Cheuk Y. Tang

MRI white matter diffusion anisotropy and PET metabolic rate in schizophrenia

A disturbance in the frontal–striatal–thalamic circuitry has been proposed for schizophrenia, but this concept has been based primarily on indirect evidence from psychopharmacology and analogies with animal research. Diffusion tensor imaging, a new MRI technique that permits direct assessment of the large axon masses stretching from the prefrontal cortex to the striatum, was used to study white matter axon bundles. Diffusion tensor images, high-resolution structural MRI and positron emission tomography scans with 18-fluorodexoyglucose were obtained on five patients with schizophrenia and six age- and sex-matched normal controls. Significantly lower diffusion anisotropy in the white matter of the prefrontal cortex in schizophrenic patients than in normal controls was observed in statistical probability maps. Co-registered PET scans revealed significantly lower correlation coefficients between metabolic rates in the prefrontal cortex and striatum in patients than in controls. These twin findings provide convergent evidence for diminished fronto–striatal connectivity in schizophrenia.

Fronto-limbic dysfunction in response to facial emotion in borderline personality disorder: An event-related fMRI study

Clinical hallmarks of borderline personality disorder (BPD) include social and emotional dysregulation. We tested a model of fronto-limbic dysfunction in facial emotion processing in BPD. Groups of 12 unmedicated adults with BPD by DSM-IV and 12 demographically-matched healthy controls (HC) viewed facial expressions (Conditions) of neutral emotion, fear and anger, and made gender discriminations during rapid event-related functional magnetic resonance imaging (fMRI). Analysis of variance of Region of Interest signal change revealed a statistically significant effect of the Group-by-Region-by-Condition interaction. This was due to the BPD group exhibiting a significantly larger magnitude of deactivation (relative to HC) in the bilateral rostral/subgenual anterior cingulate cortex (ACC) to fear and in the left ACC to fear minus neutral; and significantly greater activation in the right amygdala to fear minus neutral. There were no significant between-group differences in ROI signal change in response to anger. In voxel-wise analyses constrained within these ROIs, the BPD group exhibited significant changes in the fear minus neutral contrast, with relatively less activation in the bilateral rostral/subgenual ACC, and greater activation in the right amygdala. In the anger minus neutral contrast this pattern was reversed, with the BPD group showing greater activation in the bilateral rostral/subgenual ACC and less activation in the bilateral amygdala. We conclude that adults with BPD exhibit changes in fronto-limbic activity in the processing of fear stimuli, with exaggerated amygdala response and impaired emotion-modulation of ACC activity. The neural substrates underlying processing of anger may also be altered. These changes may represent an expression of the volumetric and serotonergic deficits observed in these brain areas in BPD.

Detection of Alzheimer's amyloid in transgenic mice using magnetic resonance microimaging.

The presence of amyloid‐β (Aβ) plaques in the brain is a hallmark pathological feature of Alzheimers disease (AD). Transgenic mice overexpressing mutant amyloid precursor protein (APP), or both mutant APP and presenilin‐1 (APP/PS1), develop Aβ plaques similar to those in AD patients, and have been proposed as animal models in which to test experimental therapeutic approaches for the clearance of Aβ. However, at present there is no in vivo whole‐brain imaging method to detect Aβ plaques in mice or men. A novel method is presented to detect Aβ plaques in the brains of transgenic mice by magnetic resonance microimaging (μMRI). This method uses Aβ1‐40 peptide, known for its high binding affinity to Aβ, magnetically labeled with either gadolinium (Gd) or monocrystalline iron oxide nanoparticles (MION). Intraarterial injection of magnetically labeled Aβ1‐40, with mannitol to transiently open the blood–brain barrier (BBB), enabled the detection of many Aβ plaques. Furthermore, the numerical density of Aβ plaques detected by μMRI and by immunohistochemistry showed excellent correlation. This approach provides an in vivo method to detect Aβ in AD transgenic mice, and suggests that diagnostic MRI methods to detect Aβ in AD patients may ultimately be feasible. Magn Reson Med 50:293–302, 2003.

Diffusion Tensor Imaging Findings in First-Episode and Chronic Schizophrenia Patients

OBJECTIVE Comparisons of diffusion tensor imaging (DTI) data between first-episode and chronic schizophrenia patients assessed in different studies have led to the suggestion that the decreased fractional anisotropy observed in chronic schizophrenia patients is less pronounced in first-episode patients. However, such comparisons of imaging data generated across studies are susceptible to numerous confounders, which may limit the interpretation of any differences. In order to address these issues and determine whether the DTI abnormalities of chronic schizophrenia are present at illness onset, the authors conducted a DTI investigation of the largest cohort of first-episode schizophrenia patients yet reported in conjunction with a group of chronic schizophrenia patients and healthy subjects for comparison. METHOD Fractional anisotropy data generated by diffusion tensor imaging with a 3-T Siemens Allegra head-dedicated MRI system were compared between 40 first-episode schizophrenia patients and 39 age- and gender-matched healthy comparison subjects and between 40 chronic schizophrenia patients and 40 age- and gender-matched healthy comparison subjects. The following regions of interest were assessed: forceps minor (bilaterally), forceps major (bilaterally), inferior longitudinal fasciculus (bilaterally), and the genu and splenium of the corpus callosum. RESULTS In most regions, chronic schizophrenia patients showed significant or trend-level lower fractional anisotropy than healthy comparison subjects, whereas the first-episode schizophrenia patients showed only trend-level lower fractional anisotropy in the inferior longitudinal fasciculus. CONCLUSIONS The cross-sectional data reported here suggest less widespread changes in white matter at illness onset in schizophrenia which progress in more chronic states. More definitive conclusions will require follow-up imaging of first-episode schizophrenia patients.

Improved biocompatibility and pharmacokinetics of silica nanoparticles by means of a lipid coating: a multimodality investigation

Silica is a promising carrier material for nanoparticle-facilitated drug delivery, gene therapy, and molecular imaging. Understanding of their pharmacokinetics is important to resolve bioapplicability issues. Here we report an extensive study on bare and lipid-coated silica nanoparticles in mice. Results obtained by use of a wide variety of techniques (fluorescence imaging, inductively coupled plasma mass spectrometry, magnetic resonance imaging, confocal laser scanning microscopy, and transmission electron microscopy) showed that the lipid coating, which enables straightforward functionalization and introduction of multiple properties, increases bioapplicability and improves pharmacokinetics.

Increased dopamine activity associated with stuttering

POSITRON emission tomography using 6-FDOPA as a marker of presynaptic dopaminergic activity was used to investigate the role of the dopamine system in stuttering. Three patients with moderate to severe developmental stuttering were compared with six normal controls. Stuttering subjects showed significantly higher 6-FDOPA uptake than normal controls in medial pre-frontal cortex, deep orbital cortex, insular cortex, extended amygdala, auditory cortex and caudate tail. Elevated 6-FDOPA uptake in ventral limbic cortical and subcortical regions is compatible with the hypothesis that stuttering is associated with an overactive pre-synaptic dopamine system in brain regions that modulate verbalization.

A Functional Magnetic Resonance Imaging Study of Deliberate Emotion Regulation in Resilience and Posttraumatic Stress Disorder

BACKGROUND Sexual violence is an important public health problem in the United States, with 13% to 26% of women reporting a history of sexual assault. While unfortunately common, there is substantial individual variability in response to sexual assault. Approximately half of rape victims develop posttraumatic stress disorder (PTSD), while others develop no psychopathology (e.g., trauma-exposed non-PTSD). In this project, we examined the neural mechanisms underlying differences in response to sexual violence, focusing specifically on the deliberate modification of emotional responses to negative stimuli. METHODS Using functional magnetic resonance imaging (fMRI) blood oxygenation level-dependent (BOLD) response, we examined the neural circuitry underlying effortful modification of emotional responses to negative pictures in 42 women: 14 with PTSD after sexual trauma, 14 with no psychiatric diagnosis after sexual trauma, and 14 nontraumatized control subjects. RESULTS In response to deliberate attempts to downregulate emotional responses, nontraumatized healthy control subjects were more successful than either trauma-exposed group (PTSD or non-PTSD) in downregulating responses to the negative pictures as measured by subjective rating and BOLD response in regions of prefrontal cortex (PFC). In contrast, after deliberate attempts to upregulate emotional responses, regions of PFC were activated by trauma-exposed non-PTSD subjects more than by healthy control subjects or PTSD subjects. CONCLUSIONS Successful downregulation of emotional responses to negative stimuli appears to be impaired by trauma exposure. In contrast, the ability to upregulate emotional responses to negative stimuli may be a protective factor in the face of trauma exposure and associated with resilience.

A positron emission tomography [18F]deoxyglucose study of developmental stuttering.

Positron emission tomography using [18F]deoxyglucose (FDG) as a marker of regional brain metabolism was used to investigate the neural substrate of stuttering. Four patients with severe developmental stuttering were studied while reading aloud to another person (stuttering condition) and while reading aloud in unison with someone else (non-stuttering condition). The patients were also compared with four normal controls reading aloud by themselves. In the stuttering condition, significant decreases in regional glucose metabolism in Brocas area, Wernickes area and frontal pole were seen compared with themselves while not stuttering. These differences were also seen in stuttering condition compared with normal controls. Significantly lower left caudate metabolism was seen in patients during both stuttering and non-stuttering conditions compared with normal controls. A circuit for stuttering is proposed based on these findings.

Diffusion tensor imaging in schizophrenia.

BACKGROUND Alignment of white matter axons as inferred from diffusion tensor imaging has indicated changes in schizophrenia in frontal and frontotemporal white matter. METHODS Diffusion tensor anisotropy and anatomical magnetic resonance images were acquired in 64 patients with schizophrenia and 55 normal volunteers. Anatomical images were acquired with a magnetization prepared rapid gradient echo sequence, and diffusion tensor images used a pulsed gradient spin-echo acquisition. Images were aligned and warped to a standard brain, and anisotropy in normal volunteers and patients was compared using significance probability mapping. RESULTS Patients showed widespread areas of reduced anisotropy, including the frontal white matter, the corpus callosum, and the frontal longitudinal fasciculus. CONCLUSIONS These findings, which are consistent with earlier reports of frontal decreases in anisotropy, demonstrate that the effects are most prominent in frontal and callosal areas and are particularly widespread in frontal white matter regions.

Molecular imaging of macrophages in atherosclerotic plaques using bimodal PEG-micelles

Pegylated, fluorescent, and paramagnetic micelles were developed. The micelles were conjugated with macrophage scavenger receptor (MSR)‐specific antibodies. The abdominal aortas of atherosclerotic apoE‐KO mice were imaged with T1‐weighted high‐resolution MRI before and 24 h after intravenous administration of the contrast agent (CA). Pronounced signal enhancement (SE) (up to 200%) was observed for apolipoprotein E knockout (apoE‐KO) mice that were injected with MSR‐targeted micelles, while the aortic vessel wall of mice injected with nontargeted micelles showed little SE. To allow fluorescence microscopy and optical imaging of the excised aorta, the micelles were made fluorescent by incorporating either a quantum dot (QD) in the micelle corona or rhodamine lipids in the micelle. Ultraviolet (UV) illumination of the aorta allowed the identification of regions with high macrophage content, while MSR‐targeted rhodamine micelles could be detected with fluorescence microscopy and were found to be associated with macrophages. In conclusion, this study demonstrates that macrophages in apoE‐KO mice can be effectively and specifically detected by molecular MRI and optical methods upon administration of a pegylated micellar CA. Magn Reson Med 58:1164–1170, 2007.