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Recently, cerebral structural covariance networks (SCNs) have been shown to partially overlap with functional networks. However, although for some of these SCNs a strong association with age is reported, less is known about the association of individual SCNs with separate cognition domains and the potential mediation effect in this of cerebral small vessel disease (SVD). In 219 participants (aged 75-96 years) with mild cognitive deficits, 8 SCNs were defined based on structural covariance of gray matter intensity with independent component analysis on 3DT1-weighted magnetic resonance imaging (MRI). Features of SVD included volume of white matter hyperintensities (WMH), lacunar infarcts, and microbleeds. Associations with SCNs were examined with multiple linear regression analyses, adjusted for age and/or gender. In addition to higher age, which was associated with decreased expression of subcortical, premotor, temporal, and occipital-precuneus networks, the presence of SVD and especially higher WMH volume was associated with a decreased expression in the occipital, cerebellar, subcortical, and anterior cingulate network. The temporal network was associated with memory (p = 0.005), whereas the cerebellar-occipital and occipital-precuneus networks were associated with psychomotor speed (p = 0.002 and p

With increasing age the prevalence of hypertension rises. High blood pressure at midlife is associated with cognitive impairment. Nevertheless, in older persons a lower rather than a higher blood pressure is associated with incident dementia. The main purpose of the work in this thesis was to explore the role of blood pressure in relation to cerebral structure, neurocognitive functioning and hemodynamics of the brain in old age. Therefore, we sought to determine whether discontinuation of antihypertensive therapy in persons aged 75 years and over with mild cognitive deficits and using antihypertensive medication (the Discontinuation of ANtihypertensive Treatment in Elderly people [DANTE] population) would improve their cognitive and psychological functioning. The assumption was that the increase in blood pressure after the discontinuation of antihypertensives would lead to a direct increase in cerebral blood flow and, as a consequence, to an improvement in cerebral functioning. An additional objective was to investigate possible underlying mechanisms in the relation between blood pressure and neurocognitive functioning. To enable this, brain MRI was used to determine whether (lower) blood pressure was associated with (micro)structural damage, cerebral small vessel disease and blood flow in the brain, and also whether the presence of cerebral (micro)structural damage was related to neurocognitive functioning.

Insomnia is a major risk factor for the development of major depressive disorder (MDD), and has a negative impact on the course of the disease and the effectivity of treatment. Prevention of depression in insomnia patients is essential to reduce the global disease burden of MDD. Targeting insomnia seems promising, yet it remains unclear whether insomnia treatment can effectively prevent depression in insomnia patients, and how insomnia treatment can best be optimized. Therefore, in this thesis we examined whether we can prevent depression in insomnia patients with therapist-guided digital interventions aimed at improving sleep. Neurobiology of insomnia and its relation to depression In chapter 2 we investigated hippocampal volume and functional connectivity of the hippocampus in insomnia patients. Hippocampal volume and functional connectivity patterns were obtained from structural and functional MRI scans. The findings indicate that compared to good sleeper controls, insomnia patients showed increased functional connectivity between the bilateral hippocampus and the left middle frontal gyrus. Impaired hippocampal-prefrontal circuits might contribute to the vulnerability of insomnia patients to develop mood disorders. In chapter 3 we assessed structural brain correlates of insomnia severity in MDD patients. We acquired cortical surface area, thickness and subcortical volume measures from 1053 MDD patients from 15 cohorts of the ENIGMA-MDD consortium. The results revealed that MDD patients with more severe insomnia had a smaller total cortical surface area. The better specificity of reduced surface area with insomnia severity than with total depression severity provide support for the possibility that insomnia may represent a symptom cluster of MDD with a distinct underlying neurobiology. Preventing depression with insomnia treatment The randomized controlled trial of chapter 4 and 5 focused on the prevention of worsening of depressive symptoms in insomnia subtypes at high risk to develop MDD. A total of 132 insomnia patients were randomized to therapist-guided digital CBT-I, CRS, CBT-I+CRS, or no treatment (NT). Depressive symptoms were measured prior to treatment, and at four follow-up assessments during the following year. Without treatment depressive symptoms worsened during the one-year follow-up in individuals with an insomnia subtype with high-risk to develop depression, while a reference group including insomnia subtypes with a low-risk of depression did not worsen over time. Therapist-guided CBT-I and CBT-I+CRS reduced depressive symptoms across all four follow-up assessments. Only CBT-I+CRS had a reduced incidence of clinical meaningful worsening during the one-year follow-up. These results demonstrate that CBT-I, especially in combination with CRS, could be an effective and feasible approach to prevent worsening of depressive symptoms. In chapter 6 we evaluated diagnoses of first-onset MDD and dysthymia in insomnia patients on average 3.6 years after they had received either therapist-guided digital CBT-I, CBT-I+CRS, or NT. People that had received CBT-I combined with CRS were less likely to be diagnosed with MDD and/or dysthymia than participants that had received either standalone CBT-I or no treatment at all. These findings extent the findings from chapter 5, by demonstrating the effectivity of CBT-I+CRS to prevent new-onset mood disorders at a long follow-up. Effect of insomnia interventions on activity in emotional brain circuits Chapter 7 focused on the effect of these therapist-guided digital insomnia interventions on activity in the brain circuits involved in emotion regulation. Pre-to-post-intervention changes in emotional brain activity, assessed with the Hariri emotion face/shape fMRI task, were compared between insomnia patients who received CBT-I, CRS, CBT- I+CRS, or NT. Combined CBT-I+CRS intervention had the longest-lasting favorable effect on mood, which was paralleled by a significant pre-to-post-intervention increase in bilateral amygdala activation in response to emotional stimuli. These results provide a better understanding of how neurobiological changes in emotional brain functioning might underlie the therapeutic effects of CBT-I+CRS.