Alan N. Simmons

Association of Major Depressive Disorder With Altered Functional Brain Response During Anticipation and Processing of Heat Pain

CONTEXT Chronic pain and depression are highly comorbid conditions, yet little is known about the neurobiological basis of pain processing in major depressive disorder (MDD). OBJECTIVE To examine the neural substrates underlying anticipation and processing of heat pain in a group of unmedicated young adults with current MDD. DESIGN Functional magnetic resonance neuroimaging data were collected during an event-related factorial experimental pain paradigm. Painful and nonpainful heat stimuli were applied to the left volar forearm while different color shapes explicitly signaled the intensity of the upcoming stimulus. SETTING University brain imaging center. Patients Fifteen (12 female) young adults with current MDD and 15 (10 female) healthy subjects with no history of MDD were recruited and matched for age and level of education. The Structured Clinical Interview for DSM-IV was administered to all participants by a board-certified psychiatrist. Main Outcome Measure Between-group differences in blood oxygen level-dependent functional magnetic resonance neuroimaging signal change to anticipation and processing of painful vs nonpainful temperature stimuli. RESULTS Subjects with MDD compared with healthy controls showed (1) increased activation in the right anterior insular region, dorsal anterior cingulate, and right amygdala during anticipation of painful relative to nonpainful stimuli, (2) increased activation in the right amygdala and decreased activation in periaqueductal gray matter and the rostral anterior cingulate and prefrontal cortices during painful stimulation relative to nonpainful stimulation, and (3) greater activation in the right amygdala during anticipation of pain, which was associated with greater levels of perceived helplessness. CONCLUSIONS These findings suggest that increased emotional reactivity during the anticipation of heat pain may lead to an impaired ability to modulate pain experience in MDD. Future studies should examine the degree to which altered functional brain response during anticipatory processing affects the ability to modulate negative affective states in MDD, which is a core characteristic of this disorder.

Anticipation of Aversive Visual Stimuli Is Associated With Increased Insula Activation in Anxiety-Prone Subjects

BACKGROUND Anticipation is a critical component of affective processing in general and for anxiety in particular. Prior research suggests that the right insula plays an important role in anticipation of affective processing during aversive images. This study aimed to test the hypothesis that individuals with increased anxiety-related temperamental traits (anxiety-prone [AP]) relative to anxiety-normative (AN) subjects would show an exaggerated insula response during anticipation of an aversive image. METHODS 16 AP and 16 AN individuals performed a task in the functional magnetic resonance imaging scanner, during which they viewed pictures of spiders and snakes. Subjects were prompted 4-6 sec before the onset of each aversive image. Blood oxygenation level-dependent signal was contrasted during cued anticipation of images versus non-anticipatory task performance as well as viewing images. RESULTS As hypothesized, AP subjects showed greater response than AN subjects in the bilateral insula during anticipation. In addition, these individuals had lower activity within the superior/medial frontal gyrus. During the image presentation phase, AN subjects showed greater activation than AP subjects in the bilateral temporal lobes and left superior frontal gyrus. Moreover, bilateral temporal lobe activation during image presentation was inversely correlated with bilateral insula activation during anticipation both within groups and in the combined group. CONCLUSIONS These data suggest that greater activation of the insula during visual anticipation is associated with visual processing of aversive stimuli in AP individuals. Insula hyperactivity might be a common feature in persons with elevated trait anxiety and, as such, might be a neuroimaging marker for anxiety proneness.

Functional subdivisions within anterior cingulate cortex and their relationship to autonomic nervous system function.

The anterior cingulate cortex (ACC) has diverse functions and several functional subdivisions. This study implemented a counting Stroop task that presented incongruent (INC) and congruent (CON) stimuli at two speeds to probe dorsal (dACC) and ventral (vACC) using functional magnetic resonance imaging (fMRI). Eighteen healthy subjects completed the task twice: once outside the scanner while heart rate variability (HRV) was recorded and once during fMRI. In both sessions, subjects completed two runs. Stimuli were presented every 2.0 s in one run and every 1.5 s in the other. fMRI data analysis revealed two important findings. First, by computing differential activation between INC and CON stimuli, a cluster of activation related to response inhibition was observed in the left dACC. Additionally, by calculating the interaction of speed with stimulus congruency, a cluster of activation was observed in the left vACC. This activation correlated significantly with high-frequency HRV (P < 0.02 for CON and P < 0.003 for INC) and represents the parasympathetic modulatory role of the vACC. This study supports the notion of functional subdivisions within the ACC and links the processes of cognitive interference and parasympathetic modulation with activation in specific subregions of the ACC, a structure that is critical for the interface between cognition and emotion.

Nothing tastes as good as skinny feels: the neurobiology of anorexia nervosa

Individuals with anorexia nervosa (AN) engage in relentless restrictive eating and often become severely emaciated. Because there are no proven treatments, AN has high rates of relapse, chronicity, and death. Those with AN tend to have childhood temperament and personality traits, such as anxiety, obsessions, and perfectionism, which may reflect neurobiological risk factors for developing AN. Restricted eating may be a means of reducing negative mood caused by skewed interactions between serotonin aversive or inhibitory and dopamine reward systems. Brain imaging studies suggest that altered eating is a consequence of dysregulated reward and/or awareness of homeostatic needs, perhaps related to enhanced executive ability to inhibit incentive motivational drives. An understanding of the neurobiology of this disorder is likely to be important for developing more effective treatments.

Anticipation of emotionally aversive visual stimuli activates right insula.

Understanding the neural substrates of anticipation is required for a comprehensive model of the ways in which anxiety influences information processing. While it is apparent that the insula and medial frontal cortex are involved in processing anticipation of physical (i.e., painful) stimuli, their role in processing anticipation of aversive affective stimuli has yet to be determined. Twenty-eight healthy non-phobic volunteers observed aversive affective images (spiders and snakes) that were preceded by an auditory signal. The insula, dorsolateral prefrontal cortex, and parahippocampal gyrus activated during anticipation of aversive affective images. These findings indicate that common neural circuitry is involved in the anticipation of (and, perhaps, the subjective experience of anticipating) aversive affective and noxious physical stimuli.

Sucrose activates human taste pathways differently from artificial sweetener

Animal models suggest that sucrose activates taste afferents differently than non-caloric sweeteners. Little information exists how artificial sweeteners engage central taste pathways in the human brain. We assessed sucrose and sucralose taste pleasantness across a concentration gradient in 12 healthy control women and applied 10% sucrose and matched sucralose during functional magnet resonance imaging. The results indicate that (1) both sucrose and sucralose activate functionally connected primary taste pathways; (2) taste pleasantness predicts left insula response; (3) sucrose elicits a stronger brain response in the anterior insula, frontal operculum, striatum and anterior cingulate, compared to sucralose; (4) only sucrose, but not sucralose, stimulation engages dopaminergic midbrain areas in relation to the behavioral pleasantness response. Thus, brain response distinguishes the caloric from the non-caloric sweetener, although the conscious mind could not. This could have important implications on how effective artificial sweeteners are in their ability to substitute sugar intake.

Resting-state functional connectivity of subgenual anterior cingulate cortex in depressed adolescents.

BACKGROUND Very few studies have been performed to understand the underlying neural substrates of adolescent major depressive disorder (MDD). Studies in depressed adults have demonstrated that the subgenual anterior cingulate cortex (sgACC) plays a pivotal role in depression and have revealed aberrant patterns of resting-state functional connectivity (RSFC). Here, we examine the RSFC of the sgACC in medication-naïve first-episode adolescents with MDD. METHODS Twenty-three adolescents with MDD and 36 well-matched control subjects underwent functional magnetic resonance imaging to assess the RSFC of the sgACC. RESULTS We observed elevated connectivity between the sgACC and the insula and between the sgACC and the amygdala in the MDD group compared with the control subjects. Decreased connectivity between the sgACC and the precuneus was also found in the MDD group relative to the control subjects. Within the MDD group, higher levels of depression significantly correlated with decreased connectivity between the sgACC and left precuneus. Increased rumination was significantly associated with reduced connectivity between sgACC and the middle and inferior frontal gyri in the MDD group. CONCLUSIONS Our study is the first to examine sgACC connectivity in medication-naïve first-episode adolescents with MDD compared with well-matched control participants. Our results suggest aberrant functional connectivity among the brain networks responsible for salience attribution, executive control, and the resting-state in the MDD group compared with the control participants. Our findings raise the possibility that therapeutic interventions that can restore the functional connectivity among these networks to that typical of healthy adolescents might be a fruitful avenue for future research.

Decreased functional coupling of the amygdala and supragenual cingulate is related to increased depression in unmedicated individuals with current major depressive disorder

BACKGROUND Individuals with major depressive disorder (MDD) show abnormal functional coupling (FC) between several nodes of a widely distributed cortico-limbic network that includes the amygdala and anterior cingulate. The aim of this study was to examine the degree to which alterations in amygdala-cingulate FC relate to severity of current depressive symptoms in a group of depressed individuals without significant co-morbidities. METHODS Fifteen young, unmedicated subjects with current MDD and 16 healthy controls (HC) with no lifetime history of psychiatric illness performed a validated emotional face-matching task during functional magnetic resonance imaging. Amygdala activity and strength of amygdala-cingulate FC during emotional face processing were contrasted between the groups. RESULTS Although both groups activated the extended amygdala (EA) during emotion processing, the MDD relative to the HC group showed more task-related co-activation of the subgenual cingulate, which is involved in processing negative self-referential information; and less co-activation of the supragenual cingulate, which is involved in the cognitive control of emotion. Greater depressive symptom severity correlated positively with decreased FC between bilateral EA and supragenual cingulate in MDD subjects. LIMITATIONS This study included a demographically homogeneous population of subjects, which may limit the generalizability of the findings. CONCLUSIONS These results elaborate current neurobiological models of MDD by providing unique evidence that decreased FC between the EA and supragenual cingulate is related to increased severity of current depressive symptoms. We speculate that the clinical manifestations of MDD may result in part from a failed ability to co-activate a cognitive control network during emotion processing.

Selective activation of the nucleus accumbens during risk-taking decision making

This study implemented a risk-taking task during fMRI to probe the brain circuitry involved in risk-taking decision-making in 12 healthy control subjects. Partially supporting the initial hypotheses, deliberation prior to selection of safe relative to risky responses generated greater activation in the inferior frontal cortex, superior temporal gyrus, and middle temporal gyrus; and deliberation prior to selection of risky relative to safe responses generated greater activation in medial frontal cortex, occipital cortex, nucleus accumbens and caudate. Additionally, accumbens activation correlated positively with the harm avoidance subscale of the Temperament and Character Inventory (TCI) 125. These findings may provide target neural systems to study in subjects who exhibit problematic risk-taking behaviors and may partially explain why certain risky behaviors occur.

Exaggerated and Disconnected Insular-Amygdalar Blood Oxygenation Level-Dependent Response to Threat-Related Emotional Faces in Women with Intimate-Partner Violence Posttraumatic Stress Disorder

BACKGROUND Intimate-partner violence (IPV) is one of the most common causes of posttraumatic stress disorder (PTSD) among women. PTSD neuroimaging studies have identified functional differences in the amygdala and anterior cingulate cortex (ACC)/medial prefrontal cortex during emotion processing. Recent investigations of the limbic sensory system and its associated neural substrate, the insular cortex, have demonstrated its importance for emotional awareness. This study examined the hypothesis that women with IPV-PTSD show a dysregulation of this limbic sensory system while processing threat-related emotional faces. METHODS 12 women with IPV-PTSD and 12 nontraumatized comparison women underwent blood oxygenation level-dependent functional magnetic resonance imaging while completing an emotional face-matching task. RESULTS IPV-PTSD subjects relative to comparison subjects displayed increased activation of the anterior insula and amygdala and decreased connectivity among the anterior insula, amygdala, and ACC while matching to fearful versus happy target faces. A similar pattern of activation differences was also observed for angry versus happy target faces. IPV-PTSD subjects relative to comparison subjects also displayed increased dorsal ACC/medial prefrontal cortex activation and decreased ventral ACC activation when matching to a male versus a female target, and the extent of increased dorsal ACC activation correlated positively with hyperarousal symptoms. CONCLUSIONS Women with IPV-PTSD display hyperactivity and disconnection among affective and limbic sensory systems while processing threat-related emotion. Furthermore, hyperactivity of cognitive-appraisal networks in IPV-PTSD may promote hypervigilant states of awareness through an exaggerated sensitivity to contextual cues, i.e., male gender, which relate to past trauma.