Vascular risk factors for depression and apathy | Part II 128 The age range and demographic characteristics of study populations were diverse. The majority of studies looked at adults and often at older adults, including communitydwelling individuals and/or (mildly or severely) functionally impaired inpatients or outpatients. Study participants resided in European, North-American and Asian countries, no data were available on residents of South- and Central-America, Africa and Australia. Overall, the WMH-apathy association was consistent across the study populations. Associations between other neuroimaging markers or the total CSVD burden and apathy have received less broad attention as yet. We next looked at measurement instruments for either CSVD or apathy and whether associations were consistent regardless of the techniques applied. CSVD was mainly investigated using magnetic resonance imaging, diffusion tensor imaging or positron emission tomography scans, with which WMH, lacunes (number or volumes), subcortical infarcts, microbleeds, perivascular spaces or total CSVD burden were assessed 20. Studies measuring WMH 30, WMH network connectivity 24 26 and total CSVD burden consistently showed associations with apathy 39 40. Studies focusing on other neuroimaging markers of CSVD were scarce or showed inconsistent results. The studies involved used a diversity of apathy scales, but most widely used and validated, i.e., the AES 8 24 37 39 54 31, the apathy scale (AS) 61 55 53 47 50 32 33, the apathy scale of the Neuropsychiatric Inventory 62 42 52 35 44 45 58 48 49 40 and the 3A scale of the Geriatric Depression Scale (GDS 3A)63 64 26 46 10. We could not establish a pattern demonstrating that one scale yielded different results regarding the CSVD-apathy association than other scales. It is known, however, that in cognitively impaired persons self-reported apathy is not as reliable as clinician of informant rated indices 8. Since evidence of a CSVD-apathy association was obtained in different populations, and not exclusively in individuals with cognitive impairment, and since many of these latter studies used clinician or informant rated scales, it is not likely that this (significantly) influenced the results. Coherence Is the causal relationship between CSVD and apathy coherent with knowledge from other sources of information? In rats, damage to the mediofrontal pathways disturbs effort-based decision making: rather than seeking large rewards at the expense of great effort, they were more likely to choose smaller rewards demanding less effort 65. In humans, apathy is a common symptom following bilateral anterior cingulotomy, a procedure for therapy resistant severe chronic pain in which the ACC is cleaved 66, and also frequently mentioned in case-reports of brain damage of the ACC 67. Apathy was also noted in a study of 114 patients with iatrogenic brain damage due to radiotherapy of the whole brain for primitive cerebral neoplasia, where the level of apathy depended on the cumulative doses of radiotherapy and was associated with the extent of the white matter damage 68.
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