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Based on promising results with adults, Acceptance and Commitment Therapy (ACT) presents as a treatment opportunity for depressed adolescents. We present a pilot study that compares ACT with treatment as usual (TAU), using random allocation of participants who were clinically referred to a psychiatric outpatient service. Participants were 30 adolescents, aged M = 14.9 (SD = 2.55), with 73.6% in the clinical range for depression. At posttreatment on measures of depression participants in the ACT condition showed significantly greater improvement statistically (d = 0.38), and 58% showed clinically reliable change with a response ratio of 1.59 in favor of ACT. Outcomes from 3-month follow-up data are tentative due to small numbers but suggest that improvement increased in magnitude. Measures of global functioning showed statistically significant improvement for both conditions, although clinical change measures favored only the ACT condition. The results support conducting a larger trial of ACT for the treatment of adolescent depression.
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Anxious temperament (AT) in human and non-human primates is a trait-like phenotype evident early in life that is characterized by increased behavioural and physiological reactivity to mildly threatening stimuli. Studies in children demonstrate that AT is an important risk factor for the later development of anxiety disorders, depression and comorbid substance abuse. Despite its importance as an early predictor of psychopathology, little is known about the factors that predispose vulnerable children to develop AT and the brain systems that underlie its expression. To characterize the neural circuitry associated with AT and the extent to which the function of this circuit is heritable, we studied a large sample of rhesus monkeys phenotyped for AT. Using 238 young monkeys from a multigenerational single-family pedigree, we simultaneously assessed brain metabolic activity and AT while monkeys were exposed to the relevant ethological condition that elicits the phenotype. High-resolution (18)F-labelled deoxyglucose positron-emission tomography (FDG-PET) was selected as the imaging modality because it provides semi-quantitative indices of absolute glucose metabolic rate, allows for simultaneous measurement of behaviour and brain activity, and has a time course suited for assessing temperament-associated sustained brain responses. Here we demonstrate that the central nucleus region of the amygdala and the anterior hippocampus are key components of the neural circuit predictive of AT. We also show significant heritability of the AT phenotype by using quantitative genetic analysis. Additionally, using voxelwise analyses, we reveal significant heritability of metabolic activity in AT-associated hippocampal regions. However, activity in the amygdala region predictive of AT is not significantly heritable. Furthermore, the heritabilities of the hippocampal and amygdala regions significantly differ from each other. Even though these structures are closely linked, the results suggest differential influences of genes and environment on how these brain regions mediate AT and the ongoing risk of developing anxiety and depression.
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The amygdalae are important, if not critical, brain regions for many affective, attentional and memorial processes, and dysfunction of the amygdalae has been a consistent finding in the study of clinical depression. Theoretical models of the functional neuroanatomy of both normal and psychopathological affective processes which posit cortical hemispheric specialization of functions have been supported by both lesion and functional neuroimaging studies in humans. Results from human neuroimaging studies in support of amygdalar hemispheric specialization are inconsistent. However, recent results from human lesion studies are consistent with hemispheric specialization. An important, yet largely ignored, feature of the amygdalae in the primate brain--derived from both neuroanatomical and electrophysiological data--is that there are virtually no direct interhemispheric connections via the anterior commissure (AC). This feature stands in stark contrast to that of the rodent brain wherein virtually all amygdalar nuclei have direct interhemispheric connections. We propose this feature of the primate brain, in particular the human brain, is a result of influences from frontocortical hemispheric specialization which have developed over the course of primate brain evolution. Results consistent with this notion were obtained by examining the nature of human amygdalar interhemispheric connectivity using both functional magnetic resonance imaging (FMRI) and positron emission tomography (PET). We found modest evidence of amygdalar interhemispheric functional connectivity in the non-depressed brain, whereas there was strong evidence of functional connectivity in the depressed brain. We interpret and discuss the nature of this connectivity in the depressed brain in the context of dysfunctional frontocortical-amygdalar interactions which accompany clinical depression.
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This article presents an overview of the author's recent electrophysiological studies of anterior cerebral asymmetries related to emotion and affective style. A theoretical account is provided of the role of the two hemispheres in emotional processing. This account assigns a major role in approach- and withdrawal-related behavior to the left and right frontal and anterior temporal regions of two hemispheres, respectively. Individual differences in approach- and withdrawal-related emotional reactivity and temperament are associated with stable differences in baseline measures of activation asymmetry in these anterior regions. Phasic state changes in emotion result in shifts in anterior activation asymmetry which are superimposed upon these stable baseline differences. Future directions for research in this area are discussed.
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OBJECTIVE: The anterior cingulate cortex has been implicated in depression. Results are best interpreted by considering anatomic and cytoarchitectonic subdivisions. Evidence suggests depression is characterized by hypoactivity in the dorsal anterior cingulate, whereas hyperactivity in the rostral anterior cingulate is associated with good response to treatment. The authors tested the hypothesis that activity in the rostral anterior cingulate during the depressed state has prognostic value for the degree of eventual response to treatment. Whereas prior studies used hemodynamic imaging, this investigation used EEG. METHOD: The authors recorded 28-channel EEG data for 18 unmedicated patients with major depression and 18 matched comparison subjects. Clinical outcome was assessed after nortriptyline treatment. Of the 18 depressed patients, 16 were considered responders 4-6 months after initial assessment. A median split was used to classify response, and the pretreatment EEG data of patients showing better (N=9) and worse (N=9) responses were analyzed with low-resolution electromagnetic tomography, a new method to compute three-dimensional cortical current density for given EEG frequency bands according to a Talairach brain atlas. RESULTS: The patients with better responses showed hyperactivity (higher theta activity) in the rostral anterior cingulate (Brodmann's area 24/32). Follow-up analyses demonstrated the specificity of this finding, which was not confounded by age or pretreatment depression severity. CONCLUSIONS: These results, based on electrophysiological imaging, not only support hemodynamic findings implicating activation of the anterior cingulate as a predictor of response in depression, but they also suggest that differential activity in the rostral anterior cingulate is associated with gradations of response.
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Two reports in the last issue of this journal attempted to replicate aspects of our previous studies on anterior electroencephalogram (EEG) asymmetry, affective style, and depression. In this commentary, an overview is provided of our model of anterior asymmetries, affective style, and psychopathology. Emphasis is placed on conceptualizing the prefrontal and anterior temporal activation patterns within a circuit that includes cortical and subcortical structures. The causal status of individual differences in asymmetric activation in the production of affective style and psychopathology is considered. Major emphasis is placed on EEG methods, particularly the need for multiple assessments to obtain estimates of asymmetric activation that better reflect an individual's true score. Issues specific to each of the two articles are also considered. Each of the articles has more consistency with our previously published data than the authors themselves suggest. Recommendations are made for future research to resolve some of the outstanding issues.
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OBJECTIVE: The anticipation of adverse outcomes, or worry, is a cardinal symptom of generalized anxiety disorder. Prior work with healthy subjects has shown that anticipating aversive events recruits a network of brain regions, including the amygdala and anterior cingulate cortex. This study tested whether patients with generalized anxiety disorder have alterations in anticipatory amygdala function and whether anticipatory activity in the anterior cingulate cortex predicts treatment response. METHOD: Functional magnetic resonance imaging (fMRI) was employed with 14 generalized anxiety disorder patients and 12 healthy comparison subjects matched for age, sex, and education. The event-related fMRI paradigm was composed of one warning cue that preceded aversive pictures and a second cue that preceded neutral pictures. Following the fMRI session, patients received 8 weeks of treatment with extended-release venlafaxine. RESULTS: Patients with generalized anxiety disorder showed greater anticipatory activity than healthy comparison subjects in the bilateral dorsal amygdala preceding both aversive and neutral pictures. Building on prior reports of pretreatment anterior cingulate cortex activity predicting treatment response, anticipatory activity in that area was associated with clinical outcome 8 weeks later following treatment with venlafaxine. Higher levels of pretreatment anterior cingulate cortex activity in anticipation of both aversive and neutral pictures were associated with greater reductions in anxiety and worry symptoms. CONCLUSIONS: These findings of heightened and indiscriminate amygdala responses to anticipatory signals in generalized anxiety disorder and of anterior cingulate cortex associations with treatment response provide neurobiological support for the role of anticipatory processes in the pathophysiology of generalized anxiety disorder.
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BACKGROUND: Studies using electroencephalogram (EEG) measures of activation asymmetry have reported differences in anterior asymmetry between depressed and nondepressed subjects. Several studies have suggested reciprocal relations between measures of anterior and posterior activation asymmetries. We hypothesized that depressed subjects would fail to show the normal activation of posterior right hemisphere regions in response to an appropriate cognitive challenge. METHODS: EEG activity was recorded from 11 depressed and 19 nondepressed subjects during the performance of psychometrically matched verbal (word finding) and spatial (dot localization) tasks. Band power was extracted from all epochs of artifact-free data and averaged within each condition. Task performance was also assessed. RESULTS: Depressed subjects showed a specific deficit in the performance of the spatial task, whereas no group differences were evident on verbal performance. In posterior scalp regions, nondepressed controls had a pattern of relative left-sided activation during the verbal task and relative right-sided activation during the spatial task. In contrast, depressed subjects failed to show activation in posterior right hemisphere regions during spatial task performance. CONCLUSIONS: These findings suggest that deficits in right posterior functioning underlie the observed impairments in spatial functioning among depressed subjects.
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BACKGROUND: The frontal lobe has been crucially involved in the neurobiology of major depression, but inconsistencies among studies exist, in part due to a failure of considering modulatory variables such as symptom severity, comorbidity with anxiety, and distinct subtypes, as codeterminants for patterns of brain activation in depression. METHODS: Resting electroencephalogram was recorded in 38 unmedicated subjects with major depressive disorder and 18 normal comparison subjects, and analyzed with a tomographic source localization method that computes the cortical three-dimensional distribution of current density for standard electroencephalogram frequency bands. Symptom severity and anxiety were measured via self-report and melancholic features via clinical interview. RESULTS: Depressed subjects showed more excitatory (beta3, 21.5-30.0 Hz) activity in the right superior and inferior frontal lobe (Brodmann's area 9/10/11) than comparison subjects. In melancholic subjects, this effect was particularly pronounced for severe depression, and right frontal activity correlated positively with anxiety. Depressed subjects showed posterior cingulate and precuneus hypoactivity. CONCLUSIONS: While confirming prior results implicating right frontal and posterior cingulate regions, this study highlights the importance of depression severity, anxiety, and melancholic features in patterns of brain activity accompanying depression.
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<p>Many powerful human emotional thoughts are generated in the absence of a precipitating event in the environment. Here, we tested whether we can decode the valence of internally driven, self-generated thoughts during task-free rest based on neural similarities with task-related affective mental states. We acquired functional magnetic resonance imaging (fMRI) data while participants generated positive and negative thoughts as part of an attribution task (Session A) and while they reported the occurrence of comparable mental states during task-free rest periods (Session B). With the use of multivariate pattern analyses (MVPA), we identified response patterns in the medial orbitofrontal cortex (mOFC) that encode the affective content of thoughts that are generated in response to an external experimental cue. Importantly, these task driven response patterns reliably predicted the occurrence of affective thoughts generated during unconstrained rest periods recorded one week apart. This demonstrates that at least certain elements of task-cued and task-free affective experiences rely on a common neural code. Furthermore, our findings reveal the role that the mOFC plays in determining the affective tone of unconstrained thoughts. More generally, our results suggest that MVPA is an important methodological tool for attempts to understand unguided subject driven mental states such as mind-wandering and daydreaming based on neural similarities with task-based experiences.</p>
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The authors examined the time course of affective responding associated with different affective dimensions--anxious apprehension, anxious arousal, and anhedonic depression--using an emotion-modulated startle paradigm. Participants high on 1 of these 3 dimensions and nonsymptomatic control participants viewed a series of affective pictures with acoustic startle probes presented before, during, and after the stimuli. All groups exhibited startle potentiation during unpleasant pictures and in anticipation of both pleasant and unpleasant pictures. Compared with control participants, symptomatic participants exhibited sustained potentiation following the offset of unpleasant stimuli and a lack of blink attenuation during and following pleasant stimuli. Common and unique patterns of affective responses in the 3 types of mood symptoms are discussed.
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Functional neuroimaging research has demonstrated that retrieving information about object-associated colors activates the left fusiform gyrus in posterior temporal cortex. Although regions near the fusiform have previously been implicated in color perception, it remains unclear whether color knowledge retrieval actually activates the color perception system. Evidence to this effect would be particularly strong if color perception cortex was activated by color knowledge retrieval triggered strictly with linguistic stimuli. To address this question, subjects performed two tasks while undergoing fMRI. First, subjects performed a property verification task using only words to assess conceptual knowledge. On each trial, subjects verified whether a named color or motor property was true of a named object (e.g., TAXI-yellow, HAIR-combed). Next, subjects performed a color perception task. A region of the left fusiform gyrus that was highly responsive during color perception also showed greater activity for retrieving color than motor property knowledge. These data provide the first evidence for a direct overlap in the neural bases of color perception and stored information about object-associated color, and they significantly add to accumulating evidence that conceptual knowledge is grounded in the brain's modality-specific systems.
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The effects of Zen breath meditation were compared with those of relaxation on college adjustment. 75 undergraduates (aged 17–40 yrs) were divided into 3 groups using randomized matching on the basis of initial anxiety scores of the College Adjustment Scales. Ss also completed the Taylor Manifest Anxiety Scale. The 3 groups included, meditation, relaxation, and control. Training for the meditation and relaxation groups took place during a 1-hr instructional session with written instructions being distributed. After 6 wks anxiety and depression scored significantly decreased for the meditation and relaxation groups. Interpersonal problem scores also significantly decreased for the meditation group.

Many investigators have hypothesized that brain response to cortisol is altered in depression. However, neural activation in response to exogenously manipulated cortisol elevations has not yet been directly examined in depressed humans. Animal research shows that glucocorticoids have robust effects on hippocampal function, and can either enhance or suppress neuroplastic events in the hippocampus depending on a number of factors. We hypothesized that depressed individuals would show 1) altered hippocampal response to exogenous administration of cortisol, and 2) altered effects of cortisol on learning. In a repeated-measures design, 19 unmedicated depressed and 41 healthy individuals completed two fMRI scans. Fifteen mg oral hydrocortisone (i.e., cortisol) or placebo (order randomized and double-blind) was administered 1 h prior to encoding of emotional and neutral words during fMRI scans. Data analysis examined the effects of cortisol administration on 1) brain activation during encoding, and 2) subsequent free recall for words. Cortisol affected subsequent recall performance in depressed but not healthy individuals. We found alterations in hippocampal response to cortisol in depressed women, but not in depressed men (who showed altered response to cortisol in other regions, including subgenual prefrontal cortex). In both depressed men and women, cortisol's effects on hippocampal function were positively correlated with its effects on recall performance assessed days later. Our data provide evidence that in depressed compared to healthy women, cortisol's effects on hippocampal function are altered. Our data also show that in both depressed men and women, cortisol's effects on emotional memory formation and hippocampal function are related.
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How does language reliably evoke emotion, as it does when people read a favorite novel or listen to a skilled orator? Recent evidence suggests that comprehension involves a mental simulation of sentence content that calls on the same neural systems used in literal action, perception, and emotion. In this study, we demonstrated that involuntary facial expression plays a causal role in the processing of emotional language. Subcutaneous injections of botulinum toxin-A (BTX) were used to temporarily paralyze the facial muscle used in frowning. We found that BTX selectively slowed the reading of sentences that described situations that normally require the paralyzed muscle for expressing the emotions evoked by the sentences. This finding demonstrates that peripheral feedback plays a role in language processing, supports facial-feedback theories of emotional cognition, and raises questions about the effects of BTX on cognition and emotional reactivity. We account for the role of facial feedback in language processing by considering neurophysiological mechanisms and reinforcement-learning theory.
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In rodents, theta rhythm has been linked to the hippocampal formation, as well as other regions, including the anterior cingulate cortex (ACC). To test the role of the ACC in theta rhythm, concurrent measurements of brain electrical activity (EEG) and glucose metabolism (PET) were performed in 29 subjects at baseline. EEG data were analyzed with a source localization technique that enabled voxelwise correlations of EEG and PET data. For theta, but not other bands, the rostral ACC (Brodmann areas 24/32) was the largest cluster with positive correlations between current density and glucose metabolism. Positive correlations were also found in right fronto-temporal regions. In control but not depressed subjects, theta within ACC and prefrontal/orbitofrontal regions was positively correlated. The results reveal a link between theta and cerebral metabolism in the ACC as well as disruption of functional connectivity within frontocingulate pathways in depression.
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The corticotrophin-releasing hormone (CRH) system integrates the stress response and is associated with stress-related psychopathology. Previous reports have identified interactions between childhood trauma and sequence variation in the CRH receptor 1 gene (CRHR1) that increase risk for affective disorders. However, the underlying mechanisms that connect variation in CRHR1 to psychopathology are unknown. To explore potential mechanisms, we used a validated rhesus macaque model to investigate association between genetic variation in CRHR1, anxious temperament (AT) and brain metabolic activity. In young rhesus monkeys, AT is analogous to the childhood risk phenotype that predicts the development of human anxiety and depressive disorders. Regional brain metabolism was assessed with (18)F-labeled fluoro-2-deoxyglucose (FDG) positron emission tomography in 236 young, normally reared macaques that were also characterized for AT. We show that single nucleotide polymorphisms (SNPs) affecting exon 6 of CRHR1 influence both AT and metabolic activity in the anterior hippocampus and amygdala, components of the neural circuit underlying AT. We also find evidence for association between SNPs in CRHR1 and metabolism in the intraparietal sulcus and precuneus. These translational data suggest that genetic variation in CRHR1 affects the risk for affective disorders by influencing the function of the neural circuit underlying AT and that differences in gene expression or the protein sequence involving exon 6 may be important. These results suggest that variation in CRHR1 may influence brain function before any childhood adversity and may be a diathesis for the interaction between CRHR1 genotypes and childhood trauma reported to affect human psychopathology.
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Cyclic AMP (cAMP) is a second messenger involved in many processes including mnemonic processing and anxiety. Memory deficits and anxiety are noted in the phenotype of fragile X (FX), the most common heritable cause of mental retardation and autism. Here we review reported observations of altered cAMP cascade function in FX and autism. Cyclic AMP is a potentially useful biochemical marker to distinguish autism comorbid with FX from autism per se and the cAMP cascade may be a viable therapeutic target for both FX and autism.
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Objective: A strong relation between negative affect and craving has been demonstrated in laboratory and clinical studies, with depressive symptomatology showing particularly strong links to craving and substance abuse relapse. Mindfulness-based relapse prevention (MBRP), shown to be efficacious for reduction of substance use, uses mindfulness-based practices to teach alternative responses to emotional discomfort and lessen the conditioned response of craving in the presence of depressive symptoms. The goal in the current study was to examine the relation between measures of depressive symptoms, craving, and substance use following MBRP. Method: Individuals with substance use disorders (N = 168; mean age 40.45 years, SD = 10.28; 36.3% female; 46.4% non-White) were recruited after intensive stabilization, then randomly assigned to either 8 weekly sessions of MBRP or a treatment-as-usual control group. Approximately 73% of the sample was retained at the final 4-month follow-up assessment. Results: Results confirmed a moderated-mediation effect, whereby craving mediated the relation between depressive symptoms (Beck Depression Inventory) and substance use (Timeline Follow-Back) among the treatment-as-usual group but not among MBRP participants. MBRP attenuated the relation between postintervention depressive symptoms and craving (Penn Alcohol Craving Scale) 2 months following the intervention (ƒ² = .21). This moderation effect predicted substance use 4 months following the intervention (ƒ² = .18). Conclusion: MBRP appears to influence cognitive and behavioral responses to depressive symptoms, partially explaining reductions in postintervention substance use among the MBRP group. Although results are preliminary, the current study provides evidence for the value of incorporating mindfulness practice into substance abuse treatment and identifies a potential mechanism of change following MBRP.

Depression is a disorder of the representation and regulation of mood and emotion. The circuitry underlying the representation and regulation of normal emotion and mood is reviewed, including studies at the animal level, human lesion studies, and human brain imaging studies. This corpus of data is used to construct a model of the ways in which affect can become disordered in depression. Research on the prefrontal cortex, anterior cingulate, hippocampus, and amygdala is reviewed and abnormalities in the structure and function of these different regions in depression is considered. The review concludes with proposals for the specific types of processing abnormalities that result from dysfunctions in different parts of this circuitry and offers suggestions for the major themes upon which future research in this area should be focused.
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Early life stress (ELS) and function of the hypothalamic-pituitary-adrenal axis predict later psychopathology. Animal studies and cross-sectional human studies suggest that this process might operate through amygdala-ventromedial prefrontal cortex (vmPFC) circuitry implicated in the regulation of emotion. Here we prospectively investigated the roles of ELS and childhood basal cortisol amounts in the development of adolescent resting-state functional connectivity (rs-FC), assessed by functional connectivity magnetic resonance imaging (fcMRI), in the amygdala-PFC circuit. In females only, greater ELS predicted increased childhood cortisol levels, which predicted decreased amygdala-vmPFC rs-FC 14 years later. For females, adolescent amygdala-vmPFC functional connectivity was inversely correlated with concurrent anxiety symptoms but positively associated with depressive symptoms, suggesting differing pathways from childhood cortisol levels function through adolescent amygdala-vmPFC functional connectivity to anxiety and depression. These data highlight that, for females, the effects of ELS and early HPA-axis function may be detected much later in the intrinsic processing of emotion-related brain circuits.
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