Mentalizing in schizophrenia: A multivariate functional MRI study

Schizophrenia is associated with mentalizing deficits that impact on social functioning and quality of life. Recently, schizophrenia has been conceptualized as a disorder of neural dysconnectivity and network level analyses offers a means of understanding the underlying deficits leading to mentalizing difficulty. Using an established mentalizing task (The Triangles Task), functional magnetic resonance images (fMRI) were acquired from 19 patients with schizophrenia and 17 age- and sex-matched healthy controls (HCs). Participants were required to watch short animations of two triangles interacting with each other with the interactions either random (no interaction), physical (patterned movement), or mental (intentional movement). Task-based Partial Least Squares (PLS) was used to analyze activation differences and commonalities between the three conditions and the two groups. Seed-based PLS was used to assess functional connectivity with peaks identified in the task-based PLS. Behavioural PLS was then performed using the accuracy from the mental conditions. Patients with schizophrenia performed worse on the mentalizing condition compared to HCs. Task-based PLS revealed one significant latent variable (LV) that explained 42.9 of the variance in the task, with theLV separating the mental condition from the physical and random conditions in patients with schizophrenia, but only the mental from physical in healthy controls. The mental animations were associated with increased modulation of the inferior frontal gyri bilaterally, left superior temporal gyrus, right postcentral gyrus, and left caudate nucleus. The physical/random animations were associated with increased modulation of the right medial frontal gyrus and left superior frontal gyrus. Seed-based PLS identified increased functional connectivity with the left inferior frontal gyrus (liFG) and caudate nucleus in patients with schizophrenia, during the mental and physical interactions, with functional connectivity with the liFG associated with increased performance on the mental animations. The results suggest that mentalizing deficits in schizophrenia may arise due to inefficient social brain networks

Regional cerebral blood flow changes as a function of delta and spindle activity during slow wave sleep in humans

In the present study, we investigated changes in regional cerebral blood flow (rCBF) in humans during the progression from relaxed wakefulness through slow wave sleep (SWS). These changes were examined as a function of spindle (12-15 Hz) and delta (1.5-4.0 Hz) electroencephalographic (EEG) activity of SWS. rCBF was studied with positron emission tomography (PET) using the H215O bolus method. A maximum of six 60 sec scans were performed per subject during periods of wakefulness and stages 1-4 of SWS, as determined by on-line EEG monitoring. Spectral analysis was performed off-line on the EEG epochs corresponding to the scans for computation of activity in specific frequency bands. The relationship between EEG frequency band activity and normalized rCBF was determined by means of a voxel-by-voxel analysis of covariance. delta activity covaried negatively with rCBF most markedly in the thalamus and also in the brainstem reticular formation, cerebellum, anterior cingulate, and orbitofrontal cortex. After the effect of delta was removed, a significant negative covariation between spindle activity and the residual rCBF was evident in the medial thalamus. These negative covariations may reflect the disfacilitation and active inhibition of thalamocortical relay neurons in association with delta and spindles, as well as the neural substrates underlying the progressive attenuation of sensory awareness, motor responsiveness, and arousal that occur during SWS. delta activity covaried positively with rCBF in the visual and auditory cortex, possibly reflecting processes of dream-like mentation purported to occur during SW

Altered cortical thickness following prenatal sodium valproate exposure

Prenatal exposure to sodium valproate (VPA) is associated with neurodevelopmental impairments. Cortical thickness was measured in 16 children exposed prenatally to VPA and 16 controls. We found increased left inferior frontal gyrus (IFG; BA45) and left pericalcarine sulcus (BA18) thickness, an association between VPA dose and right IFG thickness, and a close relationship between verbal skills and left IFG thickness. A significant interaction between group and hemispheric IFG thickness showed absence of the normal asymmetry in the IFG region of VPA-exposed children. These data provide preliminary insights into the putative neural basis of difficulties experienced by some VPA-exposed children

Modeling of the hemodynamic responses in block design fMRI studies

The hemodynarnic response function (HRF) describes the local response of brain vasculature to functional activation. Accurate HRF modeling enables the investigation of cerebral blood flow regulation and improves our ability to interpret fMRI results. Block designs have been used extensively as fMRI paradigms because detection power is maximized; however, block designs are not optimal for HRF parameter estimation. Here we assessed the utility of block design fMRI data for HRF modeling. The trueness (relative deviation), precision (relative uncertainty), and identifiability (goodness-of-fit) of different HRF models were examined and test-retest reproducibility of HRF parameter estimates was assessed using computer simulations and fMRI data from 82 healthy young adult twins acquired on two occasions 3 to 4 months apart. The effects of systematically varying attributes of the block design paradigm were also examined. In our comparison of five HRF models, the model comprising the sum of two gamma functions with six free parameters had greatest parameter accuracy and identifiability. Hemodynamic response function height and time to peak were highly reproducible between studies and width was moderately reproducible but the reproducibility of onset time was low. This study established the feasibility and test-retest reliability of estimating HRF parameters using data from block design fMRI studies

Presurgical language fMRI: Clinical practices and patient outcomes in epilepsy surgical planning

The goal of this study was to document current clinical practice and report patient outcomes in presurgical language functional MRI (fMRI) for epilepsy surgery. Epilepsy surgical programs worldwide were surveyed as to the utility, implementation, and efficacy of language fMRI in the clinic; 82 programs responded. Respondents were predominantly US (61%) academic programs (85%), and evaluated adults (44%), adults and children (40%), or children only (16%). Nearly all (96%) reported using language fMRI. Surprisingly, fMRI is used to guide surgical margins (44% of programs) as well as lateralize language (100%). Sites using fMRI for localization most often use a distance margin around activation of 10mm. While considered useful, 56% of programs reported at least one instance of disagreement with other measures. Direct brain stimulation typically confirmed fMRI findings (74%) when guiding margins, but instances of unpredicted decline were reported by 17% of programs and 54% reported unexpected preservation of function. Programs reporting unexpected decline did not clearly differ from those which did not. Clinicians using fMRI to guide surgical margins do not typically map known language-critical areas beyond Broca's and Wernicke's. This initial data shows many clinical teams are confident using fMRI not only for language lateralization but also to guide surgical margins. Reported cases of unexpected language preservation when fMRI activation is resected, and cases of language decline when it is not, emphasize a critical need for further validation. Comprehensive studies comparing commonly-used fMRI paradigms to predict stimulation mapping and post-surgical language decline remain of high importance

Elemental spatial and temporal association formation in left temporal lobe epilepsy

The mesial temporal lobe (MTL) is typically understood as a memory structure in clinical settings, with the sine qua non of MTL damage in epilepsy being memory impairment. Recent models, however, understand memory as one of a number of higher cognitive functions that recruit the MTL through their reliance on more fundamental processes, such as “self-projection” or “association formation”. We examined how damage to the left MTL influences these fundamental processes through the encoding of elemental spatial and temporal associations. We used a novel fMRI task to image the encoding of simple visual stimuli, either rich or impoverished, in spatial or spatial plus temporal information. Participants included 14 typical adults (36.4 years, sd. 10.5 years) and 14 patients with left mesial temporal lobe damage as evidenced by a clinical diagnosis of left temporal lobe epilepsy (TLE) and left MTL impairment on imaging (34.3 years, sd. 6.6 years). In-scanner behavioral performance was equivalent across groups. In the typical group whole-brain analysis revealed highly significant bilateral parahippocampal activation (right > left) during spatial associative processing and left hippocampal/parahippocampal deactivation in joint spatial-temporal associative processing. In the left TLE group identical analyses indicated patients used MTL structures contralateral to the seizure focus differently and relied on extra-MTL regions to a greater extent. These results are consistent with the notion that epileptogenic MTL damage is followed by reorganization of networks underlying elemental associative processes. In addition, they provide further evidence that task-related fMRI deactivation can meaningfully index brain function. The implications of these findings for clinical and cognitive neuropsychological models of MTL function in TLE are discussed

Transcriptomic Analysis in Diabetic Nephropathy of Streptozotocin-Induced Diabetic Rats

Diabetic nephropathy (DN) is a major complication of diabetes and is caused by an imbalance in the expression of certain genes that activate or inhibit vital cellular functions of kidney. Despite several recent advances, the pathogenesis of DN remains far from clear, suggesting the need to carry out studies identifying molecular aspects, such as gene expression, that could play a key role in the development of DN. There are several techniques to analyze transcriptome in living organisms. In this study, the suppression subtractive hybridization (SSH) method was used to generate up- and down-regulated subtracted cDNA libraries in the kidney of streptozotocin (STZ)-induced diabetic rats. Northern-blot analysis was used to confirm differential expression ratios from the obtained SSH clones to identify genes related to DN. 400 unique SSH clones were randomly chosen from the two subtraction libraries (200 of each) and verified as differentially expressed. According to blast screening and functional annotation, 20.2% and 20.9% of genes were related to metabolism proteins, 9% and 3.6% to transporters and channels, 16% and 6.3% to transcription factors, 19% and 17.2% to hypothetical proteins, and finally 24.1 and 17.2% to unknown genes, from the down- and up-regulated libraries, respectively. The down- and up-regulated cDNA libraries differentially expressed in the kidney of STZ diabetic rats have been successfully constructed and some identified genes could be highly important in DN

Pathway-based expression profiling of benign prostatic hyperplasia and prostate cancer delineates an immunophilin molecule associated with cancer progression

Aberrant restoration of AR activity is linked with prostate tumor growth, therapeutic failures and development of castrate-resistant prostate cancer. Understanding the processes leading to ARreactivation should provide the foundation for novel avenues of drug discovery. A differential gene expression study was conducted using biopsies from CaP and BPH patients to identify the components putatively responsible for reinstating AR activity in CaP. From the set of genes upregulated in CaP, FKBP52, an AR co-chaperone, was selected for further analysis. Expression of FKBP52 was positively correlated with that of c-Myc. The functional cross-talk between c-Myc and FKBP52 was established using c-Myc specific-siRNA to LNCaP cells that resulted in reduction of FKBP52. A non-canonical E-box sequence housing a putative c-Myc binding site was detected on the FKBP4 promoter using in silico search. LNCaP cells transfected with the FKBP52 promoter cloned in pGL3 basic showed increased luciferase activity which declined considerably when the promoter-construct was co-transfected with c-Myc specific-siRNA. ChIP-PCR confirmed the binding of c-Myc with the conserved E-box located in the FKBP52 promoter. c-Myc downregulation concomitantly affected expression of FGF8. Since expression of FGF8 is controlled by AR, our study unveiled a novel functional axis between c-Myc, AR and FGF8 operating through FKBP52

Genes influence the amplitude and timing of brain hemodynamic responses

In functional magnetic resonance imaging (fMRI), the hemodynamic response function (HRF) reflects regulation of regional cerebral blood flow in response to neuronal activation. The HRF varies significantly between individuals. This study investigated the genetic contribution to individual variation in HRF using fMRI data from 125 monozygotic (MZ) and 149 dizygotic (DZ) twin pairs. The resemblance in amplitude, latency, and duration of the HRF in six regions in the frontal and parietal lobes was compared between MZ and DZ twin pairs. Heritability was estimated using an ACE (Additive genetic, Common environmental, and unique Environmental factors) model. The genetic influence on the temporal profile and amplitude of HRF was moderate to strong (24%-51%). The HRF may be used in the genetic analysis of diseases with a cerebrovascular etiology. (C) 2015 Elsevier Inc. All rights reserved

Dysregulated Nephrin in Diabetic Nephropathy of Type 2 Diabetes: A Cross Sectional Study

Podocyte specific proteins are dysregulated in diabetic nephropathy, though the extent of their expression loss is not identical and may be subject to different regulatory factors. Quantifying the degree of loss may help identify the most useful protein to use as an early biomarker of diabetic nephropathy.Protein expression of synaptopodin, podocin and nephrin were quantified in 15 Type 2 diabetic renal biopsies and 12 control patients. We found statistically significant downregulation of synaptopodin (P<0.0001), podocin (P = 0.0002), and nephrin (P<0.0001) in kidney biopsies of diabetic nephropathy as compared with controls. Urinary nephrin levels (nephrinuria) were then measured in 66 patients with Type 2 diabetes and 10 healthy controls by an enzyme-linked immunosorbent assay (Exocell, Philadelphia, PA). When divided into groups according to normo-, micro-, and macroalbuminuria, nephrinuria was found to be present in 100% of diabetic patients with micro- and macroalbuminuria, as well as 54% of patients with normoalbuminuria. Nephrinuria also correlated significantly with albuminuria (rho = 0.89, p<0.001), systolic blood pressure (rho = 0.32, p = 0.007), and correlated negatively with serum albumin (rho = -0.48, p<0.0001) and eGFR (rho = -0.33, p = 0.005).These data suggest that key podocyte-specific protein expressions are significantly and differentially downregulated in diabetic nephropathy. The finding that nephrinuria is observed in a majority of these normoalbuminuric patients demonstrates that it may precede microalbuminuria. If further research confirms nephrinuria to be a biomarker of pre-clinical diabetic nephropathy, it would shed light on podocyte metabolism in disease, and raise the possibility of new and earlier therapeutic targets