Scott C. Matthews

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.

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.

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.

Functional activation and neural networks in women with posttraumatic stress disorder related to intimate partner violence

BACKGROUND Intimate partner violence (IPV) is one of the most common causes of posttraumatic stress disorder (PTSD) in women. Victims of IPV are often preoccupied by the anticipation of impending harm. This investigation tested the hypothesis that IPV-related PTSD individuals show exaggerated insula reactivity to the anticipation of aversive stimuli. METHODS Fifteen women with a history of IPV and consequent PTSD (IPV-PTSD) and 15 non-traumatized control (NTC) women performed a task involving cued anticipation to images of positive and negative events during functional magnetic resonance imaging. RESULTS Both groups showed increased activation of bilateral anterior insula during anticipation of negative images minus anticipation of positive images. Activation in right anterior/middle insula was significantly greater in the IPV-PTSD relative to the NTC group. Functional connectivity analysis revealed that changes in activation in right middle insula and bilateral anterior insula were more strongly associated with amygdala activation changes in NTC than in IPV-PTSD subjects. CONCLUSIONS This study revealed increased activation in the anterior/middle insula during negative anticipation in women with IPV-related PTSD. These findings in women with IPV could be a consequence of the IPV exposure, reflect pre-existing differences in insular function, or be due to the development of PTSD. Thus, future longitudinal studies need to examine these possibilities.

Intolerance of uncertainty correlates with insula activation during affective ambiguity

Intolerance of uncertainty (IU), or the increased affective response to situations with uncertain outcomes, is an important component process of anxiety disorders. Increased IU is observed in panic disorder (PD), obsessive compulsive disorder (OCD) and generalized anxiety disorder (GAD), and is thought to relate to dysfunctional behaviors and thought patterns in these disorders. Identifying what brain systems are associated with IU would contribute to a comprehensive model of anxiety processing, and increase our understanding of the neurobiology of anxiety disorders. Here, we used a behavioral task, Wall of Faces (WOFs), during functional magnetic resonance imaging (fMRI), which probes both affect and ambiguity, to examine the neural circuitry of IU in 14 (10 females) college age (18.8 years) subjects. All subjects completed the Intolerance of Uncertainty Scale (IUS), Anxiety Sensitivity Index (ASI), and a measure of neuroticism (i.e. the NEO-N). IUS scores but neither ASI nor NEO-N scores, correlated positively with activation in bilateral insula during affective ambiguity. Thus, the experience of IU during certain types of emotion processing may relate to the degree to which bilateral insula processes uncertainty. Previously observed insula hyperactivity in anxiety disorder individuals may therefore be directly linked to altered processes of uncertainty.

A multimodal imaging study in U.S. veterans of Operations Iraqi and Enduring Freedom with and without major depression after blast-related concussion

Although the exact number of affected individuals is unknown, it has been estimated that approximately 20% of U.S. veterans of Operations Enduring Freedom (OEF) and Iraqi Freedom (OIF) have experienced mild traumatic brain injury (mTBI) (i.e., concussion), which is defined as a brief loss or alteration of consciousness from a blow or jolt to the head. Blast exposure is among the most common causes of concussion in OEF-OIF warriors. Although the mechanism is unknown, major depressive disorder (MDD) after head injury is common. The purpose of this study was to use diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) to examine the structural and functional neural correlates of MDD in OEF-OIF combat veterans with a self-reported history of blast-related concussion. We hypothesized that subjects in the MDD group (i.e., individuals with a history of blast-related concussion who were experiencing current MDD) relative to individuals in the non-MDD group (i.e., individuals with a history of blast-related concussion but no current or lifetime history of MDD) would show amygdala hyperactivity and disruption of white matter tracts connecting prefrontal and limbic brain regions. To test these hypotheses, 11 MDD and 11 non-MDD individuals underwent DTI and performed a validated emotional face matching task during fMRI. MDD relative to non-MDD individuals showed greater activity during fear matching trials in the amygdala and other emotion processing structures, lower activity during fear matching trials in emotional control structures such as the dorsolateral prefrontal cortex and lower fractional anisotropy (FA) in several white matter tracts including the superior longitudinal fasciculus (SLF). Greater depressive symptom severity correlated negatively with FA in the SLF. These results suggest a biological basis of MDD in OEF-OIF veterans who have experienced blast-related concussion, and may contribute to the development of treatments aimed at improving the clinical care of this unique population of wounded warriors.

Altered insula activation during pain anticipation in individuals recovered from anorexia nervosa: evidence of interoceptive dysregulation.

OBJECTIVE Recent evidence raises the possibility that symptoms of anorexia nervosa (AN) could be related to impaired interoception. Pain is an interoceptive process with well-characterized neuroanatomical pathways that may overlap to a large degree with neural systems that may be dysregulated in individuals with AN, such as the insula. METHOD Functional magnetic resonance imaging (fMRI) was used to assess neural substrates of pain anticipation and processing in 10 healthy control women (CW) and 12 individuals recovered from AN (REC AN) in order to avoid the confounding effects of malnutrition. Painful heat stimuli were applied while different colors signaled the intensity of the upcoming stimuli. RESULTS REC AN compared with CW showed greater activation within right anterior insula (rAI), dorsolateral prefrontal cortex (dlPFC) and cingulate during pain anticipation, and greater activation within dlPFC and decreased activation within posterior insula during painful stimulation. Greater anticipatory rAI activation correlated positively with alexithymic feelings in REC AN participants. DISCUSSION REC AN showed a mismatch between anticipation and objective responses, suggesting altered integration and, possibly, disconnection between reported and actual interoceptive state. Alexithymia assessment provided additional evidence of an altered ability to accurately perceive bodily signals in women recovered from AN.