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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Summary
Stress disorders are among the most commonly occurring of all mental disorders. In this context, the question arises whether the stress inevitably unfolding around us has the potential to “contaminate” and compromise us. In the current multi-center study, we investigate the existence of such empathic stress (defined as a full-blown physiological stress response that arises solely by observing a target undergo a stressful situation), and whether empathic stress permeates to the core of the stress system, the hypothalamic-pituitary-adrenal (HPA) axis. Additionally, we investigate whether empathic stress responses may be modulated by the familiarity between observer and target (partners vs. strangers), the modality of observation (real-life vs. virtual) and observer sex (female vs. male). Participants were tested in dyads, paired with a loved one or a stranger of the opposite sex. While the target of the dyad (n = 151) was exposed to a psychosocial stressor, the observer (n = 211) watched through a one-way mirror or via live video transmission. Overall, 26% of the observers displayed physiologically significant cortisol increases. This empathic stress was more pronounced in intimate observer-target dyads (40%) and during the real-life representation of the stressor (30%). Empathic stress was further modulated by interindividual differences in empathy measures. Despite the higher prevalence of empathic stress in the partner and real-life observation conditions, significant cortisol responses also emerged in strangers (10%) and the virtual observation modality (24%). The occurrence of empathic stress down to the level of HPA-axis activation, in some cases even in total strangers and when only virtually witnessing another's distress, may have important implications for the development of stress-related diseases.
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In a test of the effects of cortisol on emotional memory, 90 men were orally administered placebo or 20 or 40 mg cortisol and presented with emotionally arousing and neutral stimuli. On memory tests administered within 1 hr of stimulus presentation, cortisol elevations caused a reduction in the number of errors committed on free-recall tasks. Two evenings later, when cortisol levels were no longer manipulated, inverted-U quadratic trends were found for recognition memory tasks, reflecting memory facilitation in the 20-mg group for both negative and neutral information. Results suggest that the effects of cortisol on memory do not differ substantially for emotional and neutral information. The study provides evidence of beneficial effects of acute cortisol elevations on explicit memory in humans.
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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 human brain and skull are three dimensional (3D) anatomical structures with complex surfaces. However, medical images are often two dimensional (2D) and provide incomplete visualization of structural morphology. To overcome this loss in dimension, we developed and validated a freely available, semi-automated pathway to build 3D virtual reality (VR) and hand-held, stereolithograph models. To evaluate whether surface visualization in 3D was more informative than in 2D, undergraduate students (n = 50) used the Gillespie scale to rate 3D VR and physical models of both a living patient-volunteer's brain and the skull of Phineas Gage, a historically famous railroad worker whose misfortune with a projectile tamping iron provided the first evidence of a structure-function relationship in brain. Using our processing pathway, we successfully fabricated human brain and skull replicas and validated that the stereolithograph model preserved the scale of the VR model. Based on the Gillespie ratings, students indicated that the biological utility and quality of visual information at the surface of VR and stereolithograph models were greater than the 2D images from which they were derived. The method we developed is useful to create VR and stereolithograph 3D models from medical images and can be used to model hard or soft tissue in living or preserved specimens. Compared to 2D images, VR and stereolithograph models provide an extra dimension that enhances both the quality of visual information and utility of surface visualization in neuroscience and medicine.
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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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<p>This study was designed to test the hypothesis that Japanese subjects exhibit different patterns of resting EEG asymmetry compared with Westerners. EEG was recorded from the left and right temporal and parietal scalp regions in bilingual Japanese and Western subjects during eyes-open and eyes-closed rest periods before and after the performance of a series of cognitive tasks. Alpha activity was integrated and digitized. Japanese subjects were found to exhibit greater relative right-sided parietal activation during the eyes closed condition. This difference was found to be a function of greater left hemisphere activation among the Westerners. Various possible contributors to this cross-cultural differences are discussed.</p>
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Cued spatial attention modulates functionally relevant alpha rhythms in visual cortices in humans. Here, we present evidence for analogous phenomena in primary somatosensory neocortex (SI). Using magnetoencephalography, we measured changes in the SI mu rhythm containing mu-alpha (7–14 Hz) and mu-beta (15–29 Hz) components. We found that cued attention impacted mu-alpha in the somatopically localized hand representation in SI, showing decreased power after attention was cued to the hand and increased power after attention was cued to the foot, with significant differences observed 500–1100 ms after cue. Mu-beta showed differences in a time window 800–850 ms after cue. The visual cue also drove an early evoked response beginning ∼70 ms after cue with distinct peaks modulated with cued attention. Distinct components of the tactile stimulus-evoked response were also modulated with cued attention. Analysis of a second dataset showed that, on a trial-by-trial basis, tactile detection probabilities decreased linearly with prestimulus mu-alpha and mu-beta power. These results support the growing consensus that cue-induced alpha modulation is a functionally relevant sensory gating mechanism deployed by attention. Further, while cued attention had a weaker effect on the allocation of mu-beta, oscillations in this band also predicted tactile detection.
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<p>Abstract. We explore the role of meditative practice in cultivating experiences of compassion, empathy, and altruism and address an apparent paradox: Meditation often is associated with solitary retreat, if not preoccupation with one's own concerns. How, then, does such a practice promote compassion for others? We propose a two-stage model. The first stage involves disengagement from usual preoccupation with self-reinforcing, self-defeating, or self-indulgent behaviors and reactions; the second involves a focused engagement with a universal human capacity for altruistic experience, love, and compassion. Reference is made to the limited research literature and to clinical applications of loving kindness (metta) meditation in cultivating these processes.</p>
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<p>Past research on morality has emphasized a single justice-based moral ethic. Expanding this conception of morality, Shweder has proposed a universal taxonomy of three moral rhetorics related to justice, interdependence, and purity. Five studies tested the hypothesis that American morality emphasizes the justice-based rhetoric, whereas Filipino morality is represented by all three rhetorics. In the first three studies, American examples were modally justice based, whereas Filipinos generated examples in approximately equal proportions from each rhetoric. In Study 4, Americans rated justice-based rules higher on criteria of morality than rules from other rhetorics; Filipinos rated rules from all three rhetorics as moral. In Study 5, the association between anger and moral violations was stronger for Americans than for Filipinos, consistent with American emphasis on the moral stature of justice. Discussion focused on the origins and consequences of the American emphasis on rights and the balanced representation of morality observed in Filipinos.</p>
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<p>We used multiple methods to examine two questions about emotion and culture: (1) Which facial expressions are recognised cross-culturally; and (2) does the “forced-choice” method lead to spurious findings of universality? Forty participants in the US and 40 in India were shown 14 facial expressions and asked to say what had happened to cause the person to make the face. Analyses of the social situations given and of the affect words spontaneously used showed high levels of recognition for most of the expressions. A subsequent forced-choice task using the same faces confirmed these findings. Analysis of the pattern of magnitude, discreteness, and similarity of responses across cultures and expressions led to the conclusion that there is no neat distinction between cross-culturally recognisable and nonrecognisable expressions. Results are better described as a gradient of recognition.</p>
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The authors hypothesized that teasing, a social interaction that benefits relational bonds at the expense of the self, should be viewed as more affiliative, and experienced as more pleasurable, by members of cultures that deemphasize positive self-differentiation. In four multimethod studies, Asian Americans attributed more affiliative intent to teasers and reported more positive target experience than did European Americans. Teaser behavior, attribution biases, and personality did not account for culture-related differences in teasing experience. Rather, childhood teasing may better prepare Asian American children to overlook a tease's affront to the self in favor of its relational rewards. Implications of deemphasizing positive selfdifferentiation in social interaction are discussed.
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Fragile X syndrome (FX), the most common heritable cause of mental retardation and autism, is a developmental disorder characterized by physical, cognitive, and behavioral deficits. FX results from a trinucleotide expansion mutation in the fmr1 gene that reduces levels of fragile X mental retardation protein (FMRP). Although research efforts have focused on FMRP's impact on mGluR signaling, how the loss of FMRP leads to the individual symptoms of FX is not known. Previous studies on human FX blood cells revealed alterations in the cyclic adenosine 3′, 5′-monophosphate (cAMP) cascade. We tested the hypothesis that cAMP signaling is altered in the FX nervous system using three different model systems. Induced levels of cAMP in platelets and in brains of fmr1 knockout mice are substantially reduced. Cyclic AMP induction is also significantly reduced in human FX neural cells. Furthermore, cAMP production is decreased in the heads of FX Drosophila and this defect can be rescued by reintroduction of the dfmr gene. Our results indicate that a robust defect in cAMP production in FX is conserved across species and suggest that cAMP metabolism may serve as a useful biomarker in the human disease population. Reduced cAMP induction has implications for the underlying causes of FX and autism spectrum disorders. Pharmacological agents known to modulate the cAMP cascade may be therapeutic in FX patients and can be tested in these models, thus supplementing current efforts centered on mGluR signaling.
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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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This article presents an overview of ways to think about the brain and emotion and consider the role of evolution and expression in shaping the neural circuitry of affective processing. Issues pertaining to whether there are separate unique neural modules hard-wired for emotion processing or whether affective processing uses more generalized circuitry are considered. Relations between affect and cognition--specifically, memory--are examined from the perspective of overlapping neural systems. The role of individual differences in neural function in affective style are discussed, and the concepts of affective chronometry, or the time course of emotional responding and emotion regulation, are introduced. Finally, the extent to which certain emotional traits can be viewed as trainable skills is considered, and the relevance of work on neural plasticity to the skill framework is addressed. Data from a variety of sources using different types of measures is brought to bear on these questions, including neuroimaging and psychophysiological measures, studies of individuals of different ages ranging from early childhood to old age, studies of nonhuman primates, and observations of patients with localized brain damage. Emotions are viewed as varying in both type and dimension. Honoring brain circuitry in parsing the domain of affects will result in distinctions and differentiations that are not currently incorporated in traditional classification schemes.
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<p>We have interpreted the literature showing left anterior hypoactivation in depression as reflecting a decrease in approach-related motivation and behaviour among depressed subjects. In support of this model, we have previously demonstrated a decreased responsiveness to reward in subclinically depressed dysphoric subjects. The current study was designed to replicate and extend those findings. Clinically depressed subjects who met DSM-IV criteria for major depression were compared to a group of nondepressed control subjects on a verbal memory task under three monetary payoff conditions: neutral, reward, and punishment. Although control subjects changed their pattern of responding in both the reward and punishment conditions, relative to the neutral condition, so as to maximise their earnings, depressed subjects did not do so during reward. The two groups did not differ during the punishment condition. These findings provide additional evidence of a decreased responsiveness to reward in depressed individuals, and are consistent with the hypothesis that the left prefrontal hypoactivation observed in depression reflects a deficit in approach-related behaviour.</p>
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We hypothesized that partisans who represent power and the status quo would judge their opponents less accurately than would partisans seeking change, who would be stereotyped as extremists. We surveyed the attitudes and book preferences of traditionalist and revisionist English professors, who differed in their inclinations to preserve or change the literary status quo. Both groups overestimated the differences in their attitudes and book preferences, the extremity of their opponent's conviction, and the numerical balances of the two sides. Consistent with the status quo hypotheses, traditionalists were more prone to polarize the two sides' attitudes and underestimate the book preferences they shared with their opponents, and both sides attributed more extreme convictions to revisionists. Discussion focused on mechanisms related to power-related biases.
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<p>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.</p>
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Mindfulness-based stress reduction (MBSR) is an 8-week training that is designed to teach participants mindful awareness of the present moment. In randomized clinical trials (RCTs), MBSR has demonstrated efficacy in various conditions including reducing chronic pain-related distress and improving quality of life in healthy individuals. There have, however, been no qualitative studies investigating participants' descriptions of changes experienced over multiple time points during the course of the programme. This qualitative study of an MBSR cohort (N = 8 healthy individuals) in a larger RCT examined participants' daily diary descriptions of their home-practice experiences. The study used a two-part method, combining grounded theory with a close-ended coding approach. The grounded theory analysis revealed that during the trial, all participants, to varying degrees, described moments of distress related to practice; at the end of the course, all participants who completed the training demonstrated greater detail and clarity in their descriptions, improved affect, and the emergence of an observing self. The closed-ended coding schema, carried out to shed light on the development of an observing self, revealed that the emergence of an observing self was not related to the valence of participants' experiential descriptions: even participants whose diaries contained predominantly negative characterizations of their experience throughout the trial were able, by the end of the trial, to demonstrate an observing, witnessing attitude towards their own distress. Progress in MBSR may rely less on the valence of participants' experiences and more on the way participants describe and relate to their own inner experience. Copyright © 2010 John Wiley & Sons, Ltd. Key Practitioner Message: This article • Analyses the ways in which participants in a mindfulness-based stress reduction (MBSR) clinical trial describe their experiences with mindfulness practice. • Carries out qualitative analysis of the ways in which participants' descriptions of home-based meditation practice contained in their practice diaries change over the course of an 8-week MBSR trial. • Demonstrates that the participants who successfully completed the 8-week course show a common developmental trajectory, as each participant used less reactive, judgemental language to describe their home meditative practice-based experiences by the end of the trial, even when, in the case of some participants, that experience was perceived as negative or distressing. • Suggests that progress in MBSR may rely less on the valence of participants' experience and more on the way participants describe and relate to their own inner experience.
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Because individual differences in emotion regulation are associated with risk for childhood behavioral problems, multidisciplinary investigation of the genetic and neural underpinnings of emotion regulation should be a research priority. Here, we summarize research findings from three independent laboratories to demonstrate the ways in which a variety of developmental human neuroscience-based approaches can address critical conceptual issues in the emergence of emotion regulation. To do so, we present three perspectives on how developmental neurobiology constrains and enriches theories of ER. The three perspectives of (1) genetics, (2) brain structure and function, and (3) plasticity of development are illustrated with empirical results derived from both typical and atypical samples of children and adults. These perspectives are complementary and sometimes represent different levels of analysis of the same question.
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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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Background: The diagnostic framework and clinical reasoning process in Chinese medicine emphasizes the contextual and qualitative nature of a patient's illness. Chinese medicine assessment data may help interpret clinical outcomes. Objectives: As part of a study aimed at assessing the validity and improving the inter-rater reliability of the Chinese diagnostic process, a structured assessment instrument was developed for use in clinical trials of acupuncture and other Chinese medical therapies. Study design: To foster collaboration and maximize resources and information, an interdisciplinary advisory team was assembled. Under the guidance of two group process facilitators, and in order to establish whether the assessment instrument was consistent with accepted Chinese medicine diagnostic categories (face validity) and included the full range of each concept's meaning (content validity), a panel of Traditional Chinese Medicine (TCM) expert clinicians was convened and their responses were organized using the Delphi process, an iterative, anonymous, idea-generating and consensus-building process. An aggregate rating measure was obtained by taking the mean of mean ratings for each question across all 10 experts. Results: Over three rounds, the overall rating increased from 7.4 (SD = 1.3) in Round 1 to 9.1 (SD = 0.5) in Round 3. The level of agreement among clinicians was measured by a decrease in SD. Conclusions: The final instrument TEAMSI-TCM (Traditional East Asian Medicine Structured Interview, TCM version) uses the pattern differentiation model characteristic of TCM. This modular, dynamic version was specifically designed to assess women, with a focus on gynecologic conditions; with modifications it can be adapted for use with other populations and conditions. TEAMSI-TCM is a prescriptive instrument that guides clinicians to use the proper indicators, combine them in a systematic manner, and generate conclusions. In conjunction with treatment manualization and training it may serve to increase inter-rater reliability and inter-trial reproducibility in Chinese medicine clinical trials. Testing of the validity and reliability of this instrument currently is underway.
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