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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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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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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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Cognitive deficits have been reported in children who experienced early neglect, especially children raised in institutionalized settings. Previous research suggests that early neglect may differentially affect the directional organization of white matter in the prefrontal cortex (PFC). This may be one mechanism to explain cognitive deficits associated with neglect. To test this idea, properties of white matter and neurocognitive performance were assessed in children who suffered early neglect and those raised in typical environments (n = 63, Mage  = 11.75 years). As predicted, prefrontal white matter microstructure was affected, consistent with more diffuse organization, in children that suffered early neglect and this was related to neurocognitive deficits. Such findings underscore how early adversity may affect the PFC and explain cognitive deficits associated with neglect.
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Individuals who experience early adversity, such as child maltreatment, are at heightened risk for a broad array of social and health difficulties. However, little is known about how this behavioral risk is instantiated in the brain. Here we examine a neurobiological contribution to individual differences in human behavior using methodology appropriate for use with pediatric populations paired with an in-depth measure of social behavior. We show that alterations in the orbitofrontal cortex among individuals who experienced physical abuse are related to social difficulties. These data suggest a biological mechanism linking early social learning to later behavioral outcomes.
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Asymmetry of waking electroencephalography (EEG) alpha power in frontal regions has been correlated with waking emotional reactivity and the emotional content of dream reports. Little is known regarding alpha asymmetry during sleep. The present study was performed to compare alpha power and alpha power asymmetry in various brain regions across states of sleep and wakefulness. Waking and sleep EEG were recorded in a group of patients undergoing polysomnographic evaluation for possible sleep disorders. Alpha EEG asymmetry in frontal and temporal regions was significantly correlated in waking versus sleep, particularly during rapid eye movement (REM) sleep. These results suggest that patterns of frontal alpha asymmetry are stable across sleep and waking and may be related to emotional reactivity during dreaming. During sleep, alpha power was highest during slow-wave sleep and lowest during REM sleep. Implications of these data for understanding the functional significance of alpha power during waking and sleeping are considered.
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OBJECTIVES: Randomized controlled studies on the effectiveness of body-oriented methods of treatment for children with attention-deficit hyperactivity disorder (ADHD) are lacking. Our aim was to compare the effectiveness of two methods of treatment (yoga for children vs. conventional motor exercises) in a randomized controlled pilot study. METHODS: Nineteen children with a clinical diagnosis of ADHD (according to ICD-10 criteria) were included and randomly assigned to treatment conditions according to a 2x2 cross-over design. Effects of treatment were analyzed by means of an analysis of variance for repeated measurements. RESULTS: For all outcome measures (test scores on an attention task, and parent ratings of ADHD symptoms) the yoga training was superior to the conventional motor training, with effect sizes in the medium-to-high range (0.60-0.97). All children showed sizable reductions in symptoms over time, and at the end of the study, the group means for the ADHD scales did not differ significantly from those for a representative control group. Furthermore, the training was particularly effective for children undergoing pharmacotherapy (MPH). CONCLUSIONS: The findings from this pilot study demonstrate that yoga can be an effective complementary or concomitant treatment for attention-deficit hyperactivity disorder. The study advocates further research into the impact of yoga or body-oriented therapies on the prevention and treatment of ADHD.
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OBJECTIVE: This study was designed to determine the effectiveness of a group stress reduction program based on mindfulness meditation for patients with anxiety disorders. METHOD: The 22 study participants were screened with a structured clinical interview and found to meet the DSM-III-R criteria for generalized anxiety disorder or panic disorder with or without agoraphobia. Assessments, including self-ratings and therapists' ratings, were obtained weekly before and during the meditation-based stress reduction and relaxation program and monthly during the 3-month follow-up period. RESULTS: Repeated measures analyses of variance documented significant reductions in anxiety and depression scores after treatment for 20 of the subjects--changes that were maintained at follow-up. The number of subjects experiencing panic symptoms was also substantially reduced. A comparison of the study subjects with a group of nonstudy participants in the program who met the initial screening criteria for entry into the study showed that both groups achieved similar reductions in anxiety scores on the SCL-90-R and on the Medical Symptom Checklist, suggesting generalizability of the study findings. CONCLUSIONS: A group mindfulness meditation training program can effectively reduce symptoms of anxiety and panic and can help maintain these reductions in patients with generalized anxiety disorder, panic disorder, or panic disorder with agoraphobia.
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The effectiveness of an 8-week mindfulness training for adolescents aged 11–15 years with ADHD and parallel Mindful Parenting training for their parents was evaluated, using questionnaires as well as computerized attention tests. Adolescents (N = 10), their parents (N = 19) and tutors (N = 7) completed measurements before, immediately after, 8 weeks after and 16 weeks after training. Adolescents reported on their attention and behavioral problems and mindful awareness, and were administered two computerized sustained attention tasks. Parents as well as tutors reported on adolescents’ attention and behavioral problems and executive functioning. Parents further reported on their own parenting, parenting stress and mindful awareness. Both the mindfulness training for the adolescents and their parents was delivered in group format. First, after mindfulness training, adolescents’ attention and behavior problems reduced, while their executive functioning improved, as indicated by self-report measures as well as by father and teacher report. Second, improvements in adolescent’ actual performance on attention tests were found after mindfulness training. Moreover, fathers, but not mothers, reported reduced parenting stress. Mothers reported reduced overreactive parenting, whereas fathers reported an increase. No effect on mindful awareness of adolescents or parents was found. Effects of mindfulness training became stronger at 8-week follow-up, but waned at 16-week follow-up. Our study adds to the emerging body of evidence indicating that mindfulness training for adolescents with ADHD (and their parents) is an effective approach, but maintenance strategies need to be developed in order for this approach to be effective in the longer term.

Losses in relationships, work, and other areas of life often accompany the physical discomfort of chronic pain. Often the depth and intensity of the grief associated with chronic pain are overlooked or possibly misdiagnosed and treated as depression. We used an 8-week mindfulness meditation program to determine its effectiveness in addressing the grieving process among 39 patients diagnosed with chronic pain. Eighteen patients volunteered to be in a comparison group. The study was conducted in a regional hospital's pain clinic and patients completed the Response to Loss Scale (measuring grief), the Beck Depression Inventory, and the State Trait Anxiety Inventory. Results indicated that the treatment group advanced significantly more quickly through the initial stages of grieving than the comparison group. In addition, the treatment group demonstrated significant reductions in depression and state anxiety, but no significant differences emerged when comparing groups on the final stages of grieving or trait anxiety.

Stress and negative mood during pregnancy increase risk for poor childbirth outcomes and postnatal mood problems and may interfere with mother–infant attachment and child development. However, relatively little research has focused on the efficacy of psychosocial interventions to reduce stress and negative mood during pregnancy. In this study, we developed and pilot tested an eight-week mindfulness-based intervention directed toward reducing stress and improving mood in pregnancy and early postpartum. We then conducted a small randomized trial ( n = 31) comparing women who received the intervention during the last half of their pregnancy to a wait-list control group. Measures of perceived stress, positive and negative affect, depressed and anxious mood, and affect regulation were collected prior to, immediately following, and three months after the intervention (postpartum). Mothers who received the intervention showed significantly reduced anxiety (effect size, 0.89; p < 0.05) and negative affect (effect size, 0.83; p < 0.05) during the third trimester in comparison to those who did not receive the intervention. The brief and nonpharmaceutical nature of this intervention makes it a promising candidate for use during pregnancy.

The inability to cope successfully with the enormous stress of medical education may lead to a cascade of consequences at both a personal and professional level. The present study examined the short-term effects of an 8-week meditation-based stress reduction intervention on premedical and medical students using a well-controlled statistical design. Findings indicate that participation in the intervention can effectively (1) reduce self-reported state and trait anxiety, (2) reduce reports of overall psychological distress including depression, (3) increase scores on overall empathy levels, and (4) increase scores on a measure of spiritual experiences assessed at termination of intervention. These results (5) replicated in the wait-list control group, (6) held across different experiments, and (7) were observed during the exam period. Future research should address potential long-term effects of mindfulness training for medical and premedical students.

This study describes the effects of an 8-week course in Mindfulness-Based Stress Reduction (MBSR; J. Kabat-Zinn, 1982, 1990) on affective symptoms (depression and anxiety), dysfunctional attitudes, and rumination. Given the focus of mindfulness meditation (MM) in modifying cognitive processes, it was hypothesized that the primary change in MM practice involves reductions in ruminative tendencies. We studied a sample of individuals with lifetime mood disorders who were assessed prior to and upon completion of an MBSR course. We also compared a waitlist sample matched with a subset of the MBSR completers. Overall, the results suggest that MM practice primarily leads to decreases in ruminative thinking, even after controlling for reductions in affective symptoms and dysfunctional beliefs.

OBJECTIVE: To examine yoga's effects on inner-city children's well-being. METHODS: This pilot study compared fourth- and fifth-grade students at 2 after-school programs in Bronx, New York. One program offered yoga 1 hour per week for 12 weeks (yoga) and the other program (non-yoga) did not. Preintervention and postintervention emotional well-being was assessed by Harter's Global Self-Worth and Physical Appearance subscales, which were the study's primary outcome measures. Secondary outcomes included other measures of emotional well-being assessed by 2 new scales: Perceptions of Physical Health and Yoga Teachings (including Negative Behaviors, Positive Behaviors, and Focusing/relaxation subscales). Preintervention and postintervention, physical wellbeing was assessed by measures of flexibility and balance. Subjective ratings ofyoga's effects on well-being were evaluated by an additional questionnaire completed by the yoga group only. RESULTS: Data were collected from 78% (n=39) and 86.5% (n=32) of potential yoga and non-yoga study enrollees. No differences in baseline demographics were found. Controlling for preintervention well-being differences using analysis of covariance, we found that children in the yoga group had better postintervention Negative Behaviors scores and balance than the non-yoga group (P < .05). The majority of children participating in yoga reported enhanced wellbeing, as reflected by perceived improvements in behaviors directly targeted by yoga (e.g., strength, flexibility, balance). CONCLUSIONS: Although no significant differences were found in the study's primary outcomes (global self-worth and perceptions of physical well-being), children participating in yoga reported using fewer negative behaviors in response to stress and had better balance than a comparison group. Improvements in wellbeing, specifically in behaviors directly targeted by yoga, were reported. These results suggest a possible role of yoga as a preventive intervention as well as a means of improving children's perceived well-being.
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Occupational therapists use school-based yoga programs, but these interventions typically lack manualization and evidence from well-designed studies. Using an experimental pretest–posttest control group design, we examined the effectiveness of the Get Ready to Learn (GRTL) classroom yoga program among children with autism spectrum disorders (ASD). The intervention group received the manualized yoga program daily for 16 wk, and the control group engaged in their standard morning routine. We assessed challenging behaviors with standardized measures and behavior coding before and after intervention. We completed a between-groups analysis of variance to assess differences in gain scores on the dependent variables. Students in the GRTL program showed significant decreases (p < .05) in teacher ratings of maladaptive behavior, as measured with the Aberrant Behavior Checklist, compared with the control participants. This study demonstrates that use of daily classroomwide yoga interventions has a significant impact on key classroom behaviors among children with ASD.
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We recently reported the presence of reliable asymmetries in frontal-brain electrical activity in infants that distinguished between certain positive- and negative-affect elicitors. In order to explore the degree to which these asymmetries in brain activity are associated with individual differences in affective response, 35 ten-month-old female infants were presented with a stranger-approach, mother-approach, and maternal-separation experience while an electroencephalogram (EEG) from the left- and right-frontal and left- and right-parietal scalp regions was recorded and facial and other behavioral responses were videotaped. Changes in frontal-EEG asymmetry reflected behavioral changes between conditions. In addition, individual differences in affective response to separation were related to differences in frontal-brain asymmetries. These findings indicate that lawful changes exist in asymmetries of frontal-brain activation during the expression of certain emotions in the first year of life and that individual differences in emotional responsivity are related to these measures of brain activity.
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The goal of this study was to evaluate potential mental health benefits of yoga for adolescents in secondary school. Students were randomly assigned to either regular physical education classes or to 11 weeks of yoga sessions based upon the Yoga Ed program over a single semester. Students completed baseline and end-program self-report measures of mood, anxiety, perceived stress, resilience, and other mental health variables. Independent evaluation of individual outcome measures revealed that yoga participants showed statistically significant differences over time relative to controls on measures of anger control and fatigue/inertia. Most outcome measures exhibited a pattern of worsening in the control group over time, whereas changes in the yoga group over time were either minimal or showed slight improvements. These preliminary results suggest that implementation of yoga is acceptable and feasible in a secondary school setting and has the potential of playing a protective or preventive role in maintaining mental health.
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Abstract The authors examined the effect of a 6-week mind/body intervention on college students' psychological distress, anxiety, and perception of stress. One hundred twenty-eight students were randomly assigned to an experimental group (n = 63) or a waitlist control group (n = 65). The experimental group received 6 90-minute group-training sessions in the relaxation response and cognitive behavioral skills. The Symptom Checklist-90-Revised, Spielberger State-Trait Anxiety Inventory, and the Perceived Stress Scale were used to assess the students' psychological state before and after the intervention. Ninety students (70% of the initial sample) completed the postassessment measure. Significantly greater reductions in psychological distress, state anxiety, and perceived stress were found in the experimental group. This brief mind/body training may be useful as a preventive intervention for college students, according to the authors, who called for further research to determine whether the observed treatment effect can be sustained over a longer period of time.

OBJECTIVES: Given the demands of caring for chronically ill children, it is not surprising that caregivers often experience high levels of chronic stress. A Mindfulness-Based Stress Reduction (MBSR) program may offer relief to these caregivers by providing tools for self-care and heath promotion that otherwise may be lacking. METHODS: MBSR classes were offered without restriction to parents of children attending various clinics at a large urban children's medical centre. Caregivers completed the Profile of Mood States (POMS) and Symptoms of Stress Inventory (SOSI) both before and after program participation. RESULTS: Forty-four caregivers participated in one of seven group MBSR sessions that were offered between August 2001 and February 2004. Most were mothers of children with special needs and various chronic conditions, who had been diagnosed an average of 7 years previous. Prior to the intervention, caregivers reported very high levels of stress and mood disturbance. These decreased substantially over the 8-week program, with an overall reduction in stress symptoms of 32% (p < .001), and in total mood disturbance of 56% (p < .001). CONCLUSIONS: This brief MBSR program for caregivers of chronically ill children was successful in significantly decreasing substantial stress symptoms and mood disturbance. Further studies would benefit from using more rigorous methodology and applying the program to other groups of chronically stressed caregivers.

Neuroanatomists posit that the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST) comprise two major nodes of a macrostructural forebrain entity termed the extended amygdala. The extended amygdala is thought to play a critical role in adaptive motivational behavior and is implicated in the pathophysiology of maladaptive fear and anxiety. Resting functional connectivity of the Ce was examined in 107 young anesthetized rhesus monkeys and 105 young humans using standard resting-state functional magnetic resonance imaging (fMRI) methods to assess temporal correlations across the brain. The data expand the neuroanatomical concept of the extended amygdala by finding, in both species, highly significant functional coupling between the Ce and the BST. These results support the use of in vivo functional imaging methods in nonhuman and human primates to probe the functional anatomy of major brain networks such as the extended amygdala.
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