Episodic memory impairment represents one of the hallmark clinical features of patients withAlzheimer's disease (AD) attributable to the degeneration of medial temporal and parietal regions of the brain. In contrast, a somewhat paradoxical profile of relatively intact episodic memory, particularly for non-verbal material, is observed in SD, despite marked atrophy of the hippocampus. This retrospective study investigated the neural substrates of episodic memory retrieval in 20 patients with a diagnosis of SD and 21 disease-matched cases of AD and compared their performance to that of 35 age-and education-matched healthy older were modality-specific occurring exclusively on the verbal task. Controlling for semantic processing ameliorated these deficits in SD, while memory impairments persisted in AD.Voxel-based morphometry analyses revealed significant overlap in the neural correlates of verbal episodic memory in AD and SD with predominantly anteromedial regions, including the bilateral hippocampus, strongly implicated. Controlling for semantic processing negated this effect in SD, however, a distributed network of frontal, medial temporal, and parietal regions was implicated in AD. Our study corroborates the view that episodic memory deficits in SD arise very largely as a consequence of the conceptual loading of traditional tasks. We propose that the functional integrity of frontal and parietal regions enables new learning to occur in SD in the face of significant hippocampal and anteromedial temporal lobe pathology, underscoring the inherent complexity of the episodic memory circuitry.

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Aging is known to affect nociceptive processing, e.g., the ability to inhibit pain. This study aims to investigate whether pain responses in older individuals are associated with prefrontal characteristics, namely (i) executive functioning performance and (ii) structural brain variations in the prefrontal cortex. Heat and pressure stimuli were applied to assess pressure pain sensitivity and endogenous pain inhibition in 46 healthy older individuals. Executive functioning performance was assessed in three domains (i.e., cognitive inhibition, shifting, and updating) and structural brain variations were assessed in both gray and white matter. Overall pain responses were significantly associated with the executive functioning domains cognitive inhibition and shifting. However, no specific type of pain response showed an especially strong association. Endogenous pain inhibition specifically showed a significant association with gray matter volume in the prefrontal cortex and with variations in white matter structure of tracts connecting the prefrontal cortex with the periaqueductal gray. Hierarchical regression analyses showed that these variations in the prefrontal cortex can explain variance in pain inhibition beyond what can be explained by executive functioning. This might indicate that known deficits in pain inhibition in older individuals are associated with structural variations in prefrontal areas.

Chapter 1 General introduction Chapter 2 Pain and executive functions: a systematic review Chapter 3 Does EEG activity during painful stimulation mirror more closely the noxious stimulus intensity or the subjective pain sensation? Chapter 4 Conditioned pain modulation (CPM) effects captured in facial expressions Chapter 5 Pain processing in older adults and its association with prefrontal characteristics Chapter 6 Pain processing in older adults with dementia-related cognitive impairment is associated with frontal neurodegeneration Chapter 7 General discussion Summary Samenvatting Dankwoord Curriculum vitae Chapter 1 General introduction 8 CHAPTER 1 General introductionThe proportion of older individuals in our society is increasing. 1 One of the many implications of this demographic change is that the number of individuals with pain also increases. Pain is quite prevalent in older compared to younger individuals, with more than half of the people over the age of 60 experiencing pain. 2,3 Pain is for example prevalent in older individuals with common chronic diseases such as cardiovascular, musculoskeletal and oncological diseases. 4 In order to treat pain well, it is important to study why older individuals become more vulnerable to pain.The present thesis studied the hypothesis that increased pain in older individuals might be due to decreased frontal brain functioning. We assessed frontal brain functioning by means of structural integrity of the frontal cortex and by neuropsychological performances that are linked to the function of the frontal cortex. The relation between pain and frontal functioning was not only studied in healthy older individuals but also in older individuals with dementia-related cognitive impairments, given that they might be even more vulnerable to pain due to more pronounced decreased frontal brain functioning.The rationale behind the frontal brain functioning hypothesis will be described in this general introduction. In the first part, the topic pain will be introduced, with a focus on the neurobiological pathways that mediate pain processing and the methods used to study pain processing in humans. In the second part, the current knowledge about the effect of age-and dementia-related cognitive impairment on pain processing will be discussed. At the end of this chapter, an overview of the studies described in the upcoming chapters will be given. Pain DefinitionThe newest definition of pain, updated in 2020, according to the International Association for the Study of Pain is that pain is "an aversive sensory and emotional experience typically caused by, or resembling that caused by, actual or potential tissue injury. " 5 This definition emphasizes that pain is an emotional and thus a subjective experience. Pain experience (especially acute pain) is often linked to nociceptive processes. Nociception refers to the physiological signal transduction and transmission in response to actual or potential tissue injury. 6 The two routes for nociceptive information, called the "ascending pain...