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Fragile X syndrome (FXS) is the most commonly known genetic disorder associated with autism spectrum disorder (ASD). Overlapping features in these populations include gaze aversion, communication deficits, and social withdrawal. Although the association between FXS and ASD has been well documented at the behavioral level, the underlying neural mechanisms associated with the social/emotional deficits in these groups remain unclear. We collected functional brain images and eye-gaze fixations from 9 individuals with FXS and 14 individuals with idiopathic ASD, as well as 15 typically developing (TD) individuals, while they performed a facial-emotion discrimination task. The FXS group showed a similar yet less aberrant pattern of gaze fixations compared with the ASD group. The FXS group also showed fusiform gyrus (FG) hypoactivation compared with the TD control group. Activation in FG was strongly and positively associated with average eye fixation and negatively associated with ASD characteristics in the FXS group. The FXS group displayed significantly greater activation than both the TD control and ASD groups in the left hippocampus (HIPP), left superior temporal gyrus (STG), right insula (INS), and left postcentral gyrus (PCG). These group differences in brain activation are important as they suggest unique underlying face-processing neural circuitry in FXS versus idiopathic ASD, largely supporting the hypothesis that ASD characteristics in FXS and idiopathic ASD reflect partially divergent impairments at the neural level, at least in FXS individuals without a co-morbid diagnosis of ASD.
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The experience of aversion is shaped by multiple physiological and psychological factors including one's expectations. Recent work has shown that expectancy manipulation can alter perceptions of aversive events and concomitant brain activation. Accruing evidence indicates a primary role of altered expectancies in the placebo effect. Here, we probed the mechanism by which expectation attenuates sensory taste transmission by examining how brain areas activated by misleading information during an expectancy period modulate insula and amygdala activation to a highly aversive bitter taste. In a rapid event-related fMRI design, we showed that activations in the rostral anterior cingulate cortex (rACC), orbitofrontal cortex (OFC), and dorsolateral prefrontal cortex to a misleading cue that the taste would be mildly aversive predicted decreases in insula and amygdala activation to the highly aversive taste. OFC and rACC activation to the misleading cue were also associated with less aversive ratings of that taste. Additional analyses revealed consistent results demonstrating functional connectivity among the OFC, rACC, and insula. Altering expectancies of upcoming aversive events are shown here to depend on robust functional associations among brain regions implicated in prior work on the placebo effect.
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The anterior medial prefrontal (AMPFC) and retrosplenial (RSC) cortices are active during self-referential decision-making tasks such as when participants appraise traits and abilities, or current affect. Other appraisal tasks requiring an evaluative decision or mental representation, such as theory of mind and perspective-taking tasks, also involve these regions. In many instances, these types of decisions involve a subjective opinion or preference, but also a degree of ambiguity in the decision, rather than a strictly veridical response. However, this ambiguity is generally not controlled for in studies that examine self-referential decision-making. In this functional magnetic resonance imaging experiment with 17 healthy adults, we examined neural processes associated with subjective decision-making with and without an overt self-referential component. The task required subjective decisions about colors-regarding self-preference (internal subjective decision) or color similarity (external subjective decision) under conditions where there was no objectively correct response. Results indicated greater activation in the AMPFC, RSC, and caudate nucleus during internal subjective decision-making. The findings suggest that self-referential processing, rather than subjective judgments among ambiguous response alternatives, accounted for the AMPFC and RSC response.
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BACKGROUND: Asymmetric patterns of frontal brain activity and brain corticotropin-releasing hormone (CRH) systems have both been separately implicated in the processing of normal and abnormal emotional responses. Previous studies in rhesus monkeys demonstrated that individuals with extreme right frontal asymmetric brain electrical activity have high levels of trait-like fearful behavior and increased plasma cortisol concentrations. METHODS: In this study we assessed cerebrospinal fluid (CSF) CRH concentrations in monkeys with extreme left and extreme right frontal brain electrical activity. CSF was repeatedly collected at 4, 8, 14, 40, and 52 months of age. RESULTS: Monkeys with extreme right frontal brain activity had increased CSF CRH concentrations at all ages measured. In addition, individual differences in CSF CRH concentrations were stable from 4 to 52 months of age. CONCLUSIONS: These findings suggest that, in primates, the fearful endophenotype is characterized by increased fearful behavior, a specific pattern of frontal electrical activity, increased pituitary-adrenal activity, and increased activity of brain CRH systems. Data from other preclinical studies suggests that the increased brain CRH activity may underlie the behavioral and physiological characteristics of fearful endophenotype.
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Brain Respiration (BR)-training is a unique form of breathing exercise that develops potential ability by facilitating brain function. It is recognized as an effective method of improving the scholastic aptitude and emotional stability of children. The present study was designed to investigate the characteristics of the EEG during this training. Spectral analysis was used to examine the relative power in the EEG of 12 children while they practiced BR-training, and these were compared to those of 12 matched controls. BR-trainees showed a lower θ rhythm than the controls before the training session began and lower β[sub 2] power before, during and after the session. In contrast, the BR subjects showed greater relative α[sub 1] power than the controls in the left frontal region during BR-training, which persisted throughout the BR-training schedule. There is evidence that decreased θ and β waves may be correlated with emotional maturation, whilst increased α waves are associated with educational achievement. These findings enhance our understanding of the neurophysiological basis of the effects of BR-training upon emotion and maturation.

First described for use in mapping the human visual cortex in 1991, functional magnetic resonance imaging (fMRI) is based on blood-oxygen level dependent (BOLD) changes in cortical regions that occur during specific tasks. Typically, an overabundance of oxygenated (arterial) blood is supplied during activation of brain areas. Consequently, the venous outflow from the activated areas contains a higher concentration of oxyhemoglobin, which changes the paramagnetic properties of the tissue that can be detected during a T2-star acquisition. fMRI data can be acquired in response to specific tasks or in the resting state. fMRI has been widely applied to studying physiologic and pathophysiologic diseases of the brain. This review will discuss the most common current clinical applications of fMRI as well as emerging directions.
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Functional neuroimaging research has demonstrated that retrieving information about object-associated colors activates the left fusiform gyrus in posterior temporal cortex. Although regions near the fusiform have previously been implicated in color perception, it remains unclear whether color knowledge retrieval actually activates the color perception system. Evidence to this effect would be particularly strong if color perception cortex was activated by color knowledge retrieval triggered strictly with linguistic stimuli. To address this question, subjects performed two tasks while undergoing fMRI. First, subjects performed a property verification task using only words to assess conceptual knowledge. On each trial, subjects verified whether a named color or motor property was true of a named object (e.g., TAXI-yellow, HAIR-combed). Next, subjects performed a color perception task. A region of the left fusiform gyrus that was highly responsive during color perception also showed greater activity for retrieving color than motor property knowledge. These data provide the first evidence for a direct overlap in the neural bases of color perception and stored information about object-associated color, and they significantly add to accumulating evidence that conceptual knowledge is grounded in the brain's modality-specific systems.
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The authors compared 12 pairs of cerebral [18F]-fluoro-deoxyglucose (FDG) 2D/3D image sets from a GE/Advance PET scanner, incorporating the actual corrections used on human subjects. Differences in resolution consistent with other published values were found. There is a significant difference in axial resolution between 2D and 3D, and the authors focused on this as it is a scanner feature that cannot be readily changed. Previously published values for spatial axial resolution in 2D and 3D modes were used to model the differential axial smoothing at each image voxel. This model was applied to the 2D FDG images, and the resulting smoothed data indicate the published differences in axial resolution between 2D and 3D modes can account for 30-40% of the differences between these image sets. The authors then investigated the effect this difference might have on analysis typically performed on human FDG data. A phantom containing spherical hot- and cool-spots in a warm background to mimic a typical human cerebral FDG PET scan was scanned for a variety of time durations (30, 15, 5, 1 min). Only for the 1-minute frame (total counts 2D:6M, 3D:30M) is there an advantage to using 3D mode; for the longer frames which are more typical of a human FDG protocol, the reliability for extracting regions-of-interest is the same for either mode while 2D mode shows better quantitative accuracy
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Motion correction of fMRI data is a widely used step prior to data analysis. In this study, a comparison of the motion correction tools provided by several leading fMRI analysis software packages was performed, including AFNI, AIR, BrainVoyager, FSL, and SPM2. Comparisons were performed using data from typical human studies as well as phantom data. The identical reconstruction, preprocessing, and analysis steps were used on every data set, except that motion correction was performed using various configurations from each software package. Each package was studied using default parameters, as well as parameters optimized for speed and accuracy. Forty subjects performed a Go/No-go task (an event-related design that investigates inhibitory motor response) and an N-back task (a block-design paradigm investigating working memory). The human data were analyzed by extracting a set of general linear model (GLM)-derived activation results and comparing the effect of motion correction on thresholded activation cluster size and maximum t value. In addition, a series of simulated phantom data sets were created with known activation locations, magnitudes, and realistic motion. Results from the phantom data indicate that AFNI and SPM2 yield the most accurate motion estimation parameters, while AFNI's interpolation algorithm introduces the least smoothing. AFNI is also the fastest of the packages tested. However, these advantages did not produce noticeably better activation results in motion-corrected data from typical human fMRI experiments. Although differences in performance between packages were apparent in the human data, no single software package produced dramatically better results than the others. The "accurate" parameters showed virtually no improvement in cluster t values compared to the standard parameters. While the "fast" parameters did not result in a substantial increase in speed, they did not degrade the cluster results very much either. The phantom and human data indicate that motion correction can be a valuable step in the data processing chain, yielding improvements of up to 20% in the magnitude and up to 100% in the cluster size of detected activations, but the choice of software package does not substantially affect this improvement.
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Three experiments were performed testing the effects of a variety of impedance cardiograph electrode types and recording arrangements on recorded electroencephalography (EEG) using either a monopolar single-ear reference or a physically linked ears reference. EEG was recorded either alone or concurrently with an impedance cardiograph. When the cardiograph was recorded using a spot electrode for the top current-inducing electrode, there was an overall decrease in power density of the EEG, and this effect was dependent on the location of the recording electrode. This effect was diminished when the top cardiograph spot electrode was replaced by a mylar-coated neck band electrode and EEG was recorded using a monopolar, single-ear reference. However, there tended to be an overall increase in log power density of the EEG in each frequency band below 60 Hz when less technologically advanced EEG amplifiers were used. This effect was diminished if the EEG was recorded using a physically linked ears reference. Recommendations for the concurrent recording of EEG and impedance cardiography are discussed.
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In a recent neuroimaging study of macaque monkeys, Gil-da-Costa and colleagues reported that a distributed circuit of modality-specific properties represents macaques' conceptual knowledge of social situations. The circuit identified shows striking similarities to analogous circuits in humans that represent conceptual knowledge. This parallel suggests that a common architecture underlies the conceptual systems of different species, although with additional systems extending human conceptual abilities significantly.
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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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The corticotrophin-releasing hormone (CRH) system integrates the stress response and is associated with stress-related psychopathology. Previous reports have identified interactions between childhood trauma and sequence variation in the CRH receptor 1 gene (CRHR1) that increase risk for affective disorders. However, the underlying mechanisms that connect variation in CRHR1 to psychopathology are unknown. To explore potential mechanisms, we used a validated rhesus macaque model to investigate association between genetic variation in CRHR1, anxious temperament (AT) and brain metabolic activity. In young rhesus monkeys, AT is analogous to the childhood risk phenotype that predicts the development of human anxiety and depressive disorders. Regional brain metabolism was assessed with (18)F-labeled fluoro-2-deoxyglucose (FDG) positron emission tomography in 236 young, normally reared macaques that were also characterized for AT. We show that single nucleotide polymorphisms (SNPs) affecting exon 6 of CRHR1 influence both AT and metabolic activity in the anterior hippocampus and amygdala, components of the neural circuit underlying AT. We also find evidence for association between SNPs in CRHR1 and metabolism in the intraparietal sulcus and precuneus. These translational data suggest that genetic variation in CRHR1 affects the risk for affective disorders by influencing the function of the neural circuit underlying AT and that differences in gene expression or the protein sequence involving exon 6 may be important. These results suggest that variation in CRHR1 may influence brain function before any childhood adversity and may be a diathesis for the interaction between CRHR1 genotypes and childhood trauma reported to affect human psychopathology.
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Depression is a disorder of the representation and regulation of mood and emotion. The circuitry underlying the representation and regulation of normal emotion and mood is reviewed, including studies at the animal level, human lesion studies, and human brain imaging studies. This corpus of data is used to construct a model of the ways in which affect can become disordered in depression. Research on the prefrontal cortex, anterior cingulate, hippocampus, and amygdala is reviewed and abnormalities in the structure and function of these different regions in depression is considered. The review concludes with proposals for the specific types of processing abnormalities that result from dysfunctions in different parts of this circuitry and offers suggestions for the major themes upon which future research in this area should be focused.
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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.
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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.
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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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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.
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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.
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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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