PET imaging of the neuroreceptor systems in the brain has earned a prominent role in studying normal development, neuropsychiatric illness and developing targeted drugs. The dopaminergic system is of particular interest due to its role in the development of cognitive function and mood as well as its suspected involvement in neuropsychiatric illness. Nonhuman primate animal models provide a valuable resource for relating neurochemical changes to behavior. To facilitate comparison within and between primate models, we report in vivo D2/D3 binding in a large cohort of adolescent rhesus monkeys. METHODS: In this work, the in vivo D2/D3 dopamine receptor availability was measured in a cohort of 33 rhesus monkeys in the adolescent stage of development (3.2-5.3 years). Both striatal and extrastriatal D2/D3 binding were measured using [F-18]fallypride with a high resolution small animal PET scanner. The distribution volume ratio (DVR) was measured for all subjects and group comparisons of D2/D3 binding among the cohort were made based on age and sex. Because two sequential studies were acquired from a single [F-18]fallypride batch, the effect of competing (unlabeled) ligand mass was also investigated. RESULTS: Among this cohort, the rank order of regional D2/D3 receptor binding did not vary from previous studies with adult rhesus monkeys, with: putamen>caudate>ventral striatum>amygdala approximately substantia nigra>medial dorsal thalamus>lateral temporal cortex approximately frontal cortex. The DVR coefficient of variation ranged from 14%-26%, with the greatest variance seen in the head of the caudate. There were significant sex differences in [F-18]fallypride kinetics in the pituitary gland, but this was not observed for regions within the blood-brain barrier. Furthermore, no regions in the brain showed significant sex or age related differences in DVR within this small age range. Based on a wide range of injected fallypride mass across the cohort, significant competition effects could only be detected in the substantia nigra, thalamus, and frontal cortex, and were not evident above intersubject variability in all other regions. CONCLUSION: These data represent the first report of large cohort in vivo D2/D3 dopamine whole brain binding in the adolescent brain and will serve as a valuable comparison for understanding dopamine changes during this critical time of development and provide a framework for creating a dopaminergic biochemical atlas for the rhesus monkey.
Pseudoneglect is traditionally viewed as reflecting right hemisphere specialization for processing spatial information, resulting in orienting toward the contralateral, left, hemispace. Recent evidence suggests that healthy individuals differ from each other in both direction and magnitude of orienting bias, and moreover, the bias displayed by a person is consistent across time, suggesting that it may represent a trait of the individual. Animal studies reveal consistent orienting bias within an individual, which reflects asymmetry in dopaminergic brain systems. We measured basal D2-like receptor binding using positron emission tomography and the high-affinity ligand [F-18]fallypride, to test the hypothesis that asymmetry in dopaminergic neurotransmission in healthy humans modulates the orienting bias in humans. As predicted, we found that individual differences in the direction and magnitude of the orienting bias were strongly associated with the pattern of asymmetric binding of dopamine (DA) D2 receptors in the striatum, as well as clusters in the frontal and temporal cortex. These findings show for the first time that orienting bias reflects individual differences in the lateralization of DA systems in the healthy human brain.
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.
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.
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.
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.
Asymmetry of waking electroencephalography (EEG) alpha power in frontal regions has been correlated with waking emotional reactivity and the emotional content of dream reports. Little is known regarding alpha asymmetry during sleep. The present study was performed to compare alpha power and alpha power asymmetry in various brain regions across states of sleep and wakefulness. Waking and sleep EEG were recorded in a group of patients undergoing polysomnographic evaluation for possible sleep disorders. Alpha EEG asymmetry in frontal and temporal regions was significantly correlated in waking versus sleep, particularly during rapid eye movement (REM) sleep. These results suggest that patterns of frontal alpha asymmetry are stable across sleep and waking and may be related to emotional reactivity during dreaming. During sleep, alpha power was highest during slow-wave sleep and lowest during REM sleep. Implications of these data for understanding the functional significance of alpha power during waking and sleeping are considered.
An overview of the use of EEG to assess hemispheric differences in cognitive and affective processes is presented. Some of the advantages of using EEG to assess asymmetric hemispheric differences in the study of complex mental activity are described. Following this brief introduction, two conceptual issues which are central to studies of EEG asymmetries are introduced: (1) the distinction between hemispheric specialization and activation, and (2) the importance of rostral-caudal differences for the understanding of both specialization and activation. Three methodological issues in the use of EEG to assess hemispheric differences are then presented: (1) the use of asymmetry metrics, (2) muscle artifact, and (3) appropriate reference electrode location. Finally, some empirical examples of using EEG to assess affective and cognitive processes which illustrate these conceptual and methodological issues are described.
OBJECTIVE: High-density EEG recording offers increased spatial resolution but requires careful consideration of how the density of electrodes affects the potentials being measured. Power differences as a function of electrode density and electrolyte spreading were examined and a method for correcting these differences was tested. METHODS: Separate EEG recordings from 8 participants were made using a high-density electrode net, first with 6 of 128 electrodes active followed by recordings with all electrodes active. For a subset of 4 participants measurements were counterbalanced with recordings made in the reversed order by drying the hair after the high-density recordings and using a fresh dry electrode net of the same size for the low-density recordings. Mean power values over 6 resting eyes open/closed EEG recordings at the 6 active electrodes common to both recording conditions were compared. Evidence for possible electrolyte spreading or bridging between electrodes was acquired by computing Hjorth electrical distances. Spherical spline interpolation was tested for correcting power values at electrodes affected by electrolyte spreading for these participants and for a subset of participants from a larger previous study. RESULTS: For both the complete set and the counterbalanced subset, significant decreases in power at the 6 common electrodes for the high-density recordings were observed across the range of the standard EEG bands (1-44 Hz). The number of bridges or amount of electrolyte spreading towards the reference electrode as evidenced by small Hjorth electrical distances served as a predictor of this power decrease. Spherical spline interpolation increased the power values at electrodes affected by electrolyte spreading and by a significant amount for the larger number of participants in the second group. CONCLUSIONS: Understanding signal effects caused by closely spaced electrodes, detecting electrolyte spreading and correcting its effects are important considerations for high-density EEG recordings. A combination of scalp maps of power density and plots of small Hjorth electrical distances can be used to identify electrodes affected by electrolyte spreading. Interpolation using spherical splines offers a method for correcting the potentials measured at these electrodes.
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.
The authors present an overview of the neural bases of emotion. They underscore the role of the prefrontal cortex (PFC) and amygdala in 2 broad approach- and withdrawal-related emotion systems. Components and measures of affective style are identified. Emphasis is given to affective chronometry and a role for the PFC in this process is proposed. Plasticity in the central circuitry of emotion is considered, and implications of data showing experience-induced changes in the hippocampus for understanding psychopathology and stress-related symptoms are discussed. Two key forms of affective plasticity are described--context and regulation. A role for the hippocampus in context-dependent normal and dysfunctional emotional responding is proposed. Finally, implications of these data for understanding the impact on neural circuitry of interventions to promote positive affect and on mechanisms that govern health and disease are considered.
This commentary reflects on the articles in this Special Issue. The appearance of this group of articles underscores the important idea that a major target of mindfulness practice is on emotion. Transformation in trait affect is a key goal of all contemplative traditions. This commentary addresses several key methodological and conceptual issues in the empirical study of mindfulness. The many ways in which the term "mindfulness" is used in the articles in this Special Issue are noted, and they include its reference to states, traits, and independent variables that are manipulated in an experimental context. How the term "mindfulness" is conceptualized and operationalized is crucial, and for progress to be made it is essential that we qualify the use of this term by reference to how it is being operationalized in each context. Other methodological issues are considered, such as the duration of training and how it should be measured, and the nature of control and comparison groups in studies of mindfulness-based interventions. Finally, the commentary ends with a consideration of the targets within emotion processing that are likely to be impacted by mindfulness. This collection of articles underscores the substantial progress that has occurred in the empirical study of mindfulness and it is a harbinger of a very promising future in this area.
BACKGROUND: 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.
Metacognition refers to any knowledge or cognitive process that monitors or controls cognition. We highlight similarities between metacognitive and executive control functions, and ask how these processes might be implemented in the human brain. A review of brain imaging studies reveals a circuitry of attentional networks involved in these control processes, with its source located in midfrontal areas. These areas are active during conflict resolution, error correction, and emotional regulation. A developmental approach to the organization of the anatomy involved in executive control provides an added perspective on how these mechanisms are influenced by maturation and learning, and how they relate to metacognitive activity.
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.
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.
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.
The influence of approach and avoidance tendencies on affect, reasoning, and behavior has attracted substantial interest from researchers across various areas of psychology. Currently, frontal electroencephalographic (EEG) asymmetry in favor of left prefrontal regions is assumed to reflect the propensity to respond with approach-related tendencies. To test this hypothesis, we recorded resting EEG in 18 subjects, who separately performed a verbal memory task under three incentive conditions (neutral, reward, and punishment). Using a source-localization technique, we found that higher task-independent alpha2 (10.5-12 Hz) activity within left dorsolateral prefrontal and medial orbitofrontal regions was associated with stronger bias to respond to reward-related cues. Left prefrontal resting activity accounted for 54.8% of the variance in reward bias. These findings not only confirm that frontal EEG asymmetry modulates the propensity to engage in appetitively motivated behavior, but also provide anatomical details about the underlying brain systems.
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.
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.
<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>
The development of social emotions such as compassion is crucial for successful social interactions as well as for the maintenance of mental and physical health, especially when confronted with distressing life events. Yet, the neural mechanisms supporting the training of these emotions are poorly understood. To study affective plasticity in healthy adults, we measured functional neural and subjective responses to witnessing the distress of others in a newly developed task (Socio-affective Video Task). Participants’ initial empathic responses to the task were accompanied by negative affect and activations in the anterior insula and anterior medial cingulate cortex—a core neural network underlying empathy for pain. Whereas participants reacted with negative affect before training, compassion training increased positive affective experiences, even in response to witnessing others in distress. On the neural level, we observed that, compared with a memory control group, compassion training elicited activity in a neural network including the medial orbitofrontal cortex, putamen, pallidum, and ventral tegmental area—brain regions previously associated with positive affect and affiliation. Taken together, these findings suggest that the deliberate cultivation of compassion offers a new coping strategy that fosters positive affect even when confronted with the distress of others.
It is the central hypothesis of this paper that the mental states commonly referred to as altered states of consciousness are principally due to transient prefrontal cortex deregulation. Supportive evidence from psychological and neuroscientific studies of dreaming, endurance running, meditation, daydreaming, hypnosis, and various drug-induced states is presented and integrated. It is proposed that transient hypofrontality is the unifying feature of all altered states and that the phenomenological uniqueness of each state is the result of the differential viability of various frontal circuits. Using an evolutionary approach, consciousness is conceptualized as hierarchically ordered cognitive function. Higher-order structures perform increasingly integrative functions and thus contribute more sophisticated content. Although this implies a holistic approach to consciousness, such a functional hierarchy localizes the most sophisticated layers of consciousness in the zenithal higher-order structure: the prefrontal cortex. The hallmark of altered states of consciousness is the subtle modification of behavioral and cognitive functions that are typically ascribed to the prefrontal cortex. The theoretical framework presented yields a number of testable hypotheses.
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.