Unravelling the GSK3ß-related genotypic interaction network influencing hippocampal volume in recurrent major depressive disorder.

OBJECTIVE: Glycogen synthase kinase 3ß (GSK3ß) has been implicated in mood disorders. We previously reported associations between a GSK3ß polymorphism and hippocampal volume in major depressive disorder (MDD). We then reported similar associations for a subset of GSK3ß-regulated genes. We now investigate an algorithm-derived comprehensive list of genes encoding proteins that directly interact with GSK3ß to identify a genotypic network influencing hippocampal volume in MDD. PARTICIPANTS AND METHODS: We used discovery (N=141) and replication (N=77) recurrent MDD samples. Our gene list was generated from the NetworKIN database. Hippocampal measures were derived using an optimized Freesurfer protocol. We identified interacting single nucleotide polymorphisms using the machine learning algorithm Random Forest and verified interactions using likelihood ratio tests between nested linear regression models. RESULTS: The discovery sample showed multiple two-single nucleotide polymorphism interactions with hippocampal volume. The replication sample showed a replicable interaction (likelihood ratio test: P=0.0088, replication sample; P=0.017, discovery sample; Stouffer's combined P=0.0007) between genes associated previously with endoplasmic reticulum stress, calcium regulation and histone modifications. CONCLUSION: Our results provide genetic evidence supporting associations between hippocampal volume and MDD, which may reflect underlying cellular stress responses. Our study provides evidence of biological mechanisms that should be further explored in the search for disease-modifying therapeutic targets for depression.

Cortical thickness correlates of minor neurological signs in patients with first episode psychosis.

Neurological soft signs (NSS) are subtle abnormalities of motor and sensory function that are present in the absence of localized brain pathological lesions. In psychoses they have been consistently associated with a distinct pattern of cortical and subcortical brain structural alterations at the level of the heteromodal cortex and basal ganglia. However, a more specific and accurate evaluation of the cytoarchitecture of the cortical mantle could further advance our understanding of the neurobiological substrate of psychosis. We investigated the relationship between brain structure and NSS in a sample of 66 patients at their first episode of psychosis. We used the Neurological Evaluation Scale for neurological assessment and high-resolution MRI and Freesurfer to explore cortical thickness and surface area. Higher rates of NSS were associated with a reduction of cortical thickness in the precentral and postcentral gyri, inferior-parietal, superior temporal, and fusiform gyri. Higher rates of NSS were also associated with smaller surface areas of superior temporal gyrus and frontal regions (including middle frontal, superior and orbito-frontal gyri). Finally, more sensory integration signs were also associated with larger surface area of the latero-occipital region. We conclude that the presence of NSS in psychosis is associated with distinct but widespread changes in cortical thickness and surface area, in areas crucial for sensory-motor integration and for the fluid execution of movement. Studying these morphological correlates with advanced neuroimaging techniques can continue to improve our knowledge on the neurobiological substrate of these important functional correlates of psychosis.

A Quantitative Chemotherapy Genetic Interaction Map Reveals Factors Associated with PARP Inhibitor Resistance.

Chemotherapy is used to treat most cancer patients, yet our understanding of factors that dictate response and resistance to such drugs remains limited. We report the generation of a quantitative chemical-genetic interaction map in human mammary epithelial cells charting the impact of the knockdown of 625 genes related to cancer and DNA repair on sensitivity to 29 drugs, covering all classes of chemotherapy. This quantitative map is predictive of interactions maintained in other cell lines, identifies DNA-repair factors, predicts cancer cell line responses to therapy, and prioritizes synergistic drug combinations. We identify that ARID1A loss confers resistance to PARP inhibitors in cells and ovarian cancer patients and that loss of GPBP1 causes resistance to cisplatin and PARP inhibitors through the regulation of genes involved in homologous recombination. This map helps navigate patient genomic data and optimize chemotherapeutic regimens by delineating factors involved in the response to specific types of DNA damage.

Blunted neural response to implicit negative facial affect in anorexia nervosa.

BACKGROUND: People with anorexia nervosa (AN) have difficulties in a wide range of social-emotional processes. Previous work suggests atypical involvement of the prefrontal cortex (PFC), amygdala, insula, and fusiform gyri during social-emotional processing in AN. METHODS: Twenty women with AN and twenty healthy comparison (HC) women were presented with happy, fearful, and neutral faces during a functional magnetic resonance imaging study. Group differences were investigated in the following regions of interest: lateral PFC, amygdala, insula, and fusiform gyri. RESULTS: The HC participants showed significantly increased recruitment of the ventrolateral PFC and amygdala in the fearful > neutral contrast relative to the AN participants. The AN participants showed a significantly increased recruitment of a small cluster in the right posterior insula in the happy > neutral contrast. CONCLUSIONS: These findings are in line with the hypothesis that people with AN have a blunted response to negative and atypical exaggerated response to positive emotionally provoking stimuli.

FMRI Study of Neural Responses to Implicit Infant Emotion in Anorexia Nervosa.

Difficulties in social-emotional processing have been proposed to play an important role in the development and maintenance of anorexia nervosa (AN). Few studies, thus far, have investigated neural processes that underlie these difficulties, including processing emotional facial expressions. However, the majority of these studies have investigated neural responses to adult emotional display, which may be confounded by elevated sensitivity to social rank and threat in AN. Therefore, the aim of this study was to investigate the neural processes underlying implicit processing of positively and negatively valenced infant emotional display in AN. Twenty-one adult women with AN and twenty-six healthy comparison (HC) women were presented with images of positively valenced, negatively valenced, and neutral infant faces during a fMRI scan. Significant differences between the groups in positive > neutral and negative > neutral contrasts were investigated in a priori regions of interest, including the bilateral amygdala, insula, and lateral prefrontal cortex (PFC). The findings revealed that the AN participants showed relatively increased recruitment while the HC participants showed relatively reduced recruitment of the bilateral amygdala and the right dorsolateral PFC in the positive > neutral contrast. In the negative > neutral contrast, the AN group showed relatively increased recruitment of the left posterior insula while the HC groups showed relatively reduced recruitment of this region. These findings suggest that people with AN may engage in implicit prefrontal down-regulation of elevated limbic reactivity to positively social-emotional stimuli.

Functional segregation and integration within fronto-parietal networks.

Experimental data on monkeys and functional studies in humans support the existence of a complex fronto-parietal system activating for cognitive and motor tasks, which may be anatomically supported by the superior longitudinal fasciculus (SLF). Advanced tractography methods have recently allowed the separation of the three branches of the SLF but are not suitable for their functional investigation. In order to gather comprehensive information about the functional organisation of these fronto-parietal connections, we used an innovative method, which combined tractography of the SLF in the largest dataset so far (129 participants) with 14 meta-analyses of functional magnetic resonance imaging (fMRI) studies. We found that frontal and parietal functions can be clustered into a dorsal spatial/motor network associated with the SLF I, and a ventral non-spatial/motor network associated with the SLF III. Further, all the investigated functions activated a middle network mostly associated with the SLF II. Our findings suggest that dorsal and ventral fronto-parietal networks are segregated but also share regions of activation, which may support flexible response properties or conscious processing. In sum, our novel combined approach provided novel findings on the functional organisation of fronto-parietal networks, and may be successfully applied to other brain connections.

Association between Plasma Ceramides and Phosphatidylcholines and Hippocampal Brain Volume in Late Onset Alzheimer's Disease.

Lipids such as ceramides and phosphatidylcholines (PC) have been found altered in the plasma of Alzheimer's disease (AD) patients in a number of discovery studies. For this reason, the levels of 6 ceramides and 3 PCs, with different fatty acid length and saturation levels, were measured in the plasma from 412 participants (AD n = 205, Control n = 207) using mass spectrometry coupled with ultra-performance liquid chromatography. After this, associations with AD status, brain atrophy, and age-related effects were studied. In the plasma of AD participants, cross-sectional analysis revealed elevated levels of three ceramides (Cer16:0 p < 0.01, Cer18:0 p < 0.01, Cer24:1 p < 0.05). In addition, two PCs in AD plasma (PC36:5 p < 0.05, PC38:6 p < 0.05) were found to be depleted compared to the control group, with PC36:5 also associating with hippocampal atrophy (p < 0.01). Age-specific analysis further revealed that levels of Cer16:0, Cer18:0, and Cer20:0 were associated with hippocampal atrophy only in younger participants (age < 75, p < 0.05), while all 3 PCs did so in the older participants (age > 75, p < 0.05). PC36:5 was associated with AD status in the younger group (p < 0.01), while PC38:6 and 40:6 did so in the older group (p < 0.05). In this study, elevated ceramides and depleted PCs were found in the plasma from 205 AD volunteers. Our findings also suggest that dysregulation in PC and ceramide metabolism could be occurring in different stages of AD progression.

Manual Planimetry of the Medial Temporal Lobe Versus Automated Volumetry of the Hippocampus in the Diagnosis of Alzheimer's Disease.

INTRODUCTION: Though a disproportionate rate of atrophy in the medial temporal lobe (MTA) represents a reliable marker of Alzheimer's disease (AD) pathology, measurement of the MTA is not currently widely used in daily clinical practice. This is mainly because the methods available to date are sophisticated and difficult to implement in clinical practice (volumetric methods), are poorly explored (linear and planimetric methods), or lack objectivity (visual rating). Here, we aimed to compare the results of a manual planimetric measure (the yearly rate of absolute atrophy of the medial temporal lobe, 2D-yrA-MTL) with the results of an automated volumetric measure (the yearly rate of atrophy of the hippocampus, 3D-yrA-H). METHODS: A series of 1.5T MRI studies on 290 subjects in the age range of 65-85 years, including patients with AD (n = 100), mild cognitive impairment (MCI) (n = 100), and matched controls (n = 90) from the AddNeuroMed study, were examined by two independent subgroups of researchers: one in charge of volumetric measures and the other in charge of planimetric measures. RESULTS: The means of both methods were significantly different between AD and the other two diagnostic groups. In the differential diagnosis of AD against controls, 3D-yrA-H performed significantly better than 2D-yrA-MTL while differences were not statistically significant in the differential diagnosis of AD against MCI. CONCLUSION: Automated volumetry of the hippocampus is superior to manual planimetry of the MTL in the diagnosis of AD. Nevertheless, the 2D-yrAMTL is a simpler method that could be easily implemented in clinical practice when volumetry is not available.

Emotional detachment in psychopathy: Involvement of dorsal default-mode connections.

Criminal psychopathy is defined by emotional detachment [Psychopathy Checklist - Revised (PCL-R) factor 1], and antisocial behaviour (PCL-R factor 2). Previous work has associated antisocial behaviour in psychopathy with abnormalities in a ventral temporo-amygdala-orbitofrontal network. However, little is known of the neural correlates of emotional detachment. Imaging studies have indicated that the 'default-mode network' (DMN), and in particular its dorsomedial (medial prefrontal - posterior cingulate) component, contributes to affective and social processing in healthy individuals. Furthermore, recent work suggests that this network may be implicated in psychopathy. However, no research has examined the relationship between psychopathy, emotional detachment, and the white matter underpinning the DMN. We therefore used diffusion tensor imaging (DTI) tractography in 13 offenders with psychopathy and 13 non-offenders to investigate the relationship between emotional detachment and the microstructure of white matter connections within the DMN. These included the dorsal cingulum (containing the medial prefrontal - posterior cingulate connections of the DMN), and the ventral cingulum (containing the posterior cingulate - medial temporal connections of the DMN). We found that fractional anisotropy (FA) was reduced in the left dorsal cingulum in the psychopathy group (p = .024). Moreover, within this group, emotional detachment was negatively correlated with FA in this tract portion bilaterally (left: r = -.61, p = .026; right: r = -.62, p = .023). These results suggest the importance of the dorsal DMN in the emotional detachment observed in individuals with psychopathy. We propose a 'dual-network' model of white matter abnormalities in the disorder, which incorporates these with previous findings.

Probabilistic clustering and shape modelling of white matter fibre bundles using regression mixtures.

We present a novel approach for probabilistic clustering of white matter fibre pathways using curve-based regression mixture modelling techniques in 3D curve space. The clustering algorithm is based on a principled method for probabilistic modelling of a set of fibre trajectories as individual sequences of points generated from a finite mixture model consisting of multivariate polynomial regression model components. Unsupervised learning is carried out using maximum likelihood principles. Specifically, conditional mixture is used together with an EM algorithm to estimate cluster membership. The result of clustering is a probabilistic assignment of fibre trajectories to each cluster and an estimate of cluster parameters. A statistical shape model is calculated for each clustered fibre bundle using fitted parameters of the probabilistic clustering. We illustrate the potential of our clustering approach on synthetic and real data.

A longitudinal study of diffusion tensor MRI in ALS.

In this study, we investigated whether diffusion tensor MRI (DTI) could detect progressive corticospinal tract degeneration in amyotrophic lateral sclerosis (ALS) and whether changes in diffusion variables reflected clinical deterioration. Twenty-three ALS patients and 25 healthy volunteers underwent whole brain DTI. Patients and a subset (n = 12) of controls returned for a second scan. Clinical measures of disease severity were assessed in the ALS group. Changes in fractional anisotropy (FA) and mean diffusivity (MD) were measured along the corticospinal tract using a region of interest approach. Adequate DTI data were available in 11 ALS patients and 11 controls at two time points. FA and MD differed significantly between ALS patients and controls at both time points, but neither changed significantly over time, while global measures of disease severity in patients increased with time. Although we confirmed that DTI detects corticospinal tract damage in ALS, there were no significant changes in diffusion measures over time. The sensitivity of DTI may be improved by advanced data analysis techniques, although the high dropout rate suggests that use of MRI as a biomarker in ALS may be restricted to earlier stages of disease.

Comparable fMRI activity with differential behavioural performance on mental rotation and overt verbal fluency tasks in healthy men and women.

To explicate the neural correlates of sex differences in visuospatial and verbal fluency tasks, we examined behavioural performance and blood-oxygenation-level-dependent (BOLD) regional brain activity, using functional magnetic resonance imaging, during a three-dimensional (3D) mental rotation task and a compressed sequence overt verbal fluency task in a group of healthy men (n=9) and women (n=10; tested during the low-oestrogen phase of the menstrual cycle). Men outperformed women on the mental rotation task, and women outperformed men on the verbal fluency task. For the mental rotation task, men and women activated areas in the right superior parietal lobe and the bilateral middle occipital gyrus in association with the rotation condition. In addition, men activated the left middle temporal gyrus and the right angular gyrus. For verbal fluency, men activated areas in the bilateral superior frontal gyrus, right cingulate gyrus, left precentral gyrus, left medial frontal gyrus, left inferior frontal gyrus, thalamus, left parahippocampal gyrus and bilateral lingual gyrus, and women activated areas in the bilateral inferior frontal gyrus and left caudate. Despite observing task related activation in the hypothesised areas in men and women, no areas significantly differentiated the two sexes. Our results demonstrate comparable brain activation in men and women in association with mental rotation and verbal fluency function with differential performance, and provide support for sex differences in brain-behaviour relationships.

Hippocampal myo-inositol and cognitive ability in adults with Down syndrome: an in vivo proton magnetic resonance spectroscopy study.

CONTEXT: Down syndrome (DS) is the most common genetic cause of mental retardation. However, the biological determinants of this are poorly understood. The serum sodium/myo-inositol cotransporter gene is located on chromosome 21, and myo-inositol affects neuronal survival and function. Nevertheless, few in vivo studies have examined the role of myo-inositol in DS. OBJECTIVE: To determine if people with DS have significant differences in brain myo-inositol concentration from controls and if, within people with DS, this is related to cognitive ability. DESIGN: A case-control study. SETTING: Outpatient. PARTICIPANTS: The sample was composed of 38 adults with DS without dementia (age range, 18-66 years) and 42 healthy controls (age range, 19-66 years). The DS and control groups did not differ significantly in age, sex, ethnic origin, apolipoprotein E status, or handedness. MAIN OUTCOME MEASURES: Hippocampal myo-inositol concentration and cognitive performance, as measured by the Cambridge Cognitive Examination. RESULTS: Hippocampal myo-inositol concentration was significantly higher in people with DS than in controls (P = .006), and within people with DS, increased myo-inositol concentration was significantly negatively correlated with overall cognitive ability (P = .04). CONCLUSIONS: Adults with DS have a significantly increased brain concentration of myo-inositol, and this is associated with reduced cognitive ability. Future studies are required to relate myo-inositol concentration in people with DS to brain development and increased risk for developing Alzheimer disease.

Frontotemporal white matter changes in amyotrophic lateral sclerosis.

Cognitive dysfunction can occur in some patients with amyotrophic lateral sclerosis (ALS) who are not suffering from dementia. The most striking and consistent cognitive deficit has been found using tests of verbal fluency. ALS patients with verbal fluency deficits have shown functional imaging abnormalities predominantly in frontotemporal regions using positron emission tomography (PET). This study used automated volumetric voxel-based analysis of grey and white matter densities of structural magnetic resonance imaging (MRI) scans to explore the underlying pattern of structural cerebral change in nondemented ALS patients with verbal fluency deficits. Two groups of ALS patients, defined by the presence or absence of cognitive impairment on the basis of the Written Verbal Fluency Test (ALSi, cognitively impaired, n=11; ALSu, cognitively unimpaired n=12) were compared with healthy age matched controls (n=12). A comparison of the ALSi group with controls revealed significantly (p<0.002) reduced white matter volume in extensive motor and non-motor regions, including regions corresponding to frontotemporal association fibres. These patients demonstrated a corresponding cognitive profile of executive and memory dysfunction. Less extensive white matter reductions were revealed in the comparison of the ALSu and control groups in regions corresponding to frontal association fibres. White matter volumes were also found to correlate with performance on memory tests. There were no significant reductions in grey matter volume in the comparison of either patient group with controls. The structural white matter abnormalities in frontal and temporal regions revealed here may underlie the cognitive and functional imaging abnormalities previously reported in non-demented ALS patients. The results also suggest that extra-motor structural abnormalities may be present in ALS patients with no evidence of cognitive change. The findings support the hypothesis of a continuum of extra-motor cerebral and cognitive change in this disorder.

Material-specific recognition memory deficits elicited by unilateral hippocampal electrical stimulation.

Although the medial temporal lobe is thought to be critical for recognition memory (RM), the specific role of the hippocampus in RM remains uncertain. We investigated the effects of transient unilateral hippocampal electrical stimulation (ES), subthreshold for afterdischarge, on delayed item RM in epilepsy patients implanted with bilateral hippocampal depth electrodes. RM was assessed using a novel computer-controlled test paradigm in which ES to left or right hippocampus was either absent (baseline) or synchronized with item presentation. Subsequent yes-no RM performance revealed a double dissociation between material-specific RM and the lateralization of ES. Left hippocampal ES produced word RM deficits, whereas right hippocampal ES produced face RM deficits. Our findings provide the first demonstration in humans that selective unilateral stimulation-induced hippocampal disruption is sufficient to produce impairments on delayed RM tasks and provide support for the material-specific laterality of hippocampal function with respect to RM.

Functional magnetic resonance imaging of verbal fluency and confrontation naming using compressed image acquisition to permit overt responses.

Verbal fluency and confrontation naming, two tests of word retrieval, are of great utility in the field of cognitive neuroscience. However, in the context of functional magnetic resonance imaging (fMRI), movement artefact has necessitated the use of covert paradigms, which has limited clinical application. We developed two overt fMRI paradigms that allowed for performance measurement and hence were appropriate for use with patient groups. The paradigms incorporated a blocked-design and compressed-acquisition methodology where cues were presented and responses made in a "silent" period allowing for performance measurement. The slow response pace was specifically designed for older and potentially cognitively impaired participants. Verbal fluency was associated with activation in the middle frontal gyrus (Brodmann areas 46 and 9), anterior cingulate gyrus and inferior frontal gyrus (area 44 and 45). Confrontation naming activated areas of the temporo-occipital cortices (areas 18, 19, and 37) and the inferior frontal gyrus. The two paradigms successfully activated regions involved in executive and word retrieval processes and overcame the potential artefacts resulting from overt speech during image acquisition, providing useful neuropsychological tools to investigate cognitive deficits in clinical populations.