E.C.W. van Straaten

The organization of physiological brain networks

One of the central questions in neuroscience is how communication in the brain is organized under normal conditions and how this architecture breaks down in neurological disease. It has become clear that simple activation studies are no longer sufficient. There is an urgent need to understand the brain as a complex structural and functional network. Interest in brain network studies has increased strongly with the advent of modern network theory and increasingly powerful investigative techniques such as high-density EEG, MEG, functional and structural MRI. Modern network studies of the brain have demonstrated that healthy brains self-organize towards so-called small-world networks characterized by a combination of dense local connectivity and critical long-distance connections. In addition, normal brain networks display hierarchical modularity, and a connectivity backbone that consists of interconnected hub nodes. This complex architecture is believed to arise under genetic control and to underlie cognition and intelligence. Optimal brain network organization becomes disrupted in neurological disease in characteristic ways. This review gives an overview of modern network theory and its applications to healthy brain function and neurological disease, in particular using techniques from clinical neurophysiology, such as EEG and MEG.

Measuring progression of cerebral white matter lesions on MRI: Visual rating and volumetrics

Objective: To evaluate the concordance of a volumetric method for measuring white matter lesion (WML) change with visual rating scales. Methods: The authors selected a stratified sample of 20 elderly people (mean age 72 years, range 61 to 88 years) with an MRI examination at baseline and at 3-year follow-up from the community-based Rotterdam Scan Study (RSS). Four raters assessed WML change with four different visual rating scales: the Fazekas scale, the Scheltens scale, the RSS scale, and a new visual rating scale that was designed to measure change in WML. The authors assessed concordance with a volumetric method with scatter plots and correlations, and interobserver agreement with intraclass correlation coefficients. Results: For assessment of change in WML, the Fazekas, Scheltens, and periventricular part of the RSS scale showed little correlation with volumetrics, and low interobserver agreement. The authors’ new WML change scale and the subcortical part of the RSS scale showed good correlation with volumetrics. After additional training, the new WML change scale showed good interobserver agreement for measuring WML change. Conclusions: Commonly used visual rating scales are not well suited for measuring change in white matter lesion severity. The authors’ new white matter lesion change scale is more accurate and precise, and may be of use in studies focusing on progression of white matter lesions.

The Trees and the Forest: Characterization of complex brain networks with minimum spanning trees

In recent years there has been a shift in focus from the study of local, mostly task-related activation to the exploration of the organization and functioning of large-scale structural and functional complex brain networks. Progress in the interdisciplinary field of modern network science has introduced many new concepts, analytical tools and models which allow a systematic interpretation of multivariate data obtained from structural and functional MRI, EEG and MEG. However, progress in this field has been hampered by the absence of a simple, unbiased method to represent the essential features of brain networks, and to compare these across different conditions, behavioural states and neuropsychiatric/neurological diseases. One promising solution to this problem is to represent brain networks by a minimum spanning tree (MST), a unique acyclic subgraph that connects all nodes and maximizes a property of interest such as synchronization between brain areas. We explain how the global and local properties of an MST can be characterized. We then review early and more recent applications of the MST to EEG and MEG in epilepsy, development, schizophrenia, brain tumours, multiple sclerosis and Parkinsons disease, and show how MST characterization performs compared to more conventional graph analysis. Finally, we illustrate how MST characterization allows representation of observed brain networks in a space of all possible tree configurations and discuss how this may simplify the construction of simple generative models of normal and abnormal brain network organization.

The significance of medial temporal lobe atrophy A postmortem MRI study in the very old

Background: Medial temporal lobe atrophy (MTA) is a sensitive radiologic marker for Alzheimer disease (AD) and associated with cognitive impairment. The value of MTA in the oldest old (>85 years old) is largely unknown. Methods: A total of 132 formalin-fixed brains from the Vantaa 85+ community-based study were subjected to postmortem MRI. Visual ratings of MTA were determined in a blinded fashion and compared with neuropathologic findings and clinical assessment (dementia according to Diagnostic and Statistical Manual of Mental Disorders-III-R). Results: A strong relationship was found between MTA scores and Alzheimer pathology (p < 0.001). The previously proposed cutoff MTA score >2 correctly excluded subjects with no or borderline Alzheimer-type pathology (45/48), but was not very sensitive for AD (modified National Institute on Aging-Reagan Institute criteria). MTA scores >2 were also found in subjects with other primary neurodegenerative hippocampal pathology including hippocampal sclerosis, Lewy-related pathology, and argyrophilic grain disease, either alone or in combination with Alzheimer-type pathology. High MTA scores were associated with clinical dementia—in this subgroup, sensitivity was 63% and specificity 69% for AD. Conclusion: Medial temporal lobe atrophy (MTA) on postmortem MRI is sensitive to primary degenerative hippocampal pathology in the very old, but not specific for Alzheimer-type pathology. MTA scores of 2 or less are not frequently associated with dementia. GLOSSARY: AD = Alzheimer disease; AgD = argyrophilic grain disease; CERAD = Consortium to Establish a Registry for Alzheimer’s Disease; DLB = dementia with Lewy bodies; HS = hippocampal sclerosis; L-rP = Lewy-related pathology; MCI = mild cognitive impairment; MTA = medial temporal lobe atrophy.

Incident lacunes influence cognitive decline: the LADIS study.

Background: In cerebral small vessel disease, the core MRI findings include white matter lesions (WML) and lacunar infarcts. While the clinical significance of WML is better understood, the contribution of lacunes to the rate of cognitive decline has not been established. This study investigated whether incident lacunes on MRI determine longitudinal cognitive change in elderly subjects with WML. Methods: Within the Leukoaraiosis and Disability Study (LADIS), 387 subjects were evaluated with repeated MRI and neuropsychological assessment at baseline and after 3 years. Predictors of change in global cognitive function and specific cognitive domains over time were analyzed with multivariate linear regression. Results: After controlling for demographic factors, baseline cognitive performance, baseline lacunar and WML lesion load, and WML progression, the number of new lacunes was related to subtle decrease in compound scores for executive functions (p = 0.021) and speed and motor control (p = 0.045), but not for memory or global cognitive function. Irrespective of lacunes, WML progression was associated with decrease in executive functions score (p = 0.016). Conclusion: Incident lacunes on MRI parallel a steeper rate of decline in executive functions and psychomotor speed. Accordingly, in addition to WML, lacunes determine longitudinal cognitive impairment in small vessel disease. Although the individual contribution of lacunes on cognition was modest, they cannot be considered benign findings, but indicate a risk of progressive cognitive impairment.

Simple versus complex assessment of white matter hyperintensities in relation to physical performance and cognition: the LADIS study

BackgroundWhite matter hyperintensities (WMH) on MRI are associated with disorders of gait and balance and with cognitive impairment. The most suitable method to assess WMH in relation to the clinical evaluation of disturbances in these areas has not yet been established.AimTo compare a simple visual rating scale, a detailed visual rating scale and volumetric assessment of WMH with respect to their associations with clinical measures of physical performance and cognition.MethodsData were drawn from the multicentre, multinational LADIS study. Data of 574 subjects were available. MRI analysis included assessment of WMH using the simple Fazekas scale, the more complex Scheltens scale and a semi-automated volumetric method. Disturbances of gait and balance and general cognitive function were assessed using the Short Physical Performance Battery (SPPB) and the Mini Mental State Examination (MMSE), respectively.ResultsIrrespective of the method of measuring WMH, subjects with disturbances of gait and balance (SPPB≤10) had more WMH than subjects with normal physical performance. Subjects with mild cognitive deficits (MMSE≤25) had more WMH than subjects with normal cognition. Correlations between clinical measures and WMH were equal across methods of WMH measurement (SPPB: Spearman r=−0.22, −0.25, −0.26, all p<0.001; MMSE: Spearman r=−0.11, −0.10, −0.09, all p<0.05, for Fazekas scale, Scheltens scale and volumetry, respectively). These associations remained significant and comparable after correcting for age, gender and education in multivariate linear regression analyses.ConclusionSimple and complex measures of WMH yield comparable associations with measures of physical performance and cognition. This suggests that a simple visual rating scale may be sufficient, when analyzing relationships between clinical parameters and WMH in a clinical setting.

Opportunities and methodological challenges in EEG and MEG resting state functional brain network research

Electroencephalogram (EEG) and magnetoencephalogram (MEG) recordings during resting state are increasingly used to study functional connectivity and network topology. Moreover, the number of different analysis approaches is expanding along with the rising interest in this research area. The comparison between studies can therefore be challenging and discussion is needed to underscore methodological opportunities and pitfalls in functional connectivity and network studies. In this overview we discuss methodological considerations throughout the analysis pipeline of recording and analyzing resting state EEG and MEG data, with a focus on functional connectivity and network analysis. We summarize current common practices with their advantages and disadvantages; provide practical tips, and suggestions for future research. Finally, we discuss how methodological choices in resting state research can affect the construction of functional networks. When taking advantage of current best practices and avoid the most obvious pitfalls, functional connectivity and network studies can be improved and enable a more accurate interpretation and comparison between studies.

Diabetes mellitus, hypertension and medial temporal lobe atrophy : the LADIS study

Hypothesisu2002 Based on recent findings on the association between vascular risk factors and hippocampal atrophy, we hypothesized that hypertension and diabetes mellitus (DM) are associated with medial temporal lobe atrophy (MTA) in subjects without disability, independent of the severity of white matter hyperintensities.

Medial temporal lobe atrophy and white matter hyperintensities are associated with mild cognitive deficits in non-disabled elderly people: the LADIS study

Objective: To assess the associations of medial temporal lobe atrophy (MTA) and white matter hyperintensities (WMH) with cognitive function in a large group of independently functioning elderly people. Methods: Data were drawn from the multicentre, multinational leukoaraiosis and disability (LADIS) project which is studying prospectively the role of WMH as an independent predictor of the transition to disability in non-disabled elderly people. In all, 639 participants were enrolled in the LADIS study. For the present analysis, data on 581 subjects were available. Cognitive function was assessed by the mini-mental state examination (MMSE). Visual ratings of WMH and MTA were undertaken on magnetic resonance images (MRI). Results: The presence of either severe WMH or MTA was associated with a modest but non-significant increase in frequency of mild cognitive deficits (severe WMH: odds ratio (OR)u200a=u200a1.9 (95% confidence interval (CI), 1.0 to 3.7); MTA present: ORu200a=u200a1.5 (95% CI, 0.8 to 2.8)). However, subjects with the combination of MTA and severe WMH had a more than fourfold increase in frequency of mild cognitive deficits (ORu200a=u200a4.1 (95% CI, 2.3 to 7.4)). Analysis of variance with post hoc Bonferroni t tests showed that subjects with both MTA and severe WMH performed worse on MMSE than those with either no MRI abnormality or a single MRI abnormality (p<0.05). Conclusions: These results provide further evidence for the combined involvement of both Alzheimer type pathology and vascular pathology in the earliest stages of cognitive decline and suggest an additive effect of WMH and MTA.

Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects with age-related white-matter changes: the LADIS study

Objectives: In cerebral small vessel disease, white-matter hyperintensities (WMH) and lacunes are both related to cognition. Still, their respective contribution in older people remains unclear. The purpose of this study is to assess the topographic distribution of lacunes and determine whether it has an impact on cognitive functions in a sample of non-disabled patients with age-related white-matter changes. Methods: Data were drawn from the baseline evaluation of the LADIS (Leucoaraioisis and Disability study) cohort of non-disabled subjects beyond 65 years of age. The neuropsychological evaluation was based on the Mini Mental Status Examination (MMSE), a modified Alzheimer Diseases Assessment Scale for global cognitive functions, and compound Z scores for memory, executive functions, speed and motor control. WMH were rated according to the Fazekas scale; the number of lacunes was assessed in the following areas: lobar white matter, putamen/pallidum, thalamus, caudate nucleus, internal/external capsule, infratentorial areas. An analysis of covariance was performed after adjustment for possible confounders. Results: Among 633 subjects, 47% had at least one lacune (31% at least one within basal ganglia). The presence of lacunes in the thalamus was associated with lower scores of MMSE (βu200a=u200a−0.61; pu200a=u200a0.043), and worse compound scores for speed and motor control (βu200a=u200a−0.25; pu200a=u200a0.006), executive functions (βu200a=u200a−0.19; pu200a=u200a0.022) independently of the cognitive impact of WMH. There was also a significant negative association between the presence of lacunes in putamen/pallidum and the memory compound Z score (βu200a=u200a−0.13; pu200a=u200a0.038). By contrast, no significant negative association was found between cognitive parameters and the presence of lacunes in internal capsule, lobar white matter and caudate nucleus. Conclusion: In non-disabled elderly subjects with leucoaraisosis, the location of lacunes within subcortical grey matter is a determinant of cognitive impairment, independently of the extent of WMH.