Adversity specificity and life period exposure on cognitive aging.

This study set out to examine the role of different adversities experienced at different life course stages on cognitive aging (i.e., level and change). Data from the longitudinal study: Survey of Health, Ageing, and Retirement in Europe (SHARE) with the selection of participants over 60 years were used (N = 2662, Mdnage = 68, SDage = 5.39) in a Structural Equation Modeling. In early life, the experience of hunger predicted lower delayed recall (ß = - 0.10, p < 0.001) and verbal fluency (ß = - 0.06, p = 0.001) performance in older age, whereas financial hardship predicted lower verbal fluency (ß = - 0.06, p = 0.005) performance and steeper decline in delayed recall (ß = - 0.11, p < 0.001). In early adulthood, financial hardship and stress predicted better delayed recall (financial hardship: ß = 0.08, p = 0.001; stress: ß = 0.07, p = 0.003) and verbal fluency performance (financial hardship: ß = 0.08, p = 0.001; stress ß = 0.10, p < 0.001), but no adversities were associated with a change in cognitive performance. In middle adulthood, no adversities were associated with the level of cognitive performance, but financial hardship predicted lower decline in delayed recall (ß = 0.07, p = 0.048). This study highlights the importance of disentangling the period effect from the specific effect of the adversity experienced in the association between adversity and cognition in older age. Moreover, differential results for delayed recall and verbal fluency measures suggest that it is also important to consider the cognitive outcome domains examined.

Temporal trajectory of brain tissue property changes induced by electroconvulsive therapy.

BACKGROUND: After more than eight decades of electroconvulsive therapy (ECT) for pharmaco-resistant depression, the mechanisms governing its anti-depressant effects remain poorly understood. Computational anatomy studies using longitudinal T1-weighted magnetic resonance imaging (MRI) data have demonstrated ECT effects on hippocampus volume and cortical thickness, but they lack the interpretational specificity about underlying neurobiological processes. METHODS: We sought to fill in the gap of knowledge by acquiring quantitative MRI indicative for brain's myelin, iron and tissue water content at multiple time-points before, during and after ECT treatment. We adapted established tools for longitudinal spatial registration of MRI data to the relaxometry-based multi-parameter maps aiming to preserve the initial total signal amount and introduced a dedicated multivariate analytical framework. RESULTS: The whole-brain voxel-based analysis based on a multivariate general linear model showed that there is no brain tissue oedema contributing to the predicted ECT-induced hippocampus volume increase neither in the short, nor in the long-term observations. Improvements in depression symptom severity over time were associated with changes in both volume estimates and brain tissue properties expanding beyond mesial temporal lobe structures to anterior cingulate cortex, precuneus and striatum. CONCLUSION: The obtained results stemming from multi-contrast MRI quantitative data provided a fingerprint of ECT-induced brain tissue changes over time that are contrasted against the background of established morphometry findings. The introduced data processing and statistical testing algorithms provided a reliable analytical framework for longitudinal multi-parameter brain maps. The results, particularly the evidence of lack of ECT impact on brain tissue water, should be considered preliminary considering the small sample size of the study.

New tissue priors for improved automated classification of subcortical brain structures on MRI.

Despite the constant improvement of algorithms for automated brain tissue classification, the accurate delineation of subcortical structures using magnetic resonance images (MRI) data remains challenging. The main difficulties arise from the low gray-white matter contrast of iron rich areas in T1-weighted (T1w) MRI data and from the lack of adequate priors for basal ganglia and thalamus. The most recent attempts to obtain such priors were based on cohorts with limited size that included subjects in a narrow age range, failing to account for age-related gray-white matter contrast changes. Aiming to improve the anatomical plausibility of automated brain tissue classification from T1w data, we have created new tissue probability maps for subcortical gray matter regions. Supported by atlas-derived spatial information, raters manually labeled subcortical structures in a cohort of healthy subjects using magnetization transfer saturation and R2* MRI maps, which feature optimal gray-white matter contrast in these areas. After assessment of inter-rater variability, the new tissue priors were tested on T1w data within the framework of voxel-based morphometry. The automated detection of gray matter in subcortical areas with our new probability maps was more anatomically plausible compared to the one derived with currently available priors. We provide evidence that the improved delineation compensates age-related bias in the segmentation of iron rich subcortical regions. The new tissue priors, allowing robust detection of basal ganglia and thalamus, have the potential to enhance the sensitivity of voxel-based morphometry in both healthy and diseased brains.

16p11.2 Locus modulates response to satiety before the onset of obesity.

BACKGROUND: The 600 kb BP4-BP5 copy number variants (CNVs) at the 16p11.2 locus have been associated with a range of neurodevelopmental conditions including autism spectrum disorders and schizophrenia. The number of genomic copies in this region is inversely correlated with body mass index (BMI): the deletion is associated with a highly penetrant form of obesity (present in 50% of carriers by the age of 7 years and in 70% of adults), and the duplication with being underweight. Mechanisms underlying this energy imbalance remain unknown. OBJECTIVE: This study aims to investigate eating behavior, cognitive traits and their relationships with BMI in carriers of 16p11.2 CNVs. METHODS: We assessed individuals carrying a 16p11.2 deletion or duplication and their intrafamilial controls using food-related behavior questionnaires and cognitive measures. We also compared these carriers with cohorts of individuals presenting with obesity, binge eating disorder or bulimia. RESULTS: Response to satiety is gene dosage-dependent in pediatric CNV carriers. Altered satiety response is present in young deletion carriers before the onset of obesity. It remains altered in adolescent carriers and correlates with obesity. Adult deletion carriers exhibit eating behavior similar to that seen in a cohort of obesity without eating disorders such as bulimia or binge eating. None of the cognitive measures are associated with eating behavior or BMI. CONCLUSIONS: These findings suggest that abnormal satiety response is a strong contributor to the energy imbalance in 16p11.2 CNV carriers, and, akin to other genetic forms of obesity, altered satiety responsiveness in children precedes the increase in BMI observed later in adolescence.

The concept of schizotypy - A computational anatomy perspective.

Despite major progress in diagnostic accuracy and symptomatic treatment of mental disorders, there is an ongoing debate about their classification aiming to follow current advances in neurobiology. The main goal of this review is to provide a comprehensive summary of the put forward schizotypy concept that follows the needs for objective assessment of schizophrenia-like personality traits in the general population. We focus on major achievements in the field from the perspective of magnetic resonance imaging-based computational anatomy of the brain. Particular interest is devoted to overlapping brain structure findings in schizotypy and schizophrenia to promote a dimensional view on schizophrenia as extension of phenotype traits in the non-clinical general population.

The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity.

Anatomical structures and mechanisms linking genes to neuropsychiatric disorders are not deciphered. Reciprocal copy number variants at the 16p11.2 BP4-BP5 locus offer a unique opportunity to study the intermediate phenotypes in carriers at high risk for autism spectrum disorder (ASD) or schizophrenia (SZ). We investigated the variation in brain anatomy in 16p11.2 deletion and duplication carriers. Beyond gene dosage effects on global brain metrics, we show that the number of genomic copies negatively correlated to the gray matter volume and white matter tissue properties in cortico-subcortical regions implicated in reward, language and social cognition. Despite the near absence of ASD or SZ diagnoses in our 16p11.2 cohort, the pattern of brain anatomy changes in carriers spatially overlaps with the well-established structural abnormalities in ASD and SZ. Using measures of peripheral mRNA levels, we confirm our genomic copy number findings. This combined molecular, neuroimaging and clinical approach, applied to larger datasets, will help interpret the relative contributions of genes to neuropsychiatric conditions by measuring their effect on local brain anatomy.

Disentangling in vivo the effects of iron content and atrophy on the ageing human brain.

Evidence from magnetic resonance imaging (MRI) studies shows that healthy aging is associated with profound changes in cortical and subcortical brain structures. The reliable delineation of cortex and basal ganglia using automated computational anatomy methods based on T1-weighted images remains challenging, which results in controversies in the literature. In this study we use quantitative MRI (qMRI) to gain an insight into the microstructural mechanisms underlying tissue ageing and look for potential interactions between ageing and brain tissue properties to assess their impact on automated tissue classification. To this end we acquired maps of longitudinal relaxation rate R1, effective transverse relaxation rate R2* and magnetization transfer - MT, from healthy subjects (n=96, aged 21-88 years) using a well-established multi-parameter mapping qMRI protocol. Within the framework of voxel-based quantification we find higher grey matter volume in basal ganglia, cerebellar dentate and prefrontal cortex when tissue classification is based on MT maps compared with T1 maps. These discrepancies between grey matter volume estimates can be attributed to R2* - a surrogate marker of iron concentration, and further modulation by an interaction between R2* and age, both in cortical and subcortical areas. We interpret our findings as direct evidence for the impact of ageing-related brain tissue property changes on automated tissue classification of brain structures using SPM12. Computational anatomy studies of ageing and neurodegeneration should acknowledge these effects, particularly when inferring about underlying pathophysiology from regional cortex and basal ganglia volume changes.

[Novel aspects of diagnostics and therapy of spinal cord diseases]. / Neues aus Diagnostik und Therapie der spinalen Erkrankungen.

BACKGROUND: Both non-traumatic and traumatic spinal cord injuries have in common that a relatively minor structural lesion can cause profound sensorimotor and autonomous dysfunction. Besides treating the cause of the spinal cord injury the main goal is to restore lost function as far as possible. AIM: This article provides an overview of current innovative diagnostic (imaging) and therapeutic approaches (neurorehabilitation and neuroregeneration) aiming for recovery of function after non-traumatic and traumatic spinal cord injuries. MATERIAL AND METHODS: An analysis of the current scientific literature regarding imaging, rehabilitation and rehabilitation strategies in spinal cord disease was carried out. RESULTS: Novel magnetic resonance imaging (MRI) based techniques (e.g. diffusion-weighted MRI and functional MRI) allow visualization of structural reorganization and specific neural activity in the spinal cord. Robotics-driven rehabilitative measures provide training of sensorimotor function in a targeted fashion, which can even be continued in the homecare setting. From a preclinical point of view, defined stem cell transplantation approaches allow for the first time robust structural repair of the injured spinal cord. CONCLUSION: Besides well-established neurological and functional scores, MRI techniques offer the unique opportunity to provide robust and reliable "biomarkers" for restorative therapeutic interventions. Function-oriented robotics-based rehabilitative interventions alone or in combination with stem cell based therapies represent promising approaches to achieve substantial functional recovery, which go beyond current rehabilitative treatment efforts.

Regional specificity of MRI contrast parameter changes in normal ageing revealed by voxel-based quantification (VBQ).

Normal ageing is associated with characteristic changes in brain microstructure. Although in vivo neuroimaging captures spatial and temporal patterns of age-related changes of anatomy at the macroscopic scale, our knowledge of the underlying (patho)physiological processes at cellular and molecular levels is still limited. The aim of this study is to explore brain tissue properties in normal ageing using quantitative magnetic resonance imaging (MRI) alongside conventional morphological assessment. Using a whole-brain approach in a cohort of 26 adults, aged 18-85years, we performed voxel-based morphometric (VBM) analysis and voxel-based quantification (VBQ) of diffusion tensor, magnetization transfer (MT), R1, and R2* relaxation parameters. We found age-related reductions in cortical and subcortical grey matter volume paralleled by changes in fractional anisotropy (FA), mean diffusivity (MD), MT and R2*. The latter were regionally specific depending on their differential sensitivity to microscopic tissue properties. VBQ of white matter revealed distinct anatomical patterns of age-related change in microstructure. Widespread and profound reduction in MT contrasted with local FA decreases paralleled by MD increases. R1 reductions and R2* increases were observed to a smaller extent in overlapping occipito-parietal white matter regions. We interpret our findings, based on current biophysical models, as a fingerprint of age-dependent brain atrophy and underlying microstructural changes in myelin, iron deposits and water. The VBQ approach we present allows for systematic unbiased exploration of the interaction between imaging parameters and extends current methods for detection of neurodegenerative processes in the brain. The demonstrated parameter-specific distribution patterns offer insights into age-related brain structure changes in vivo and provide essential baseline data for studying disease against a background of healthy ageing.

Genotype-phenotype interactions in primary dystonias revealed by differential changes in brain structure.

Our understanding of how genotype determines phenotype in primary dystonia is limited. Familial young-onset primary dystonia is commonly due to the DYT1 gene mutation. A critical question, given the 30% penetrance of clinical symptoms in DYT1 mutation carriers, is why the same genotype leads to differential clinical expression and whether non-DYT1 adult-onset primary dystonia, with and without family history share pathophysiological mechanisms with DYT1 dystonia. This study examines the relationship between dystonic phenotype and the DYT1 gene mutation by monitoring whole-brain structure using voxel-based morphometry. We acquired magnetic resonance imaging data of symptomatic and asymptomatic DYT1 mutation carriers, of non-DYT1 primary dystonia patients, with and without family history and control subjects with normal DYT1 alleles. By crossing the factors genotype and phenotype we demonstrate a significant interaction in terms of brain anatomy confined to the basal ganglia bilaterally. The explanation for this effect differs according to both gene and dystonia status: non-DYT1 adult-onset dystonia patients and asymptomatic DYT1 carriers have significantly larger basal ganglia compared to healthy subjects and symptomatic DYT1 mutation carriers. There is a significant negative correlation between severity of dystonia and basal ganglia size in DYT1 mutation carriers. We propose that differential pathophysiological and compensatory mechanisms lead to brain structure changes in non-DYT1 primary adult-onset dystonias and DYT1 gene carriers. Given the range of age of onset, there may be differential genetic modulation of brain development that in turn determines clinical expression. Alternatively, a DYT1 gene dependent primary defect of motor circuit development may lead to stress-induced remodelling of the basal ganglia and hence dystonia.

Automatic detection of preclinical neurodegeneration: presymptomatic Huntington disease.

BACKGROUND: Treatment of neurodegenerative diseases is likely to be most beneficial in the very early, possibly preclinical stages of degeneration. We explored the usefulness of fully automatic structural MRI classification methods for detecting subtle degenerative change. The availability of a definitive genetic test for Huntington disease (HD) provides an excellent metric for judging the performance of such methods in gene mutation carriers who are free of symptoms. METHODS: Using the gray matter segment of MRI scans, this study explored the usefulness of a multivariate support vector machine to automatically identify presymptomatic HD gene mutation carriers (PSCs) in the absence of any a priori information. A multicenter data set of 96 PSCs and 95 age- and sex-matched controls was studied. The PSC group was subclassified into three groups based on time from predicted clinical onset, an estimate that is a function of DNA mutation size and age. RESULTS: Subjects with at least a 33% chance of developing unequivocal signs of HD in 5 years were correctly assigned to the PSC group 69% of the time. Accuracy improved to 83% when regions affected by the disease were selected a priori for analysis. Performance was at chance when the probability of developing symptoms in 5 years was less than 10%. CONCLUSIONS: Presymptomatic Huntington disease gene mutation carriers close to estimated diagnostic onset were successfully separated from controls on the basis of single anatomic scans, without additional a priori information. Prior information is required to allow separation when degenerative changes are either subtle or variable.

Training-induced structural changes in the adult human brain.

Structural and functional brain reorganisation can occur beyond the developmental maturation period and this was recently recognised as an intrinsic property of the human central nervous system. Brain injury or altered afferent input due to environmental changes, novel experience and learning new skills are known as modulators of brain function and underlying neuroanatomic circuitry. During the past decade invasive animal studies and in vivo imaging techniques have delineated the correlates of experience dependent reorganisation. The major future challenge is to understand the behavioural consequences and cellular mechanisms underlying training-induced neuroanatomic plasticity in order to adapt treatment strategies for patients with brain injury or neurodegenerative disorders.

Anti-basal ganglia antibodies and Tourette's syndrome: a voxel-based morphometry and diffusion tensor imaging study in an adult population.

Anti-basal ganglia antibodies (ABGAs) have been suggested to be a hallmark of autoimmunity in Gilles de la Tourette's syndrome (GTS), possibly related to prior exposure to streptococcal infection. In order to detect whether the presence of ABGAs was associated with subtle structural changes in GTS, whole-brain analysis using independent sets of T(1) and diffusion tensor imaging MRI-based methods were performed on 22 adults with GTS with (n = 9) and without (n = 13) detectable ABGAs in the serum. Voxel-based morphometry analysis failed to detect any significant difference in grey matter density between ABGA-positive and ABGA-negative groups in caudate nuclei, putamina, thalami and frontal lobes. These results suggest that ABGA synthesis is not related to structural changes in grey and white matter (detectable with these methods) within frontostriatal circuits.

Affective components and intensity of pain correlate with structural differences in gray matter in chronic back pain patients.

Although chronic back pain is one of the most frequent reasons for permanent impairment in people under 65, the neurobiological mechanisms of chronification remain vague. Evidence suggests that cortical reorganisation, so-called functional plasticity, may play a role in chronic back pain patients. In the search for the structural counterpart of such functional changes in the CNS, we examined 18 patients suffering from chronic back pain with voxel-based morphometry and compared them to 18 sex and age matched healthy controls. We found a significant decrease of gray matter in the brainstem and the somatosensory cortex. Correlation analysis of pain unpleasantness and the intensity of pain on the day of scanning revealed a strong negative correlation (i.e. a decrease in gray matter with increasing unpleasantness/increasing intensity of pain) in these areas. Additionally, we found a significant increase in gray matter bilaterally in the basal ganglia and the left thalamus. These data support the hypothesis that ongoing nociception is associated with cortical and subcortical reorganisation on a structural level, which may play an important role in the process of the chronification of pain.

Decrease of thalamic gray matter following limb amputation.

Modern neuroscience has elucidated general mechanisms underlying the functional plasticity of the adult mammalian brain after limb deafferentation. However, little is known about possible structural alterations following amputation and chronic loss of afferent input in humans. Using voxel-based morphometry (VBM), based on high-resolution magnetic resonance images, we investigated the brain structure of 28 volunteers with unilateral limb amputation and compared them to healthy controls. Subjects with limb amputation exhibited a decrease in gray matter of the posterolateral thalamus contralateral to the side of the amputation. The thalamic gray matter differences were positively correlated with the time span after the amputation but not with the frequency or magnitude of coexisting phantom pain. Phantom limb pain was unrelated to thalamic structural variations, but was positively correlated to a decrease in brain areas related to the processing of pain. No gray matter increase was detected. The unilateral thalamic differences may reflect a structural correlate of the loss of afferent input as a secondary change following deafferentation.

Gray matter decrease in patients with chronic tension type headache.

Using MRI and voxel-based morphometry, the authors investigated 20 patients with chronic tension type headache (CTTH) and 20 patients with medication-overuse headache and compared them to 40 controls with no headache history. Only patients with CTTH demonstrated a significant gray matter decrease in regions known to be involved in pain processing. The finding implies that the alterations are specific to CTTH rather than a response to chronic head pain or chronification per se.

Selective activation of ectopic grey matter during motor task.

The role of ectopic grey matter in neuronal migration disorders is still a matter of debate. Using fMRI we studied the activation pattern of ectopic and regular cortical neurons in a female patient with subcortical bilateral laminar heterotopia (double cortex syndrome) performing a simple motor task. We demonstrate a synchronous activation pattern of the motor cortex and the adjacent subcortical ectopic grey matter layer during finger-tapping. We also observed activation in the cerebellum ipsilaterally and in the basal ganglia contralaterally. The present findings are consistent with the hypothesis that ectopic neurons may be functionally integrated in motor circuits during repetitive voluntary movements.

"Motor circuit" gray matter changes in idiopathic cervical dystonia.

BACKGROUND: Idiopathic cervical dystonia (ICD), the most common adult-onset focal dystonia, is clinically characterized by involuntary uni- or bilateral contractions of head and neck musculature. One crucial criterion for the diagnosis of ICD is normal results on MRI of the brain. OBJECTIVE: To test the hypothesis whether subtle brain structure changes occur in ICD. METHODS: Using voxel-based morphometry, the authors compared the brain structure of 10 patients with ICD with that of 10 healthy sex- and age-matched controls using high-resolution MRI. RESULTS: Patients with ICD showed an increase in gray matter density bilaterally in the motor cortex and in the cerebellar flocculus and unilaterally in the right globus pallidus internus. In addition, a decrease in gray matter density was observed in the right caudal supplementary motor area as well as in the right dorsal lateral prefrontal and visual cortex. CONCLUSIONS: These results demonstrate for the first time in vivo subtle morphologic alterations in ICD. These data challenge the principal concept that patients with ICD have no brain structure abnormalities and that this movement disorder is solely due to abnormal cerebral function.

Analysis of CO2 vasomotor reactivity and vessel diameter changes by simultaneous venous and arterial Doppler recordings.

BACKGROUND AND PURPOSE: The use of flow velocity changes in the middle cerebral artery (MCA) measured by Doppler techniques as an index of corresponding cerebral blood flow (CBF) changes is based on the assumption that the insonated arterial diameter remains stable. The postulate of unchanging vessel calibers during CBF changes, however, is still under debate. We performed simultaneous measurements of arterial and venous blood flow velocities by transcranial Doppler ultrasound during various stages of hypercapnia to analyze diameter changes in the insonated vessels by comparing differences in the vasomotor reactivity. METHODS: Simultaneous Doppler recordings of 1 MCA and of a contralateral venous vessel thought to represent the sphenoparietal sinus (SPS) were carried out with a pair of 2-MHz range-gated transducers in 16 young healthy subjects during variations of end-tidal PaCO2. RESULTS: During hypercapnia the mean blood flow velocity of the MCA rose from 62. 5+/-10.2 to a maximum of 99+/-12.2 cm/s (vasomotor reactivity of 60. 1+/-17.3%). The corresponding values in the SPS were significantly higher (P<0.001), revealing a rise from 17.8+/-5.7 to 34.9+/-14.3 cm/s (vasomotor reactivity of 91.4+/-25.9%). Exponential and linear regression analyses revealed an identical high correlation (r2=0.97 and 0.98 for the MCA and SPS, respectively). Slopes were 0.034+/-0. 01 on the arterial and 0.048+/-0.01 on the venous side. The CO2 reactivity (percentage per mm Hg, EtCO2) was found to be 4.5+/-1%/mm Hg in the MCA and 6.8+/-1.5%/mm Hg in the SPS. This difference indicates a vasodilation of the MCA in comparison to the venous vessel. CONCLUSIONS: We have demonstrated a different reaction pattern between intracranial venous and arterial vessels related to end-tidal CO2. Relating the flow velocities to the square of the vessel diameter and assuming a global rise of CBF and not extensible sinus walls, our results indicate that the MCA undergoes a vasodilation of 9.5+/-7% in maximal hypercapnia.