Brandon Whitcher

Single-dose serotonergic stimulation shows widespread effects on functional brain connectivity

The serotonergic system is widely distributed throughout the central nervous system. It is well known as a mood regulating system, although it also contributes to many other functions. With resting state functional magnetic resonance imaging (RS-fMRI) it is possible to investigate whole brain functional connectivity. We used this non-invasive neuroimaging technique to measure acute pharmacological effects of the selective serotonin reuptake inhibitor sertraline (75 mg) in 12 healthy volunteers. In this randomized, double blind, placebo-controlled, crossover study, RS-fMRI scans were repeatedly acquired during both visits (at baseline and 3, 5, 7 and 9h after administering sertraline or placebo). Within-group comparisons of voxelwise functional connectivity with ten functional networks were examined (p<0.005, corrected) using a mixed effects model with cerebrospinal fluid, white matter, motion parameters, heart rate and respiration as covariates. Sertraline induced widespread effects on functional connectivity with multiple networks; the default mode network, the executive control network, visual networks, the sensorimotor network and the auditory network. A common factor among these networks was the involvement of the precuneus and posterior cingulate cortex. Cognitive and subjective measures were taken as well, but yielded no significant treatment effects, emphasizing the sensitivity of RS-fMRI to pharmacological challenges. The results are consistent with the existence of an extensive serotonergic system relating to multiple brain functions with a possible key role for the precuneus and cingulate.

Balanced translocation linked to psychiatric disorder, glutamate, and cortical structure/function

Rare genetic variants of large effect can help elucidate the pathophysiology of brain disorders. Here we expand the clinical and genetic analyses of a family with a (1;11)(q42;q14.3) translocation multiply affected by major psychiatric illness and test the effect of the translocation on the structure and function of prefrontal, and temporal brain regions. The translocation showed significant linkage (LOD score 6.1) with a clinical phenotype that included schizophrenia, schizoaffective disorder, bipolar disorder, and recurrent major depressive disorder. Translocation carriers showed reduced cortical thickness in the left temporal lobe, which correlated with general psychopathology and positive psychotic symptom severity. They showed reduced gyrification in prefrontal cortex, which correlated with general psychopathology severity. Translocation carriers also showed significantly increased activation in the caudate nucleus on increasing verbal working memory load, as well as statistically significant reductions in the right dorsolateral prefrontal cortex glutamate concentrations. These findings confirm that the t(1;11) translocation is associated with a significantly increased risk of major psychiatric disorder and suggest a general vulnerability to psychopathology through altered cortical structure and function, and decreased glutamate levels.

Effects of a Balanced Translocation between Chromosomes 1 and 11 Disrupting the DISC1 Locus on White Matter Integrity.

Objective Individuals carrying rare, but biologically informative genetic variants provide a unique opportunity to model major mental illness and inform understanding of disease mechanisms. The rarity of such variations means that their study involves small group numbers, however they are amongst the strongest known genetic risk factors for major mental illness and are likely to have large neural effects. DISC1 (Disrupted in Schizophrenia 1) is a gene containing one such risk variant, identified in a single Scottish family through its disruption by a balanced translocation of chromosomes 1 and 11; t(1;11) (q42.1;q14.3). Method Within the original pedigree, we examined the effects of the t(1;11) translocation on white matter integrity, measured by fractional anisotropy (FA). This included family members with (n = 7) and without (n = 13) the translocation, along with a clinical control sample of patients with psychosis (n = 34), and a group of healthy controls (n = 33). Results We report decreased white matter integrity in five clusters in the genu of the corpus callosum, the right inferior fronto-occipital fasciculus, acoustic radiation and fornix. Analysis of the mixed psychosis group also demonstrated decreased white matter integrity in the above regions. FA values within the corpus callosum correlated significantly with positive psychotic symptom severity. Conclusions We demonstrate that the t(1;11) translocation is associated with reduced white matter integrity in frontal commissural and association fibre tracts. These findings overlap with those shown in affected patients with psychosis and in DISC1 animal models and highlight the value of rare but biologically informative mutations in modeling psychosis.

The cortical thickness phenotype of individuals with DISC1 translocation resembles schizophrenia

BACKGROUND. The disrupted in schizophrenia 1 (DISC1) gene locus was originally identified in a Scottish pedigree with a high incidence of psychiatric disorders that is associated with a balanced t(1;11)(q42.1;q14.3) chromosomal translocation. Here, we investigated whether members of this family carrying the t(1;11)(q42.1;q14.3) translocation have a common brain-related phenotype and whether this phenotype is similar to that observed in schizophrenia (SCZ), using multivariate pattern recognition techniques. METHODS. We measured cortical thickness, cortical surface area, subcortical volumes, and regional cerebral blood flow (rCBF) in healthy controls (HC) (n = 24), patients diagnosed with SCZ (n = 24), patients diagnosed with bipolar disorder (BP) (n = 19), and members of the original Scottish family (n = 30) who were either carriers (T+) or noncarriers (T–) of the DISC1 translocation. Binary classification models were developed to assess the differences and similarities across groups. RESULTS. Based on cortical thickness, 72% of the T– group were assigned to the HC group, 83% of the T+ group were assigned to the SCZ group, and 45% of the BP group were classified as belonging to the SCZ group, suggesting high specificity of this measurement in predicting brain-related phenotypes. Shared brain-related phenotypes between SCZ and T+ individuals were found for cortical thickness only. Finally, a classification accuracy of 73% was achieved when directly comparing the pattern of cortical thickness of T+ and T– individuals. CONCLUSION. Together, the results of this study suggest that the DISC1 translocation may increase the risk of psychiatric disorders in this pedigree by affecting neurostructural phenotypes such as cortical thickness. FUNDING. This work was supported by the National Health Service Research Scotland, the Scottish Translational Medicine Research Collaboration, the Innovative Medicines Initiative (IMI), the Engineering and Physical Sciences Research Council (EPSRC), The Wellcome Trust, the National Institute of Health Research (NIHR), and Pfizer.

Verbal working memory and functional large-scale networks in schizophrenia

The aim of this study was to test whether bilinear and nonlinear effective connectivity (EC) measures of working memory fMRI data can differentiate between patients with schizophrenia (SZ) and healthy controls (HC). We applied bilinear and nonlinear Dynamic Causal Modeling (DCM) for the analysis of verbal working memory in 16 SZ and 21 HC. The connection strengths with nonlinear modulation between the dorsolateral prefrontal cortex (DLPFC) and the ventral tegmental area/substantia nigra (VTA/SN) were evaluated. We used Bayesian Model Selection at the group and family levels to compare the optimal bilinear and nonlinear models. Bayesian Model Averaging was used to assess the connection strengths with nonlinear modulation. The DCM analyses revealed that SZ and HC used different bilinear networks despite comparable behavioral performance. In addition, the connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area showed differences between SZ and HC. The adoption of different functional networks in SZ and HC indicated neurobiological alterations underlying working memory performance, including different connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area. These novel findings may increase our understanding of connectivity in working memory in schizophrenia.

S20 18f-fluorodeoxyglucose (18fdg) Pet Pulmonary Imaging: Comparative Methodology In Copd Patients

Introduction 18FDG PET/CT imaging may be a useful tool to study COPD and lung inflammation; however the optimal protocol for this imaging biomarker has yet to be established. Method We aimed to develop a combined 18FDG-PET/CT imaging protocol optimised to quantify lung inflammation. Six patients with moderate-to-severe COPD underwent dynamic 18FDG-PET imaging combined with blood sampling (both arterial and venous over 60 min) to determine the localised plasma activity time curve. High resolution CT (HRCT) was utilised to segmentate the lung and determine areas of emphysema. 3 sets of comparative input functions were analysed (arterial, venous and image derived arterial input functions). 18FDG kinetics was fitted using the Patlak method. Results Similar results were obtained using time activity curves from all three input functions. The arterial input was always found to be slightly higher than the others (Figure 1). Patlak analysis of the time-activity curves for each of the CT derived lung lobes allowed generation of images of slope (influx constant Ki) and intercept (initial volume of distribution) (Figure 1). The acquisition of HRCT co-registered to FDG-PET allows more accurate demarcation and quantification of FDG in emphysematous areas of the lung. Attempt to improve the signal by excluding voxels without COPD tissue (-935 to -300 HU) has been undertaken as well. The reproducibility of this technique is currently being studied where 20 patients are being scanned twice 4 weeks apart and compared to a baseline scan from 5 healthy controls. Abstract S20 Figure 1 Shows an example of time activity curves from arterial, venous and image derived techniques (on left) and (on right) a Patlak image from venous plasma slope (1st row), intercept (2nd row) and CT (3rd row) Conclusion 18FDG PET/CT imaging has the potential to be a non-invasive biomarker of lung inflammation in COPD.

Measuring the Impact Intradaily Events Have on the Persistent Nature of Volatility

In this chapter we measure the effect a scheduled event, like the opening or closing of a regional foreign exchange market, or a unscheduled act, such as a market crash, a political upheaval, or a surprise news announcement, has on the foreign exchange rate’s level of volatility and its well documented long-memory behavior. Volatility in the foreign exchange rate is modeled as a non-stationary, long-memory, stochastic volatility process whose fractional differencing parameter is allowed to vary over time. This non-stationary model of volatility reveals that long-memory is not a spurious property associated with infrequent structural changes, but is a integral part of the volatility process. Over most of the sample period, volatility exhibits the strong persistence of a long-memory process. It is only after a market surprise or unanticipated economic news announcement that volatility briefly sheds its strong persistence.