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

Automated Assessment of Cerebral Arterial Perforator Function on 7T MRI

BACKGROUND: Blood flow velocity and pulsatility of small cerebral perforating arteries can be measured using 7T quantitative 2D phase contrast (PC) MRI. However, ghosting artifacts arising from subject movement and pulsating large arteries cause false positives when applying a previously published perforator detection method. PURPOSE: To develop a robust, automated method to exclude perforators located in ghosting artifacts. STUDY TYPE: Retrospective. SUBJECTS: Fifteen patients with vascular cognitive impairment or carotid occlusive disease and 10 healthy controls. FIELD STRENGTH/SEQUENCE: 7T/cardiac-gated 2D PC MRI. ASSESSMENT: Perforators were automatically excluded from ghosting regions, which were defined as bands in the phase-encoding direction of large arteries. As reference, perforators were manually excluded by two raters (T.A., J.J.M.Z.), based on perforator location with respect to visible ghosting artifacts. The performance of both censoring methods was assessed for the number of (Nincluded ), mean velocity (Vmean ), and pulsatility index (PI) of the included perforators. STATISTICAL TESTS: For within-method comparisons, inter- and intrarater reliability were assessed for the manual method, and test-retest reliability was assessed for both methods from repeated 2D PC scans (without repositioning). Intraclass correlation coefficients (ICCs) and their 95% confidence intervals (CIs) were determined for Nincluded , Vmean , and PI for all within-method comparisons. The ICC to compare between the two methods was determined with the use of both (test-retest) scans using a multilevel nonlinear mixed model. RESULTS: The automated censoring method showed a moderate to good ICC (95% CI) vs. manual censoring for Nincluded (0.73 [0.58-0.87]) and Vmean (0.90 [0.84-0.96]), and a moderate ICC for PI (0.57 [0.37-0.76]). The test-retest reliability of the manual censoring method was considerably lower than the interrater and intrarater reliability, indicating that scanner noise dominates the uncertainty of the analysis. DATA CONCLUSION: The proposed automated censoring method can reliably exclude small perforators affected by ghosting artifacts. LEVEL OF EVIDENCE: 3. TECHNICAL EFFICACY STAGE: 1

Velocity and Pulsatility Measures in the Perforating Arteries of the Basal Ganglia at 3T MRI in Reference to 7T MRI

Cerebral perforating artery flow velocity and pulsatility can be measured using 7 tesla (T) MRI. Enabling these flow metrics on more widely available 3T systems would make them more employable. It is currently unknown whether these measurements can be performed at 3T MRI due to the lower signal-to-noise ratio (SNR). Therefore, the aim of this study is to investigate if flow velocity and pulsatility in the perforating arteries of the basal ganglia (BG) can be measured at 3T MRI and assess the agreement with 7T MRI measurements as reference. Twenty-nine subjects were included, of which 14 patients with aortic coarctation [median age 29 years (21-72)] and 15 controls [median age 27 years (22-64)]. Using a cardiac-gated 2D phase-contrast MRI sequence BG perforating arteries were imaged at 3T and 7T MRI and perforating artery density (N density , #/cm2), flow velocity (V mean , cm/s) and pulsatility index (PI) were determined. Agreement between scanner modalities was assessed using correlation and difference plots with linear regression. A p-value ≤ 0.05 indicated statistical significance. It was shown that perforating artery flow velocity and pulsatility can be measured at 3T MRI (N density = 0.21 ± 0.11; V mean = 6.04 ± 1.27; PI = 0.49 ± 0.19), although values differed from 7T MRI measurements (N density = 0.95 ± 0.21; V mean = 3.89 ± 0.56; PI = 0.28 ± 0.08). The number of detected arteries was lower at 3T (5 ± 3) than 7T MRI (24 ± 6), indicating that 3T MRI is on average a factor 4.8 less sensitive to detect cerebral perforating arteries. Comparison with 7T MRI as reference showed some agreement in N density , but little to no agreement for V mean and PI. Equalizing the modalities' sensitivity by comparing the detected arteries on 7T MRI with the highest velocity with all vessels detected on 3T MRI, showed some improvement in agreement for PI, but not for V mean . This study shows that it is possible to measure cerebral perforating artery flow velocity and pulsatility at 3T MRI, although an approximately fivefold sample size is needed at 3T relative to 7T MRI for a given effect size, and the measurements should be performed with equal scanner field strength and protocol

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