Nadine D. Wolf

Default-mode network changes in preclinical Huntington's disease

The default-mode network (DMN) refers to as a set of brain regions which are active when the brain does not engage in a cognitive task and which are deactivated with task-related cognitive effort. Altered function of the DMN has been associated with a decline of cognition in several neurodegenerative diseases and related at-risk conditions. In Huntingtons disease, an autosomal dominant inherited neurodegenerative disorder, several studies so far have shown abnormal task-related brain activation patterns even in preclinical carriers of the Huntingtons disease gene mutation (preHD). To date, however, the functional integrity of the DMN has not been addressed in this population. The aim of this study was to study the functional connectivity of the DMN in 18 preHD and 18 healthy controls who underwent functional magnetic resonance imaging during an attention task. A group independent component analysis identified spatiotemporally distinct patterns of two DMN subsystems. The spatial distribution of these components in preHD was similar to controls. However, preHD showed lower subsystem-specific connectivity in the anterior medial prefrontal cortex, the left inferior parietal and the posterior cingulate cortex (p<0.05, cluster-corrected). Connectivity between the two DMN subsystems was increased in preHD compared to controls. In preHD individuals lower functional connectivity of the left inferior parietal cortex was associated with shorter reaction times in the attention task. This suggests that some functionally critical regions of the DMN may have to remain active to maintain or optimise cognitive performance in preHD.

Magnetic resonance perfusion imaging of resting-state cerebral blood flow in preclinical Huntington's disease

Magnetic resonance imaging (MRI) of the brain could be a powerful tool for discovering early biomarkers in clinically presymptomatic carriers of the Huntingtons disease gene mutation (preHD). The aim of this study was to investigate the sensitivity of resting-state perfusion MRI in preHD and to identify neural changes, which could serve as biomarkers for future clinical trials. Differences in regional cerebral blood flow (rCBF) in 18 preHD and 18 controls were assessed with a novel MRI method based on perfusion images obtained with continuous arterial spin labeling. High-resolution structural data were collected to test for changes of brain volume. Compared with controls, preHD individuals showed decreased rCBF in medial and lateral prefrontal regions and increased rCBF in the precuneus. PreHD near to symptom onset additionally showed decreased rCBF in the putamen and increased rCBF in the hippocampus. Network analyses revealed an abnormal lateral prefrontal pattern in preHD far and near to motor onset. These data suggest early changes of frontostriatal baseline perfusion in preHD independent of substantial reductions of gray matter volume. This study also shows the feasibility of detecting neural changes in preHD with a robust MRI technique that would be suitable for longitudinal multisite application.

Longitudinal functional magnetic resonance imaging of cognition in preclinical Huntington's disease.

Neuropsychological and functional neuroimaging studies have revealed early changes of cognition and brain function in individuals with the Huntingtons disease (HD) gene mutation who are presymptomatic for the motor symptoms of the disease (preHD). However, little is known about whether changes of neural function progress over time. In this study, we used neuropsychological tests of attention, working memory and executive function, functional magnetic resonance imaging and voxel-based analyses of high-resolution structural data to explore the temporal dynamics of potential cognitive, functional and structural biomarkers in far from onset preHD (n=13, mean time to the estimated motor symptom onset=19.5 years) and healthy controls (n=13) followed over a 2-year period. Behavioral measures were similar in preHD individuals and controls at baseline and remained normal 2 years later. At both time points, the left dorsolateral prefrontal cortex was less active in preHD than in controls during working memory performance. The left dorsolateral prefrontal cortex did not exhibit further loss of activity over time. Regions showing less gray matter volume in preHD at baseline did not show further volume loss over time. These data indicate that the activity in brain regions contributing to working memory processing differs consistently in HD expansion mutation carriers while cognitive performance remains normal. However, the present data do not support the notion of a progressive decline of left prefrontal cortex activity in far from onset preHD followed over a 2-year period.

Brain activation and functional connectivity in premanifest Huntington's disease during states of intrinsic and phasic alertness

Previous functional neuroimaging studies have shown brain activation abnormalities in clinically presymptomatic carriers of the Huntingtons disease (preHD) gene mutation when performing complex cognitive tasks. However, little is known about the neural correlates of attentional processes in preHD. In this study, we used functional magnetic resonance imaging to investigate basic aspects of attentional processing in preHD individuals (n = 18) compared to healthy participants (n = 18) during an alertness task. Uni‐ and multivariate statistical techniques were used to assess task‐related regional brain activation and functional network connectivity. Compared to healthy controls, preHD individuals near to the estimated onset of clinical signs showed lower activation of right frontostriatal regions during phasic alertness (P < 0.001, uncorrected). Decreased striatal activation in this preHD subgroup was also evident when compared with those preHD individuals far from the estimated onset of HD signs. Lower putaminal activity was associated with longer reaction times and with proximity to onset. In addition, preHD participants near to onset had lower functional connectivity of motor regions when compared with controls and preHD individuals far from onset. Our data suggest that while alertness‐related performance remains normal, the underlying frontostriatal activity and motor cortex connectivity decline only when approaching the onset of unequivocal signs of HD. However, these attentional network changes might not be the sole explanation for the differences in cognitive task performance previously observed in preHD. Hum Brain Mapp 33:2161–2173, 2012.

Motor dysfunction within the schizophrenia-spectrum: A dimensional step towards an underappreciated domain

At the beginning of the 20th century, genuine motor abnormalities (GMA) were considered to be intricately linked to schizophrenia. Subsequently, however, GMA have been increasingly regarded as unspecific transdiagnostic phenomena or related to side effects of antipsychotic treatment. Despite possible medication confounds, within the schizophrenia spectrum GMA have been categorized into three broad categories, i.e. neurological soft signs, abnormal involuntary movements and catatonia. Schizophrenia patients show a substantial overlap across a broad range of distinct motor signs and symptoms suggesting a prominent involvement of the motor system in disease pathophysiology. There have been several attempts to increase reliability and validity in diagnosing schizophrenia based on behavior and neurobiology, yet relatively little attention has been paid to the motor domain in the past. Nevertheless, accumulating neuroscientific evidence suggests the possibility of a motor endophenotype in schizophrenia, and that GMA could represent a specific dimension within the schizophrenia-spectrum. Here, we review current neuroimaging research on GMA in schizophrenia with an emphasis on distinct and common mechanisms of brain dysfunction. Based on a dimensional approach we show that multimodal neuroimaging combined with fine-grained clinical examination can result in a comprehensive characterization of structural and functional brain changes that are presumed to underlie core GMA in schizophrenia. We discuss the possibility of a distinct motor domain, together with its implications for future research. Investigating GMA by means of multimodal neuroimaging can essentially contribute at identifying novel and biologically reliable phenotypes in psychiatry.

Specificity of abnormal brain volume in major depressive disorder: A comparison with borderline personality disorder

BACKGROUND Abnormal brain volume has been frequently demonstrated in major depressive disorder (MDD). It is unclear if these findings are specific for MDD since aberrant brain structure is also present in disorders with depressive comorbidity and affective dysregulation, such as borderline personality disorder (BPD). In this transdiagnostic study, we aimed to investigate if regional brain volume loss differentiates between MDD and BPD. Further, we tested for associations between brain volume and clinical variables within and between diagnostic groups. METHODS 22 Females with a DSM-IV diagnosis of MDD, 17 females with a DSM-IV diagnosis of BPD and without comorbid posttraumatic stress disorder, and 22 age-matched female healthy controls (HC) were investigated using magnetic resonance imaging. High-resolution structural data were analyzed using voxel-based morphometry. RESULTS A significant (p<0.05, cluster-corrected) volume decrease of the anterior cingulate cortex (ACC) was found in MDD compared to HC, as opposed to volume decreases of the amygdala in BPD compared to both HC and MDD. Sensitivity and specificity of regional gray matter volume for a diagnosis of MDD were modest to fair. Amygdala volume was related to depressive symptoms across the entire patient sample. LIMITATIONS Potential limitations of this study include the modest sample size and the heterogeneous psychotropic drug treatment. CONCLUSIONS ACC volume reduction is more pronounced in MDD with an intermediate degree of volume loss in BPD compared to HC. In contrast, amygdala volume loss is more pronounced in BPD compared to MDD, yet amygdala volume is associated with affective symptom expression in both disorders.

Brain Structure in Preclinical Huntington's Disease: A Multi-Method Approach

Background: Structural magnetic resonance imaging (MRI) of the brain could be a powerful tool for discovering early biomarkers in clinically presymptomatic carriers of the Huntingtons disease gene mutation (preHD). So far, structural changes have been found mainly in preHD approaching the estimated motor onset of the disease (i.e. less than 15 years from onset), whereas structural findings in preHD far from the estimated motor onset have been inconclusive. Objectives: The aims of this study were to investigate the sensitivity of different methodological approaches to structural data in far-from-onset preHD (mean estimated time to motor onset = 21.4 years) and to explore the relationship between brain structure, clinical variables and cognition. Methods: High-resolution MRI data at 3 T were obtained from 20 preHD individuals and 20 healthy participants and subsequently analyzed using voxel-based morphometry (VBM), cortical surface modeling and subcortical segmentation analysis techniques. Results: VBM analyses did not reveal significant between-group differences, whereas cortical surface modeling and subcortical segmentation analyses showed significant regional cortical thinning and striatal changes in preHD compared to controls. Significant correlations were found between striatal structure, estimated time to motor onset and executive performance, whereas cortical changes were not significantly correlated with these parameters. Conclusion: These data suggest that a combined methodological approach to structural MRI data could increase the sensitivity for detecting subtle neurobiological changes in early preHD. As consistently shown across different methods, the association between striatal structure and clinical measures supports the notion that changes in striatal volume could represent a more robust marker of disease progression than cortical changes.

Magnetic resonance perfusion imaging of auditory verbal hallucinations in patients with schizophrenia

Auditory verbal hallucinations (AVH) are a core symptom of schizophrenia and related spectrum-disorders. So far, magnetic resonance imaging (MRI) has been employed to study the functional neuroanatomy of AVH using two distinct methods, either by capturing symptoms during the actively hallucinating state or by investigating neural responses during explicit cognitive processing (Allen et al. 2008; Hugdahl 2009). Both approaches, however, face certain limitations. For instance, the self-identification of AVH is accompanied by the cognitive and motor response associated with this event, together with increased self-awareness. This interaction might change the participants subjective experience and quality of the hallucinatory symptom. On the other hand, interactions between experimental stimuli and symptoms could drive activation patterns that may not represent the “pure” neural substrate of AVH. In this study, we investigated the neural correlates at rest of AVH in schizophrenia using an MRI-based technique of perfusion imaging using continuous arterial spin labelling [CASL] (Theberge 2008). The objectives of our study were threefold: first, we tested the hypothesis that patients with schizophrenia with treatment-refractory AVH would exhibit symptom-related perfusion changes within a speech-related network, as predicted by AVHmodels of dysfunctional speech generation and misattribution (Stephane et al. 2001; Allen et al. 2008). Second, we investigated the symptom-specificity of brain perfusion abnormalities in AVH patients by including a group of non-hallucinating schizophrenic patients. Third, we explored the relationship between regional cerebral blood flow (rCBF) and multiple dimensions of AVH, as assessed by symptom-specific psychometrics. We studied 20 medicated patients with schizophrenia (paranoid subtype according to DSM-IV); see Supplementary material for details on inclusion/exclusion criteria, medication and psychometric scores. Patients with AVH (n=10; 4 female; mean age=36.5 years) were classified as being medication resistant for AVH, as defined by persistent symptoms in the presence of at least two clinically ineffective drug trials (each>6 weeks of treatment) with different antipsychotics at adequate dosage. Further, patients with AVH were only included if they did not show pronounced formal thought disorder symptoms and if they had sufficient insight into their hallucinatory experience such as to provide self-reports about their symptoms. A second group of patients with schizophrenia consisted of 10 participants (2 female; mean age=32.1 years) who either never experienced AVH or who experienced AVH in the past, while being fully remitted from AVH at least 12 months before being included in the study. The healthy control group consisted of 14 participants (7 female; mean age=33.7 years) matched for age, education and handedness. The project was approved by the local research ethics committee. All experimental procedures were carried out with the understanding and written consent of the participants. Imaging was performed on a 3T Magnetom Allegra (Siemens, Germany) MRI system. Scanning was performed under resting-state conditions; see also the Supplementary material for a detailed description of the technical details. Preprocessing and analyses of an MRI perfusion block of approximately 5 min were performed using Statistical Parametric Mapping (SPM5) in combination with software implemented in MATLAB 7.3 for use as a toolbox under SPM5; see also the Supplementary material for a detailed description of the data analysis. For the individual (first level) analysis, mean rCBF images were computed for each participant. Group comparisons between controls and patients were conducted at the second level using an analysis of variance. A threshold of pb0.005 (uncorrected at the voxel level) and a cluster-size threshold of at least 50 contiguous voxel was chosen for all between-group comparisons. Furthermore, correlations (FDR adjusted pb0.0259) were calculated using psychometric data and rCBF values extracted from clusters showing significant between-group differences. Compared to controls, AVH patients had increased rCBF in the left inferior frontal gyrus (IFG), the left anterior cingulate cortex (ACC), the supplementary motor area (SMA), in a cluster including the left middle temporal gyrus (MTG) and superior temporal gyrus (STG), the left insula, the right MTG and the right supramarginal gyrus (SMG), extending to the right temporoparietal cortex (TPC); see Fig. 1 and Supplementary material Fig. 2, and Table 2. Compared to patients without AVH, the group of hallucinating patients exhibited significantly increased rCBF in the left STG and right SMG, extending to the right TPC (Fig. 1 and Table 2, Supplementary material). Compared to healthy participants, patients without AVH showed increased rCBF in the left MTG, left STG, left SMG and in the left insula. Patients with AVH demonstrated positive correlations between rCBF and overall AVH severity (asmeasured by the auditory hallucinations scale [AHS] of the Psychotic Symptoms Rating Scales [PsyRatS]) in the left STG, ACC and IFG (Fig. 2, Supplementary material). Different correlation patterns emerged when correlating rCBF values with scores from the PsyRatSAHS emotional, physical and cognitive subscales (see Supplementary material Fig. 3). The comparison of patients with persistent AVH against controls yielded results that support the notion of dysfunctional neural activity in brain regions associated with the generation, perception and monitoring of speech as a the central mechanism underlying AVH (McGuire et al. 1995; Stephane et al. 2006; Hugdahl 2009). Increased rCBF in non-hallucinating patients was detected in the left MTG, left STG, left SMG and left insula when compared to controls. This pattern may reflect a common neurophysiological abnormality in both groups irrespective of the presence or absence of AVH (Mechelli et al. 2007). When contrasting hallucinating against non-hallucinating patients, patients with AVH still demonstrated increased rCBF in the left STG and the right SMG/TPC, indicating two critical network nodes associated with AVH, in the presence of an otherwise comparable clinical diagnosis. This suggests that the left STG may lie at the core of a final common pathway which ultimately accounts for the perceptual nature of AVH, i.e. for the subjective experience of “hearing voices”, in Schizophrenia Research 134 (2012) 285–287

Quality of life after restorative proctocolectomy and ileal pouch–anal anastomosis in patients with familial adenomatous polyposis: a matter of adjustment

Aim  Favourable outcomes for health‐related quality of life (HRQL) have been reported in patients with familial adenomatous polyposis (FAP) after restorative proctocolectomy and ileal pouch–anal anastomosis (RPC). However, less is known about patients’ subjective experience and adjustment to postoperative impairment. Using a multidimensional psychometric assessment, we investigated patient‐reported HRQL to determine the impact of the patient’s subjective experience together with medical, functional and psychosocial factors on HRQL.

Common and distinct structural network abnormalities in major depressive disorder and borderline personality disorder

Major depressive disorder (MDD) and borderline personality disorder (BPD) show substantial overlap in both affective symptom expression and in regional brain volume reduction. To address the specificity of structural brain change for the respective diagnostic category, we investigated structural networks in MDD and BPD to identify shared and distinct patterns of abnormal brain volume associated with these phenotypically related disorders. Using magnetic resonance imaging at 3 T, we studied 22 females with MDD, 17 females with BPD and without comorbid posttraumatic stress disorder, and 22 age-matched female healthy controls. We used “source-based morphometry” (SBM) to investigate naturally grouping patterns of gray matter volume variation (i.e. “structural networks”) and the magnitude of their expression between groups. SBM identified three distinct structural networks which showed a significant group effect (p b 0.05, FDR-corrected). A bilateral frontostriatal network showed reduced volume in MDD compared to both controls and BPD patients. A medial temporal/medial frontal network was found to be significantly reduced in BPD compared to both controls and MDD patients. Decreased cingulate and lateral prefrontal volume was found in both MDD and BPD when compared to healthy individuals. In MDD significant relationships were found between depressive symptoms and a cingulate/lateral prefrontal structural pattern. In contrast, overall BPD symptoms and impulsivity scores were significantly associated with medial temporal/medial frontal network volume. The data suggest both distinct and common patterns of abnormal brain volume in MDD and BPD. Alterations of distinct structural networks differentially modulate clinical symptom expression in these disorders.