Biomedical subjects

Andrew L Alexander

Publications and source records attributed to Andrew L Alexander.

At least 19 recordsLinked to original sources

PubMed2006

Gaze-fixation, brain activation, and amygdala volume in unaffected siblings of individuals with autism.

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.

Adolescent↗

PubMed2006

Diffusion tensor imaging of the corpus callosum in Autism.

The corpus callosum is the largest commissural white matter pathway that connects the hemispheres of the human brain. In this study, diffusion tensor imaging (DTI) was performed on subject groups with high-functioning autism and controls matched for age, handedness, IQ, and head size. DTI and volumetric measurements of the total corpus callosum and subregions (genu, body and splenium) were made and compared between groups. The results showed that there were significant differences in volume, fractional anisotropy, mean diffusivity, and radial diffusivity between groups. These group differences appeared to be driven by a subgroup of the autism group that had small corpus callosum volumes, high mean diffusivity, low anisotropy, and increased radial diffusivity. This subgroup had significantly lower performance IQ measures than either the other individuals with autism or the control subjects. Measurements of radial diffusivity also appeared to be correlated with processing speed measured during the performance IQ tests. The subgroup of autism subjects with high mean diffusivity and low fractional anisotropy appeared to cluster with the highest radial diffusivities and slowest processing speeds. These results suggest that the microstructure of the corpus callosum is affected in autism, which may be related to nonverbal cognitive performance.

Adolescent↗

PubMed2006

Amygdala and ventromedial prefrontal cortex are inversely coupled during regulation of negative affect and predict the diurnal pattern of cortisol secretion among older adults.

Among younger adults, the ability to willfully regulate negative affect, enabling effective responses to stressful experiences, engages regions of prefrontal cortex (PFC) and the amygdala. Because regions of PFC and the amygdala are known to influence the hypothalamic-pituitary-adrenal axis, here we test whether PFC and amygdala responses during emotion regulation predict the diurnal pattern of salivary cortisol secretion. We also test whether PFC and amygdala regions are engaged during emotion regulation in older (62- to 64-year-old) rather than younger individuals. We measured brain activity using functional magnetic resonance imaging as participants regulated (increased or decreased) their affective responses or attended to negative picture stimuli. We also collected saliva samples for 1 week at home for cortisol assay. Consistent with previous work in younger samples, increasing negative affect resulted in ventral lateral, dorsolateral, and dorsomedial regions of PFC and amygdala activation. In contrast to previous work, decreasing negative affect did not produce the predicted robust pattern of higher PFC and lower amygdala activation. Individuals demonstrating the predicted effect (decrease < attend in the amygdala), however, exhibited higher signal in ventromedial prefrontal cortex (VMPFC) for the same contrast. Furthermore, participants displaying higher VMPFC and lower amygdala signal when decreasing compared with the attention control condition evidenced steeper, more normative declines in cortisol over the course of the day. Individual differences yielded the predicted link between brain function while reducing negative affect in the laboratory and diurnal regulation of endocrine activity in the home environment.

Age Factors↗

PubMed2006

Amygdala volume and nonverbal social impairment in adolescent and adult males with autism.

BACKGROUND: Autism is a syndrome of unknown cause, marked by abnormal development of social behavior. Attempts to link pathological features of the amygdala, which plays a key role in emotional processing, to autism have shown little consensus. OBJECTIVE: To evaluate amygdala volume in individuals with autism spectrum disorders and its relationship to laboratory measures of social behavior to examine whether variations in amygdala structure relate to symptom severity. DESIGN: We conducted 2 cross-sectional studies of amygdala volume, measured blind to diagnosis on high-resolution, anatomical magnetic resonance images. Participants were 54 males aged 8 to 25 years, including 23 with autism and 5 with Asperger syndrome or pervasive developmental disorder not otherwise specified, recruited and evaluated at an academic center for developmental disabilities and 26 age- and sex-matched community volunteers. The Autism Diagnostic Interview-Revised was used to confirm diagnoses and to validate relationships with laboratory measures of social function. MAIN OUTCOME MEASURES: Amygdala volume, judgment of facial expressions, and eye tracking. RESULTS: In study 1, individuals with autism who had small amygdalae were slowest to distinguish emotional from neutral expressions (P=.02) and showed least fixation of eye regions (P=.04). These same individuals were most socially impaired in early childhood, as reported on the Autism Diagnostic Interview-Revised (P<.04). Study 2 showed smaller amygdalae in individuals with autism than in control subjects (P=.03) and group differences in the relation between amygdala volume and age. Study 2 also replicated findings of more gaze avoidance and childhood impairment in participants with autism with the smallest amygdalae. Across the combined sample, severity of social deficits interacted with age to predict different patterns of amygdala development in autism (P=.047). CONCLUSIONS: These findings best support a model of amygdala hyperactivity that could explain most volumetric findings in autism. Further psychophysiological and histopathological studies are indicated to confirm these findings.

Adolescent↗

PubMed2006

Motion correction and the use of motion covariates in multiple-subject fMRI analysis.

The impact of using motion estimates as covariates of no interest was examined in general linear modeling (GLM) of both block design and rapid event-related functional magnetic resonance imaging (fMRI) data. The purpose of motion correction is to identify and eliminate artifacts caused by task-correlated motion while maximizing sensitivity to true activations. To optimize this process, a combination of motion correction approaches was applied to data from 33 subjects performing both a block-design and an event-related fMRI experiment, including analysis: (1) without motion correction; (2) with motion correction alone; (3) with motion-corrected data and motion covariates included in the GLM; and (4) with non-motion-corrected data and motion covariates included in the GLM. Inclusion of covariates was found to be generally useful for increasing the sensitivity of GLM results in the analysis of event-related data. When motion parameters were included in the GLM for event-related data, it made little difference if motion correction was actually applied to the data. For the block design, inclusion of motion covariates had a deleterious impact on GLM sensitivity when even moderate correlation existed between motion and the experimental design. Based on these results, we present a general strategy for block designs, event-related designs, and hybrid designs to identify and eliminate probable motion artifacts while maximizing sensitivity to true activations.

Adolescent↗

PubMed2006

Investigation of anomalous estimates of tensor-derived quantities in diffusion tensor imaging.

The diffusion tensor is typically assumed to be positive definite. However, noise in the measurements may cause the eigenvalues of the tensor estimate to be negative, thereby violating this assumption. Negative eigenvalues in diffusion tensor imaging (DTI) data occur predominately in regions of high anisotropy and may cause the fractional anisotropy (FA) to exceed unity. Two constrained least squares methods for eliminating negative eigenvalues are explored. These methods, the constrained linear least squares method (CLLS) and the constrained nonlinear least squares method (CNLS), are compared with other commonly used algebraic constrained methods. The CLLS tensor estimator can be shown to be equivalent to the linear least squares (LLS) tensor estimator when the LLS tensor estimate is positive definite. Similarly, the CNLS tensor estimator can be shown to be equivalent to the nonlinear least squares (NLS) tensor estimator when the NLS tensor estimate is positive definite. The constrained least squares methods for eliminating negative eigenvalues are evaluated with both simulations and in vivo human brain DTI data. Simulation results show that the CNLS method is, in terms of mean squared error for estimating trace and FA, the most effective method for correcting negative eigenvalues.

Anisotropy↗

PubMed2006

Comparison of diffusion tensor imaging measurements at 3.0 T versus 1.5 T with and without parallel imaging.

The diffusion properties of biological tissues are independent of magnetic field strength. Field strength, however, does affect the signal-to-noise ratio (SNR) and artifacts of diffusion-weighted (DW) images, which ultimately will influence the quantitative and spatial accuracy of diffusion tensor imaging (DTI). In this article, the effects of field strength on DTI are reviewed. The effects of parallel imaging also are discussed. A small study comparing DTI measurements both as a function of field strength (1.5 T and 3.0 T) and parallel imaging was performed. Overall, the SNR of the DW images roughly doubled going from 1.5 T to 3.0 T, and there was a relatively small decrease in SNR (15% to 30%) when parallel imaging was used. The increased SNR at 3.0 T resulted in smaller variances in the estimated mean diffusivities and fractional anisotropies. As expected, the amount of echo-planar image distortion roughly doubled going from 1.5 T to 3.0 T, but was reduced by 50% when using parallel imaging. In summary, DTI studies at 3.0 T using parallel imaging will provide significantly improved DTI measurements relative to studies at 1.5 T.

Brain↗

PubMed2006

Generation and visualization of four-dimensional MR angiography data using an undersampled 3-D projection trajectory.

Time-resolved contrast-enhanced magnetic resonance (MR) angiography (CE-MRA) has gained in popularity relative to X-ray Digital Subtraction Angiography because it provides three-dimensional (3-D) spatial resolution and it is less invasive. We have previously presented methods that improve temporal resolution in CE-MRA while providing high spatial resolution by employing an undersampled 3-D projection (3D PR) trajectory. The increased coverage and isotropic resolution of the 3D PR acquisition simplify visualization of the vasculature from any perspective. We present a new algorithm to develop a set of time-resolved 3-D image volumes by preferentially weighting the 3D PR data according to its acquisition time. An iterative algorithm computes a series of density compensation functions for a regridding reconstruction, one for each time frame, that exploit the variable sampling density in 3D PR. The iterative weighting procedure simplifies the calculation of appropriate density compensation for arbitrary sampling patterns, which improve sampling efficiency and, thus, signal-to-noise ratio and contrast-to-noise ratio, since it is does not require a closed-form calculation based on geometry. Current medical workstations can display these large four-dimensional studies, however, interactive cine animation of the data is only possible at significantly degraded resolution. Therefore, we also present a method for interactive visualization using powerful graphics cards and distributed processing. Results from volunteer and patient studies demonstrate the advantages of dynamic imaging with high spatial resolution.

Algorithms↗

PubMed2005

Application of Brodmann's area templates for ROI selection in white matter tractography studies.

Brodmann's areas are part of the common vernacular used by neuroscientists to indicate specific location of brain activity in functional brain imaging studies. Here, we have employed a template based on the Brodmann's areas as a means of compartmentalizing underlying white matter pathways. White matter tractography was performed on the diffusion tensor data of sixteen subjects using a streamline tracking technique with Runge-Kutta integration. After co-registration, the Brodmann template was utilized for ROI selection. Tracts were segmented based on their termination in a particular area of the template. Binary masks were generated based on the tractography segmentation for a given Brodmann's area in each individual subject. Following registration to a normalized coordinate space, the binary masks were averaged, generating a map that estimates the probability of tractography connectivity for particular white matter pathways to a specific Brodmann's area. The probability maps were color-coded and overlaid on anatomical images to provide perspective. In this study, particular attention was given to the areas of the frontal cortex. A composite map of these areas was generated by assigning each voxel to the Brodmann's area with the highest probability of connectivity, based on the average results. The average maps generated with this method reveal consistent patterns of connectivity across subjects. The use of a normalized template for ROI selection automates the process of segmenting tractography data, making it particularly useful for multi-subject studies. In the future, this method could be used to help elucidate relationships between function and anatomical structure.

Adult↗

PubMed2005

Stability of amygdala BOLD response to fearful faces over multiple scan sessions.

We used fMRI to examine amygdala activation in response to fearful facial expressions, measured over multiple scanning sessions. 15 human subjects underwent three scanning sessions, at 0, 2 and 8 weeks. During each session, functional brain images centered about the amygdala were acquired continuously while participants were shown alternating blocks of fearful, neutral and happy facial expressions. Intraclass correlation coefficients calculated across the sessions indicated stability of response in left amygdala to fearful faces (as a change from baseline), but considerably less left amygdala stability in responses to neutral expressions and for fear versus neutral contrasts. The results demonstrate that the measurement of fMRI BOLD responses in amygdala to fearful facial expressions might be usefully employed as an index of amygdala reactivity over extended periods. While signal change to fearful facial expressions appears robust, the experimental design employed here has yielded variable responsivity within baseline or comparison conditions. Future studies might manipulate the experimental design to either amplify or attenuate this variability, according to the goals of the research.

Adult↗

PubMed2005

Cortical thickness analysis in autism with heat kernel smoothing.

We present a novel data smoothing and analysis framework for cortical thickness data defined on the brain cortical manifold. Gaussian kernel smoothing, which weights neighboring observations according to their 3D Euclidean distance, has been widely used in 3D brain images to increase the signal-to-noise ratio. When the observations lie on a convoluted brain surface, however, it is more natural to assign the weights based on the geodesic distance along the surface. We therefore develop a framework for geodesic distance-based kernel smoothing and statistical analysis on the cortical manifolds. As an illustration, we apply our methods in detecting the regions of abnormal cortical thickness in 16 high functioning autistic children via random field based multiple comparison correction that utilizes the new smoothing technique.

Adolescent↗

PubMed2005

Gaze fixation and the neural circuitry of face processing in autism.

Diminished gaze fixation is one of the core features of autism and has been proposed to be associated with abnormalities in the neural circuitry of affect. We tested this hypothesis in two separate studies using eye tracking while measuring functional brain activity during facial discrimination tasks in individuals with autism and in typically developing individuals. Activation in the fusiform gyrus and amygdala was strongly and positively correlated with the time spent fixating the eyes in the autistic group in both studies, suggesting that diminished gaze fixation may account for the fusiform hypoactivation to faces commonly reported in autism. In addition, variation in eye fixation within autistic individuals was strongly and positively associated with amygdala activation across both studies, suggesting a heightened emotional response associated with gaze fixation in autism.

Adolescent↗

PubMed2005

Axial asymmetry of water diffusion in brain white matter.

The diffusion tensor (DT) is a three-dimensional (3D) model of diffusivity in biological tissues. In white matter (WM), the major eigenvector, which is the direction of greatest diffusivity, is generally assumed to align with the direction of the fiber bundles. The distribution of major eigenvectors in WM has been investigated using color-based maps and WM tractography (WMT). However, anatomical patterns in the medium and minor eigenvector directions have largely been ignored in DTI studies of the human brain. In this study, the patterns of medium and minor eigenvectors in the brain were investigated using both color-based maps and WMT. Specific WM structures, such as the corona radiata, internal and external capsules, sagittal stratum, cingulum, and superior longitudinal fasciculus, demonstrated coherent patterns in the medium and minor eigenvector directions. These patterns were consistent across subjects. The orthogonal or axial diffusion asymmetry may be explained by merging, diverging, or crossing fiber geometries. The effects of orthogonal diffusion asymmetry on WMT were also investigated. This study shows that WM axial asymmetry causes anisotropic dispersion patterns in the estimated tract trajectories. The medium and minor eigenvector patterns may be useful for elucidating the local dispersion distributions of WM tracts.

Adolescent↗

PubMed2005

The cerebral response during subjective choice with and without self-reference.

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.

Adult↗

PubMed2005

Principal diffusion direction in peritumoral fiber tracts: Color map patterns and directional statistics.

The ability of diffusion tensor imaging (DTI) to probe the ultrastructural properties of biological tissues presents new possibilities for DTI-based tissue characterization, with the potential for greater pathologic specificity than conventional imaging methods. This is urgently needed in the diagnosis and treatment of cerebral neoplasms, where clinical decisions depend on the ability to discriminate tumor-involved from uninvolved tissue, a major shortcoming of conventional imaging. Several investigators have attempted to make this determination on the basis of the apparent diffusion coefficient (ADC) or the fractional anisotropy (FA), with mixed results. The directionally encoded color map, with hues reflecting tensor orientation and intensity weighted by FA, provides an aesthetic and informative summary of DTI features throughout the brain in an easily interpreted format. The use of these maps is becoming increasingly common in both basic and clinical research, as well as in purely clinical settings. These examples serve to demonstrate our approach to the quantitation of regional diffusion tensor distributions using directional statistical methods.

Anisotropy↗

PubMed2005

Diffusion tensor imaging of the corticospinal tract before and after mass resection as correlated with clinical motor findings: preliminary data.

BACKGROUND AND PURPOSE: The role of diffusion tensor imaging (DTI) in neurosurgical planning and follow-up is currently being defined and needs clinical validation. To that end, we sought correlations between preoperative and postoperative DTI and clinical motor deficits in patients with space-occupying lesions involving the corticospinal tract (CST). METHODS: DTI findings in four patients with masses near the CST and not involving motor cortex were retrospectively reviewed and compared with contralateral motor strength. CST involvement was determined from anisotropy and eigenvector directional color maps. The CST was considered involved if it was substantially deviated or had decreased anisotropy. Interpretations of the DTIs were blinded to assessments of motor strength, and vice versa. RESULTS: Of the four patients with potential CST involvement before surgery, DTI confirmed CST involvement in three, all of whom had preoperative motor deficits. The patient without CST involvement on DTI had no motor deficit. After surgery, DTI showed CST preservation and normalization of the position and/or anisotropy in two of the three patients with preoperative deficits, and both of those patients had improvement in motor strength. The other patient with preoperative deficits had evidence of wallerian degeneration on DTI and had only equivocal clinical improvement. CONCLUSION: Preoperative CST involvement, as determined on DTI, was predictive of the presence or absence of motor deficits, and postoperative CST normalization on DTI was predictive of clinical improvement. Further study is warranted to define the role of DTI in planning tumor resections and predicting postoperative motor function.

Adult↗

PubMed2004

Bootstrap white matter tractography (BOOT-TRAC).

White matter tractography is a noninvasive method for estimating and visualizing the white matter connectivity patterns in the human brain using diffusion tensor imaging (DTI) data. Sources of experimental noise may induce errors in the measured fiber directions, which will reduce the accuracy of the estimated white matter trajectories. In this study, a statistical nonparametric bootstrap method is described for estimating the dispersion and other errors in white matter tractography results. Prior studies have derived models of tractography error using the signal-to-noise ratio (SNR) and diffusion anisotropy of the DTI data. Tractography errors measured using bootstrap methods were generally consistent with an analytic model of tractography error except in areas where branching was evident. White matter tractography with bootstrap resampling is also applied to estimate the probabilities of connection between brain regions. The approach was used to generate probabilistic connectivity maps between the cerebral peduncles and specific cortical regions.

Brain↗

PubMed2004

Human amygdala responses during presentation of happy and neutral faces: correlations with state anxiety.

BACKGROUND: Previous functional imaging studies demonstrating amygdala response to happy facial expressions have all included the presentation of negatively valenced primary comparison expressions within the experimental context. This study assessed amygdala response to happy and neutral facial expressions in an experimental paradigm devoid of primary negatively valenced comparison expressions. METHODS: Sixteen human subjects (eight female) viewed 16-sec blocks of alternating happy and neutral faces interleaved with a baseline fixation condition during two functional magnetic resonance imaging scans. RESULTS: Within the ventral amygdala, a negative correlation between happy versus neutral signal changes and state anxiety was observed. The majority of the variability associated with this effect was explained by a positive relationship between state anxiety and signal change to neutral faces. CONCLUSIONS: Interpretation of amygdala responses to facial expressions of emotion will be influenced by considering the contribution of each constituent condition within a greater subtractive finding, as well as 1) their spatial location within the amygdaloid complex; and 2) the experimental context in which they were observed. Here, an observed relationship between state anxiety and ventral amygdala response to happy versus neutral faces was explained by response to neutral faces.

Adult↗