Stephen J. Fromm

Hierarchical and asymmetric temporal sensitivity in human auditory cortices

Lateralization of function in auditory cortex has remained a persistent puzzle. Previous studies using signals with differing spectrotemporal characteristics support a model in which the left hemisphere is more sensitive to temporal and the right more sensitive to spectral stimulus attributes. Here we use single-trial sparse-acquisition fMRI and a stimulus with parametrically varying segmental structure affecting primarily temporal properties. We show that both left and right auditory cortices are remarkably sensitive to temporal structure. Crucially, beyond bilateral sensitivity to timing information, we uncover two functionally significant interactions. First, local spectrotemporal signal structure is differentially processed in the superior temporal gyrus. Second, lateralized responses emerge in the higher-order superior temporal sulcus, where more slowly modulated signals preferentially drive the right hemisphere. The data support a model in which sounds are analyzed on two distinct timescales, 25–50 ms and 200–300 ms.

Relationship Between Amygdala Responses to Masked Faces and Mood State and Treatment in Major Depressive Disorder

CONTEXT Major depressive disorder (MDD) is associated with behavioral and neurophysiological evidence of mood-congruent processing biases toward explicitly presented, emotionally valenced stimuli. However, few studies have investigated such biases toward implicitly presented stimuli. OBJECTIVE To investigate differential amygdala responses to sad, happy, and neutral faces presented below the level of explicit conscious awareness using a backward masking task in unmedicated participants with MDD and healthy controls (HCs). DESIGN Initial cross-sectional design followed by a longitudinal treatment trial using functional magnetic resonance imaging. SETTING Psychiatric outpatient clinic at the National Institute of Mental Health. PARTICIPANTS We studied 22 unmedicated, currently depressed people with MDD (dMDD), 16 unmedicated individuals with MDD in full remission (rMDD), and 25 HCs. INTERVENTION Ten dMDD participants underwent 8 weeks of antidepressant treatment with the selective serotonin reuptake inhibitor sertraline hydrochloride. MAIN OUTCOME MEASURES Amygdala region-of-interest and whole-brain analyses evaluated the hemodynamic response during exposure to masked sad vs masked happy faces, to masked sad vs neutral faces, and to masked happy vs neutral faces. RESULTS The dMDD participants showed greater amygdala responses than HCs to masked sad faces, whereas HCs showed greater amygdala responses to masked happy faces. The bias toward sad faces also was evident in rMDD participants relative to HCs and did not differ between dMDD and rMDD participants. This processing bias reversed toward the normative pattern in dMDD participants after sertraline treatment. CONCLUSIONS Emotional-processing biases occur in amygdala responses to sad faces presented below the level of conscious awareness in dMDD or rMDD individuals and to happy faces in HCs. By influencing the salience of social stimuli, mood-congruent processing biases in the amygdala may contribute to dysfunction in conscious perceptions and social interactions in MDD. Our data suggest, however, that the negative bias resolves and a positive bias develops in patients with MDD during selective serotonin reuptake inhibitor treatment.

A developmental examination of amygdala response to facial expressions

Several lines of evidence implicate the amygdala in face-emotion processing, particularly for fearful facial expressions. Related findings suggest that face-emotion processing engages the amygdala within an interconnected circuitry that can be studied using a functional-connectivity approach. Past work also underscores important functional changes in the amygdala during development. Taken together, prior research on amygdala function and development reveals a need for more work examining developmental changes in the amygdalas response to fearful faces and in amygdala functional connectivity during face processing. The present study used event-related functional magnetic resonance imaging to compare 31 adolescents (917 years old) and 30 adults (2140 years old) on activation to fearful faces in the amygdala and other regions implicated in face processing. Moreover, these data were used to compare patterns of amygdala functional connectivity in adolescents and adults. During passive viewing, adolescents demonstrated greater amygdala and fusiform activation to fearful faces than did adults. Functional connectivity analysis revealed stronger connectivity between the amygdala and the hippocampus in adults than in adolescents. Within each group, variability in age did not correlate with amygdala response, and sex-related developmental differences in amygdala response were not found. Eye movement data collected outside of the magnetic resonance imaging scanner using the same task suggested that developmental differences in amygdala activation were not attributable to differences in eye-gaze patterns. Amygdala hyperactivation in response to fearful faces may explain increased vulnerability to affective disorders in adolescence; stronger amygdala-hippocampus connectivity in adults than adolescents may reflect maturation in learning or habituation to facial expressions.

Amygdala Activation During Emotion Processing of Neutral Faces in Children With Severe Mood Dysregulation Versus ADHD or Bipolar Disorder

OBJECTIVE To understand disorder-unique and common pathophysiology, studies in multiple patient groups with overlapping symptoms are needed. Deficits in emotion processing and hyperarousal symptoms are prominent features of bipolar disorder, attention deficit hyperactivity disorder (ADHD), and severe mood dysregulation. The authors compared amygdala response during emotional and nonemotional ratings of neutral faces in youths with these disorders as well as a group of healthy comparison youths. METHOD Blood-oxygen-level-dependent (BOLD) signal in the amygdala was examined in children with bipolar disorder (N=43), ADHD (N=18), and severe mood dysregulation (N=29) and healthy comparison subjects (N=37). During functional magnetic resonance imaging (fMRI), participants attended to emotional and nonemotional aspects of neutral faces. RESULTS While rating subjective fear of neutral faces, youths with ADHD demonstrated left amygdala hyperactivity relative to the other three groups, whereas youths with severe mood dysregulation demonstrated hypoactivity. CONCLUSIONS These findings support the role of unique neural correlates in face-emotion processing among youths with bipolar disorder, ADHD, and severe mood dysregulation.

Common and Distinct Amygdala-Function Perturbations in Depressed vs Anxious Adolescents

CONTEXT Few studies directly compare amygdala function in depressive and anxiety disorders. Data from longitudinal research emphasize the need for such studies in adolescents. OBJECTIVE To compare amygdala response to varying attention and emotion conditions among adolescents with major depressive disorder (MDD) or anxiety disorders, relative to adolescents with no psychopathology. DESIGN Case-control study. SETTING Government clinical research institute. PARTICIPANTS Eighty-seven adolescents matched on age, sex, intelligence, and social class: 26 with MDD (14 with and 12 without anxiety disorders), 16 with anxiety disorders but no depression, and 45 without psychopathology. MAIN OUTCOME MEASURES Blood oxygen level-dependent signal in the amygdala, measured by means of event-related functional magnetic resonance imaging. During imaging, participants viewed facial expressions (neutral, fearful, angry, and happy) while attention was constrained (afraid, hostility, and nose-width ratings) or unconstrained (passive viewing). RESULTS Left and right amygdala activation differed as a function of diagnosis, facial expression, and attention condition both when patients with comorbid MDD and anxiety were included and when they were excluded (group x emotion x attention interactions, P < or = .03). Focusing on fearful face-viewing events, patients with anxiety and those with MDD both differed in amygdala responses from healthy participants and from each other during passive viewing. However, both MDD and anxiety groups, relative to healthy participants, exhibited similar signs of amygdala hyperactivation to fearful faces when subjectively experienced fear was rated. CONCLUSIONS Adolescent MDD and anxiety disorders exhibit common and distinct functional neural correlates during face processing. Attention modulates the degree to which common or distinct amygdala perturbations manifest in these patient groups, relative to healthy peers.

Serotonin transporter binding in bipolar disorder assessed using [11C]DASB and positron emission tomography.

BACKGROUND Evidence from neuroimaging post-mortem, and genetic studies suggests that bipolar disorder (BD) is associated with abnormalities of the serotonin-transporter (5-HTT) system. Because of various limitations of these studies, however, it has remained unclear whether 5-HTT binding is abnormal in unmedicated BD-subjects. This study used PET and [(11)C]DASB, a radioligand that afforded higher sensitivity and specificity for the 5-HTT than previously available radioligands, to compare 5-HTT binding between BD and control subjects. METHODS The 5-HTT binding-potential (BP) was assessed in 18 currently-depressed, unmedicated BD-subjects and 37 healthy controls using PET and [(11)C]DASB. RESULTS In BD, the mean 5-HTT BP was increased in thalamus, dorsal cingulate cortex (DCC), medial prefrontal cortex and insula and decreased in the brainstem at the level of the pontine raphe-nuclei. Anxiety ratings correlated positively with 5-HTT BP in insula and DCC, and BP in these regions was higher in subjects manifesting pathological obsessions and compulsions relative to BD-subjects lacking such symptoms. Subjects with a history of suicide attempts showed reduced 5-HTT binding in the midbrain and increased binding in anterior cingulate cortex versus controls and to BD-subjects without attempts. CONCLUSIONS This is the first study to report abnormalities in 5-HTT binding in unmedicated BD-subjects. The direction of abnormality in the brainstem was opposite to that found in the cortex, thalamus, and striatum. Elevated 5-HTT binding in the cortex may be related to anxiety symptoms and syndromes associated with BD.

Neural Response to Catecholamine Depletion in Unmedicated Subjects With Major Depressive Disorder in Remission and Healthy Subjects

CONTEXT The pathophysiologic mechanism of major depressive disorder (MDD) has been consistently associated with altered catecholaminergic function, especially with decreased dopamine neurotransmission, by various sources of largely indirect evidence. An instructive paradigm for more directly investigating the relationship between catecholaminergic function and depression has involved the mood response to experimental catecholamine depletion (CD). OBJECTIVES To determine whether catecholaminergic dysfunction represents a trait abnormality in MDD and to identify brain circuitry abnormalities involved in the pathophysiologic mechanism of MDD. DESIGN Randomized, double-blind, placebo-controlled, crossover, single-site experimental trial. SETTING Psychiatric outpatient clinic. PARTICIPANTS Fifteen unmedicated subjects with MDD in full remission (hereinafter referred to as RMDD subjects) and 13 healthy controls. INTERVENTION Induction of CD by oral administration of alpha-methylparatyrosine. Sham depletion used identical capsules containing hydrous lactose. MAIN OUTCOME MEASURES Quantitative positron emission tomography of regional cerebral glucose utilization to study the neural effects of CD and sham depletion. Behavioral assessments included the Montgomery-Asberg Depression Rating Scale and the Snaith-Hamilton Pleasure Scale (anhedonia). RESULTS Depressive and anhedonic symptoms increased during CD to a greater extent in RMDD subjects than in controls. In both groups, CD increased metabolism in the anteroventral striatum and decreased metabolism in the orbital gyri. In a limbic-cortical-striatal-pallidal-thalamic network previously implicated in MDD, composed of the ventromedial frontal polar cortex, midcingulate and subgenual anterior cingulate cortex, temporopolar cortex, ventral striatum, and thalamus, metabolism increased in RMDD subjects but decreased or remained unchanged in controls. Metabolic changes induced by CD in the left ventromedial frontal polar cortex correlated positively with depressive symptoms, whereas changes in the anteroventral striatum were correlated with anhedonic symptoms. CONCLUSIONS This study provides direct evidence for catecholaminergic dysfunction as a trait abnormality in MDD. It demonstrates that depressive and anhedonic symptoms as a result of decreased catecholaminergic neurotransmission are related to elevated activity within the limbic-cortical-striatal-pallidal-thalamic circuitry.

Neural connectivity in children with bipolar disorder: impairment in the face emotion processing circuit.

BACKGROUND Pediatric bipolar disorder (BD), a highly debilitating illness, is characterized by amygdala abnormalities, i.e., volume reduction and hyperactivation during face processing. Evidence of perturbed amygdala functional connectivity with other brain regions would implicate a distributed neural circuit in the pathophysiology of BD, and would further elucidate the neural mechanisms associated with BD face emotion misinterpretation. METHODS Thirty-three BD and 24 healthy age, gender, and IQ-matched subjects completed a functional magnetic resonance imaging (fMRI) task of face emotion identification in which attention was directed to emotional (hostility, fearfulness) and nonemotional (nose width) aspects of faces. Voxel-wise analyses examined whole brain functional connectivity with the left amygdala. RESULTS Compared to healthy subjects, BD subjects had significantly reduced connectivity between the left amygdala and two regions: right posterior cingulate/precuneus and right fusiform gyrus/parahippocampal gyrus. Deficits were evident regardless of mood state and comorbid diagnoses. CONCLUSIONS BD youth exhibit deficient connectivity between the amygdala and temporal association cortical regions previously implicated in processing facial expressions and social stimuli. In conjunction with previously documented volumetric and functional perturbations in these brain regions, dysfunction in this distributed neural circuit may begin to clarify the pathophysiology of the face emotion misperceptions and social deficits seen in BD youth.

Cerebral Blood Flow in Immediate and Sustained Anxiety

The goal of this study was to compare cerebral blood flow (CBF) changes associated with phasic cued fear versus those associated with sustained contextual anxiety. Positron emission tomography images of CBF were acquired using [O-15]H2O in 17 healthy human subjects as they anticipated unpleasant electric shocks that were administered predictably (signaled by a visual cue) or unpredictably (threatened by the context). Presentation of the cue in either threat condition was associated with increased CBF in the left amygdala. A cue that specifically predicted the shock was associated with CBF increases in the ventral prefrontal cortex (PFC), hypothalamus, anterior cingulate cortex, left insula, and bilateral putamen. The sustained threat context increased CBF in the right hippocampus, mid-cingulate gyrus, subgenual PFC, midbrain periaqueductal gray, thalamus, bilateral ventral striatum, and parieto-occipital cortex. This study showed distinct neuronal networks involved in cued fear and contextual anxiety underlying the importance of this distinction for studies on the pathophysiology of anxiety disorders.

Increased Amygdala Activity During Successful Memory Encoding in Adolescent Major Depressive Disorder: An fMRI Study

BACKGROUND Although major depressive disorder (MDD) represents one of the most serious psychiatric problems afflicting adolescents, efforts to understand the neural circuitry of adolescent MDD have lagged behind those of adult MDD. This study tests the hypothesis that adolescent MDD is associated with abnormal amygdala activity during evocative-face viewing. METHODS Using functional magnetic resonance imaging (fMRI), between-group differences among MDD (n = 10), anxious (n = 11), and non-psychiatric comparisons (n = 23) were examined during successful vs. unsuccessful face encoding, with encoding success measured post-scan. RESULTS Compared to healthy adolescents, MDD patients exhibited poorer memory for faces. fMRI analyses accounted for this performance difference through event-related methods. In an analysis comparing successful vs. unsuccessful face encoding, MDD patients exhibited greater left amygdala activation relative to healthy and anxious youth. CONCLUSIONS Given prior findings among adults, this study suggests that adolescent and adult MDD may involve similar underlying abnormalities in amygdala functioning.