Deficit actual tool use in schizophrenia is linked to structural alterations in key regions of planning and executing of tool use and connecting fibers

Introduction: Schizophrenia patients frequently suffer from complex motor abnormalities including fine and gross motor disturbances, abnormal involuntary movements, neurological soft signs and parkinsonism. These symptoms occur early in the course of the disease, continue in chronic patients and may deteriorate with antipsychotic medication. Furthermore gesture performance is impaired in patients, including the pantomime of tool use. Whether schizophrenia patients would show difficulties of actual tool use has not yet been investigated. Human tool use is complex and relies on a network of distinct and distant brain areas. We therefore aim to test if schizophrenia patients had difficulties in tool use and to assess associations with structural brain imaging using voxel based morphometry (VBM) and tract based spatial statistics (TBSS). Methode: In total, 44 patients with schizophrenia (DSM-5 criteria; 59% men, mean age 38) underwent structural MR imaging and performed the Tool-Use test. The test examines the use of a scoop and a hammer in three conditions: pantomime (without the tool), demonstration (with the tool) and actual use (with a recipient object). T1-weighted images were processed using SPM8 and DTI-data using FSL TBSS routines. To assess structural alterations of impaired tool use we first compared gray matter (GM) volume in VBM and white matter (WM) integrity in TBSS data of patients with and without difficulties of actual tool use. Next we explored correlations of Tool use scores and VBM and TBSS data. Group comparisons were family wise error corrected for multiple tests. Correlations were uncorrected (p < 0.001) with a minimum cluster threshold of 17 voxels (equivalent to a map-wise false positive rate of alpha < 0.0001 using a Monte Carlo procedure). Results: Tool use was impaired in schizophrenia (43.2% pantomime, 11.6% demonstration, 11.6% use). Impairment was related to reduced GM volume and WM integrity. Whole brain analyses detected an effect in the SMA in group analysis. Correlations of tool use scores and brain structure revealed alterations in brain areas of the dorso-dorsal pathway (superior occipital gyrus, superior parietal lobule, and dorsal premotor area) and the ventro-dorsal pathways (middle occipital gyrus, inferior parietal lobule) the action network, as well as the insula and the left hippocampus. Furthermore, significant correlations within connecting fiber tracts - particularly alterations within the bilateral corona radiata superior and anterior as well as the corpus callosum -were associated with Tool use performance. Conclusions: Tool use performance was impaired in schizophrenia, which was associated with reduced GM volume in the action network. Our results are in line with reports of impaired tool use in patients with brain lesions particularly of the dorso-dorsal and ventro-dorsal stream of the action network. In addition an effect of tool use on WM integrity was shown within fiber tracts connecting regions important for planning and executing tool use. Furthermore, hippocampus is part of a brain system responsible for spatial memory and navigation.The results suggest that structural brain alterations in the common praxis network contribute to impaired tool use in schizophrenia.

White matter integrity associated with volitional motor activity

Variations of white matter integrity have been associated with interindividual differences in brain function. Still, little is known about the impact of white matter integrity on quantitative motor behaviour. Diffusion tensor imaging and continuous wrist actigraphy were measured on the same day in 12 individuals. Fractional anisotropy as measure of white matter integrity was correlated with the motor activity level. Positive correlations of fractional anisotropy and activity level were detected in the cingulum and the right superior longitudinal fasciculus underneath the precentral gyrus. Negative correlations were found in the left corticobulbar tract, in the right posterior corpus callosum and in the left superior longitudinal fasciculus. Volitional motor activity was associated with white matter integrity in motor relevant fiber tracts.

Alterations of white matter integrity related to the season of birth in schizophrenia: a DTI study

In schizophrenia there is a consistent epidemiological finding of a birth excess in winter and spring. Season of birth is thought to act as a proxy indicator for harmful environmental factors during foetal maturation. There is evidence that prenatal exposure to harmful environmental factors may trigger pathologic processes in the neurodevelopment, which subsequently increase the risk of schizophrenia. Since brain white matter alterations have repeatedly been found in schizophrenia, the objective of this study was to investigate whether white matter integrity was related to the season of birth in patients with schizophrenia. Thirty-four patients with schizophrenia and 33 healthy controls underwent diffusion tensor imaging. Differences in the fractional anisotropy maps of schizophrenia patients and healthy controls born in different seasons were analysed with tract-based spatial statistics. A significant main effect of season of birth and an interaction of group and season of birth showed that patients born in summer had significantly lower fractional anisotropy in widespread white matter regions than those born in the remainder of the year. Additionally, later age of schizophrenia onset was found in patients born in winter months. The current findings indicate a relationship of season of birth and white matter alterations in schizophrenia and consequently support the neurodevelopmental hypothesis of early pathological mechanisms in schizophrenia.

Alterations of white matter integrity related to motor activity in schizophrenia

Altered structural connectivity is a key finding in schizophrenia, but the meaning of white matter alterations for behavior is rarely studied. In healthy subjects, motor activity correlated with white matter integrity in motor tracts. To explore the relation of motor activity and fractional anisotropy (FA) in schizophrenia, we investigated 19 schizophrenia patients and 24 healthy control subjects using Diffusion Tensor Imaging (DTI) and actigraphy on the same day. Schizophrenia patients had lower activity levels (AL). In both groups linear relations of AL and FA were detected in several brain regions. Schizophrenia patients had lower FA values in prefrontal and left temporal clusters. Furthermore, using a general linear model, we found linear negative associations of FA and AL underneath the right supplemental motor area (SMA), the right precentral gyrus and posterior cingulum in patients. This effect within the SMA was not seen in controls. This association in schizophrenia patients may contribute to the well known dysfunctions of motor control. Thus, structural disconnectivity could lead to disturbed motor behavior in schizophrenia.

Frontal white matter integrity is related to psychomotor retardation in major depression

Altered frontal white matter integrity has been reported in major depression. Still, the behavioral correlates of these alterations are not established. In healthy subjects, motor activity correlated with white matter integrity in the motor system. To explore the relation of white matter integrity and motor activity in major depressive disorder, we investigated 21 medicated patients with major depressive disorder and 21 matched controls using diffusion tensor imaging and wrist actigraphy at the same day. Patients had lower activity levels (AL) compared with controls. Fractional anisotropy (FA) differed between groups in frontal white matter regions and the posterior cingulum. AL was linearly associated with white matter integrity in two clusters within the motor system. Controls had an exclusive positive association of FA and AL in white matter underneath the right dorsal premotor cortex. Only patients had a positive association within the posterior cingulum. Furthermore, patients had negative associations of FA and AL underneath the left primary motor cortex and within the left parahippocampal gyrus white matter. These differences in the associations between structure and behavior may contribute to well-known impaired motor planning or gait disturbances in major depressive disorder. Therefore, signs of psychomotor slowing in major depressive disorder may be linked to changes of the white matter integrity of the motor system.

Effects of thoracic epidural analgesia on lower urinary tract function in women

The need for an indwelling transurethral catheter in patients with postoperative thoracic epidural analgesia (TEA) is a matter of controversy. Subjective observations are ambivalent and the literature addressing this issue is scarce. As segmental blockade can be achieved with epidural analgesia, we hypothesized that analgesia within segments T4-T11 has no or minimal influence on lower urinary tract function. Thus, we evaluated the effect of TEA on lower urinary tract function by urodynamic studies.

Cortico-cortical white matter motor pathway microstructure is related to psychomotor retardation in major depressive disorder

Alterations of brain structure and function have been associated with psychomotor retardation in major depressive disorder (MDD). However, the association of motor behaviour and white matter integrity of motor pathways in MDD is unclear. The aim of the present study was to first investigate structural connectivity of white matter motor pathways in MDD. Second, we explore the relation of objectively measured motor activity and white matter integrity of motor pathways in MDD. Therefore, 21 patients with MDD and 21 healthy controls matched for age, gender, education and body mass index underwent diffusion tensor imaging and 24 hour actigraphy (measure of the activity level) the same day. Applying a probabilistic fibre tracking approach we extracted connection pathways between the dorsolateral prefrontal cortex (dlPFC), the rostral anterior cingulate cortex (rACC), the pre-supplementary motor area (pre-SMA), the SMA-proper, the primary motor cortex (M1), the caudate nucleus, the putamen, the pallidum and the thalamus. Patients had lower activity levels and demonstrated increased mean diffusivity (MD) in pathways linking left pre-SMA and SMA-proper, and right SMA-proper and M1. Exploratory analyses point to a positive association of activity level and mean-fractional anisotropy in the right rACC-pre-SMA connection in MDD. Only MDD patients with low activity levels had a negative linear association of activity level and mean-MD in the left dlPFC-pre-SMA connection. Our results point to structural alterations of cortico-cortical white matter motor pathways in MDD. Altered white matter organisation of rACC-pre-SMA and dlPFC-pre-SMA pathways may contribute to movement initiation in MDD.

White matter anisotropy related to electrophysiology of first episode schizophrenia during NoGo inhibition

Patients with schizophrenia have reduced execution functions and white matter alterations indicating cerebral disconnectivity. Here we investigated the relationship between white matter integrity and event related potentials (ERP) during a continuous performance test (CPT). Anisotropy values were correlated with the brain electrical P300 microstate duration and P300 latency associated to the NoGo- and the Go-stimuli of the CPT in 11 patients with first episode schizophrenia and 11 matched healthy controls. Both groups showed significant positive correlations of the NoGo-microstate duration with the white matter signal in the superior frontal region, the optic radiation, the posterior cingulate, and the inferolateral fascicle. In addition, patients with first episode schizophrenia had significant correlations with the right radiation and the left genu of the corpus callosum, bilateral geniculate, and the left middle and the superior temporal regions. We interpreted these findings as a sign of functional correlates of extended circuits for the active inhibition of a motor response in the visual CPT as compared to controls.

White matter microstructure alterations of the medial forebrain bundle in melancholic depression

BACKGROUND The medial forebrain bundle (MFB) is a key structure of the reward system and connects the ventral tegmental area (VTA) with the nucleus accumbens (NAcc), the medial and lateral orbitofrontal cortex (mOFC, lOFC) and the dorsolateral prefrontal cortex (dlPFC). Previous diffusion tensor imaging (DTI) studies in major depressive disorder point to white matter alterations of regions which may be incorporated in the MFB. Therefore, it was the aim of our study to probe white matter integrity of the MFB using a DTI-based probabilistic fibre tracking approach. METHODS 22 patients with major depressive disorder (MDD) (12 melancholic-MDD patients, 10 non-melancholic-MDD patients) and 21 healthy controls underwent DTI scans. We used a bilateral probabilistic fibre tracking approach to extract pathways between the VTA and NACC, mOFC, lOFC, dlPFC respectively. Mean fractional anisotropy (FA) values were used to compare structural connectivity between groups. RESULTS Mean-FA did not differ between healthy controls and all MDD patients. Compared to healthy controls melancholic MDD-patients had reduced mean-FA in right VTA-lOFC and VTA-dlPFC connections. Furthermore, melancholic-MDD patients had lower mean-FA than non-melancholic MDD-patients in the right VTA-lOFC connection. Mean-FA of these pathways correlated negatively with depression scale rating scores. LIMITATIONS Due to the small sample size and heterogeneous age group comparisons between melancholic and non-melancholic MDD-patients should be regarded as preliminary. CONCLUSIONS Our results suggest that the melancholic subtype of MDD is characterized by white matter microstructure alterations of the MFB. White matter microstructure is associated with both depression severity and anhedonia.

White matter in aphasia: a historical review of the Dejerines' studies

The Objective was to describe the contributions of Joseph Jules Dejerine and his wife Augusta Dejerine-Klumpke to our understanding of cerebral association fiber tracts and language processing. The Dejerines (and not Constantin von Monakow) were the first to describe the superior longitudinal fasciculus/arcuate fasciculus (SLF/AF) as an association fiber tract uniting Broca's area, Wernicke's area, and a visual image center in the angular gyrus of a left hemispheric language zone. They were also the first to attribute language-related functions to the fasciculi occipito-frontalis (FOF) and the inferior longitudinal fasciculus (ILF) after describing aphasia patients with degeneration of the SLF/AF, ILF, uncinate fasciculus (UF), and FOF. These fasciculi belong to a functional network known as the Dejerines' language zone, which exceeds the borders of the classically defined cortical language centers. The Dejerines provided the first descriptions of the anatomical pillars of present-day language models (such as the SLF/AF). Their anatomical descriptions of fasciculi in aphasia patients provided a foundation for our modern concept of the dorsal and ventral streams in language processing.

On the stratigraphic integrity of leaf-wax biomarkers in loess paleosols

Paleoenvironmental and paleoclimate reconstructions based on molecular proxies, such as those derived from leaf-wax biomarkers, in loess-paleosol sequences represent a promising line of investigation in Quaternary research. The main premise of such reconstructions is the synsedimentary deposition of biomarkers and dust, which has become a debated subject in recent years. This study uses two independent approaches to test the stratigraphic integrity of leaf-wax biomarkers: (i) long-chain n-alkanes and fatty acids are quantified in two sediment-depth profiles in glacial till on the Swiss Plateau, consisting of a Holocene topsoil and the underlying B and C horizons. Since glacial sediments are initially very poor in organic matter, significant amounts of leaf-wax biomarkers in the B and C horizons of those profiles would reflect postsedimentary root-derived or microbial contributions. (ii) Compound-specific radiocarbon measurements are conducted on n-alkanes and n-alkanoic (fatty) acids from several depth intervals in the loess section "Crvenka", Serbia, and the results are compared to independent estimates of sediment age. We find extremely low concentrations of plant-wax n-alkanes and fatty acids in the B and C horizons below the topsoils in the sediment profiles. Moreover, compound-specific radiocarbon analysis yields plant-wax 14C ages that agree well with published luminescence ages and stratigraphy of the Serbian loess deposit. Both approaches confirm that postsedimentary, root-derived or microbial contributions are negligible in the two investigated systems. The good agreement between the ages of odd and even homologues also indicates that reworking and incorporation of fossil leaf waxes is not particularly relevant either.

Limbic white matter microstructure plasticity reflects recovery from depression

BACKGROUND White matter microstructure alterations of limbic and reward pathways have been reported repeatedly for depressive episodes in major depressive disorder (MDD) and bipolar disorder (BD). However, findings during remission are equivocal. It was the aim of this study to investigate if white matter microstructure changes during the time course of clinical remission. METHODS Fifteen depressed patients (11 MDD, 4 BD) underwent diffusion-weighted MRI both during depression, and during remission following successful antidepressive treatment (average time interval between scans=6 months). Fractional anisotropy (FA) was sampled along reconstructions of the supero-lateral medial forebrain bundle (slMFB), the cingulum bundle (CB), the uncinate fasciculus (UF), the parahippocampal cingulum (PHC) and the fornix. Repeated measures ANCOVAs controlling for the effect of age were calculated for each tract. RESULTS There was a significant main effect of time (inter-scan interval) for mean-FA for the right CB and for the left PHC. For both pathways there was a significant time×age interaction. In the right CB, FA increased in younger patients, while FA decreased in older patients. In the left PHC, a reverse pattern was seen. FA changes in the right CB correlated positively with symptom reductions. Mean-FA of UF, slMFB and fornix did not change between the two time points. LIMITATIONS All patients were medicated, sample size, and lack of control group. CONCLUSIONS Right CB and left PHC undergo age-dependent plastic changes during the course of remission and may serve as a state marker in depression. UF, slMFB and FO microstructure remains stable.

White matter matters: a multimodal approach to investigate white matter microstructure and metabolism

White matter connects different brain areas and applies electrical insulation to the neuron’s axons with myelin sheaths in order to enable quick signal transmission. Due to its modulatory properties in signal conduction, white matter plays an essential role in learning, cognition and psychiatric disorders (Fields, 2008a). In respect thereof, the non-invasive investigation of white matter anatomy and function in vivo provides the unique opportunity to explore the most complex organ of our body. Thus, the present thesis aimed to apply a multimodal neuroimaging approach to investigate different white matter properties in psychiatric and healthy populations. On the one hand, white matter microstructural properties were investigated in a psychiatric population; on the other hand, white matter metabolic properties were assessed in healthy adults providing basic information about the brain’s wiring entity. As a result, three research papers are presented here. The first paper assessed the microstructural properties of white matter in relation to a frequent epidemiologic finding in schizophrenia. As a result, reduced white matter integrity was observed in patients born in summer and autumn compared to patients born in winter and spring. Despite the large genetic basis of schizophrenia, accumulating evidence indicates that environmental exposures may be implicated in the development of schizophrenia (A. S. Brown, 2011). Notably, epidemiologic studies have shown a 5–8% excess of births during winter and spring for patients with schizophrenia on the Northern Hemisphere at higher latitudes (Torrey, Miller, Rawlings, & Yolken, 1997). Although the underlying mechanisms are unclear, the seasonal birth effect may indicate fluctuating environmental risk factors for schizophrenia. Thus, exposure to harmful factors during foetal development may result in the activation of pathologic neural circuits during adolescence or young adulthood, increasing the risk of schizophrenia (Fatemi & Folsom, 2009). While white matter development starts during the foetal period and continues until adulthood, its major development is accomplished by the age of two years (Brody, Kinney, Kloman, & Gilles, 1987; Huang et al., 2009). This indicates a vulnerability period of white matter that may coincide with the fluctuating environmental risk factors for schizophrenia. Since microstructural alterations of white matter in schizophrenia are frequently observed, the current study provided evidence for the neurodevelopmental hypothesis of schizophrenia. In the second research paper, the perfusion of white matter showed a positive correlation between white matter microstructure and its perfusion with blood across healthy adults. This finding was in line with clinical studies indicating a tight coupling between cerebral perfusion and WM health across subjects (Amann et al., 2012; Chen, Rosas, & Salat, 2013; Kitagawa et al., 2009). Although relatively little is known about the metabolic properties of white matter, different microstructural properties, such as axon diameter and myelination, might be coupled with the metabolic demand of white matter. Furthermore, the ability to detect perfusion signal in white matter was in accordance with a recent study showing that technical improvements, such as pseudo-continuous arterial spin labeling, enabled the reliable detection of white matter perfusion signal (van Osch et al., 2009). The third paper involved a collaboration within the same department to assess the interrelation between functional connectivity networks and their underlying structural connectivity.

Neuroanatomy of intergroup bias: A white matter microstructure study of individual differences

Intergroup bias - the tendency to behave more positively towards an ingroup member than an outgroup member - is a powerful social force, for good and ill. And though it is widely demonstrated, intergroup bias is not universal, as it is characterized by significant individual differences. Recently, attention has begun to turn to whether neuroanatomy might explain these individual differences in intergroup bias. However, no research to date has examined whether white matter microstructure could help determine differences in behavior towards ingroup and outgroup members. In the current research, we examine intergroup bias with the third-party punishment paradigm and white matter integrity and connectivity strength as determined by diffusion tensor imaging (DTI). We found that both increased white matter integrity at the right temporal-parietal junction (TPJ) and connectivity strength between the right TPJ and the dorsomedial prefrontal cortex (DMPFC) were associated with increased impartiality in the third-party punishment paradigm, i.e., reduced intergroup bias. Further, consistent with the role that these brain regions play in the mentalizing network, we found that these effects were mediated by mentalizing processes. Participants with greater white matter integrity at the right TPJ and connectivity strength between the right TPJ and the DMPFC employed mentalizing processes more equally for ingroup and outgroup members, and this non-biased use of mentalizing was associated with increased impartiality. The current results help shed light on the mechanisms of bias and, potentially, on interventions that promote impartiality over intergroup bias.