The anatomy of excitement:Understanding and improving the effectiveness of electroconvulsive therapy

Electroconvulsive therapy (ECT) is an effective treatment for severe depression. In this thesis, I studied electroconvulsive therapy (ECT) research with the objective to improve the clinical outcome after treatment and to gain a better understanding of its working mechanisms. Multiple methods in ECT research were explored, varying with respect to sample selection (i.e., single- versus multi-center data), study design (i.e., observational retrospective study versus prospective RCT, controlled versus non-controlled), type of data (i.e., clinical, EEG, and [f]MRI), and the applied statistical models to analyze the data (i.e., frequentist versus Bayesian models). Additionally, I proposed a taxonomy of ECT research. The main chapters can be considered as specific case-examples of the child-nodes of this taxonomy. Thereby, this thesis contributes to improving the clinical outcome and understanding of the working mechanisms of ECT. Based on the findings in this thesis, I have discussed the methods that are commonly used in ECT research and which future directions this may take

Visuospatial neglect after stroke:heterogeneity, diagnosis and treatment.

The general objective of this thesis was to better understand and treat visuospatial neglect, a frequent and disabling disorder in lateralized attention. The first aim was to further unravel visuospatial neglect by focusing on several subtypes. In neglect research, mostly patients with left-sided neglect are included. Knowledge regarding neglect is, therefore, mainly based on a subset of patients. This is unfortunate, however, as our study showed that left- and right-sided neglect are both common after stroke. Furthermore, both patients with left- and right-sided neglect are less independent in mobility and self-care. It is, therefore, of great importance to adequately diagnose and treat both subtypes. Another subtype regards region-specific neglect. We studied neural substrates of peripersonal (i.e. within arm length) and extrapersonal (i.e. beyond arm length) neglect, and found that several right temporal and thalamic regions were related to both peripersonal and extrapersonal neglect, and several additional right temporal, parietal and occipital regions were only related to extrapersonal neglect. None of the brain regions were only related to peripersonal neglect. It seems that mostly shared anatomical regions are related to peripersonal and extrapersonal neglect. Today’s diagnosis of neglect lacks sensitivity, and discrepancies exist between performance on paper-and-pencil tasks and patient functioning in daily life. This is problematic for accurate diagnosis of neglect and for proper evaluation of rehabilitation interventions. We evaluated a dynamic multitask to assess neglect in a sensitive manner: the Mobility Assessment Course. An association existed between performance on the Mobility Assessment Course and performance on standard paper-and-pencil neglect tasks. Especially patients who were ‘recovered’, based on the paper-and-pencil tasks, showed neglect during the Mobility Assessment Course. This fits the hypothesis that this task may detect neglect in patients who do not show neglect during standard paper-and-pencil tasks. Next, we evaluated the potential of digitized neuropsychological testing. Next to the attentional bias, other cognitive processes that may relate to attention can be evaluated in more detail, such as search organization, involved in many daily processes and often disturbed after stroke. We studied search organization in stroke patients and found that, although disorganized search is related to neglect, this is only a weak relation, and it might be a separate cognitive construct. We conclude that analysing measures of search provides useful additional insights into the lower-order visuospatial processes of stroke patients. Finally, we evaluated the long-term effects of early treatment with prism adaptation compared to sham adaptation on neglect behaviour in daily life.Both patient groups (i.e., receiving sham adaptation and prism adaptation) improved on dynamic and static outcome measures of neglect. However, no differences were seen between groups. One of the main reasons for these neutral results could relate to the heterogeneity of the disorder, enhanced by the spontaneous neurobiological recovery in especially the subacute phase post-stroke onset or standard treatment effects (care as usual). They could have overshadowed the potential effects of prism adaptation. To conclude, prism adaptation is not effective for all patients with neglect, and, based on these results, should not be implemented in clinical practice

Obesity-induced chronic inflammation in C57Bl6J mice, a novel risk factor in the progression of renal AA amyloidosis?

Background: Compelling evidence links obesity induced systemic inflammation to the development of chronic kidney disease (CKD). This systemic inflammation may result from exacerbated adipose inflammation. Besides the known detrimental effects of typical pro-inflammatory factors secreted by the adipose tissue (TNF-α, MCP-1 and IL-6) on the kidney, we hypothesize the enhanced obesity-induced secretion of serum amyloid A (SAA), an acute inflammatory protein, to play a key role in aggravating obesity-induced CKD. Methods: Groups of male C57Bl/6J mice (n = 99 in total) were fed a low (10% lard) or high (45% lard) fat diet for a maximum of 52 weeks. Mice were sacrificed after 24, 40 and 52 weeks. Whole blood samples, kidneys and adipose tissues were collected. The development of adipose and renal tissue inflammation was assessed on gene expression and protein level. Adipocytokine levels were measured in plasma samples. Results: A distinct inflammatory phenotype was observed in the adipose tissue of HFD mice prior to renal inflammation, which was associated with an early systemic elevation of TNF-α, leptin and SAA (1A-C). With aging, sclerotic lesions appeared in the kidney, the extent of which was severely aggravated by HFD feeding. Lesions exhibited typical amyloid characteristics (2A) and pathological severity positively correlated with bodyweight (2B). Interestingly, more SAA protein was detected in lesions of HFD mice. Conclusion: Our data suggest a causal link between obesity induced chronic inflammation and AA amyloidosis in C57Bl/6J mice. Though future studies are necessary to prove this causal link and to determine its relevance for the human situation, obesity may hence be considered a risk factor for the development and progression of renal AA amyloidosis in the course of CKD. (Figure Presented)