Daniel A. Fitzgerald

Neural Substrates for Voluntary Suppression of Negative Affect: A Functional Magnetic Resonance Imaging Study

BACKGROUND Successful control of affect partly depends on the capacity to modulate negative emotional responses through the use of cognitive strategies. Although the capacity to regulate emotions is critical to mental well-being, its neural substrates remain unclear. METHODS We used functional magnetic resonance imaging to ascertain brain regions involved in the voluntary regulation of emotion and whether dynamic changes in negative emotional experience can modulate their activation. Fourteen healthy subjects were scanned while they either maintained the negative affect evoked by highly arousing and aversive pictures (e.g., experience naturally) or suppressed their affect using cognitive reappraisal. In addition to a condition-based analysis, online subjective ratings of intensity of negative affect were used as covariates of brain activity. RESULTS Inhibition of negative affect was associated with activation of dorsal anterior cingulate, dorsal medial prefrontal, and lateral prefrontal cortices, and attenuation of brain activity within limbic regions (e.g., nucleus accumbens/extended amygdala). Furthermore, activity within dorsal anterior cingulate was inversely related to intensity of negative affect, whereas activation of the amygdala was positively covaried with increasing negative affect. CONCLUSIONS These findings highlight a functional dissociation of corticolimbic brain responses, involving enhanced activation of prefrontal cortex and attenuation of limbic areas, during volitional suppression of negative emotion.

Association between amygdala hyperactivity to harsh faces and severity of social anxiety in generalized social phobia

BACKGROUND Previous functional brain imaging studies of social anxiety have implicated amygdala hyperactivity in response to social threat, though its relationship to quantitative measures of clinical symptomatology remains unknown. The primary aim of this study was to examine the association between response to emotionally harsh faces in the amygdala, a region implicated in social and threat-related processing, and severity of social anxiety symptoms in patients with generalized social phobia (GSP). METHODS Ten subjects with GSP naive to psychotropic medications and without psychiatric comorbidity and ten healthy comparison subjects matched on age, gender, ethnicity, and education completed the Liebowitz Social Anxiety Scale and underwent high-field (4Tesla) functional magnetic resonance imaging while viewing blocks of emotionally salient faces. RESULTS Relative to happy faces, activation of the amygdala in response to harsh (angry, disgusted, fearful) faces was greater in GSP patients than in controls, and the extent of amygdala activation was positively correlated with severity of social anxiety symptoms, but not general state or trait anxiety levels. CONCLUSIONS Our findings suggest that amygdala activation to interpersonal threat can be specifically linked to the severity of social anxiety symptoms of individual GSP patients, and thus, may serve as a useful functional marker of disease severity.

Amygdala and orbitofrontal reactivity to social threat in individuals with impulsive aggression

BACKGROUND Converging evidence from animal and human lesion studies implicates the amygdala and orbitofrontal cortex (OFC) in emotional regulation and aggressive behavior. However, it remains unknown if functional deficits exist in these specific brain regions in clinical populations in which the cardinal symptom is impulsive aggression. We have previously shown that subjects diagnosed with intermittent explosive disorder (IED), a psychiatric disorder characterized by reactive aggressive behavior, perform poorly on facial emotion recognition tasks. In this study we employed a social-emotional probe of amygdala-OFC function in individuals with impulsive aggression. METHODS Ten unmedicated subjects with IED and 10 healthy, matched comparison subjects (HC) underwent functional magnetic resonance imaging while viewing blocks of emotionally salient faces. We compared amygdala and OFC reactivity to faces between IED and HC subjects, and examined the relationship between the extent of activation in these regions and extent of prior history of aggressive behavior. RESULTS Relative to controls, individuals with IED exhibited exaggerated amygdala reactivity and diminished OFC activation to faces expressing anger. Extent of amygdala and OFC activation to angry faces were differentially related to prior aggressive behavior across subjects. Unlike controls, aggressive subjects failed to demonstrate amygdala-OFC coupling during responses to angry faces. CONCLUSIONS These findings provide evidence of amygdala-OFC dysfunction in response to an ecologically-valid social threat signal (processing angry faces) in individuals with a history of impulsive aggressive behavior, and further substantiate a link between a dysfunctional cortico-limbic network and aggression.

Beyond threat: amygdala reactivity across multiple expressions of facial affect.

The amygdala has been consistently isolated as a key neural substrate for processing facial displays of affect. Recent evidence from human lesion and functional neuroimaging studies have begun to challenge the notion that the amygdala is reserved for signals of threat (fear/anger). We performed a 4 T fMRI study in which 20 subjects viewed a contemporary set of photographs displaying 6 different facial expressions (fearful, disgusted, angry, sad, neutral, happy) while performing a task with minimal cognitive demand. Across subjects, the left amygdala was activated by each face condition separately, and its response was not selective for any particular emotion category. These results challenge the notion that the amygdala has a specialized role in processing certain emotions and suggest that the amygdala may have a more general-purpose function in processing salient information from faces.

Real-time fMRI of temporolimbic regions detects amygdala activation during single-trial self-induced sadness

Temporolimbic circuits play a crucial role in the regulation of human emotion. A highly sensitive single-shot multiecho functional magnetic resonance imaging (fMRI) technique with gradient compensation of local magnetic field inhomogeneities and real-time data analysis were used to measure increases in amygdala activation during single 60-s trials of self-induced sadness. Six healthy male and female subjects performed a validated mood induction paradigm with randomized presentation of sad or neutral faces in 10 trials per scan. Subjects reported the intensity of experienced sadness after each trial. Immediate feedback of amygdala activation was given to the subjects during the ongoing scan to reinforce mood induction. Correspondence between increased intensity of predominantly left sided amygdala activation and self-rating of sadness was found in 78% of 120 sad trials, in contrast to only 14% of neutral trials. Amygdala activation was reproducible during repeated scanning sessions and displayed the strongest correlation with self-rating among all regions. These results suggest that amygdala activation may be closely associated with self-induced sadness. This novel real-time fMRI technology is applicable to a wide range of neuroscience studies, particularly those of the limbic system, and to neuropsychiatric conditions, such as depression, in which pathology of the amygdala has been implicated.

Modulation of resting-state amygdala-frontal functional connectivity by oxytocin in generalized social anxiety disorder.

Generalized social anxiety disorder (GSAD) is characterized by aberrant patterns of amygdala-frontal connectivity to social signals of threat and at rest. The neuropeptide oxytocin (OXT) modulates anxiety, stress, and social behaviors. Recent functional neuroimaging studies suggest that these effects are mediated through OXT’s effects on amygdala reactivity and/or amygdala-frontal connectivity. The aim of the current study was to examine OXT’s effects on amygdala-frontal resting-state functional connectivity (rsFC) in GSAD patients and healthy controls (HCs). In a randomized, double-blind, cross-over design, 18 GSAD and 18 HC participants received intranasal OXT (24 IU or 40.32 μg) or placebo (PBO) before resting-state functional magnetic resonance imaging. In individuals with GSAD, OXT enhanced rsFC of the left and right amygdala with rostral anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC), and in doing so, reversed (ie, ‘normalized’) the reduced amygdala-frontal connectivity observed relative to HCs evident on PBO. Higher social anxiety severity in GSAD subjects correlated with lower amygdala-ACC/mPFC connectivity on PBO and higher social anxiety also correlated with greater enhancement in amygdala-frontal connectivity induced by OXT. These findings show that OXT modulates a neural circuit known for social threat processing and emotion regulation, suggesting a neural mechanism by which OXT may have a role in the pathophysiology and treatment of social anxiety disorder.

Anterior cingulate neurochemistry in social anxiety disorder: 1H-MRS at 4 Tesla

Recent studies suggest exaggerated responses in the limbic system of patients with generalized social anxiety disorder in response to threat/anxiety-related social situations and aversive conditioning, processes mediated by the glutamatergic system. This single-voxel, high-field 1H-magnetic resonance spectroscopy study examined concentrations of glutamate, and other metabolites, in the anterior cingulate cortex and occipital cortex (control region) of 10 medication-naive patients with generalized social anxiety and 10 matched healthy comparison subjects. Glutamate (relative to creatine) levels were significantly higher in patients than controls in the anterior cingulate, but not occipital, cortex. Anterior cingulate glutamate/creatine levels were also correlated with intensity of social anxiety symptoms. These findings provide new evidence of glutamates involvement in the neural mechanism underlying social phobia.

Neural correlates of internally-generated disgust via autobiographical recall: a functional magnetic resonance imaging investigation

Converging lines of evidence suggest the involvement of the insula and basal ganglia in the processing of disgust, an important primary emotion that guides the avoidance of potential physical contamination and disease. Prior human lesion and functional brain imaging studies have employed exteroceptive sensory stimuli such as facial expressions of disgust, and disgust-eliciting pictures. Thus, the neural substrates underlying the internal experience of disgust remain unknown. The present fMRI study examined the neural correlates of self-induced disgust aided by the recall and re-experience of personally salient life events. Subjects were scanned while they recalled and re-experienced either a recent situation that evoked intense disgust or a time-matched, equally vivid neutral/non-emotional event. Relative to the emotionally neutral condition, self-induced disgust was associated with activation of the insula, hippocampus, anterior and posterior cingulate cortex, basal ganglia, thalamus, and primary visual cortex. These findings suggest that areas previously associated with the perception of disgust (e.g., insula, basal ganglia) are also involved interoceptive experience of disgust.

Oxytocin Modulation of Amygdala Functional Connectivity to Fearful Faces in Generalized Social Anxiety Disorder

The neuropeptide oxytocin (OXT) is thought to attenuate anxiety by dampening amygdala reactivity to threat in individuals with generalized social anxiety disorder (GSAD). Because the brain is organized into networks of interconnected areas, it is likely that OXT impacts functional coupling between the amygdala and other socio-emotional areas of the brain. Therefore, the aim of the current study was to examine the effects of OXT on amygdala functional connectivity during the processing of fearful faces in GSAD subjects and healthy controls (HCs). In a randomized, double-blind, placebo (PBO)-controlled, within-subjects design, 18 HCs and 17 GSAD subjects performed a functional magnetic resonance imaging task designed to probe amygdala response to fearful faces following acute intranasal administration of PBO or OXT. Functional connectivity between the amygdala and the rest of the brain was compared between OXT and PBO sessions using generalized psychophysiological interaction analyses. Results indicated that within individuals with GSAD, but not HCs, OXT enhanced functional connectivity between the amygdala and the bilateral insula and middle cingulate/dorsal anterior cingulate gyrus during the processing of fearful faces. These findings suggest that OXT may have broad pro-social implications such as enhancing the integration and modulation of social responses.

Real-time fmri of cortico-limbic brain activity during emotional processing

The ability to detect dynamic changes in brain activity during affective processing within individual subjects in real-time can advance our understanding of the neural mechanisms of emotion, psychiatric illness, and therapeutic intervention. We investigated whether activity in limbic and paralimbic regions elicited by blocks of aversive (AV) and neutral (NEU) pictures can be detected by real-time fMRI. Real-time analysis of signal change during each block revealed that activations in insula and medial frontal cortex were more frequent during AV than NEU epochs. Single subject and group analysis off-line with conventional statistical parametric mapping methods matched the results obtained in real-time. Detecting cortico-limbic brain activation during perception and experience of emotionally salient visual stimuli with real-time fMRI technology is feasible.