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Many investigators have hypothesized that brain response to cortisol is altered in depression. However, neural activation in response to exogenously manipulated cortisol elevations has not yet been directly examined in depressed humans. Animal research shows that glucocorticoids have robust effects on hippocampal function, and can either enhance or suppress neuroplastic events in the hippocampus depending on a number of factors. We hypothesized that depressed individuals would show 1) altered hippocampal response to exogenous administration of cortisol, and 2) altered effects of cortisol on learning. In a repeated-measures design, 19 unmedicated depressed and 41 healthy individuals completed two fMRI scans. Fifteen mg oral hydrocortisone (i.e., cortisol) or placebo (order randomized and double-blind) was administered 1 h prior to encoding of emotional and neutral words during fMRI scans. Data analysis examined the effects of cortisol administration on 1) brain activation during encoding, and 2) subsequent free recall for words. Cortisol affected subsequent recall performance in depressed but not healthy individuals. We found alterations in hippocampal response to cortisol in depressed women, but not in depressed men (who showed altered response to cortisol in other regions, including subgenual prefrontal cortex). In both depressed men and women, cortisol's effects on hippocampal function were positively correlated with its effects on recall performance assessed days later. Our data provide evidence that in depressed compared to healthy women, cortisol's effects on hippocampal function are altered. Our data also show that in both depressed men and women, cortisol's effects on emotional memory formation and hippocampal function are related.
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In rodents, theta rhythm has been linked to the hippocampal formation, as well as other regions, including the anterior cingulate cortex (ACC). To test the role of the ACC in theta rhythm, concurrent measurements of brain electrical activity (EEG) and glucose metabolism (PET) were performed in 29 subjects at baseline. EEG data were analyzed with a source localization technique that enabled voxelwise correlations of EEG and PET data. For theta, but not other bands, the rostral ACC (Brodmann areas 24/32) was the largest cluster with positive correlations between current density and glucose metabolism. Positive correlations were also found in right fronto-temporal regions. In control but not depressed subjects, theta within ACC and prefrontal/orbitofrontal regions was positively correlated. The results reveal a link between theta and cerebral metabolism in the ACC as well as disruption of functional connectivity within frontocingulate pathways in depression.
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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.
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Individual variation in the experience and expression of pleasure may relate to differential patterns of lateral frontal activity. Brain electrical measures have been used to study the asymmetric involvement of lateral frontal cortex in positive emotion, but the excellent time resolution of these measures has not been used to capture second-by-second changes in ongoing emotion until now. The relationship between pleasure and second-by-second lateral frontal activity was examined with the use of hierarchical linear modeling in a sample of 128 children ages 6-10 years. Electroencephalographic activity was recorded during "pop-out toy," a standardized task that elicits pleasure. The task consisted of 3 epochs: an anticipation period sandwiched between 2 play periods. The amount of pleasure expressed during the task predicted the pattern of nonlinear change in lateral frontal activity. Children who expressed increasing amounts of pleasure during the task exhibited increasing left lateral frontal activity during the task, whereas children who expressed contentment exhibited increasing right/decreasing left activity. These findings indicate that task-dependent changes in pleasure relate to dynamic, nonlinear changes in lateral frontal activity as the task unfolds.
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Cognitive deficits have been reported in children who experienced early neglect, especially children raised in institutionalized settings. Previous research suggests that early neglect may differentially affect the directional organization of white matter in the prefrontal cortex (PFC). This may be one mechanism to explain cognitive deficits associated with neglect. To test this idea, properties of white matter and neurocognitive performance were assessed in children who suffered early neglect and those raised in typical environments (n = 63, Mage  = 11.75 years). As predicted, prefrontal white matter microstructure was affected, consistent with more diffuse organization, in children that suffered early neglect and this was related to neurocognitive deficits. Such findings underscore how early adversity may affect the PFC and explain cognitive deficits associated with neglect.
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Individuals who experience early adversity, such as child maltreatment, are at heightened risk for a broad array of social and health difficulties. However, little is known about how this behavioral risk is instantiated in the brain. Here we examine a neurobiological contribution to individual differences in human behavior using methodology appropriate for use with pediatric populations paired with an in-depth measure of social behavior. We show that alterations in the orbitofrontal cortex among individuals who experienced physical abuse are related to social difficulties. These data suggest a biological mechanism linking early social learning to later behavioral outcomes.
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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.
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OBJECTIVE: This study was undertaken to identify brain structures associated with emotion in normal elderly subjects. METHOD: Eight normal subjects aged 55-78 years were shown film clips intended to provoke the emotions of happiness, fear, or disgust as well as a neutral state. During emotional activation, regional cerebral blood flow was measured with the use of [15O]H2O positron emission tomography imaging, and subjective emotional responses were recorded. Data were analyzed by subtracting the values during the neutral condition from the values in the various emotional activations. RESULTS: The stimuli produced a general activation in visual pathways that included the primary and secondary visual cortex, involving regions associated with object and spatial recognition. In addition, the specific emotions produced different regional limbic activations, which suggests that different pathways may be used for different types of emotional stimuli. CONCLUSIONS: Emotional activation in normal elderly subjects was associated with increases in blood flow in limbic and paralimbic brain structures. Brain activation may be specific to the emotion being elicited but probably involves complex sensory, association, and memory circuitry. Further studies are needed to identify activations that are specific for emotion.
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In two prior studies, we investigated the neural mechanisms of spatial attention using a combined event-related potential (ERP) and positron emission tomography (PET) approach (Heinze et al. [1994]: Nature 392:543-546; Mangun et al. [1997]: Hum Brain Mapp 5:273-279). Neural activations in extrastriate cortex were observed in the PET measures for attended stimuli, and these effects were related to attentional modulations in the ERPs at specific latencies. The present study used functional magnetic resonance imaging (fMRI) and ERPs in single subjects to investigate the intersubject variability in extrastriate spatial attention effects, and to qualitatively compare this to variations in ERP attention effects. Activations in single subjects replicated our prior group-averaged PET findings, showing attention-related increases in blood flow in the posterior fusiform and middle occipital gyri in the hemisphere contralateral to attended visual stimuli. All subjects showed attentional modulations of the occipital P1 component of the ERPs. These findings in single subjects demonstrate the consistency of extrastriate attention effects, and provide information about the feasibility of this approach for integration of electrical and functional imaging data.
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BACKGROUND: Relationships between aberrant social functioning and depression have been explored via behavioral, clinical, and survey methodologies, highlighting their importance in the etiology of depression. The neural underpinnings of these relationships, however, have not been explored. METHODS: Nine depressed participants and 14 never-depressed control subjects viewed emotional and neutral pictures at two functional magnetic resonance imaging (fMRI) scanning sessions approximately 22 weeks apart. In the interim, depressed patients received the antidepressant Venlafaxine. Positively rated images were parsed into three separate comparisons: social interaction, human faces, and sexual images; across scanning session, activation to these images was compared with other positively rated images. RESULTS: For each of the three social stimulus types (social interaction, faces, sexual images), a distinguishable circuitry was activated equally in non-depressed control subjects and post-treatment depressed subjects but showed a hypo-response in the depressed group pre-treatment. These structures include regions of prefrontal, temporal, and parietal cortices, insula, basal ganglia, and the hippocampus. CONCLUSIONS: The neural hypo-response to positively valenced social stimuli that is observed in depression remits as response to antidepressant medication occurs, suggesting a state-dependent deficiency in response to positive social incentives. These findings underscore the importance of addressing social dysfunction in research and treatment of depression.
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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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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.
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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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Major depression is a heterogeneous condition, and the search for neural correlates specific to clinically defined subtypes has been inconclusive. Theoretical considerations implicate frontostriatal, particularly subgenual prefrontal cortex (PFC), dysfunction in the pathophysiology of melancholia--a subtype of depression characterized by anhedonia--but no empirical evidence has been found yet for such a link. To test the hypothesis that melancholic, but not nonmelancholic depression, is associated with the subgenual PFC impairment, concurrent measurement of brain electrical (electroencephalogram, EEG) and metabolic (positron emission tomography, PET) activity were obtained in 38 unmedicated subjects with DSM-IV major depressive disorder (20 melancholic, 18 nonmelancholic subjects), and 18 comparison subjects. EEG data were analyzed with a tomographic source localization method that computed the cortical three-dimensional distribution of current density for standard frequency bands, allowing voxelwise correlations between the EEG and PET data. Voxel-based morphometry analyses of structural magnetic resonance imaging (MRI) data were performed to assess potential structural abnormalities in melancholia. Melancholia was associated with reduced activity in the subgenual PFC (Brodmann area 25), manifested by increased inhibitory delta activity (1.5-6.0 Hz) and decreased glucose metabolism, which themselves were inversely correlated. Following antidepressant treatment, depressed subjects with the largest reductions in depression severity showed the lowest post-treatment subgenual PFC delta activity. Analyses of structural MRI revealed no group differences in the subgenual PFC, but in melancholic subjects, a negative correlation between gray matter density and age emerged. Based on preclinical evidence, we suggest that subgenual PFC dysfunction in melancholia may be associated with blunted hedonic response and exaggerated stress responsiveness.
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The relationships between brain electrical and metabolic activity are being uncovered currently in animal models using invasive methods; however, in the human brain this relationship remains not well understood. In particular, the relationship between noninvasive measurements of electrical activity and metabolism remains largely undefined. To understand better these relations, cerebral activity was measured simultaneously with electroencephalography (EEG) and positron emission tomography using [(18)f]-fluoro-2-deoxy-D-glucose (PET-FDG) in 12 normal human subjects during rest. Intracerebral distributions of current density were estimated, yielding tomographic maps for seven standard EEG frequency bands. The PET and EEG data were registered to the same space and voxel dimensions, and correlational maps were created on a voxel-by-voxel basis across all subjects. For each band, significant positive and negative correlations were found that are generally consistent with extant understanding of EEG band power function. With increasing EEG frequency, there was an increase in the number of positively correlated voxels, whereas the lower alpha band (8.5-10.0 Hz) was associated with the highest number of negative correlations. This work presents a method for comparing EEG signals with other more traditionally tomographic functional imaging data on a 3-D basis. This method will be useful in the future when it is applied to functional imaging methods with faster time resolution, such as short half-life PET blood flow tracers and functional magnetic resonance imaging.
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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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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.
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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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