [conditioned stimulus (CS)], while the others, safety cues, systematically varied in width by ±20, 40, and 60% [generalization stimuli (GS)] compared with the CS. We derived an index reflecting vmPFC functioning from the BOLD reactivity on a continuum of threat (CS) to safety (GS least similar to CS); patients with GAD showed less discrimination between threat and safety cues, compared with healthy controls (Greenberg et al., 2013b). Using structural, functional (i.e., resting-state), and diffusion MRI, we measured vmPFC thickness, vmPFC functional connectivity, and vmPFC structural connectivity within the corticolimbic systems. The results demonstrate that all three factors predict individual variability of vmPFC threat assessment in an independent fashion. Moreover, these neural features are also linked to GAD, most likely via an vmPFC fear generalization. Our results strongly suggest that vmPFC threat processing is closely associated with broader corticolimbic circuit anomalies, which may synergistically contribute to clinical anxiety.

Small-world network properties in prefrontal cortex correlate with predictors of psychopathology risk in young children: A NIRS study

Near infrared spectroscopy (NIRS) is an emerging imaging technique that is relatively inexpensive, portable, and particularly well suited for collecting data in ecological settings. Therefore, it holds promise as a potential neurodiagnostic for young children. We set out to explore whether NIRS could be utilized in assessing the risk of developmental psychopathology in young children. A growing body of work indicates that temperament at young age is associated with vulnerability to psychopathology later on in life. In particular, it has been shown that low effortful control (EC), which includes the focusing and shifting of attention, inhibitory control, perceptual sensitivity, and a low threshold for pleasure, is linked to conditions such as anxiety, depression and attention deficit hyperactivity disorder (ADHD). Physiologically, EC has been linked to a control network spanning among other sites the prefrontal cortex. Several psychopathologies, such as depression and ADHD, have been shown to result in compromised small-world network properties. Therefore we set out to explore the relationship between EC and the small-world properties of PFC using NIRS. NIRS data were collected from 44 toddlers, ages 3-5, while watching naturalistic stimuli (movie clips). Derived complex network measures were then correlated to EC as derived from the Childrens Behavior Questionnaire (CBQ). We found that reduced levels of EC were associated with compromised small-world properties of the prefrontal network. Our results suggest that the longitudinal NIRS studies of complex network properties in young children hold promise in furthering our understanding of developmental psychopathology.

Influence of the BDNF Genotype on Amygdalo-Prefrontal White Matter Microstructure is Linked to Nonconscious Attention Bias to Threat

Cognitive processing biases, such as increased attention to threat, are gaining recognition as causal factors in anxiety. Yet, little is known about the anatomical pathway by which threat biases cognition and how genetic factors might influence the integrity of this pathway, and thus, behavior. For 40 normative adults, we reconstructed the entire amygdalo-prefrontal white matter tract (uncinate fasciculus) using diffusion tensor weighted MRI and probabilistic tractography to test the hypothesis that greater fiber integrity correlates with greater nonconscious attention bias to threat as measured by a backward masked dot-probe task. We used path analysis to investigate the relationship between brain-derived nerve growth factor genotype, uncinate fasciculus integrity, and attention bias behavior. Greater structural integrity of the amygdalo-prefrontal tract correlates with facilitated attention bias to nonconscious threat. Genetic variability associated with brain-derived nerve growth factor appears to influence the microstructure of this pathway and, in turn, attention bias to nonconscious threat. These results suggest that the integrity of amygdalo-prefrontal projections underlie nonconscious attention bias to threat and mediate genetic influence on attention bias behavior. Prefrontal cognition and attentional processing in high bias individuals appear to be heavily influenced by nonconscious threat signals relayed via the uncinate fasciculus.

Neural Correlates of Aggression in Medication-Naive Children with ADHD: Multivariate Analysis of Morphometry and Tractography.

Aggression is widely observed in children with attention deficit/hyperactivity disorder (ADHD) and has been frequently linked to frustration or the unsatisfied anticipation of reward. Although animal studies and human functional neuroimaging implicate altered reward processing in aggressive behaviors, no previous studies have documented the relationship between fronto-accumbal circuitry—a critical cortical pathway to subcortical limbic regions—and aggression in medication-naive children with ADHD. To address this, we collected behavioral measures and parental reports of aggression and impulsivity, as well as structural and diffusion MRI, from 30 children with ADHD and 31 healthy controls (HC) (mean age, 10±2.1 SD). Using grey matter morphometry and probabilistic tractography combined with multivariate statistical modeling (partial least squares regression and support vector regression), we identified anomalies within the fronto-accumbal circuit in childhood ADHD, which were associated with increased aggression. More specifically, children with ADHD showed reduced right accumbal volumes and frontal-accumbal white matter connectivity compared with HC. The magnitude of the accumbal volume reductions within the ADHD group was significantly correlated with increased aggression, an effect mediated by the relationship between the accumbal volume and impulsivity. Furthermore, aggression, but not impulsivity, was significantly explained by multivariate measures of fronto-accumbal white matter connectivity and cortical thickness within the orbitofrontal cortex. Our multi-modal imaging, combined with multivariate statistical modeling, indicates that the fronto-accumbal circuit is an important substrate of aggression in children with ADHD. These findings suggest that strategies aimed at probing the fronto-accumbal circuit may be beneficial for the treatment of aggressive behaviors in childhood ADHD.

Hyper-reactive human ventral tegmental area and aberrant mesocorticolimbic connectivity in overgeneralization of fear in generalized anxiety disorder.

The ventral tegmental area (VTA) has been primarily implicated in reward-motivated behavior. Recently, aberrant dopaminergic VTA signaling has also been implicated in anxiety-like behaviors in animal models. These findings, however, have yet to be extended to anxiety in humans. Here we hypothesized that clinical anxiety is linked to dysfunction of the mesocorticolimbic circuit during threat processing in humans; specifically, excessive or dysregulated activity of the mesocorticolimbic aversion circuit may be etiologically related to errors in distinguishing cues of threat versus safety, also known as “overgeneralization of fear.” To test this, we recruited 32 females with generalized anxiety disorder and 25 age-matched healthy control females. We measured brain activity using fMRI while participants underwent a fear generalization task consisting of pseudo-randomly presented rectangles with systematically varying widths. A mid-sized rectangle served as a conditioned stimulus (CS; 50% electric shock probability) and rectangles with widths of CS ±20%, ±40%, and ±60% served as generalization stimuli (GS; never paired with electric shock). Healthy controls showed VTA reactivity proportional to the cues perceptual similarity to CS (threat). In contrast, patients with generalized anxiety disorder showed heightened and less discriminating VTA reactivity to GS, a feature that was positively correlated with trait anxiety, as well as increased mesocortical and decreased mesohippocampal coupling. Our results suggest that the human VTA and the mesocorticolimbic system play a crucial role in threat processing, and that abnormalities in this system are implicated in maladaptive threat processing in clinical anxiety.

Increased Default Mode Network Connectivity in Individuals at High Familial Risk for Depression.

Research into the pathophysiology of major depressive disorder (MDD) has focused largely on individuals already affected by MDD. Studies have thus been limited in their ability to disentangle effects that arise as a result of MDD from precursors of the disorder. By studying individuals at high familial risk for MDD, we aimed to identify potential biomarkers indexing risk for developing MDD, a critical step toward advancing prevention and early intervention. Using resting-state functional connectivity MRI (rs-fcMRI) and diffusion MRI (tractography), we examined connectivity within the default mode network (DMN) and between the DMN and the central executive network (CEN) in 111 individuals, aged 11–60 years, at high and low familial risk for depression. Study participants were part of a three-generation longitudinal, cohort study of familial depression. Based on rs-fcMRI, individuals at high vs low familial risk for depression showed increased DMN connectivity, as well as decreased DMN-CEN-negative connectivity. These findings remained significant after excluding individuals with a current or lifetime history of depression. Diffusion MRI measures based on tractography supported the findings of decreased DMN-CEN-negative connectivity. Path analyses indicated that decreased DMN-CEN-negative connectivity mediated a relationship between familial risk and a neuropsychological measure of impulsivity. Our findings suggest that DMN and DMN-CEN connectivity differ in those at high vs low risk for depression and thus suggest potential biomarkers for identifying individuals at risk for developing MDD.

Functional and structural amygdala – Anterior cingulate connectivity correlates with attentional bias to masked fearful faces

An attentional bias to threat has been causally related to anxiety. Recent research has linked nonconscious attentional bias to threat with variability in the integrity of the amygdala - anterior cingulate pathway, which sheds light on the neuroanatomical basis for a behavioral precursor to anxiety. However, the extent to which structural variability in amygdala - anterior cingulate integrity relates to the functional connectivity within this pathway and how such functional connectivity may relate to attention bias behavior, remain critical missing pieces of the puzzle. In 15 individuals we measured the structural integrity of the amygdala - prefrontal pathway with diffusion tensor-weighted MRI (magnetic resonance imaging), amygdala-seeded intrinsic functional connectivity to the anterior cingulate, and attentional bias toward backward masked fearful faces with a dot-probe task. We found that greater biases in attention to threat predicted greater levels of uncinate fasciculus integrity, greater positive amygdala - anterior cingulate functional connectivity, and greater amygdala coupling with a broader social perception network including the superior temporal sulcus, tempoparietal junction (TPJ), and somatosensory cortex. Additionally, greater levels of uncinate fasciculus integrity correlated with greater levels of amygdala - anterior cingulate intrinsic functional connectivity. Thus, high bias individuals displayed a heightened degree of amygdala - anterior cingulate connectivity during basal conditions, which we believe predisposes these individuals to focus their attention on signals of threat within their environment.

Abnormal reward circuitry in anorexia nervosa: A longitudinal, multimodal MRI study

Anorexia nervosa (AN) is a debilitating illness and existing interventions are only modestly effective. This study aimed to determine whether AN pathophysiology is associated with altered connections within fronto‐accumbal circuitry subserving reward processing. Diffusion and resting‐state functional MRI scans were collected in female inpatients with AN (n = 22) and healthy controls (HC; n = 18) between the ages of 16 and 25 years. Individuals with AN were scanned during the acute, underweight phase of the illness and again following inpatient weight restoration. HC were scanned twice over the same timeframe. Based on univariate and multivariate analyses of fronto‐accumbal circuitry, underweight individuals with AN were found to have increased structural connectivity (diffusion probabilistic tractography), increased white matter anisotropy (tract‐based spatial statistics), increased functional connectivity (seed‐based correlation in resting‐state fMRI), and altered effective connectivity (spectral dynamic causal modeling). Following weight restoration, fronto‐accumbal structural connectivity continued to be abnormally increased bilaterally with large (partial η2 = 0.387; right NAcc‐OFC) and moderate (partial η2 = 0.197; left NAcc‐OFC) effect sizes. Increased structural connectivity within fronto‐accumbal circuitry in the underweight state correlated with severity of eating disorder symptoms. Taken together, the findings from this longitudinal, multimodal neuroimaging study offer converging evidence of atypical fronto‐accumbal circuitry in AN. Hum Brain Mapp 37:3835–3846, 2016.

Alterations in amygdala–prefrontal circuits in infants exposed to prenatal maternal depression

Prenatal exposure to maternal depression is common and puts offspring at risk for developing a range of neuropsychiatric disorders. Despite its prevalence and adverse associations, neurobiological processes by which prenatal maternal depression (PMD) confers risk remain poorly understood. Maternal mood and fetal behavior were assessed between 34 and 37 gestational weeks. Using resting-state functional magnetic resonance imaging (fMRI) and diffusion MRI, we examined functional and structural connectivity within amygdala–prefrontal circuits in 64 infants (mean age=5.8±1.7 weeks) with (n=20) and without (n=44) in utero exposure to PMD. Resting fMRI and diffusion MRI both indicated atypical amygdala–prefrontal connectivity in PMD-exposed infants: Resting fMRI indicated increased inverse, or negative, functional connectivity between the amygdala and the dorsal prefrontal cortex (PFC), bilaterally, and diffusion MRI indicated decreased structural connectivity between the right amygdala and the right ventral PFC. Spectral dynamic causal modeling supported these findings suggesting altered amygdala–PFC effective (or directed) connectivity in PMD-exposed infants. Last, path analyses supported a mechanistic account relating PMD to a third-trimester fetal behavior: PMD alters amygdala–PFC connectivity, which in turn, is associated with an increase in fetal heart rate reactivity to in utero perturbation. These data suggest that the maturation and coordination of central and peripheral physiology are altered by prenatal exposure to maternal depression. To the best of our knowledge, this is the first study to directly associate infant MRI measures with a behavior—fetal heart rate response, and supports hypotheses that PMD-associated variations in the development of amygdala–PFC circuits are relevant for future neurobehavioral maturation.

Evidence for Thalamocortical Circuit Abnormalities and Associated Cognitive Dysfunctions in Underweight Individuals with Anorexia Nervosa.

Anorexia nervosa (AN) is characterized by extremely low body weight resulting from pathological food restriction, and carries a mortality rate among the highest of any psychiatric illness. AN, particularly during the acute, underweight state of the illness, has been associated with abnormalities across a range of brain regions, including the frontal cortex and basal ganglia. Few studies of AN have investigated the thalamus, a key mediator of information flow through frontal-basal ganglia circuit loops. We examined both thalamic surface morphology using anatomical MRI and thalamo-frontal functional connectivity using resting-state functional MRI. Individuals with AN (n=28) showed localized inward deformations of the thalamus relative to healthy controls (HC, n=22), and abnormal functional connectivity between the thalamus and the dorsolateral and anterior prefrontal cortices. Alterations in thalamo-frontal connectivity were associated with deficits in performance on tasks probing cognitive control (Stroop task) and working memory (Letter-Number Sequencing (LNS) task). Our findings suggest that abnormalities in thalamo-frontal circuits may have a role in mediating aspects of cognitive dysfunction in underweight individuals with AN.