Hippocampal overshadowing : exploring the underlying mechanisms

The aim of the current thesis was to evaluate the underlying mechanisms of hippocampal (HPC) overshadowing. One theory to explain this phenomenon predicts that perceptual representation of an event is stored in non-HPC cortical areas. Following multiple distributed exposure to the same or similar event, this representation becomes stable and the cellular activation patterns can be recalled in the absence of HPC input. Through a series of experiments, the hypothesis that the dysgraunlar layer of the retrosplenial cortex (RSD) fulfill these requirements was tested. Using double in-situ hybridization for the mRNA of immediate-early genes Arc and Homer1a, the cellular activation patterns in HPC subregion CA1 and RSD were evaluated. In addition, temporary inactivation of HPC was used to evaluate cellular activation patterns of a HPC-independent memory in RSD. The results presented here support the idea that cellular activation patterns for may be stored – at least in part – in the RSD

The role of the hippocampus and post-learning hippocampal activity in long-term consolidation of context memory

x, 85 leaves : ill. ; 29 cmSutherland, Sparks and Lehmann (2010) proposed a new theory of memory consolidation, termed Distributed Reinstatement Theory (DRT), where the hippocampus (HPC) is needed for initial encoding but some types of memories are established in non-HPC systems through post-learning HPC activity. An evaluation of the current methodology of temporary inactivation was conducted experimentally. By permanently implanting two bilateral guide cannulae in the HPC and infusing ropivacaine cellular activity could be reduced by 97%. Rats were trained in a context-fear paradigm. Six learning episodes distributed across three days made the memory resistant to HPC inactivation while three episodes did not. Blocking post-learning HPC activity following three of six training sessions failed to reduce the rat’s memory of the fearful context. These results fail to support DRT and indicate that one or more memory systems outside the HPC can acquire context memory without HPC post-event activity

CADASIL Affects Multiple Aspects of Cerebral Small Vessel Function on 7T-MRI

International audienceObjective: Cerebral small vessel diseases (cSVDs) are a major cause of stroke and dementia. We used cutting-edge 7T-MRI techniques in patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), to establish which aspects of cerebral small vessel function are affected by this monogenic form of cSVD. Methods: We recruited 23 CADASIL patients (age 51.1 AE 10.1 years, 52% women) and 13 age-and sex-matched controls (46.1 AE 12.6, 46% women). Small vessel function measures included: basal ganglia and centrum semiovale perforating artery blood flow velocity and pulsatility, vascular reactivity to a visual stimulus in the occipital cortex and reactivity to hypercapnia in the cortex, subcortical gray matter, white matter, and white matter hyperintensities. Results: Compared with controls, CADASIL patients showed lower blood flow velocity and higher pulsatility index within perforating arteries of the centrum semiovale (mean difference À 0.09 cm/s, p = 0.03 and 0.20, p = 0.009) and basal ganglia (mean difference À 0.98 cm/s, p = 0.003 and 0.17, p = 0.06). Small vessel reactivity to a short visual stimulus was decreased (blood-oxygen-level dependent [BOLD] mean difference À0.21%, p = 0.04) in patients, while reactivity to hypercapnia was preserved in the cortex, subcortical gray matter, and normal appearing white matter. Among patients, reactivity to hypercapnia was decreased in white matter hyperintensities compared to normal appearing white matter (BOLD mean difference À0.29%, p = 0.02). Interpretation: Multiple aspects of cerebral small vessel function on 7T-MRI were abnormal in CADASIL patients, indicative of increased arteriolar stiffness and regional abnormalities in reactivity, locally also in relation to white matter injury. These observations provide novel markers of cSVD for mechanistic and intervention studies

Zooming in on cerebral small vessel function in small vessel diseases with 7T MRI: Rationale and design of the “ZOOM@SVDs” study

Background: Cerebral small vessel diseases (SVDs) are a major cause of stroke and dementia. Yet, specific treatment strategies are lacking in part because of a limited understanding of the underlying disease processes. There is therefore an urgent need to study SVDs at their core, the small vessels themselves. Objective: This paper presents the rationale and design of the ZOOM@SVDs study, which aims to establish measures of cerebral small vessel dysfunction on 7T MRI as novel disease markers of SVDs. Methods: ZOOM@SVDs is a prospective observational cohort study with two years follow-up. ZOOM@SVDs recruits participants with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL, N = 20), sporadic SVDs (N = 60), and healthy controls (N = 40). Participants undergo 7T brain MRI to assess different aspects of small vessel function including small vessel reactivity, cerebral perforating artery flow, and pulsatility. Extensive work-up at baseline and follow-up further includes clinical and neuropsychological assessment as well as 3T brain MRI to assess conventional SVD imaging markers. Measures of small vessel dysfunction are compared between patients and controls, and related to the severity of clinical and conventional MRI manifestations of SVDs. Discussion: ZOOM@SVDs will deliver novel markers of cerebral small vessel function in patients with monogenic and sporadic forms of SVDs, and establish their relation with disease burden and progression. These small vessel markers can support etiological studies in SVDs and may serve as surrogate outcome measures in future clinical trials to show target engagement of drugs directed at the small vessels

Imaging NeuroVascular, Endothelial and STructural Integrity in prepAration to TrEat Small Vessel Diseases. The INVESTIGATE-SVDs study Protocol

Background: Sporadic cerebral small vessel disease (SVD) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) share clinical and neuroimaging features and possibly vascular dysfunction(s). However few studies have included both conditions, assessed more than one vascular dysfunction simultaneously, or included more than one centre. The INVESTIGATE-SVDs study will assess several cerebrovascular dysfunctions with MRI in participants with sporadic SVD or CADASIL at three European centres. Methods: We will recruit participants with sporadic SVDs (ischaemic stroke or vascular cognitive impairment) and CADASIL in Edinburgh, Maastricht and Munich. We will perform detailed clinical and neuropsychological phenotyping of the participants, and neuroimaging including structural MRI, cerebrovascular reactivity MRI (CVR: using carbon dioxide challenge), phase contrast MRI (arterial, venous and CSF flow and pulsatility), dynamic contrast-enhanced MRI (blood brain barrier (BBB) leakage) and multishell diffusion imaging. Participants will measure their blood pressure (BP) and its variability over seven days using a telemetric device. Discussion: INVESTIGATE-SVDs will assess the relationships of BBB integrity, CVR, pulsatility and CSF flow in sporadic SVD and CADASIL using a multisite, multimodal MRI protocol. We aim to establish associations between these measures of vascular function, risk factors particularly BP and its variability, and brain parenchymal lesions in these two SVD phenotypes. Additionally we will test feasibility of complex multisite MRI, provide reliable intermediary outcome measures and sample size estimates for future trials

New perspectives on the cerebral small vessels with 7T MRI

Pathological research suggests that conditions such as small vessel disease originate from abnormalities of the cerebral small blood vessels. Currently, 7T MRI enables us to measure blood flow velocity and pulsatility of the small cerebral perforating arteries. In this thesis these blood flow velocity and pulsatility measures play a central role, and various aspects of these measurements are investigated. First, we focused on improving the accuracy and employability of the metrics. We therefore improved an existing method to detect the cerebral perforating arteries on MRI images, by decreasing the impact of subject movement during MRI scanning on the measurements. In addition, we aimed to increase the employability of the blood flow velocity and pulsatility measurements, by showing measurement feasibility on the much more available 3T MRI scanners. Secondly, we investigated the cerebral perforating arteries within the cardiovascular system. We showed that the blood flow velocity and pulsatility measurements in the perforating arteries are altered in people with flow disruptions or arterial stiffness changes in the larger vessels preceding the perforating arteries. This indicates that perforating artery blood flow velocity and pulsatility are related to the functioning of the cardiovascular system. Finally, we showed alterations of multiple aspects of the microvasculature in patients with a hereditary form of cerebrovascular disease. These findings also benefit research of non-hereditary small vessel disease due to their similarities. This thesis increases the understanding of the role of the microvasculature in small vessel disease, and shows its dynamic nature and functioning as part of the cardiovascular system

Impact of model and dose uncertainty on model-based selection of oropharyngeal cancer patients for proton therapy

Background: Proton therapy is becoming increasingly available, so it is important to apply objective and individualized patient selection to identify those who are expected to benefit most from proton therapy compared to conventional intensity modulated radiation therapy (IMRT). Comparative treatment planning using normal tissue complication probability (NTCP) evaluation has recently been proposed. This work investigates the impact of NTCP model and dose uncertainties on model-based patient selection. Material and Methods: We used IMRT and intensity modulated proton therapy (IMPT) treatment plans of 78 oropharyngeal cancer patients, which were generated based on automated treatment planning and evaluated based on three published NTCP models. A reduction in NTCP of more than a certain threshold (e.g. 10% lower NTCP) leads to patient selection for IMPT, referred to as ‘nominal’ selection. To simulate the effect of uncertainties in NTCP-model coefficients (based on reported confidence intervals) and planned doses on the accuracy of model-based patient selection, the Monte Carlo method was used to sample NTCP-model coefficients and doses from a probability distribution centered at their nominal values. Patient selection accuracy within a certain sample was defined as the fraction of patients which had similar selection in both the ‘nominal’ and ‘sampled’ scenario. Results: For all three NTCP models, the median patient selection accuracy was found to be above 70% when only NTCP-model uncertainty was considered. Selection accuracy decreased with increasing uncertainty resulting from differences between planned and delivered dose. In case of excessive dose uncertainty, selection accuracy decreased to 60%. Conclusion: Model and dose uncertainty highly influence the accuracy of model-based patient selection for proton therapy. A reduction of NTCP-model uncertainty is necessary to reach more accurate model-based patient selection