BACKGROUND: Functional magnetic resonance imaging (fMRI) holds promise as a noninvasive means of identifying neural responses that can be used to predict treatment response before beginning a drug trial. Imaging paradigms employing facial expressions as presented stimuli have been shown to activate the amygdala and anterior cingulate cortex (ACC). Here, we sought to determine whether pretreatment amygdala and rostral ACC (rACC) reactivity to facial expressions could predict treatment outcomes in patients with generalized anxiety disorder (GAD).
METHODS: Fifteen subjects (12 female subjects) with GAD participated in an open-label venlafaxine treatment trial. Functional magnetic resonance imaging responses to facial expressions of emotion collected before subjects began treatment were compared with changes in anxiety following 8 weeks of venlafaxine administration. In addition, the magnitude of fMRI responses of subjects with GAD were compared with that of 15 control subjects (12 female subjects) who did not have GAD and did not receive venlafaxine treatment.
RESULTS: The magnitude of treatment response was predicted by greater pretreatment reactivity to fearful faces in rACC and lesser reactivity in the amygdala. These individual differences in pretreatment rACC and amygdala reactivity within the GAD group were observed despite the fact that 1) the overall magnitude of pretreatment rACC and amygdala reactivity did not differ between subjects with GAD and control subjects and 2) there was no main effect of treatment on rACC-amygdala reactivity in the GAD group.
CONCLUSIONS: These findings show that this pattern of rACC-amygdala responsivity could prove useful as a predictor of venlafaxine treatment response in patients with GAD.
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The capacity to anticipate aversive circumstances is central not only to successful adaptation but also to understanding the abnormalities that contribute to excessive worry and anxiety disorders. Forecasting and reacting to aversive events mobilize a host of affective and cognitive capacities and corresponding brain processes. Rapid event-related functional magnetic resonance imaging (fMRI) in 21 healthy volunteers assessed the overlap and divergence in the neural instantiation of anticipating and being exposed to aversive pictures. Brain areas jointly activated by the anticipation of and exposure to aversive pictures included the dorsal amygdala, anterior insula, dorsal anterior cingulate cortex (ACC), right dorsolateral prefrontal cortex (DLPFC), and right posterior orbitofrontal cortex (OFC). Anticipatory processes were uniquely associated with activations in rostral ACC, a more superior sector of the right DLPFC, and more medial sectors of the bilateral OFC. Activation of the right DLPFC in anticipation of aversion was associated with self-reports of increased negative affect, whereas OFC activation was associated with increases in both positive and negative affect. These results show that anticipation of aversion recruits key brain regions that respond to aversion, thereby potentially enhancing adaptive responses to aversive events.
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Diminished gaze fixation is one of the core features of autism and has been proposed to be associated with abnormalities in the neural circuitry of affect. We tested this hypothesis in two separate studies using eye tracking while measuring functional brain activity during facial discrimination tasks in individuals with autism and in typically developing individuals. Activation in the fusiform gyrus and amygdala was strongly and positively correlated with the time spent fixating the eyes in the autistic group in both studies, suggesting that diminished gaze fixation may account for the fusiform hypoactivation to faces commonly reported in autism. In addition, variation in eye fixation within autistic individuals was strongly and positively associated with amygdala activation across both studies, suggesting a heightened emotional response associated with gaze fixation in autism.
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BACKGROUND: The broad autism phenotype includes subclinical autistic characteristics found to have a higher prevalence in unaffected family members of individuals with autism. These characteristics primarily affect the social aspects of language, communication, and human interaction. The current research focuses on possible neurobehavioral characteristics associated with the broad autism phenotype.
METHODS: We used a face-processing task associated with atypical patterns of gaze fixation and brain function in autism while collecting brain functional magnetic resonance imaging (fMRI) and eye tracking in unaffected siblings of individuals with autism.
RESULTS: We found robust differences in gaze fixation and brain function in response to images of human faces in unaffected siblings compared with typically developing control individuals. The siblings' gaze fixations and brain activation patterns during the face processing task were similar to that of the autism group and showed decreased gaze fixation along with diminished fusiform activation compared with the control group. Furthermore, amygdala volume in the siblings was similar to the autism group and was significantly reduced compared with the control group.
CONCLUSIONS: Together, these findings provide compelling evidence for differences in social/emotional processing and underlying neural circuitry in siblings of individuals with autism, supporting the notion of unique endophenotypes associated with the broad autism phenotype.
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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.
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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.
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The prefrontal cortex (PFC) has been well known for its role in higher order cognition, affect regulation and social reasoning. Although the precise underpinnings have not been sufficiently described, increasing evidence also supports a prefrontal involvement in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis. Here we investigate the PFC's role in HPA axis regulation during a psychosocial stress exposure in 14 healthy humans. Regional brain metabolism was assessed using positron emission tomography (PET) and injection of fluoro-18-deoxyglucose (FDG). Depending on the exact location within the PFC, increased glucose metabolic rate was associated with lower or higher salivary cortisol concentration in response to a psychosocial stress condition. Metabolic glucose rate in the rostral medial PFC (mPFC) (Brodman area (BA) 9 and BA 10) was negatively associated with stress-induced salivary cortisol increases. Furthermore, metabolic glucose rate in these regions was inversely coupled with changes in glucose metabolic rate in other areas, known to be involved in HPA axis regulation such as the amygdala/hippocampal region. In contrast, metabolic glucose rate in areas more lateral to the mPFC was positively associated with saliva cortisol. Subjective ratings on task stressfulness, task controllability and self-reported dispositional mood states also showed positive and negative associations with the glucose metabolic rate in prefrontal regions. These findings suggest that in humans, the PFC is activated in response to psychosocial stress and distinct prefrontal metabolic glucose patterns are linked to endocrine stress measures as well as subjective ratings on task stressfulness, controllability as well as dispositional mood states.
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We present a new subcortical structure shape modeling framework using heat kernel smoothing constructed with the Laplace-Beltrami eigenfunctions. The cotan discretization is used to numerically obtain the eigenfunctions of the Laplace-Beltrami operator along the surface of subcortical structures of the brain. The eigenfunctions are then used to construct the heat kernel and used in smoothing out measurements noise along the surface. The proposed framework is applied in investigating the influence of age (38-79 years) and gender on amygdala and hippocampus shape. We detected a significant age effect on hippocampus in accordance with the previous studies. In addition, we also detected a significant gender effect on amygdala. Since we did not find any such differences in the traditional volumetric methods, our results demonstrate the benefit of the current framework over traditional volumetric methods.
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18F-Fallypride and 11C-FLB457 are commonly used PET radioligands for imaging extrastriatal dopamine D2/D3 receptors, but differences in their in vivo kinetics may affect the sensitivity for measuring subtle changes in receptor binding. Focusing on regions of low binding, a direct comparison of the kinetics of 18F-fallypride and 11C-FLB457 was made using a MI protocol. Injection protocols were designed to estimate K1, k2, fNDkon, Bmax, and koff in the midbrain and cortical regions of the rhesus monkey. 11C-FLB457 cleared from the arterial plasma faster and yielded a ND space distribution volume (K1/k2) that is three times higher than 18F-fallypride, primarily due to a slower k2 (FAL:FLB; k2=0.54 min−1:0.18 min−1). The dissociation rate constant, koff, was slower for 11C-FLB457, resulting in a lower KDapp than 18F-fallypride (FAL:FLB; 0.39 nM:0.13 nM). Specific D2/D3 binding could be detected in the cerebellum for 11C-FLB457 but not 18F-fallypride. Both radioligands can be used to image extrastriatal D2/D3 receptors, with 11C-FLB457 providing greater sensitivity to subtle changes in low-receptor-density cortical regions and 18F-fallypride being more sensitive to endogenous dopamine displacement in medium-to-high-receptor-density regions. In the presence of specific D2/D3 binding in the cerebellum, reference region analysis methods will give a greater bias in BPND with 11C-FLB457 than with 18F-fallypride.
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Recent years have seen an explosion of interest in using neural oscillations to characterize the mechanisms supporting cognition and emotion. Oftentimes, oscillatory activity is indexed by mean power density in predefined frequency bands. Some investigators use broad bands originally defined by prominent surface features of the spectrum. Others rely on narrower bands originally defined by spectral factor analysis (SFA). Presently, the robustness and sensitivity of these competing band definitions remains unclear. Here, a Monte Carlo-based SFA strategy was used to decompose the tonic ("resting" or "spontaneous") electroencephalogram (EEG) into five bands: delta (1-5Hz), alpha-low (6-9Hz), alpha-high (10-11Hz), beta (12-19Hz), and gamma (>21Hz). This pattern was consistent across SFA methods, artifact correction/rejection procedures, scalp regions, and samples. Subsequent analyses revealed that SFA failed to deliver enhanced sensitivity; narrow alpha sub-bands proved no more sensitive than the classical broadband to individual differences in temperament or mean differences in task-induced activation. Other analyses suggested that residual ocular and muscular artifact was the dominant source of activity during quiescence in the delta and gamma bands. This was observed following threshold-based artifact rejection or independent component analysis (ICA)-based artifact correction, indicating that such procedures do not necessarily confer adequate protection. Collectively, these findings highlight the limitations of several commonly used EEG procedures and underscore the necessity of routinely performing exploratory data analyses, particularly data visualization, prior to hypothesis testing. They also suggest the potential benefits of using techniques other than SFA for interrogating high-dimensional EEG datasets in the frequency or time-frequency (event-related spectral perturbation, event-related synchronization/desynchronization) domains.
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<p>Imaging techniques provide ways of knowing structure and function in biology at different scales. The multidisciplinary nature and rapid advancement of imaging sciences requires imaging education to begin early in the biology curriculum. Guided by the National Institutes of Health (NIH) Roadmap initiatives, we incorporated a nanoimaging, molecular imaging, and medical imaging teaching unit into three 1-h class periods of an introductory course on ways of knowing biology. Activities were derived from NIH Roadmap initiatives in nanomedicine, regenerative medicine, and nuclear medicine. The course materials we describe contributed positively to student learning gains in quantifying and interpreting images, in characterizing imaging methods that provide ways of knowing biological structure and function, and in understanding scale in biology and imaging. The NIH Roadmap provides a useful context to educate students about the multidisciplinary imaging continuum.</p>
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Using functional magnetic resonance imaging, we examined whether individual differences in amygdala activation in response to negative relative to neutral information are related to differences in the speed with which such information is evaluated, the extent to which such differences are associated with medial prefrontal cortex function, and their relationship with measures of trait anxiety and psychological well-being (PWB). Results indicated that faster judgments of negative relative to neutral information were associated with increased left and right amygdala activation. In the prefrontal cortex, faster judgment time was associated with relative decreased activation in a cluster in the ventral anterior cingulate cortex (ACC, BA 24). Furthermore, people who were slower to evaluate negative versus neutral information reported higher PWB. Importantly, higher PWB was strongly associated with increased activation in the ventral ACC for negative relative to neutral information. Individual differences in trait anxiety did not predict variation in judgment time or in amygdala or ventral ACC activity. These findings suggest that people high in PWB effectively recruit the ventral ACC when confronted with potentially aversive stimuli, manifest reduced activity in subcortical regions such as the amygdala, and appraise such information as less salient as reflected in slower evaluative speed.
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The degree to which perceived controllability alters the way a stressor is experienced varies greatly among individuals. We used functional magnetic resonance imaging to examine the neural activation associated with individual differences in the impact of perceived controllability on self-reported pain perception. Subjects with greater activation in response to uncontrollable (UC) rather than controllable (C) pain in the pregenual anterior cingulate cortex (pACC), periaqueductal gray (PAG), and posterior insula/SII reported higher levels of pain during the UC versus C conditions. Conversely, subjects with greater activation in the ventral lateral prefrontal cortex (VLPFC) in anticipation of pain in the UC versus C conditions reported less pain in response to UC versus C pain. Activation in the VLPFC was significantly correlated with the acceptance and denial subscales of the COPE inventory [Carver, C. S., Scheier, M. F., & Weintraub, J. K. Assessing coping strategies: A theoretically based approach. Journal of Personality and Social Psychology, 56, 267-283, 1989], supporting the interpretation that this anticipatory activation was associated with an attempt to cope with the emotional impact of uncontrollable pain. A regression model containing the two prefrontal clusters (VLPFC and pACC) predicted 64% of the variance in pain rating difference, with activation in the two additional regions (PAG and insula/SII) predicting almost no additional variance. In addition to supporting the conclusion that the impact of perceived controllability on pain perception varies highly between individuals, these findings suggest that these effects are primarily top-down, driven by processes in regions of the prefrontal cortex previously associated with cognitive modulation of pain and emotion regulation.
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The present study investigated the premise that individual differences in autonomic physiology could be used to specify the nature and consequences of information processing taking place in medial prefrontal regions during cognitive reappraisal of unpleasant pictures. Neural (blood oxygenation level-dependent functional magnetic resonance imaging) and autonomic (electrodermal [EDA], pupil diameter, cardiac acceleration) signals were recorded simultaneously as twenty-six older people (ages 64-66 years) used reappraisal to increase, maintain, or decrease their responses to unpleasant pictures. EDA was higher when increasing and lower when decreasing compared to maintaining. This suggested modulation of emotional arousal by reappraisal. By contrast, pupil diameter and cardiac acceleration were higher when increasing and decreasing compared to maintaining. This suggested modulation of cognitive demand. Importantly, reappraisal-related activation (increase, decrease>maintain) in two medial prefrontal regions (dorsal medial frontal gyrus and dorsal cingulate gyrus) was correlated with greater cardiac acceleration (increase, decrease>maintain) and monotonic changes in EDA (increase>maintain>decrease). These data indicate that these two medial prefrontal regions are involved in the allocation of cognitive resources to regulate unpleasant emotion, and that they modulate emotional arousal in accordance with the regulatory goal. The emotional arousal effects were mediated by the right amygdala. Reappraisal-related activation in a third medial prefrontal region (subgenual anterior cingulate cortex) was not associated with similar patterns of change in any of the autonomic measures, thus highlighting regional specificity in the degree to which cognitive demand is reflected in medial prefrontal activation during reappraisal.
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Musically proficient and non-proficient right-handed subjects were requested to list in a pre-experimental questionnaire three familiar songs, whose words and melody were well known. They were then instructed in two separate experiments, to whistle the melody of a song, talk the lyrics to a song, or sing a song each for 3 1-min trials performed with eyes closed. EEG was recorded from the left and right occipital areas (O1 and O2) in Experiment I and from the left and right parietal areas (P3 and P4) in Experiment II, and filtered for 8–13 Hz activity on-line. Comparable results were obtained in both experiments and indicated that non-musically trained subjects show significantly greater relative right hemisphere activation while whistling the melody of a song vs talking the lyrics to a song. Musically trained subjects show no differences in EEG asymmetry between these tasks. In addition, there were no group differences in asymmetry during the talking and singing conditions. These data are consistent with recent evidence suggesting that musical training is associated with the adoption of an analytic and sequential processing mode toward melodic information, and suggest that long term training in complex cognitive skills has functional neural concomitants.
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A current limitation for imaging of brain function is the potential confound of anatomical differences or registration error, which may manifest via apparent functional "activation" for between-subject analyses. With respect to functional activations, underlying tissue mismatches can be regarded as a nuisance variable. We propose adding the probability of gray matter at a given voxel as a covariate (nuisance variable) in the analysis of voxelwise multisubject functional data using standard statistical techniques. A method is presented to assess the extent to which a functional activation can reliably be explained by underlying anatomical differences, and simultaneously, to assess the component of the functional activation which cannot be attributed to anatomical difference and thus is likely due to functional difference alone. Extension of the method to other intermodal imaging applications is discussed. Two exemplary data sets, one PET and one fMRI, are used to demonstrate the implementation and utility of this method, which apportions the relative contributions of anatomy and function for an apparent functional activation. The examples show two distinct types of results. First, a so-called functional activation may actually be caused by a systematic anatomical difference which, when modeled, diminishes the functional effect. In the second result type, including the anatomical differences in the model can account for a large component of otherwise unmodeled variance, yielding an increase in the functional effect cluster size and/or magnitude. In either case, ignoring the readily available structural information can lead to misinterpretation of functional results.
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It has been argued that emotion, pain, and cognitive control are functionally segregated in distinct subdivisions of the cingulate cortex. But recent observations encourage a fundamentally different view. Imaging studies indicate that negative affect, pain, and cognitive control activate an overlapping region of dorsal cingulate, the anterior midcingulate cortex (aMCC). Anatomical studies reveal that aMCC constitutes a hub where information about reinforcers can be linked to motor centers responsible for expressing affect and executing goal-directed behavior. Computational modeling and other kinds of evidence suggest that this intimacy reflects control processes that are common to all three domains. These observations compel a reconsideration of dorsal cingulate’s contribution to negative affect and pain.
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Attention to internal body sensations is practiced in most meditation traditions. Many traditions state that this practice results in increased awareness of internal body sensations, but scientific studies evaluating this claim are lacking. We predicted that experienced meditators would display performance superior to that of nonmeditators on heartbeat detection, a standard noninvasive measure of resting interoceptive awareness. We compared two groups of meditators (Tibetan Buddhist and Kundalini) to an age- and body mass index-matched group of nonmeditators. Contrary to our prediction, we found no evidence that meditators were superior to nonmeditators in the heartbeat detection task, across several sessions and respiratory modulation conditions. Compared to nonmeditators, however, meditators consistently rated their interoceptive performance as superior and the difficulty of the task as easier. These results provide evidence against the notion that practicing attention to internal body sensations, a core feature of meditation, enhances the ability to sense the heartbeat at rest.
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Based upon suggestions that the two cerebral hemispheres may be differentially involved in the perception and regulation of autonomic activity, three studies were designed to explore differences in the relationship between left versus right hand finger tapping and the heartbeat. In each study, right-handed subjects were asked to tap with either their left versus right forefingers regularly at the rate of approximately once per second. When the time from the R-spike immediately preceding their tap to the tap was examined, a significant difference between the two hands was obtained in two of the studies, with the left hand tapping closer to the last R-spike compared with the right. A variety of additional conditions in the experiments suggest that this effect may depend upon tapping rhythmically. The implications of these findings for the differential role of the left and right hemispheres in the perception and regulation of cardiac activity are considered.
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Social contact promotes enhanced health and well-being, likely as a function of the social regulation of emotional responding in the face of various life stressors. For this functional magnetic resonance imaging (fMRI) study, 16 married women were subjected to the threat of electric shock while holding their husband's hand, the hand of an anonymous male experimenter, or no hand at all. Results indicated a pervasive attenuation of activation in the neural systems supporting emotional and behavioral threat responses when the women held their husband's hand. A more limited attenuation of activation in these systems occurred when they held the hand of a stranger. Most strikingly, the effects of spousal hand-holding on neural threat responses varied as a function of marital quality, with higher marital quality predicting less threat-related neural activation in the right anterior insula, superior frontal gyrus, and hypothalamus during spousal, but not stranger, hand-holding.
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Autism is a neurodevelopmental disorder affecting behavioral and social cognition, but there is little understanding about the link between the functional deficit and its underlying neuroanatomy. We applied a 2D version of voxel-based morphometry (VBM) in differentiating the white matter concentration of the corpus callosum for the group of 16 high functioning autistic and 12 normal subjects. Using the white matter density as an index for neural connectivity, autism is shown to exhibit less white matter concentration in the region of the genu, rostrum, and splenium removing the effect of age based on the general linear model (GLM) framework. Further, it is shown that the less white matter concentration in the corpus callosum in autism is due to hypoplasia rather than atrophy.
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Diffusion tensor imaging (DTI) plays a key role in analyzing the physical structures of biological tissues, particularly in reconstructing fiber tracts of the human brain in vivo. On the one hand, eigenvalues of diffusion tensors (DTs) estimated from diffusion weighted imaging (DWI) data usually contain systematic bias, which subsequently biases the diffusivity measurements popularly adopted in fiber tracking algorithms. On the other hand, correctly accounting for the spatial information is important in the construction of these diffusivity measurements since the fiber tracts are typically spatially structured. This paper aims to establish test-based approaches to identify anisotropic water diffusion areas in the human brain. These areas in turn indicate the areas passed by fiber tracts. Our proposed test statistic not only takes into account the bias components in eigenvalue estimates, but also incorporates the spatial information of neighboring voxels. Under mild regularity conditions, we demonstrate that the proposed test statistic asymptotically follows a $\chi^2$ distribution under the null hypothesis. Simulation and real DTI data examples are provided to illustrate the efficacy of our proposed methods.
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