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.
Although the co-occurrence of negative affect and pain is well recognized, the mechanism underlying their association is unclear. To examine whether a common self-regulatory ability impacts the experience of both emotion and pain, we integrated neuroimaging, behavioral, and physiological measures obtained from three assessments separated by substantial temporal intervals. Our results demonstrated that individual differences in emotion regulation ability, as indexed by an objective measure of emotional state, corrugator electromyography, predicted self-reported success while regulating pain. In both emotion and pain paradigms, the amygdala reflected regulatory success. Notably, we found that greater emotion regulation success was associated with greater change of amygdalar activity following pain regulation. Furthermore, individual differences in degree of amygdalar change following emotion regulation were a strong predictor of pain regulation success, as well as of the degree of amygdalar engagement following pain regulation. These findings suggest that common individual differences in emotion and pain regulatory success are reflected in a neural structure known to contribute to appraisal processes.
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.
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.
On the basis of a review of the extant literature describing emotion-cognition interactions, the authors propose 4 methodological desiderata for studying how task-irrelevant affect modulates cognition and present data from an experiment satisfying them. Consistent with accounts of the hemispheric asymmetries characterizing withdrawal-related negative affect and visuospatial working memory (WM) in prefrontal and parietal cortices, threat-induced anxiety selectively disrupted accuracy of spatial but not verbal WM performance. Furthermore, individual differences in physiological measures of anxiety statistically mediated the degree of disruption. A second experiment revealed that individuals characterized by high levels of behavioral inhibition exhibited more intense anxiety and relatively worse spatial WM performance in the absence of threat, solidifying the authors' inference that anxiety causally mediates disruption. These observations suggest a revision of extant models of how anxiety sculpts cognition and underscore the utility of the desiderata.
Theories typically emphasize affordances or intentions as the primary determinant of an object's perceived function. The HIPE theory assumes that people integrate both into causal models that produce functional attributions. In these models, an object's physical structure and an agent's action specify an affordance jointly, constituting the immediate causes of a perceived function. The object's design history and an agent's goal in using it constitute distant causes. When specified fully, the immediate causes are sufficient for determining the perceived function--distant causes have no effect (the causal proximity principle). When the immediate causes are ambiguous or unknown, distant causes produce inferences about the immediate causes, thereby affecting functional attributions indirectly (the causal updating principle). Seven experiments supported HIPE's predictions.
Objective: The purpose of the study was to examine the association of temporal factors, in particular days of the week and seasons of the year and death from suicide in the United States. Method: Data were pooled from the Multiple Cause of Death Files. Hierarchical logistic regression models were fitted to all deaths occurring in 2000 through 2004 by suicide. Results: The incidence of suicide was significantly higher on Wednesdays, compared to Sunday. Specifically, individuals were 99% more likely to kill themselves on Wednesday than on Sunday. Suicides were more prevalent in the summer months, and they were less likely to occur in winter. The state suicide rate significantly elevated individual suicide risk. The results held even after controlling for the potentially confounding effects of socio-economic and demographic variables at both the individual and state levels. Conclusion: It was concluded that the observed association between seasonality and suicide cannot be discounted as a mere coincidence. Future research ought to focus on integrating individual level data and contextual variables when testing for seasonality effects.
Biological systems are particularly prone to variation, and the authors argue that such variation must be regarded as important data in its own right. The authors describe a method in which individual differences are studied within the framework of a general theory of the population as a whole and illustrate how this method can be used to address three types of issues: the nature of the mechanisms that give rise to a specific ability, such as mental imagery; the role of psychological or biological mediators of environmental challenges, such as the biological bases for differences in dispositional mood; and the existence of processes that have nonadditive effects with behavioral and physiological variables, such as factors that modulate the response to stress and its effects on the immune response.
The anterior medial prefrontal (AMPFC) and retrosplenial (RSC) cortices are active during self-referential decision-making tasks such as when participants appraise traits and abilities, or current affect. Other appraisal tasks requiring an evaluative decision or mental representation, such as theory of mind and perspective-taking tasks, also involve these regions. In many instances, these types of decisions involve a subjective opinion or preference, but also a degree of ambiguity in the decision, rather than a strictly veridical response. However, this ambiguity is generally not controlled for in studies that examine self-referential decision-making. In this functional magnetic resonance imaging experiment with 17 healthy adults, we examined neural processes associated with subjective decision-making with and without an overt self-referential component. The task required subjective decisions about colors-regarding self-preference (internal subjective decision) or color similarity (external subjective decision) under conditions where there was no objectively correct response. Results indicated greater activation in the AMPFC, RSC, and caudate nucleus during internal subjective decision-making. The findings suggest that self-referential processing, rather than subjective judgments among ambiguous response alternatives, accounted for the AMPFC and RSC response.
Some children show emotion that is not consistent with normative appraisal of the context and can therefore be defined as context inappropriate (CI). The authors used individual growth curve modeling and hierarchical multiple regression analyses to examine whether CI anger predicts differences in hypothalamic-pituitary-adrenal axis activity, as manifest in salivary cortisol measures. About 23% of the 360 children (ages 6-10 years, primarily 7-8) showed at least 1 expression of CI anger in situations designed to elicit positive affect. Expression of anger across 2 positive assessments was less common (around 4%). CI anger predicted the hypothesized lower levels of cortisol beyond that attributed to context appropriate anger. Boys' CI anger predicted lower morning cortisol and flatter slopes. Results suggest that this novel approach to studying children's emotion across varying contexts can provide insight into affective style.
Motion correction of fMRI data is a widely used step prior to data analysis. In this study, a comparison of the motion correction tools provided by several leading fMRI analysis software packages was performed, including AFNI, AIR, BrainVoyager, FSL, and SPM2. Comparisons were performed using data from typical human studies as well as phantom data. The identical reconstruction, preprocessing, and analysis steps were used on every data set, except that motion correction was performed using various configurations from each software package. Each package was studied using default parameters, as well as parameters optimized for speed and accuracy. Forty subjects performed a Go/No-go task (an event-related design that investigates inhibitory motor response) and an N-back task (a block-design paradigm investigating working memory). The human data were analyzed by extracting a set of general linear model (GLM)-derived activation results and comparing the effect of motion correction on thresholded activation cluster size and maximum t value. In addition, a series of simulated phantom data sets were created with known activation locations, magnitudes, and realistic motion. Results from the phantom data indicate that AFNI and SPM2 yield the most accurate motion estimation parameters, while AFNI's interpolation algorithm introduces the least smoothing. AFNI is also the fastest of the packages tested. However, these advantages did not produce noticeably better activation results in motion-corrected data from typical human fMRI experiments. Although differences in performance between packages were apparent in the human data, no single software package produced dramatically better results than the others. The "accurate" parameters showed virtually no improvement in cluster t values compared to the standard parameters. While the "fast" parameters did not result in a substantial increase in speed, they did not degrade the cluster results very much either. The phantom and human data indicate that motion correction can be a valuable step in the data processing chain, yielding improvements of up to 20% in the magnitude and up to 100% in the cluster size of detected activations, but the choice of software package does not substantially affect this improvement.
Greater levels of conscientiousness have been associated with lower levels of negative affect. We focus on one mechanism through which conscientiousness may decrease negative affect: effective emotion regulation, as reflected by greater recovery from negative stimuli. In 273 adults who were 35-85 years old, we collected self-report measures of personality including conscientiousness and its self-control facet, followed on average 2 years later by psychophysiological measures of emotional reactivity and recovery. Among middle-aged adults (35-65 years old), the measures of conscientiousness and self-control predicted greater recovery from, but not reactivity to, negative emotional stimuli. The effect of conscientiousness and self-control on recovery was not driven by other personality variables or by greater task adherence on the part of high conscientiousness individuals. In addition, the effect was specific to negative emotional stimuli and did not hold for neutral or positive emotional stimuli.
We present a novel data smoothing and analysis framework for cortical thickness data defined on the brain cortical manifold. Gaussian kernel smoothing, which weights neighboring observations according to their 3D Euclidean distance, has been widely used in 3D brain images to increase the signal-to-noise ratio. When the observations lie on a convoluted brain surface, however, it is more natural to assign the weights based on the geodesic distance along the surface. We therefore develop a framework for geodesic distance-based kernel smoothing and statistical analysis on the cortical manifolds. As an illustration, we apply our methods in detecting the regions of abnormal cortical thickness in 16 high functioning autistic children via random field based multiple comparison correction that utilizes the new smoothing technique.
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.
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.
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.
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.
Sensitivity, specificity, and reproducibility are vital to interpret neuroscientific results from functional magnetic resonance imaging (fMRI) experiments. Here we examine the scan-rescan reliability of the percent signal change (PSC) and parameters estimated using Dynamic Causal Modeling (DCM) in scans taken in the same scan session, less than 5 min apart. We find fair to good reliability of PSC in regions that are involved with the task, and fair to excellent reliability with DCM. Also, the DCM analysis uncovers group differences that were not present in the analysis of PSC, which implies that DCM may be more sensitive to the nuances of signal changes in fMRI data.
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.
Muscle or electromyogenic (EMG) artifact poses a serious risk to inferential validity for any electroencephalography (EEG) investigation in the frequency-domain owing to its high amplitude, broad spectrum, and sensitivity to psychological processes of interest. Even weak EMG is detectable across the scalp in frequencies as low as the alpha band. Given these hazards, there is substantial interest in developing EMG correction tools. Unfortunately, most published techniques are subjected to only modest validation attempts, rendering their utility questionable. We review recent work by our laboratory quantitatively investigating the validity of two popular EMG correction techniques, one using the general linear model (GLM), the other using temporal independent component analysis (ICA). We show that intra-individual GLM-based methods represent a sensitive and specific tool for correcting on-going or induced, but not evoked (phase-locked) or source-localized, spectral changes. Preliminary work with ICA shows that it may not represent a panacea for EMG contamination, although further scrutiny is strongly warranted. We conclude by describing emerging methodological trends in this area that are likely to have substantial benefits for basic and applied EEG research.
This commentary reflects on the articles in this Special Issue. The appearance of this group of articles underscores the important idea that a major target of mindfulness practice is on emotion. Transformation in trait affect is a key goal of all contemplative traditions. This commentary addresses several key methodological and conceptual issues in the empirical study of mindfulness. The many ways in which the term "mindfulness" is used in the articles in this Special Issue are noted, and they include its reference to states, traits, and independent variables that are manipulated in an experimental context. How the term "mindfulness" is conceptualized and operationalized is crucial, and for progress to be made it is essential that we qualify the use of this term by reference to how it is being operationalized in each context. Other methodological issues are considered, such as the duration of training and how it should be measured, and the nature of control and comparison groups in studies of mindfulness-based interventions. Finally, the commentary ends with a consideration of the targets within emotion processing that are likely to be impacted by mindfulness. This collection of articles underscores the substantial progress that has occurred in the empirical study of mindfulness and it is a harbinger of a very promising future in this area.
BACKGROUND: Two core characteristics of pathologic fear are its rapid onset and resistance to cognitive regulation. We hypothesized that activation of the amygdala early in the presentation of fear-relevant visual stimuli would distinguish phobics from nonphobics. METHODS: Chronometry of amygdala activation to phobia-relevant pictures was assessed in 13 spider phobics and 14 nonphobics using functional magnetic resonance imaging (fMRI). RESULTS: Blood oxygen level-dependent (BOLD) responses in the amygdala early in picture processing consistently differentiated between phobic and nonphobic subjects, as well as between phobogenic and nonphobogenic stimuli among phobics. Furthermore, amygdalar BOLD responses associated with timing but not magnitude of activation predicted affective responses to phobogenic stimuli. Computational modeling procedures were used to identify patterns of neural activation in the amygdala that could yield the observed BOLD data. These data suggest that phobic responses were characterized by strong but brief amygdala responses, whereas nonphobic responses were weaker and more sustained. CONCLUSIONS: Results are discussed in the context of the amygdala's role in rapid threat detection and the vigilance-avoidance hypothesis of anxiety. These data highlight the importance of examining the neural substrates of the immediate impact of phobogenic stimuli for understanding pathological fear.
It is the central hypothesis of this paper that the mental states commonly referred to as altered states of consciousness are principally due to transient prefrontal cortex deregulation. Supportive evidence from psychological and neuroscientific studies of dreaming, endurance running, meditation, daydreaming, hypnosis, and various drug-induced states is presented and integrated. It is proposed that transient hypofrontality is the unifying feature of all altered states and that the phenomenological uniqueness of each state is the result of the differential viability of various frontal circuits. Using an evolutionary approach, consciousness is conceptualized as hierarchically ordered cognitive function. Higher-order structures perform increasingly integrative functions and thus contribute more sophisticated content. Although this implies a holistic approach to consciousness, such a functional hierarchy localizes the most sophisticated layers of consciousness in the zenithal higher-order structure: the prefrontal cortex. The hallmark of altered states of consciousness is the subtle modification of behavioral and cognitive functions that are typically ascribed to the prefrontal cortex. The theoretical framework presented yields a number of testable hypotheses.
Recent studies have identified a distributed network of brain regions thought to support cognitive reappraisal processes underlying emotion regulation in response to affective images, including parieto-temporal regions and lateral/medial regions of prefrontal cortex (PFC). A number of these commonly activated regions are also known to underlie visuospatial attention and oculomotor control, which raises the possibility that people use attentional redeployment rather than, or in addition to, reappraisal as a strategy to regulate emotion. We predicted that a significant portion of the observed variance in brain activation during emotion regulation tasks would be associated with differences in how participants visually scan the images while regulating their emotions. We recorded brain activation using fMRI and quantified patterns of gaze fixation while participants increased or decreased their affective response to a set of affective images. fMRI results replicated previous findings on emotion regulation with regulation differences reflected in regions of PFC and the amygdala. In addition, our gaze fixation data revealed that when regulating, individuals changed their gaze patterns relative to a control condition. Furthermore, this variation in gaze fixation accounted for substantial amounts of variance in brain activation. These data point to the importance of controlling for gaze fixation in studies of emotion regulation that use visual stimuli.
Although there are many imaging studies on traditional ROI-based amygdala volumetry, there are very few studies on modeling amygdala shape variations. This paper presents a unified computational and statistical framework for modeling amygdala shape variations in a clinical population. The weighted spherical harmonic representation is used to parameterize, smooth out, and normalize amygdala surfaces. The representation is subsequently used as an input for multivariate linear models accounting for nuisance covariates such as age and brain size difference using the SurfStat package that completely avoids the complexity of specifying design matrices. The methodology has been applied for quantifying abnormal local amygdala shape variations in 22 high functioning autistic subjects.