Mark S. Bolding

Assessments of Function and Biochemistry of the Anterior Cingulate Cortex in Schizophrenia

BACKGROUND Neuroimaging and electrophysiologic studies have consistently provided evidence of impairment in anterior cingulate cortex/medial frontal cortex function in people with schizophrenia. In this study, we sought to clarify the nature of this abnormality by combining proton magnetic resonance spectroscopy (1H-MRS) with functional magnetic resonance imaging (fMRI) at 3T. METHODS We used single-voxel MRS acquired in the dorsal anterior cingulate cortex and fMRI during performance of a Stroop color-naming task to investigate the neurochemistry and functional response of the anterior cingulate cortex/medial frontal cortex in 26 stable, medicated subjects with schizophrenia and 23 matched healthy control subjects. RESULTS In schizophrenia subjects, we found decreased blood oxygen level-dependent signal in the medial frontal wall, with significant clusters restricted to more dorsal regions compared with healthy subjects. In addition, we observed a trend-level decrease in N-acetylaspartate/creatine (NAA/Cr) levels and a significant positive correlation between NAA/Cr level and the blood oxygen level-dependent signal in schizophrenia subjects that did not exist in healthy subjects. Furthermore, in this group of medicated subjects, we did not find evidence of decreased glutamate + glutamine(Glx)/Cr levels, but there was a significant negative correlation between Glx/Cr levels and negative symptoms. CONCLUSIONS Our results suggest that abnormal NAA levels, which may reflect a neuronal dysfunction related to schizophrenia, affect neuronal physiology, as evidenced by reduced blood oxygen level-dependent response.

Ventral tegmental area/midbrain functional connectivity and response to antipsychotic medication in schizophrenia.

Medication management in schizophrenia is a lengthy process, as the lack of clinical response can only be confirmed after at least 4 weeks of antipsychotic treatment at a therapeutic dose. Thus, there is a clear need for the discovery of biomarkers that have the potential to accelerate the management of treatment. Using resting-state functional MRI, we examined the functional connectivity of the ventral tegmental area (VTA), the origin of the mesocorticolimbic dopamine projections, in 21 healthy controls and 21 unmedicated patients with schizophrenia at baseline (pre-treatment) and after 1 week of treatment with the antipsychotic drug risperidone (1-week post-treatment). Group-level functional connectivity maps were obtained and group differences in connectivity were assessed on the groups’ participant-level functional connectivity maps. We also examined the relationship between pre-treatment/1-week post-treatment functional connectivity and treatment response. Compared with controls, patients exhibited significantly reduced pre-treatment VTA/midbrain connectivity to multiple cortical and subcortical regions, including the dorsal anterior cingulate cortex (dACC) and thalamus. After 1 week of treatment, VTA/midbrain connectivity to bilateral regions of the thalamus was re-established. Pre-treatment VTA/midbrain connectivity strength to dACC was positively correlated with good response to a 6-week course of risperidone, whereas pre-treatment VTA/midbrain connectivity strength to the default mode network was negatively correlated. Our findings suggest that VTA/midbrain resting-state connectivity may be a useful biomarker for the prediction of treatment response.

Multimodal analysis of the hippocampus in schizophrenia using proton magnetic resonance spectroscopy and functional magnetic resonance imaging

BACKGROUND Studies have shown that individuals with schizophrenia suffer from memory impairments. In this study, we combined proton magnetic resonance spectroscopy (¹H-MRS) and functional magnetic resonance imaging (fMRI) to clarify the neurobiology of memory deficits in schizophrenia. METHODS We used single-voxel MRS acquired in the left hippocampus and fMRI during performance of a memory task to obtain measures of neurochemistry and functional response in 28 stable, medicated participants with schizophrenia (SZ) and 28 matched healthy controls (HC). RESULTS The SZ group had significantly decreased blood oxygen level-dependent (BOLD) signal in left inferior frontal gyrus (IFG) during encoding and in the anterior cingulate cortex (ACC) and superior temporal gyrus (STG) during retrieval. We did not find significant differences in N-acetylaspartate/creatine (NAA/Cr) or glutamate+glutamine (Glx/Cr) levels between the groups, but did find a significant positive correlation between NAA/Cr and Glx/Cr in the HC group that was absent in the SZ group. There were no significant correlations between BOLD and MRS measured in the hippocampus. Further analyses revealed a negative correlation between left IFG BOLD and task performance in the SZ group. Finally, in the HC group, the left IFG BOLD was positively correlated with Glx/Cr. CONCLUSIONS We replicated findings of reduced BOLD signal in left IFG and of an altered relationship between IFG BOLD response and task performance in the SZ. The absence of correlation between NAA/Cr and Glx/Cr levels in patients might suggest underlying pathologies of the glutamate-glutamine cycle and/or mitochondria.

Antipsychotic Drugs Alter Functional Connectivity between the Medial Frontal Cortex, Hippocampus, and Nucleus Accumbens as Measured by H215O PET.

To evaluate changes in functional connectivity as a result of treatment with antipsychotic drugs (APDs) in subjects with schizophrenia (SZ), we identified a limited number of regions that have been implicated in the mechanism of action of APDs and that are part of a neuronal network known to be modulated by dopamine (DA). These regions consisted of the nucleus accumbens (NAcc), the hippocampus (Hip), and the medial frontal cortex (MFC). SZ participants were blindly randomized into a haloperidol treatment group (n = 12) and an olanzapine treatment group (n = 17). Using PET with 15O, we evaluated changes in functional connectivity between these regions during rest and task performance at three treatment time points: (1) at baseline, after withdrawal of all psychotropic medication (2 weeks), (2) after 1 week on medication, and (3) after 6 weeks on medication. Results from the two treatment groups were combined during analysis to investigate the common effects of APDs on functional connectivity. We found that the functional connectivity between MFC and NAcc significantly increased at week one, and then significantly decreased from week one to week 6. The functional connectivity between MFC and Hip significantly decreased at week one and week 6 relative to baseline. Critically, the strength of the functional connectivity between the MFC and Hip after 1 week of treatment was predictive of treatment response. This pattern of changes may represent an important biomarker for indexing treatment response. The regulation by APDs of the balance between prefrontal and limbic inputs to the striatum may be crucial to restoring adaptive behavior.

Association Between Expiratory Central Airway Collapse and Respiratory Outcomes Among Smokers

IMPORTANCE Central airway collapse greater than 50% of luminal area during exhalation (expiratory central airway collapse [ECAC]) is associated with cigarette smoking and chronic obstructive pulmonary disease (COPD). However, its prevalence and clinical significance are unknown. OBJECTIVE To determine whether ECAC is associated with respiratory morbidity in smokers independent of underlying lung disease. DESIGN, SETTING, AND PARTICIPANTS Analysis of paired inspiratory-expiratory computed tomography images from a large multicenter study (COPDGene) of current and former smokers from 21 clinical centers across the United States. Participants were enrolled from January 2008 to June 2011 and followed up longitudinally until October 2014. Images were initially screened using a quantitative method to detect at least a 30% reduction in minor axis tracheal diameter from inspiration to end-expiration. From this sample of screen-positive scans, cross-sectional area of the trachea was measured manually at 3 predetermined levels (aortic arch, carina, and bronchus intermedius) to confirm ECAC (>50% reduction in cross-sectional area). EXPOSURES Expiratory central airway collapse. MAIN OUTCOMES AND MEASURES The primary outcome was baseline respiratory quality of life (St Georges Respiratory Questionnaire [SGRQ] scale 0 to 100; 100 represents worst health status; minimum clinically important difference [MCID], 4 units). Secondary outcomes were baseline measures of dyspnea (modified Medical Research Council [mMRC] scale 0 to 4; 4 represents worse dyspnea; MCID, 0.7 units), baseline 6-minute walk distance (MCID, 30 m), and exacerbation frequency (events per 100 person-years) on longitudinal follow-up. RESULTS The study included 8820 participants with and without COPD (mean age, 59.7 [SD, 6.9] years; 4667 [56.7%] men; 4559 [51.7%] active smokers). The prevalence of ECAC was 5% (443 cases). Patients with ECAC compared with those without ECAC had worse SGRQ scores (30.9 vs 26.5 units; P < .001; absolute difference, 4.4 [95% CI, 2.2-6.6]) and mMRC scale scores (median, 2 [interquartile range [IQR], 0-3]) vs 1 [IQR, 0-3]; P < .001]), but no significant difference in 6-minute walk distance (399 vs 417 m; absolute difference, 18 m [95% CI, 6-30]; P = .30), after adjustment for age, sex, race, body mass index, forced expiratory volume in the first second, pack-years of smoking, and emphysema. On follow-up (median, 4.3 [IQR, 3.2-4.9] years), participants with ECAC had increased frequency of total exacerbations (58 vs 35 events per 100 person-years; incidence rate ratio [IRR], 1.49 [95% CI, 1.29-1.72]; P < .001) and severe exacerbations requiring hospitalization (17 vs 10 events per 100 person-years; IRR, 1.83 [95% CI, 1.51-2.21]; P < .001). CONCLUSIONS AND RELEVANCE In a cross-sectional analysis of current and former smokers, the presence of ECAC was associated with worse respiratory quality of life. Further studies are needed to assess long-term associations with clinical outcomes.

Magnetic Transfer Contrast Accurately Localizes Substantia Nigra Confirmed by Histology

BACKGROUND Magnetic resonance imaging (MRI) has multiple contrast mechanisms. Like various staining techniques in histology, each contrast type reveals different information about the structure of the brain. However, it is not always clear how structures visible in MRI correspond to structures previously identified by histology. The purpose of this study was to determine if magnetic transfer contrast (MTC) or T2 contrast MRI was better at delineating the substantia nigra (SN). METHODS MRI scans were acquired in vivo from two nonhuman primates (NHPs). The NHPs were subsequently euthanized, perfused, and their brains sectioned for histologic analyses. Each slice was photographed before sectioning. Each brain was sectioned into approximately 500 sections, 40 μm each, encompassing most of the cortex, midbrain, and dorsal parts of the hindbrain. Levels corresponding to anatomic MRI images were selected. From these, adjacent sections were stained using Kluver-Barrera (myelin and cell bodies) or tyrosine hydroxylase (dopaminergic neurons) immunohistochemistry. The resulting images were coregistered to the block-face images using a moving least squares algorithm with similarity transformations. MR images were similarly coregistered to the block-face images, allowing the structures on MRI to be identified with structures on the histologic images. RESULTS We found that hyperintense (light) areas in MTC images were coextensive with the SN as delineated histologically. The hypointense (dark) areas in T2-weighted images were not coextensive with the SN but extended partially into the SN and partially into the cerebral peduncles. CONCLUSIONS MTC is more accurate than T2-weighting for localizing the SN in vivo.

Basal ganglia volume in unmedicated patients with schizophrenia is associated with treatment response to antipsychotic medication.

We investigated the relationship between basal ganglia volume and treatment response to the atypical antipsychotic medication risperidone in unmedicated patients with schizophrenia. Basal ganglia volumes included the bilateral caudate, putamen, and pallidum and were measured using the Freesurfer automated segmentation pipeline in 23 subjects. Also, baseline symptom severity, duration of illness, age, gender, time off medication, and exposure to previous antipsychotic were measured. Treatment response was significantly correlated with all three regions of the bilateral basal ganglia (caudate, putamen, and pallidum), baseline symptom severity, duration of illness, and age but not gender, time off antipsychotic medication, or exposure to previous antipsychotic medication. The caudate volume was the basal ganglia region that demonstrated the strongest correlation with treatment response and was significantly negatively correlated with patient age. Caudate volume was not significantly correlated with any other measure. We demonstrated a novel finding that the caudate volume explains a significant amount of the variance in treatment response over the course of 6 weeks of risperidone pharmacotherapy even when controlling for baseline symptom severity and duration of illness.

Smaller regional gray matter volume in homeless african american cocaine-dependent men: a preliminary report.

Models of addiction include abnormalities in parts of the brain involving executive function/inhibitory control. Although previous studies have reported evidence of structural abnormalities in cocaine-dependent individuals, none have specifically targeted the homeless. The present preliminary study investigated brain structure in such an understudied group, homeless, crack-cocaine-dependent African American men (n = 9), comparing it to that in healthy controls (n = 8). Structural data were analyzed using voxel based morphometry (VBM) and a regions of interest (ROI) analysis. Homeless cocaine-dependent individuals had smaller gray matter volume in dorsolateral prefrontal cortex, anterior cingulate, the cerebellum, insula, and superior temporal gyrus. Most of these areas subserve executive function or inhibitory control. These results are similar to those found in most previous studies of non-homeless cocaine-dependent individuals. Reduced gray matter in executive function/inhibitory control regions of the brain in cocaine-dependent individuals may be a preexisting risk factor for the development of addiction and/or a consequence of drug abuse.

Shape-dependent cellular behaviors and relaxivity of iron oxide-based T1 MRI contrast agents

Recent research efforts about iron oxide nanoparticles has focused on the development of iron oxide-based T1 contrast agents for magnetic resonance imaging (MRI), such as ultrasmall iron oxide nanospheres (USNPs <4 nm) and ultrathin nanowires (NW, diameter <4 nm). In this paper, we report the cellular uptake behaviors of these two types of ultrasmall scale nanostructures on HepG2 cells. Both these two nanostructures were functionalized with tannic acid and their physical and chemical properties were carefully analyzed before cellular tests. Both USNPs and NWs exhibited strong paramagnetic signals, a property suitable for T1 MRI contrast agents. The distinct shapes also caused much difference in their cellular uptake behaviors. Specifically, the uptake of USNPs was five times higher than that of NWs after 72 hours incubation. The shape-dependent cellular uptake can potentially lead to different blood circulation times, and subsequently different applications of these two types of ultrasmall nanostructures.

Examination of value of the future and health beliefs to explain dietary and physical activity behaviors

BACKGROUND Studies have shown a negative association between value of the future (preference for long-term vs. short-term rewards) and harmful addictive behaviors; however, research in the area of preventive behaviors is limited and has shown conflicting results. OBJECTIVES The primary objectives were: (1) to examine the association among value of the future and diet and physical activity (PA) behaviors, and (2) to assess whether value of the future explained additional variance in behaviors after controlling for theory-based health beliefs related to coronary heart disease (CHD). METHODS An online survey was conducted in adults (N = 172) with no prior history of CHD. A delay discounting task was administered to measure value of the future. Questionnaire items were based on the Health Belief Model (HBM) and included CHD knowledge, perceived risk, perceived severity, perceived benefits of and barriers to behavior change, self-efficacy, cues to action, diet and PA behaviors and demographic variables. RESULTS High value of the future was associated with younger age, lower BMI, more healthful diet, and increased PA. After controlling for HBM components and demographics, value of the future did not explain any additional variance in diet or PA behaviors. Significant predictors of healthful diet included female gender (P = .013), increased age (P = .029), greater than high school education (P = .023), greater diet-related self-efficacy (P = .021), and not having received a healthcare provider recommendation to improve diet (P = .018). Significant predictors of PA level included income between