Different patterns of white matter degeneration using multiple diffusion indices and volumetric data in mild cognitive impairment and Alzheimer patients

Alzheimeŕs disease (AD) represents the most prevalent neurodegenerative disorder that causes cognitive decline in old age. In its early stages, AD is associated with microstructural abnormalities in white matter (WM). In the current study, multiple indices of diffusion tensor imaging (DTI) and brain volumetric measurements were employed to comprehensively investigate the landscape of AD pathology. The sample comprised 58 individuals including cognitively normal subjects (controls), amnestic mild cognitive impairment (MCI) and AD patients. Relative to controls, both MCI and AD subjects showed widespread changes of anisotropic fraction (FA) in the corpus callosum, cingulate and uncinate fasciculus. Mean diffusivity and radial changes were also observed in AD patients in comparison with controls. After controlling for the gray matter atrophy the number of regions of significantly lower FA in AD patients relative to controls was decreased; nonetheless, unique areas of microstructural damage remained, e.g., the corpus callosum and uncinate fasciculus. Despite sample size limitations, the current results suggest that a combination of secondary and primary degeneration occurrs in MCI and AD, although the secondary degeneration appears to have a more critical role during the stages of disease involving dementia

Affective and cognitive prefrontal cortex projections to the lateral habenula in humans

Anterior insula (AI) and dACC are known to process information about pain, loss, adversities, bad, harmful or suboptimal choices and consequences that threaten survival or well-being. Pain and loss activate also pregenual ACC (pgACC), linked to sad thoughts, hurt and regrets. The lateral habenula (LHb) is stimulated by predicted and received pain, discomfort, aversive outcome, loss. Its chronic stimulation makes us feel worse/low and gradually stops us choosing and moving for suboptimal, hurtful or punished choices, by direct and indirect (via RMTg) inhibition of DRN and VTA/SNc. Response selectivity of LHb neurons suggests their cortical input from affective and cognitive evaluative regions that make expectations about bad or suboptimal outcomes. Based on these facts I predicted direct corticohabenular projections from the dACC, pgACC and AI, as part of the adversity processing circuit that learns to avoid bad outcomes by suppressing dopamine and serotonin signal. Using DTI I found dACC, pgACC, AI, adjacent caudolateral and lateral OFC projections to LHb. I predicted no corticohabenular projections from the reward processing regions: medial OFC and vACC because both respond most strongly to good, high value stimuli and outcomes, inducing serotonin and dopamine release respectively. This lack of LHb projections was confirmed for vACC and likely for mOFC. The surprising findings were the corticohabenular projections from the cognitive prefrontal cortex regions, known for flexible reasoning, planning and combining whatever information are relevant for reaching current goals. I propose that prefrontohabenular projections provide a teaching signal for value-based choice behaviour, to learn to deselect, avoid or inhibit the potentially harmful, low valued or wrong choices, goals, strategies, predictions, models and ways of doing things, to prevent bad or suboptimal consequences.Comment: I renamed the medioventral part of the anterior thalamus via which the PFC to LHb fibre tracts from ventral anterior (AV) to medial anterior thalamic region. Apologies for that. My co-author decided to remove his nam

Acute modulation of brain connectivity in Parkinson disease after automatic mechanical peripheral stimulation: A pilot study

The present study shows the results of a double-blind sham-controlled pilot trial to test whether measurable stimulus-specific functional connectivity changes exist after Automatic Mechanical Peripheral Stimulation (AMPS) in patients with idiopathic Parkinson Disease.Eleven patients (6 women and 5 men) with idiopathic Parkinson Disease underwent brain fMRI immediately before and after sham or effective AMPS. Resting state Functional Connectivity (RSFC) was assessed using the seed-ROI based analysis. Seed ROIs were positioned on basal ganglia, on primary sensory-motor cortices, on the supplementary motor areas and on the cerebellum. Individual differences for pre- and post-effective AMPS and pre- and post-sham condition were obtained and first entered in respective one-sample t-test analyses, to evaluate the mean effect of condition.Effective AMPS, but not sham stimulation, induced increase of RSFC of the sensory motor cortex, nucleus striatum and cerebellum. Secondly, individual differences for both conditions were entered into paired group t-test analysis to rule out sub-threshold effects of sham stimulation, which showed stronger connectivity of the striatum nucleus with the right lateral occipital cortex and the cuneal cortex (max Z score 3.12) and with the right anterior temporal lobe (max Z score 3.42) and of the cerebellum with the right lateral occipital cortex and the right cerebellar cortex (max Z score 3.79).Our results suggest that effective AMPS acutely increases RSFC of brain regions involved in visuo-spatial and sensory-motor integration.This study provides Class II evidence that automatic mechanical peripheral stimulation is effective in modulating brain functional connectivity of patients with Parkinson Disease at rest.Clinical Trials.gov NCT01815281

Opioids depress cortical centers responsible for the volitional control of respiration

Respiratory depression limits provision of safe opioid analgesia and is the main cause of death in drug addicts. Although opioids are known to inhibit brainstem respiratory activity, their effects on cortical areas that mediate respiration are less well understood. Here, functional magnetic resonance imaging was used to examine how brainstem and cortical activity related to a short breath hold is modulated by the opioid remifentanil. We hypothesized that remifentanil would differentially depress brain areas that mediate sensory-affective components of respiration over those that mediate volitional motor control. Quantitative measures of cerebral blood flow were used to control for hypercapnia-induced changes in blood oxygen level-dependent (BOLD) signal. Awareness of respiration, reflected by an urge-to-breathe score, was profoundly reduced with remifentanil. Urge to breathe was associated with activity in the bilateral insula, frontal operculum, and secondary somatosensory cortex. Localized remifentanil-induced decreases in breath hold-related activity were observed in the left anterior insula and operculum. We also observed remifentanil-induced decreases in the BOLD response to breath holding in the left dorsolateral prefrontal cortex, anterior cingulate, the cerebellum, and periaqueductal gray, brain areas that mediate task performance. Activity in areas mediating motor control (putamen, motor cortex) and sensory-motor integration (supramarginal gyrus) were unaffected by remifentanil. Breath hold-related activity was observed in the medulla. These findings highlight the importance of higher cortical centers in providing contextual awareness of respiration that leads to appropriate modulation of respiratory control. Opioids have profound effects on the cortical centers that control breathing, which potentiates their actions in the brainstem

Combination antiretroviral therapy improves cognitive performance and functional connectivity in treatment-naïve HIV-infected individuals.

Our study aimed to investigate the short-term effect of combination antiretroviral therapy (cART) on cognitive performance and functional and structural connectivity and their relationship to plasma levels of antiretroviral (ARV) drugs. Seventeen ARV treatment-naïve HIV-infected individuals (baseline mean CD4 cell count, 479 ± 48 cells/mm3) were age matched with 17 HIV-uninfected individuals. All subjects underwent a detailed neurocognitive and functional assessment and magnetic resonance imaging. HIV-infected subjects were scanned before starting cART and 12 weeks after initiation of treatment. Uninfected subjects were assessed once at baseline. Functional connectivity (FC) was assessed within the default mode network while structural connectivity was assessed by voxel-wise analysis using tract-based spatial statistics (TBSS) and probabilistic tractography within the DMN. Tenofovir and emtricitabine blood concentration were measured at week 12 of cART. Prior to cART, HIV-infected individuals had significantly lower cognitive performance than control subjects as measured by the total Z-score from the neuropsychological tests assessing six cognitive domains (p = 0.020). After 12 weeks of cART treatment, there remained only a weak cognitive difference between HIV-infected and HIV-uninfected subjects (p = 0.057). Mean FC was lower in HIV-infected individuals compared with those uninfected (p = 0.008), but FC differences became non-significant after treatment (p = 0.197). There were no differences in DTI metrics between HIV-infected and HIV-uninfected individuals using the TBSS approach and limited evidence of decreased structural connectivity within the DMN in HIV-infected individuals. Tenofovir and emtricitabine plasma concentrations did not correlate with either cognitive performance or imaging metrics.ConclusionsTwelve weeks of cART improves cognitive performance and functional connectivity in ARV treatment-naïve HIV-infected individuals with relatively preserved immune function. Longer periods of observation are necessary to assess whether this effect is maintained

Alterations in white matter microstructure in neurofibromatosis-1.

Neurofibromatosis (NF1) represents the most common single gene cause of learning disabilities. NF1 patients have impairments in frontal lobe based cognitive functions such as attention, working memory, and inhibition. Due to its well-characterized genetic etiology, investigations of NF1 may shed light on neural mechanisms underlying such difficulties in the general population or other patient groups. Prior neuroimaging findings indicate global brain volume increases, consistent with neural over-proliferation. However, little is known about alterations in white matter microstructure in NF1. We performed diffusion tensor imaging (DTI) analyses using tract-based spatial statistics (TBSS) in 14 young adult NF1 patients and 12 healthy controls. We also examined brain volumetric measures in the same subjects. Consistent with prior studies, we found significantly increased overall gray and white matter volume in NF1 patients. Relative to healthy controls, NF1 patients showed widespread reductions in white matter integrity across the entire brain as reflected by decreased fractional anisotropy (FA) and significantly increased absolute diffusion (ADC). When radial and axial diffusion were examined we found pronounced differences in radial diffusion in NF1 patients, indicative of either decreased myelination or increased space between axons. Secondary analyses revealed that FA and radial diffusion effects were of greatest magnitude in the frontal lobe. Such alterations of white matter tracts connecting frontal regions could contribute to the observed cognitive deficits. Furthermore, although the cellular basis of these white matter microstructural alterations remains to be determined, our findings of disproportionately increased radial diffusion against a background of increased white matter volume suggest the novel hypothesis that one potential alteration contributing to increased cortical white matter in NF1 may be looser packing of axons, with or without myelination changes. Further, this indicates that axial and radial diffusivity can uniquely contribute as markers of NF1-associated brain pathology in conjunction with the typically investigated measures

Arbeiten zur Optischen Kohärenztomographie, Magnetresonanzspektroskopie und Ultrahochfeld-Magnetresonanztomographie

Abstrakt (Deutsch) Hintergrund: Die Multiple Sklerose ist eine der häufigsten neurologischen Erkrankungen, die zu Behinderung bereits im jungen Erwachsenenalter führen kann. Hierzu tragen im Krankheitsprozess sowohl neuroinflammatorische wie auch neurodegenerative Komponenten bei. Moderne bildgebende Verfahren wie die Ultrahochfeld-Magnetresonanztomographie (UHF-MRT), die Optische Kohärenztomographie (OCT) und die Magnetresonanzspektroskopie (MRS) können benutzt werden, um diese neurodegenerativen Prozesse näher zu charakterisieren und im zeitlichen Verlauf zu beobachten. Zielsetzung: Ziel ist es, die genannten Verfahren zur Charakterisierung von Kohorten von MS-Patienten einzusetzen und die Verfahren zueinander, sowie mit klinischen Parametern in Beziehung zu setzen oder diagnostisch zu nutzen. Methodik: Patienten mit Multipler Sklerose oder Neuromyelitis optica wurden klinisch-neurologisch, mit Optischer Kohärenztomographie, Sehprüfungen, Untersuchungen der visuell evozierten Potentiale (VEP), (Ultrahochfeld-) Magnetresonanztomographie und Magnetresonanzspektroskopie untersucht. Ergebnisse: Die in der Studie eingesetzten bildgebenden Verfahren konnten dazu beitragen, Neuroinflammation und Neurodegeneration bei an Multiple Sklerose erkrankten Patienten näher zu charakterisieren. So steht eine mittels OCT messbare Verdünnung retinaler Nervenfaserschichten (RNFL) in Zusammenhang mit dem per MRT gemessenen Hirnparenchymvolumen und Neurodegeneration anzeigenden Parametern, die mithilfe der Magnetresonanzspektroskopie untersucht wurden. Mithilfe der UHF-MRT konnte ein Zusammenhang zwischen dem Volumen und der entzündlichen Läsionslast der Sehstrahlung, der RNFL-Dicke, VEP-Latenzen und Einschränkungen des Sehvermögens dargestellt werden. Außerdem ließen sich mit der UHF-MRT auch neurogenerative Aspekte im Sinne von bleibenden Parenchymdefekten innerhalb entzündlicher Läsionen und einer Verschmächtigung der Sehstrahlung nachweisen und die Detektion insbesondere kortikaler MS-Läsionen wurde im Vergleich zur konventionellen MRT verbessert. Zusammenfassung: OCT, MRS und UHF-MRT sind Verfahren, die eine genauere Beschreibung von Neuroinflammation und Neurodegeneration bei MS-Patienten ermöglichen, wie hier vor allem für die Sehbahn gezeigt wurde. Sie sind nichtinvasiv und lassen sich zur näheren Charakterisierung des aktuellen Zustandes und zur Beobachtung des Krankheitsverlaufs von MS-Patienten benutzen.Abstract (English) Background: Multiple sclerosis (MS) is the most common disabling neurologic disease, that causes impairment in younger people. Both neuroinflammatory and neurodegenerative processes contribute to the pathogenesis of multiple sclerosis. Innovative imaging methods, such as ultra-high field magnetic resonance tomography (UHF-MRI), optic coherence tomography (OCT) and magnetic resonance spectroscopy (MRS) can be used for characterizing these neurodegenerative processes in detail and over time course. Objective: To use the imaging methods mentioned above to further characterize cohorts of MS patients and to correlate the parameters with themselves as well as with clinical parameters and to evaluate their prognostic and diagnostic relevance. Methods: Patients with multiple sclerosis were examined clinically, by OCT, visual acuity testing, examination of visually evoked potentials, ultra high field magnetic resonance tomography and magnetic resonance spectroscopy. Results: The imaging methods used in these studies contributed to further characterize neuroinflammation und neurodegeneration in multiple sclerosis patients. A thinning of the retinal nerve fiber layer (RNFL) is correlated with brain parenchyma volume measured by MRI, and markers indicating ongoing neurodegenerative processes as detected by MRS. Using UHF-MRI, a correlation between optic radiation properties (such as inflammatory lesion load and its volume) and RNFL thickness, VEP latencies and visual impairment could be demonstrated. Furthermore, UHF-MRI demonstrated neurodegenerative aspects such as parenchymal defects within inflammatory lesions, an optic radiation thinning and allowed a more precise detection of MS lesions than conventional MRI, in particular cortical grey matter lesions. Summary: OCT, MRS and UHF-MRI are feasible methods to provide a more detailed description of neuroinflammation and neurodegeneration in MS patients, as demonstrated in these studies particularly for the visual pathway. They are non-invasive and can be utilized for clinical to study the disease course and also in differential diagnostic procedures

White matter differences between healthy young ApoE4 carriers and non-carriers identified with tractography and support vector machines.

The apolipoprotein E4 (ApoE4) is an established risk factor for Alzheimer's disease (AD). Previous work has shown that this allele is associated with functional (fMRI) changes as well structural grey matter (GM) changes in healthy young, middle-aged and older subjects. Here, we assess the diffusion characteristics and the white matter (WM) tracts of healthy young (20-38 years) ApoE4 carriers and non-carriers. No significant differences in diffusion indices were found between young carriers (ApoE4+) and non-carriers (ApoE4-). There were also no significant differences between the groups in terms of normalised GM or WM volume. A feature selection algorithm (ReliefF) was used to select the most salient voxels from the diffusion data for subsequent classification with support vector machines (SVMs). SVMs were capable of classifying ApoE4 carrier and non-carrier groups with an extremely high level of accuracy. The top 500 voxels selected by ReliefF were then used as seeds for tractography which identified a WM network that included regions of the parietal lobe, the cingulum bundle and the dorsolateral frontal lobe. There was a non-significant decrease in volume of this WM network in the ApoE4 carrier group. Our results indicate that there are subtle WM differences between healthy young ApoE4 carriers and non-carriers and that the WM network identified may be particularly vulnerable to further degeneration in ApoE4 carriers as they enter middle and old age

An exploration of social and economic outcome and associated health-related quality of life after critical illness in general intensive care unit survivors: a 12-month follow-up study.

INTRODUCTION: The socio-economic impact of critical illnesses on patients and their families in Europe has yet to be determined. The aim of this exploratory study was to estimate changes in family circumstances, social and economic stability, care requirements and access to health services for patients during their first 12 months after ICU discharge. METHODS: Multi-center questionnaire-based study of survivors of critical illness at 6 and 12 months after ICU discharge. RESULTS: Data for 293 consenting patients who spent greater than 48 hours in one of 22 UK ICUs were obtained at 6 and 12 months post-ICU discharge. There was little evidence of a change in accommodation or relationship status between pre-admission and 12 months following discharge from an ICU. A negative impact on family income was reported by 33% of all patients at 6 months and 28% at 12 months. There was nearly a 50% reduction in the number of patients who reported employment as their sole source of income at 12 months (19% to 11%) compared with pre-admission. One quarter of patients reported themselves in need of care assistance at 6 months and 22% at 12 months. The majority of care was provided by family members (80% and 78%, respectively), for half of whom there was a negative impact on employment. Amongst all patients receiving care, 26% reported requiring greater than 50 hours a week. Following discharge, 79% of patients reported attending their primary care physician and 44% had seen a community nurse. Mobility problems nearly doubled between pre-admission and 6 months (32% to 64%). Furthermore, 73% reported moderate or severe pain at 12 months and 44% remained significantly anxious or depressed. CONCLUSIONS: Survivors of critical illness in the UK face a negative impact on employment and commonly have a care requirement after discharge from hospital. This has a corresponding negative impact on family income. The majority of the care required is provided by family members. This effect was apparent by 6 months and had not materially improved by 12 months. This exploratory study has identified the potential for a significant socio-economic burden following critical illness