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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The LASS theory proposes that Language and Situated Simulation both play central roles in conceptual processing. Depending on stimuli and task conditions, different mixtures of language and simulation occur. When a word is processed in a conceptual task, it first activates other linguistic forms, such as word associates. More slowly, the word activates a situated simulation to represent its meaning in neural systems for perception, action, and mental states. An fMRI experiment tested the LASS account. In a first scanning session, participants performed the property generation task to provide a measure of conceptual processing. In a second scanning session a week later, participants performed two localizer tasks measuring word association and situated simulation. Conjunction analyses supported predictions of the LASS theory. Activations early in conceptual processing overlapped with activations for word association. Activations late in conceptual processing overlapped with activations for situation generation. These results, along with others in the literature, indicate that conceptual processing uses multiple representations, not one. Furthermore, researchers must be careful drawing conclusions about conceptual processing, given that different paradigms are likely to produce different mixtures of language and simulation. Whereas some paradigms produce high levels of linguistic processing and low levels of simulation, other paradigms produce the opposite pattern.
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Previous research indicates that drug motivational systems are instantiated in structures that process information related to incentive, motivational drive, memorial, motor/habit, craving, and cognitive control processing. The present research tests the hypothesis that activity in such systems will be powerfully affected by the combination of drug anticipation and drug withdrawal. Event-related fMRI was used to examine activation in response to a preinfusion warning cue in two experimental sessions that manipulated withdrawal status. Significant cue-induced effects were seen in the caudate, ventral anterior nucleus of the thalamus, the insula, subcallosal gyrus, nucleus accumbens, and anterior cingulate. These results suggest that withdrawal and nicotine anticipation produce (1) different motor preparatory and inhibitory response processing and (2) different craving related processing.
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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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<p>BACKGROUND: Functional magnetic resonance imaging (fMRI) techniques were used to identify the neural circuitry underlying emotional processing in control and depressed subjects. Depressed subjects were studied before and after treatment with venlafaxine. This new technique provides a method to noninvasively image regional brain function with unprecedented spatial and temporal resolution. METHOD: Echo-planar imaging was used to acquire whole brain images while subjects viewed positively and negatively valenced visual stimuli. Two control subjects and two depressed subjects who met DSM-IV criteria for major depression were scanned at baseline and 2 weeks later. Depressed subjects were treated with venlafaxine after the baseline scan. RESULTS: Preliminary results from this ongoing study revealed three interesting trends in the data. Both depressed patients demonstrated considerable symptomatic improvement at the time of the second scan. Across control and depressed subjects, the negative compared with the positive pictures elicited greater global activation. In both groups, activation induced by the negative pictures decreased from the baseline scan to the 2-week scan. This decrease in activation was also present in the control subjects when they were exposed to the positive pictures. In contrast, when the depressed subjects were presented with the positive pictures they showed no activation at baseline, whereas after 2 weeks of treatment an area of activation emerged in right secondary visual cortex. CONCLUSION: While preliminary, these results demonstrate the power of using fMRI to study emotional processes in normal and depressed subjects and to examine mechanisms of action of antidepressant drugs.</p>
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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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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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According to the Conceptual Act Theory of Emotion, the situated conceptualization used to construe a situation determines the emotion experienced. A neuroimaging experiment tested two core hypotheses of this theory: (1) different situated conceptualizations produce different forms of the same emotion in different situations, (2) the composition of a situated conceptualization emerges from shared multimodal circuitry distributed across the brain that produces emotional states generally. To test these hypotheses, the situation in which participants experienced an emotion was manipulated. On each trial, participants immersed themselves in a physical danger or social evaluation situation and then experienced fear or anger. According to Hypothesis 1, the brain activations for the same emotion should differ as a function of the preceding situation (after removing activations that arose while constructing the situation). According to Hypothesis 2, the critical activations should reflect conceptual processing relevant to the emotion in the current situation, drawn from shared multimodal circuitry underlying emotion. The results supported these predictions and demonstrated the compositional process that produces situated conceptualizations dynamically.
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BACKGROUND: Although it has been hypothesized that glucocorticoid hypersecretion in depressed patients leads to neuronal atrophy in the hippocampus, magnetic resonance imaging (MRI) -based morphometry studies of the hippocampus to date have produced mixed results.
METHODS: In our MRI study, hippocampal volumes were measured in 25 depressed patients (13 with melancholia and 12 without melancholia) and 15 control subjects.
RESULTS: No significant differences in hippocampus volumes were found between any of the subject groups, although within subjects right hippocampal volumes were found to be significantly larger than left hippocampal volumes. Additionally, right and total (left + right) hippocampal volumes in control and depressed subjects were found to be positively correlated with trait anxiety as measured by the state/trait anxiety inventory.
CONCLUSIONS: Because our subject group is younger than those in studies reporting hippocampal atrophy, we conclude that longitudinal studies will be necessary for investigation of the lifelong course of hippocampal volumetry.
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Echo-Planar functional magnetic resonance imaging (EP-fMRI) was used to study the activity of the amygdala while three normal female subjects viewed alternating blocks of affectively neutral and affectively negative still pictures. Bilateral activation in the amygdala that was significantly correlated with the changing valence of the visual stimuli was found in all three subjects. These findings are consistent with the large corpus of data from non-human studies suggesting that the amygdala is a key structure for extracting the affective significance from external stimuli. This is the first known report of phasic amygdala activation detected with EP-fMRI in normal human subjects responding to affective stimuli.
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Neurosurgical treatment of psychiatric disorders has been influenced by evolving neurobiological models of symptom generation. The advent of functional neuroimaging and advances in the neurosciences have revolutionized understanding of the functional neuroanatomy of psychiatric disorders. This article reviews neuroimaging studies of depression from the last 3 decades and describes an emerging neurocircuitry model of mood disorders, focusing on critical circuits of cognition and emotion, particularly those networks involved in the regulation of evaluative, expressive and experiential aspects of emotion. The relevance of this model for neurotherapeutics is discussed, as well as the role of functional neuroimaging of psychiatric disorders.
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Areas associated with the default mode network (DMN) are substantially similar to those associated with meditation practice. However, no studies on DMN connectivity during resting states have been conducted on meditation practitioners. It was hypothesized that meditators would show heightened functional connectivity in areas of cortical midline activity. Thirty-five meditation practitioners and 33 healthy controls without meditation experience were included in this study. All subjects received 4.68-min resting state functional scanning runs. The posterior cingulate cortex and medial prefrontal cortex were chosen as seed regions for the DMN map. Meditation practitioners demonstrated greater functional connectivity within the DMN in the medial prefrontal cortex area (x y z = 3 39 −21) than did controls. These results suggest that the long-term practice of meditation may be associated with functional changes in regions related to internalized attention even when meditation is not being practiced.
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<p>Several recent studies using functional magnetic resonance imaging (fMRI) during recognition memory tests have suggested that the ability to neuromodulate as a function of cognitive demand may be impaired in older adults due to age-related cell loss and neural volume reduction in memory specific regions. In the current study, older adults (ages 59-77) were tested with fMRI during a delayed-recognition task in which memory load for faces was varied across trials. Activity was greater in amplitude for three- versus one-face stimuli within the superior, middle, and inferior frontal gyri, intraparietal sulcus, and fusiform gyrus. It was concluded that the ability to modulate activity with increasing load is preserved in older adults despite reductions in neural volume.</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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<p>We conducted two fMRI studies to investigate the sensitivity of delay-period activity to changes in memory load during a delayed-recognition task for faces. In Experiment 1, each trial began with the presentation of a memory array consisting of one, two, or three faces that lasted for 3 sec. A 15-sec delay period followed during which no stimuli were present. The delay interval concluded with a one-face probe to which subjects made a button press response indicating whether this face was part of the memory array. Experiment 2 was similar in design except that the delay period was lengthened to 24 sec, and the memory array consisted of only one or three faces. We hypothesized that memory maintenance processes that spanned the delay interval would be revealed by their sensitivity to memory load. Long delay intervals were employed to temporally dissociate phasic activity engendered by the memory array from sustained activity reflecting maintenance. Regions of interest (ROIs) were defined anatomically for the superior frontal gyri (SFG), middle frontal gyri (MFG), and inferior frontal gyri (IFG), intraparietal sulci (IPS), and fusiform gyri (FFG) on a subject-by-subject basis. The mean time course of activity was determined for all voxels within these regions and for that subset of voxels within each ROI that correlated significantly with an empirically determined reference waveform. In both experiments, memory load significantly influenced activation 6--9 sec following the onset of the memory array with larger amplitude responses for higher load levels. Responses were greatest within MFG, IPS, and FFG. In both experiments, however, these load-sensitive differences declined over successive time intervals and were no longer significant at the end of the delay interval. Although insensitive to our load manipulation, sustained activation was present at the conclusion of the delay interval within MFG and other prefrontal regions. IPS delay activity returned to prestimulus baseline levels prior to the end of the delay period in Experiment 2, but not in Experiment 1. Within FFG, delay activity returned to prestimulus baseline levels prior to the conclusion of the delay interval in both experiments. Thus, while phasic processes engendered by the memory array were strongly affected by memory load, no evidence for load-sensitive delay-spanning maintenance processes was obtained.</p>
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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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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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