Effects of Cognitive Behavioral Therapy on Neural Processing of Agoraphobia-Specific Stimuli in Panic Disorder and Agoraphobia.

BACKGROUND: Patients suffering from panic disorder and agoraphobia are significantly impaired in daily life due to anxiety about getting into a situation due to apprehension about experiencing a panic attack, especially if escape may be difficult. Dysfunctional beliefs and behavior can be changed with cognitive behavioral therapy; however, the neurobiological effects of such an intervention on the anticipation and observation of agoraphobia-specific stimuli are unknown. METHODS: We compared changes in neural activation by measuring the blood oxygen level-dependent signal of 51 patients and 51 healthy controls between scans before and those after treatment (group by time interaction) during anticipation and observation of agoraphobia-specific compared to neutral pictures using 3-T fMRI. RESULTS: A significant group by time interaction was observed in the ventral striatum during anticipation and in the right amygdala during observation of agoraphobia-specific pictures; the patients displayed a decrease in ventral striatal activation during anticipation from pre- to posttreatment scans, which correlated with clinical improvement measured with the Mobility Inventory. During observation, the patients displayed decreased activation in the amygdala. These activational changes were not observed in the matched healthy controls. CONCLUSIONS: For the first time, neural effects of cognitive behavioral therapy were shown in patients suffering from panic disorder and agoraphobia using disorder-specific stimuli. The decrease in activation in the ventral striatum indicates that cognitive behavioral therapy modifies anticipatory anxiety and may ameliorate abnormally heightened salience attribution to expected threatening stimuli. The decreased amygdala activation in response to agoraphobia-specific stimuli indicates that cognitive behavioral therapy can alter the basal processing of agoraphobia-specific stimuli in a core region of the fear network.

Reward and loss anticipation in panic disorder: An fMRI study.

Anticipatory anxiety and harm avoidance are essential features of panic disorder (PD) and may involve deficits in the reward system of the brain, in particular in the ventral striatum. While neuroimaging studies on PD have focused on fearful and negative affective stimulus processing, no investigations have directly addressed deficits in reward and loss anticipation. To determine whether the ventral striatum shows abnormal neural activity in PD patients during anticipation of loss or gain, an event-related functional magnetic resonance imaging experiment using a monetary incentive delay task was employed in 10 patients with PD and 10 healthy controls. A repeated-measures ANOVA to identify effects of group (PD vs. Control) and condition (anticipation of loss vs. gain vs. neutral outcome) revealed that patients with PD showed significantly reduced bilateral ventral striatal activation during reward anticipation but increased activity during loss anticipation. Within the patient group, the degree of activation in the ventral striatum during loss-anticipation was positively correlated with harm avoidance and negatively correlated with novelty seeking. These findings suggest that behavioural impairments in panic disorder may be related to abnormal neural processing of motivational cues.

Affective responses across psychiatric disorders-A dimensional approach.

Studying psychiatric disorders across nosological boundaries aims at a better understanding of mental disorders by identifying comprehensive signatures of core symptoms. Here, we studied neurobiological correlates of emotion processing in several major psychiatric disorders. We assessed differences between diagnostic groups, and investigated whether there is a psychopathological correlate of emotion processing that transcends disorder categories. 135 patient with psychiatric disorders (alcohol dependence, n=29; schizophrenia, n=37; major depressive disorder (MDD), n=25; acute manic episode of bipolar disorder, n=12; panic disorder, n=12, attention deficit/hyperactivity disorder (ADHD), n=20) and healthy controls (n=40) underwent an functional magnetic resonance imaging (fMRI) experiment with affectively positive, aversive and neutral pictures from the International Affective Picture System (IAPS). Between-group differences were assessed with full-factorial ANOVAs, with age, gender and smoking habits as covariates. Self-ratings of depressed mood and anxiety were correlated with activation clusters showing significant stimulus-evoked fMRI activation. Furthermore, we examined functional connectivity with the amygdala as seed region during the processing of aversive pictures. During the presentation of pleasant stimuli, we observed across all subjects significant activation of the ventromedial prefrontal cortex (vmPFC), bilateral middle temporal gyrus and right precuneus, while a significant activation of the left amygdala and the bilateral middle temporal gyrus was found during the presentation of aversive stimuli. We did neither find any significant interaction with diagnostic group, nor any correlation with depression and anxiety scores at the activated clusters or with amygdala connectivity. Positive and aversive IAPS-stimuli were consistently processed in limbic and prefrontal brain areas, irrespective of diagnostic category. A dimensional correlate of these neural activation patterns was not found.

Dimensional psychiatry: reward dysfunction and depressive mood across psychiatric disorders.

RATIONALE: A dimensional approach in psychiatry aims to identify core mechanisms of mental disorders across nosological boundaries. OBJECTIVES: We compared anticipation of reward between major psychiatric disorders, and investigated whether reward anticipation is impaired in several mental disorders and whether there is a common psychopathological correlate (negative mood) of such an impairment. METHODS: We used functional magnetic resonance imaging (fMRI) and a monetary incentive delay (MID) task to study the functional correlates of reward anticipation across major psychiatric disorders in 184 subjects, with the diagnoses of alcohol dependence (n = 26), schizophrenia (n = 44), major depressive disorder (MDD, n = 24), bipolar disorder (acute manic episode, n = 13), attention deficit/hyperactivity disorder (ADHD, n = 23), and healthy controls (n = 54). Subjects' individual Beck Depression Inventory-and State-Trait Anxiety Inventory-scores were correlated with clusters showing significant activation during reward anticipation. RESULTS: During reward anticipation, we observed significant group differences in ventral striatal (VS) activation: patients with schizophrenia, alcohol dependence, and major depression showed significantly less ventral striatal activation compared to healthy controls. Depressive symptoms correlated with dysfunction in reward anticipation regardless of diagnostic entity. There was no significant correlation between anxiety symptoms and VS functional activation. CONCLUSION: Our findings demonstrate a neurobiological dysfunction related to reward prediction that transcended disorder categories and was related to measures of depressed mood. The findings underline the potential of a dimensional approach in psychiatry and strengthen the hypothesis that neurobiological research in psychiatric disorders can be targeted at core mechanisms that are likely to be implicated in a range of clinical entities.

Context insensitivity during positive and negative emotional expectancy in depression assessed with functional magnetic resonance imaging.

Patients with depression show an enhanced preoccupation with negative expectations and are often unable to look forward to positive events. Here we studied anticipatory emotional processes in unmedicated depressed patients using functional magnetic resonance imaging. Consistent with a negative processing bias, we hypothesized enhanced responses to negative and attenuated responses to positive expectancy cues in brain areas associated with emotional expectancy. Participants comprised 19 drug-free depressed patients and 19 matched healthy control subjects who viewed affective photographs. Pictures were preceded by an expectancy cue which signaled the emotional valence of the upcoming picture in half of the trials. Depressed patients showed attenuated blood-oxygen-level-dependent responses in the left lateral prefrontal cortex (inferior frontal gyrus, Brodmann area 44) during positive expectancy and-contrary to our hypothesis-in the right lateral orbitofrontal cortex (middle frontal gyrus, Brodmann area 47) during negative expectancy. This attenuation was specific for the anticipation (as opposed to the perception) of emotional pictures and correlated with a clinical measure of depressive symptoms. The observed attenuation suggests emotion-context insensitivity rather than a negative processing bias during anticipatory emotional processes in depression. This hyporeactivity may contribute to clinical features like anergia, apathy, and loss of motivation in the context of both positive and negative incentives.

Hemispheric asymmetry for affective stimulus processing in healthy subjects--a fMRI study.

BACKGROUND: While hemispheric specialization of language processing is well established, lateralization of emotion processing is still under debate. Several conflicting hypotheses have been proposed, including right hemisphere hypothesis, valence asymmetry hypothesis and region-specific lateralization hypothesis. However, experimental evidence for these hypotheses remains inconclusive, partly because direct comparisons between hemispheres are scarce. METHODS: The present fMRI study systematically investigated functional lateralization during affective stimulus processing in 36 healthy participants. We normalized our functional data on a symmetrical template to avoid confounding effects of anatomical asymmetries. Direct comparison of BOLD responses between hemispheres was accomplished taking two approaches: a hypothesis-driven region of interest analysis focusing on brain areas most frequently reported in earlier neuroimaging studies of emotion; and an exploratory whole volume analysis contrasting non-flipped with flipped functional data using paired t-test. RESULTS: The region of interest analysis revealed lateralization towards the left in the medial prefrontal cortex (BA 10) during positive stimulus processing; while negative stimulus processing was lateralized towards the right in the dorsolateral prefrontal cortex (BA 9 & 46) and towards the left in the amygdala and uncus. The whole brain analysis yielded similar results and, in addition, revealed lateralization towards the right in the premotor cortex (BA 6) and the temporo-occipital junction (BA 19 & 37) during positive stimulus processing; while negative stimulus processing showed lateralization towards the right in the temporo-parietal junction (BA 37,39,42) and towards the left in the middle temporal gyrus (BA 21). CONCLUSION: Our data suggests region-specific functional lateralization of emotion processing. Findings show valence asymmetry for prefrontal cortical areas and left-lateralized negative stimulus processing in subcortical areas, in particular, amygdala and uncus.

Functional neuroanatomy of emotion processing in major depressive disorder is altered after successful antidepressant therapy.

Major Depressive Disorder (MDD) is associated with impaired processing and regulation of emotions. A vast body of research has elucidated the altered neural processes that occur in response to emotional stimuli, while little is known about anticipatory processes. Here we used functional magnetic resonance imaging (fMRI) to investigate neural activation during the presentation and anticipation of negative stimuli. Furthermore, we examined the effects of an 8-week antidepressant treatment with escitalopram. We matched 12 unmedicated MDD patients and 12 healthy control participants to perform a task involving affective pictures. The design of our event-related task consisted of presenting positive, negative, and neutral pictures from the International Affective Picture System (IAPS) across two runs and under opposite conditions. For the 'expected' condition, the pictures were cued by a word indicating their emotional valence; whereas the 'unexpected' condition had a combination of random letters precede the emotion picture. MDD patients displayed greater amygdala activation when anticipating negative pictures and greater prefrontal activation when confronted with them without the anticipatory cues. After antidepressant treatment, both amygdala and prefrontal activation decreased significantly in the treated MDD patients relative to controls. These findings show that the neural mechanisms of emotion anticipation and processing are altered in patients with MDD and that these alterations are able to normalize after treatment with an antidepressant.

Hyporeactivity of ventral striatum towards incentive stimuli in unmedicated depressed patients normalizes after treatment with escitalopram.

Major Depressive Disorder (MDD) involves deficits in the reward system. While neuroimaging studies have focused on affective stimulus processing, few investigations have directly addressed deficits in the anticipation of incentives. We examined neural responses during gain and loss anticipation in patients with MDD before and after treatment with a selective serotonin reuptake inhibitor (SSRI). Fifteen adults with MDD and 15 healthy participants, matched for age, verbal IQ and smoking habits, were investigated in a functional magnetic resonance imaging (fMRI) study using a monetary incentive delay task. Patients were scanned drug-free and after 6 weeks of open-label treatment with escitalopram; controls were scanned twice at corresponding time points. We compared the blood oxygenation level dependent (BOLD) response during the anticipation of gain and loss with a neutral condition. A repeated measures ANOVA was calculated to identify effects of group (MDD vs. controls), time (first vs. second scan) and group-by-time interaction. Severity of depression was measured with the Hamilton Rating Scale of Depression and the Beck Depression Inventory. MDD patients showed significantly less ventral striatal activation during anticipation of gain and loss compared with controls before, but not after, treatment. There was a significant group-by-time interaction during anticipation of loss in the left ventral striatum due to a signal increase in patients after treatment. Ventral striatal hyporesponsiveness was associated with the severity of depression and in particular anhedonic symptoms. These findings suggest that MDD patients show ventral striatal hyporesponsiveness during incentive cue processing, which normalizes after successful treatment.

Reward processing in male adults with childhood ADHD--a comparison between drug-naïve and methylphenidate-treated subjects.

RATIONALE: Dysfunctional reward processing has been proposed as a main deficit in attention-deficit/hyperactivity disorder (ADHD), which could be modulated by treatment with methylphenidate (MPH). OBJECTIVES: We examined differences in reward processing in adulthood (independent of actual ADHD) depending on MPH treatment during childhood. METHODS: Eleven males with childhood ADHD treated with MPH, 12 drug-naïve males with childhood ADHD, and 12 controls matched by age, handedness, and smoking behavior were studied drug-free using functional magnetic resonance imaging. BOLD-responses were compared during a monetary incentive delay task using an ANOVA design focusing on the ventral striatum during anticipation and the orbitofrontal cortex during outcome. RESULTS: Controls, drug-naïve, and treated subjects did not differ significantly in their activations in the ventral striatum and orbitofrontal cortex. Explorative analyses revealed decreased insula activation during outcome of loss avoidance in drug-naïve subjects in comparison to both groups, while treated subjects did not differ from controls. Insula activation correlated significantly positive with harm avoidance in the treated group. Furthermore, comparing subjects with actual ADHD symptoms, remitters and controls we observed decreased putamen activition in ADHD persisters. CONCLUSIONS: Basal ganglia reward processing seemed to be unrelated to MPH pretreatment, but was related to remission. On the other hand, the revealed differences between treated and drug-naïve subjects with childhood ADHD, i.e., in the insula, give evidence for more pronounced abnormal activation in reward-associated brain regions in untreated subjects with childhood ADHD and underpin the need of prospective studies on long-term effects of psychostimulant treatment.

Childhood methylphenidate treatment of ADHD and response to affective stimuli.

Neural correlates of emotional dysregulation in attention-deficit/hyperactivity disorder (ADHD) and persisting influence of Methylphenidate (MPH) still remain insufficiently understood. Decreased activation in the subgenual cingulate and the ventral striatum were found during the perception of positive and negative affective pictures in drug-naïve males with ADHD during childhood (n=10). Males with ADHD during childhood treated with MPH (n=10) did not show any significant differences compared to healthy controls (n=10). Further prospective studies need to clarify direct and indirect mechanisms of MPH treatment that may contribute to emotional processing, which is dysfunctional in males without pharmacological treatment in childhood.

Stress hormones during flooding therapy and their relationship to therapy outcome in patients with panic disorder and agoraphobia.

In spite of excessive fear during a panic attack, studies have found no or little evidence for an activation of cortisol during natural panic attacks. Whether this phenomenon is related to psychopathology or outcome of psychotherapy is unknown. In this study, 10 patients with panic disorder and agoraphobia were treated with cognitive behavioural therapy including 3 in-vivo exposures (flooding) to individual phobic situations. Before, during and after exposure, the level of subjective fear was assessed and blood was collected simultaneously. Cortisol and ACTH were analysed from plasma. Ten matched healthy control subjects went through the same procedure. Fear and stress hormones during exposure were compared in patients and controls as well as related to therapy outcome at the end of therapy and 2 follow-ups in patients. Results showed that the concentrations of cortisol and ACTH did not significantly increase during exposure. Patients' cortisol concentrations were higher than those of controls at baseline and during exposure, while ACTH concentrations were comparable before and during exposure, and even lower than those of controls at recovery. Cortisol concentrations were moderately but consistently correlated to therapy outcome, i.e. patients with least cortisol release during exposure profited least from therapy. The study showed that a lack of stimulation of the HPA system at repeated confrontation with the phobic situation was related to therapeutic outcome. Mechanisms of action via the influence of cortisol on extinction learning or the inhibition of central excitatory neurotransmission are conceivable.

Delineating self-referential processing from episodic memory retrieval: common and dissociable networks.

Self-referential processing involves a complex set of cognitive functions, posing challenges to delineating its independent neural correlates. While self-referential processing has been considered functionally intertwined with episodic memory, the present study explores their overlap and dissociability. Standard tasks for self-referential processing and episodic memory were combined into a single fMRI experiment. Contrasting the effects of self-relatedness and retrieval success allowed for the two processes to be delineated. Stimuli judged as self-referential specifically activated the posterior cingulate/anterior precuneus, the medial prefrontal cortex, and an inferior division of the inferior parietal lobule. In contrast, episodic memory retrieval specifically involved the posterior precuneus, the right anterior prefrontal cortex, and a superior division of the inferior parietal lobule (extending into superior parietal lobule). Overlapping activations were found in intermediate zones in the precuneus and the inferior parietal lobule, but not in the prefrontal cortex. While our data show common networks for both processes in the medial and lateral parietal cortex, three functional differentiations were also observed: (1) an anterior-posterior differentiation within the medial parietal cortex; (2) a medial-anterolateral differentiation within the prefrontal cortex; and, (3) an inferior-superior differentiation within the lateral parietal cortex for self-referential processing versus episodic memory retrieval.

Altered representation of expected value in the orbitofrontal cortex in mania.

OBJECTIVE: Increased responsiveness to appetitive and reduced responsiveness to aversive anticipatory cues may be associated with dysfunction of the brain reward system in mania. Here we studied neural correlates of gain and loss expectation in mania using functional magnetic resonance imaging (fMRI). METHOD: Fifteen manic patients and 26 matched healthy control individuals performed a monetary incentive delay task, during which subjects anticipated to win or lose a varying amount of money. Varying both magnitude and valence (win, loss) of anticipatory cues allowed us to isolate the effects of magnitude, valence and expected value (magnitude-by-valence interaction). RESULTS: Response times and total gain amount did not differ significantly between groups. FMRI data indicated that the ventral striatum responded according to cued incentive magnitude in both groups, and this effect did not significantly differ between groups. However, a significant group difference was observed for expected value representation in the left lateral orbitofrontal cortex (OFC; BA 11 and 47). In this region, patients showed increasing BOLD responses during expectation of increasing gain and decreasing responses during expectation of increasing loss, while healthy subjects tended to show the inverse effect. In seven patients retested after remission OFC responses adapted to the response pattern of healthy controls. CONCLUSIONS: The observed alterations are consistent with a state-related affective processing bias during the expectation of gains and losses which may contribute to clinical features of mania, such as the enhanced motivation for seeking rewards and the underestimation of risks and potential punishments.

Acute exercise ameliorates reduced brain-derived neurotrophic factor in patients with panic disorder.

The neurotrophin brain-derived neurotrophic factor (BDNF) has been implicated in depression and anxiety. Antidepressants and exercise increase BDNF expression, and both have an antidepressant and anxiolytic activity. To further characterize the association of anxiety, BDNF and exercise, we studied panic disorder patients (n=12) and individually matched healthy control subjects (n=12) in a standardized exercise paradigm. Serum samples for BDNF analyses were taken before and after 30min of exercise (70 VO(2max)) or quiet rest. The two conditions were separated by 1 week and the order was randomized. Non-parametric statistical analyses were performed. There was a negative correlation of BDNF concentrations and subjective arousal at baseline (r=-0.42, p=0.006). Compared to healthy control subjects, patients with panic disorder had significantly reduced BDNF concentrations at baseline and 30min of exercise significantly increased BDNF concentrations only in these patients. Our results suggest that acute exercise ameliorates reduced BDNF concentrations in panic disorder patients and raise the question whether this is also found after long-term exercise training and if it is related to the therapeutic outcome.

5-HTT genotype effect on prefrontal-amygdala coupling differs between major depression and controls.

RATIONALE: In major depression, prefrontal regulation of limbic brain areas may be a key mechanism that is impaired during the processing of affective information. This prefrontal-limbic interaction has been shown to be modulated by serotonin (5-HTT) genotype, indicating a higher risk for major depressive disorder (MDD) with increasing number of 5-HTT low-expression alleles. OBJECTIVE: Functional magnetic resonance imaging was used to assess neural response to uncued unpleasant affective pictures in 21 unmedicated patients with MDD compared to 21 matched healthy controls, taking into account genetic influences of the 5-HTT (SCL6A4) high- and low-expression genotype. RESULTS: Healthy controls displayed greater prefrontal activation (BA10) to uncued negative pictures compared to patients with MDD. While in healthy controls prefrontal (BA10) activation and BA10-amygdala coupling increased with the number of 5-HTT low-expression risk alleles, this effect was abolished, and even reversed, in patients with MDD. In MDD, connectivity decreased with severity of depressive symptoms (HAMD total score). CONCLUSION: These findings suggest that increased medial prefrontal (BA10) activation and BA10-amygdala connectivity may counteract the risk for MDD in healthy carriers of 5-HTT low-expression alleles, while this protective factor might be lost in patients who actually suffer from MDD. Prefrontal-limbic regulation in risk populations could be a target of early interventions and should be the focus of further research.

A preliminary study of increased amygdala activation to positive affective stimuli in mania.

OBJECTIVES: The present study in hypomanic and manic patients explored how amygdala responses to affective stimuli depend on the valence of the stimuli presented. METHODS: We compared 10 patients with 10 matched healthy control subjects. We measured blood oxygen level-dependent (BOLD) responses in the amygdala while subjects passively viewed photographs taken from the International Affective Picture System. After the fMRI session, subjects saw the pictures again and subjectively rated the emotional valence and intensity of each picture. RESULTS: Compared to healthy individuals, hypomanic or manic patients showed higher valence ratings in positive pictures and associated larger BOLD responses in the left amygdala during positive versus neutral picture viewing. This enhanced amygdala activation was correlated with Young Mania Rating Scale scores and with euphoric as opposed to irritable symptom presentation. CONCLUSIONS: Increased valence ratings and amygdala responses to positive affective stimuli may reflect a positive processing bias contributing to elevated mood states characteristic for euphoric mania.

Reward anticipation and outcomes in adult males with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) has been suggested to involve deficits in reward processing. We used functional magnetic resonance imaging (fMRI) to compare the neural responses to reward anticipation and outcomes in 10 adults with ADHD and 10 controls as they played a monetary incentive delay task. Adults with ADHD were unmedicated, and groups were matched for age, verbal IQ and smoking habits. Adults with ADHD showed decreased activation in the ventral striatum during the anticipation of gain, but increased activation of the orbitofrontal cortex in response to gain outcomes. Ventral striatal activation in adults with ADHD during gain anticipation was negatively correlated with self-rated symptoms of hyperactivity and impulsivity. These findings suggest that male adults with ADHD show neural signs of abnormal reward processing. Future studies will have to investigate whether these dysfunctional patterns might be normalized by treatment.