Fatigue is increasingly becoming recognized as a significant debilitating symptom and side effect experienced by many patients engaged in long-term hemodialysis treatment (HD) [1,2,3,4,5,6,7]. Its prevalence ranges from 60 to 97% of the hemodialysis population and it is one of the most frequent complaints of dialysis patients because of the considerable effect on their quality of life (QoL) up to the point that is viewed as being more important than survival by some patients [4, 8].
The etiology of fatigue is multifactorial, however, to date its specific causes in HD patients are still not well understood. Research in other chronic illness conditions suggested that fatigue can be divided into two dimensions, i.e. 1) the physical, encompassing muscle weakness and lack of energy (peripheral fatigue), and 2) the mental, including emotional and cognitive qualities (central fatigue) [9, 10], and that is mediated by inflammation. In line with this, previous studies in HD patients shown that fatigue causes include both muscular and central nervous system activation failures [11], and an association between fatigue onset and laboratory variables related to chronic inflammation has been demonstrated [1].
Indeed, it has been suggested that essentially central fatigue is related to chronic inflammation in patients with chronic disease [12]. Associations between fatigue and inflammatory markers (primarily Interleukin-6, Tumor Necrosis Factor-alpha (TNFα) and C-reactive protein, an acute phase protein) have been previously documented in various medical conditions, including cancer, chronic inflammatory disease, autoimmunity, neurological diseases, and mood disorders [13,14,15]. With regard, specifically, to end-stage renal disease an association between fatigue and serum IL-6 levels or tryptophan has been recently demonstrated [1, 16].
Inflammatory processes have also been shown to influence the functioning of basal ganglia and therefore it has been postulated that dysfunction in this subcortical structure may underpin a reduced motivation and altered reward processes in chronic populations [9, 10, 12]. Stimulation of the immune system or the administration of inflammatory cytokines to laboratory animals and humans results in a repertoire of behavioral changes, many of which overlap with those experienced during medical illness and those that have been classically described in depression. Many of these symptoms are also consistent with disruption of the basal ganglia and dopamine function, including anhedonia, fatigue, psychomotor disturbance, and changes in sleep [17, 18]. There is also evidence, by structural and functional magnetic resonance imaging, alongside diffusion tensor imaging and functional connectivity studies, of significant brain indicators of fatigue essentially in the frontal lobe, parietal lobe, limbic system and basal ganglia [19].
Indeed, basal ganglia together with cortico-frontal brain structures control the reward system that is responsible for regulating motivational disposition mechanisms that predispose to the activation or inhibition of the action. Accordingly, an impairment in motivation and reward mechanisms have been hypothesized to have a role in chronic patients’ fatigue experience [12].
In order to better understand the relationship between fatigue and reward system in patients on hemodialysis treatment, Gray’s Behavioural Inhibition System (BIS) and Behavioural Activation System (BAS) model [20, 21] may holds potential for exploring behavioral motivational responses that are relevant to approach and withdrawal behavior. Indeed, according to this model two fundamental motivational systems, BIS and BAS, may explain individuals motivation and emotion at four different levels: behavioral, neural (i.e., defining the brain structures and activity related to motivational behaviors), computational, and personality level, that reflects individual differences in the functioning of the basic systems of motivation [22].
Going down with the specifics, BAS was conceptualized as a motivational system that is sensitive to signals of reward, engaging approach behavior, and positive emotional attitudes. BIS reflects the sensitivity to punishment that promotes negative reinforcement of avoidance, withdrawal behavior [20, 21]. Previously BIS/BAS components have been related to prefrontal cortex structures, and while left prefrontal area was linked approach-related motivations and emotions, the right prefrontal area was shown to be associated to withdrawal-related motivations and emotions [23, 24]. In addition to prefrontal brain areas, Angelides and colleagues (2017) have recently demonstrated a novel correlation between BAS fun seeking construct and resting-state connectivity, between middle orbitofrontal cortex and putamen, implying that spontaneous synchrony between reward-processing brain regions (even subcortical basal ganglia regions) may play a role in defining personality characteristics related to impulsivity [25]. Former findings suggested it is necessary to consider gender-related characteristics to develop a more complete understanding of the shared factors that influence BIS/BAS functioning and related behavioral outcomes [26, 27]. Indeed, BIS and the prevalence rates of various affective disturbances, such as anxiety, depression and, dysthymia are higher in females than males [28, 29]. While BAS and incidence rates of substance abuse, impulsive behaviors, compulsive behaviors and aggression, are higher in males [30]. Besides previous studies suggested a possible correlation between behavioral inhibition and activation systems, reflecting motivational dispositions, levels of fatigue and different patients’ experiences of chronic conditions, comparable to hemodialysis treatment [12, 31, 32]. Taken together, these evidences allowed us to suppose that BIS/BAS theoretical framework and related measurement scale could be interesting firstly to measure motivational tendency in HD patients and then to be linked to possible differences in their fatigue severity levels.
On the other hand, relatively recent theoretical frameworks for understanding the construct of fatigue proposed the conceptualization of this symptom as a “multi-dimensional fatigue” that is experienced by chronic hemodialysis patients and that can be categorized into four inextricably linked domains: physiological/physical, dialysis-related, psychological/behavioral (including affective and cognitive aspects), and sociodemographic [4]. Jhamb and colleagues (2008) summarized relevant psychological contributing factors to fatigue manifestation in HD patients such as anxiety, stress, depression, sleep disorders and substance use, and sociodemographic factors (age, sex, race, employment status, marital status, education and social support) [8, 33, 34]. Interestingly, gender has been suggested to be a moderating variable in the ability to resist to fatigue between males and females: a greater resistance to fatigue seems to be presented by females when compared to males in chronic condition [35].
Besides these factors, research in nephrology identified relevant psychosocial variables to fatigue in hemodialysis patients thanks to the use of qualitative techniques that disclosed the viewpoint of patients (e.g. the international Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) initiative) [2, 5, 7, 36]. Indeed, with the aim to explore chronic HD patients’ lived experiences, fatigue experience, illness representation and coping strategies, former research using semi-structured interviews identified many interesting topics, such as patients’ intentional isolation (because they decreased interest, motivation and apathy to the surroundings), change in lifestyle/adopting a healthy lifestyle, coping with fatigue, seeking religious support, realizing the long-term, irreversible nature of the disease and many others [37,38,39].
Also, other previous qualitative studies focusing on individual experiences of patients on chronic hemodialysis identified interesting analytic themes connected also to motivational and fatigue issue [32, 40,41,42,43,44,45,46]. Qualitative techniques could be considered a useful method to bring out underlying dimensions of chronic HD treatment that are usually covert or merely observed and these could be related to other relevant constructs, such as fatigue and motivation. Thus, we believe that given the theoretical conceptualization of BIS/BAS as possible moderators of fatigue, the added value of including qualitative components could be the reinforcement and elucidation of motivational and fatigue related aspects in this chronic population. So far, to our knowledge, only one previous study investigated the association between BIS/BAS motivational systems, fatigue severity and words belonging to psychosocial topics emerging from interviews applied to hemodialysis patients [32]. This novel preliminary evidence highlighted how HD patients narratives analysis allowed to suggest an association on one side between higher levels of BIS and patients’ tendency to stress more the negative aspects of their daily routine, from the other side between patients with high and medium levels of BAS and their use of a vocabulary associated to approach behavior, such as the use of words related to their role in seeking strategies to face chronic conditions.
For this reason, the main aims of this study are firstly to investigate a possible link between BIS/BAS components, reflecting behavioral motivational responses that are relevant to approach and withdrawal behavior, and fatigue severity in HD patients; secondly, to examine the influence of gender in the relationship between BIS/BAS and fatigue; thirdly, to explore how HD patients’ lived experiences further reflect and may reinforce the relationship between BIS/BAS and fatigue.
In line with these main objectives we firstly hypothesized a positive correlation between high levels of BIS and higher fatigue severity scores and a negative correlation between BAS and fatigue scores. Moreover, gender was hypothesized to affect the relationship between BIS/BAS and fatigue. Then, BIS and Fatigue Severity Scale (FSS) were supposed to be positively linked to the presence of more negative themes emerging from HD patients’ semi-structured interviews. On the other hand, BAS component was expected to correlate with more positive themes and lower pervasiveness and interference of the HD treatment.