People with chronic diseases, such as CF, are at increased risk of depression and autonomic deficits. In addition, many aspects of the disease itself can lead to high levels of anxiety. We report significantly high scores of BAI and BDI-II in CF patients over healthy controls, consistent with previous studies [26, 27]. Also, we found that CF patients had a lower overall MoCA scores and this change was most significant in the visuospatial/executive sub domains. Several brain sites, including cerebellum, hippocampus, amygdala, insula, prefrontal, and temporal sites showed tissue changes based on GM density or T2-relaxometry procedures, areas that are involved in cognition, mood, and autonomic functions. Neuronal damage meditated through hypoxia and/or hypercapnia is considered to be one of the key mechanisms in pulmonary diseases [28, 29]. Both hypoxia and hypercapnia are often present in CF patients along with mutated CFTR gene and are potential underlying causes for the observed neural findings.
CF patients showed cognitive dysfunction, including the executive function, and mood deficits. Executive function is associated with skills requiring higher mental activities, such as setting goals, abstract logical thinking, planning, taking into account the long-term consequences, initiating intentional actions, creating different possible alternative reactions, or modifying own activity in response to changing conditions. Abnormal executive function has been found in other diseases with respiratory compromise, such as chronic obstructive pulmonary disease, asthma, obstructive sleep apnea [30–32], and abnormal function in CF patients may contribute to such diminished actions. Depression and anxiety, as observed in our study, affects disease management, including clinic attendance and adherence to prescribed treatments, leading to increased hospitalization and healthcare costs, worse pulmonary function, and decreased health-related quality of life [27, 33–35]. These findings reiterate the need for annual screening for depression and anxiety in patient with CF.
Although cognitive and mood symptoms are considered to be due to aspects surrounding the diagnosis of the disease, our findings show that CF patients have a brain structural basis for these symptoms. CF patients showed increased GM density and reduced T2-relaxation values in several brain areas, though GM density measures indicated more changes over T2-relaxometry. Such particular brain tissue changes were evident in the cerebellum, hippocampus, amygdala, superior temporal cortices, basal forebrain, insula, parietal cortices, and frontal and prefrontal cortices. The increased GM density or reduced T2-relaxation values in our patient population might be due to increased neuronal and axonal swelling (although the disease is chronic, the condition is associated with ongoing hypoxia), increased size neurons, increased glial cell size or number, higher vascular density to support sustained increased metabolic demand, more connective tissue, dendritic outgrowth, or synaptogenesis [36, 37]. Higher neuronal numbers may result from an abnormal developmental process, including accentuated neuronal birth rate or the survival of excess neurons . In addition, the elevated GM density may be related to pre-apoptotic osmotic changes or hypertrophy, marking areas of early neuronal deficits. Previous depression studies indicated increased glucose metabolism [38, 39] resulting from the inhibition of reciprocal connections between the prefrontal cortex and the amygdala in limbic-thalamic-cortical circuit or limbic-cortical-striatal-pallidal-thalamic circuit enlarging amygdala [37, 40], and such processing may be operating in other structures as observed here.
The hippocampus, prefrontal cortices, and amygdala regions are highly interconnected and constitute the neuroanatomical network for mood regulation [40, 41], and these areas showed increased GM density or altered T2-relaxation values in our study. Activation of the amygdala has been demonstrated to increase dopamine in the nucleus accumbens and other motor control centers, resulting in increased fear behaviors and anxiety and might be plausible explanation for higher anxiety in CF patients. The amygdala and hippocampus have projections from the prefrontal cortices and other limbic-related forebrain structures that are involved in several cognitive domains, and increased GM volume or altered T2-relaxation values in these sites, as found in our study, may suggest abnormal cognition. The superior temporal gyrus has connections to limbic and prefrontal regions , and right superior temporal structures in particular have been associated with responses to emotional prosody . The superior temporal lobe along with insula and cingulate regions form a part of the salience network that is involved in the coordination of the behavioral responses. The anterior insula displays altered functional connectivity within the salience network and with other brain network in depression condition. Another brain region that showed increased GM density and tissue changes was cerebellum, where climbing fiber codes error signal reflecting the motor performance failure and works to depress the synaptic transmission between parallel fibers and Purkinje cell that can lead to depression and autonomic deficits [44, 45]. Furthermore, the cerebellum contributes to cognitive processing in several cognitive domains, including executive and visuospatial functioning and extensively interconnected with the cerebral hemisphere, both in feed-forward and feed-backward directions, and provides a structural basis for cognitive deficits in CF patients.
Patients with CF experience a wide spectrum of chronic pain, including headache, chest pain, back pain, abdominal pain, and limb pain . Brain regions that showed increased GM density or altered T2-relaxation values, including the insula and hippocampus, are subjected to pain modulation and stress-induced changes [47, 48]. Stress can lead to microglial proliferation in areas around the third ventricle, including hippocampus, and activate microglia that can cause neuronal damage with the release of proinflammatory and cytotoxic factors and plausibly increase GM density or alter T2-relaxation values as observed in our study. Several brain areas showed reduced T2-relaxation values in CF patients which could result from increased astrocyte and microglial activation due to chronic pain. Earlier human postmortem studies reported reduced T2-relaxation values due to pronounced reactive microgliosis and astrogliosis , and showed the association between chronic pain and prolonged astrocyte activation at the level of the primary afferent synapse [49, 50].
Multiple diseases have demonstrated altered GM and white matter volume and tissue integrity [10–12, 51, 52]. However, this is the first study that shows significant brain structural (GM density and brain tissue integrity) changes in CF patients, which could account for the symptomatology reported in the condition. Several basic and clinical studies, particularly those using neuroimaging techniques, report that specific brain regions play essential roles in cognitive, autonomic, depression, and anxiety regulation [51, 52]. The altered brain regions we encountered in CF patients have a considerably important role in their cognitive and mood wellbeing. With a high incidence of psychological symptoms in adult CF patients, this study highlights the importance for improved early identification and management strategies for adult CF patients.
One of the limitations of this study is the small sample size that may affect the statistical analyses with findings not corrected for multiple comparisons, and may limit the magnitude of the significant alterations, as well as with type 1 error that we observed in various brain regions of CF patients. Also, T2-relaxometry procedures had poor resolution in slice thickness direction, resulting to less sites with damage over GM density measures. Thus, procedures with higher resolution would be required with bigger sample size to examine extend of tissue damage. We used MoCA, BDI-II, and BAI screening instruments to identify cognitive impairment and symptoms of depression and anxiety, combined with comprehensive clinical tests should be used for future studies.