Background: Patients with head and neck cancer (HNC) experience psychoneurological symptoms (PNS, i.e., depression, fatigue, sleep disturbance, pain, and cognitive dysfunction) during intensity-modulated radiotherapy (IMRT) that decrease their functional status, quality of life, and survival rates. The purposes of this study were to examine and visualize the relationships among PNS within networks over time and evaluate for demographic and clinical characteristics associated with symptom networks.
Methods: A total of 172 patients (mean age 59.8±9.9 years, 73.8% male, 79.4% White) completed symptom questionnaires four times, namely, prior to IMRT (T1), one month (T2), three months (T3), and 12 months (T4) post IMRT. Network analysis was used to examine the symptom-symptom relationships among PNS. Centrality indices, including strength, closeness, and betweenness, were used to describe the degrees of symptom network interconnections. Network comparison test was used to assess the differences between two symptom networks.
Results: Depression was associated with the other four symptoms, and fatigue was associated with the other three symptoms across the four assessments. Based on the centrality indices, depression (rstrength=1.3–1.4, rcloseness=0.06–0.08, rbetweeness=4–10) was the core symptom in all symptom networks, followed by fatigue. Female gender, higher levels of stress, and no alcohol use were associated with stronger symptom networks in network global strength prior to IMRT.
Conclusion: Network analysis provides a novel approach to gain insights into the relationships among self-reported PNS and identify the core symptoms and associated characteristics. Clinicians may use this information to develop symptom management interventions that target core symptoms and interconnections within a network.
Objective:
Psychological and physical symptoms commonly occur in patients with metastatic lung cancer and are associated with reduced quality of life and decreased survival. Previous work has associated these symptoms with inflammation. The experience of Early Childhood Adversity (ECA) is linked to chronic inflammation and may identify adult cancer patients who are at-risk for psychological and physical symptoms. We thus hypothesized that ECA in lung cancer patients would be associated with increased psychological symptoms (distress, anxiety, and depression) and physical symptoms and that this relationship would be explained by inflammation.
Methods:
Patients with metastatic lung cancer (n = 92) were evaluated for ECA using the Risky Families Questionnaire. Concomitant assessments were made of distress (Distress Thermometer and Problem List [DT&PL]), anxiety (Generalized Anxiety Disorder-7), depression (Patient Hospital Questionniare-9), physical symptoms (DT&PL), and inflammation (C-reactive protein [CRP]). Multivariate models were created to explain associations of ECA with depression, anxiety, distress, number of physical problems, and inflammation.
Results:
ECA was associated with distress (r = 0.24, p = .03), anxiety (r = 0.30, p = .004), depression (r = 0.35, p = .001), greater physical problems (r = 0.25, p = .03), younger age (r = -0.29, p = .006), and elevated CRP (r = 0.22, p = .04). Multivariate analyses of outcomes found that depression severity was independently explained by both ECA and inflammation (β = 0.37, p = .001) but not distress or anxiety, while controlling for age and sex. Number of physical problems were also associated with ECA (β = 0.35, p = .004) but not inflammation. The association between ECA and physical problems was not significant after controlling for depression.
Conclusion:
ECA is associated with increased depression and physical symptoms independent of inflammation. Moreover, depression appears to mediate the impact of ECA on physical symptoms. ECA may identify patients at risk for psychological and physical symptoms.
Objective: To explore biopsychosocial factors (beliefs, depression, catastrophizing cytokines) in individuals newly diagnosed with lung cancer and no pain to determine their relationship at diagnosis and across time and to determine whether these factors contribute to pain intensity or pain interference with function at pain onset. Materials and Methods: A longitudinal, exploratory, pilot study was implemented in a private medical center and a VA medical center in the southeast. Twelve subjects not experiencing pain related to cancer of the lung or its treatment were recruited. A Karnofsky status of 40% and hemoglobin of 8 g were required. Five questionnaires were completed and 10mL of blood was drawn at baseline; 4 questionnaires and blood draws were repeated monthly for 5 months. One baseline questionnaire and a pain assessment were added at final. Demographic, clinical, and questionnaire data were summarized; standardized scale scores were calculated. Results: Biopsychosocial scores that were low at baseline increased from T1-T4 but decreased slightly T5-T6. Individuals with higher pain intensity and higher pain interference at final had higher psychosocial scores at baseline than individuals with lower pain intensity and lower pain interference at final. Conclusions: Unrelated to disease stage, metastasis, or treatment, unique levels of biopsychosocial factors are observed in patients newly diagnosed with lung cancer who report higher levels of pain intensity and higher levels of pain interference at the time pain occurs. Replication studies are needed to validate this response pattern and determine the value of repeated individual assessments.
Reduced basal ganglia function has been associated with fatigue in neurologic disorders, as well as in patients exposed to chronic immune stimulation. Patients with chronic fatigue syndrome (CFS) have been shown to exhibit symptoms suggestive of decreased basal ganglia function including psychomotor slowing, which in turn was correlated with fatigue. In addition, CFS patients have been found to exhibit increased markers of immune activation. In order to directly test the hypothesis of decreased basal ganglia function in CFS, we used functional magnetic resonance imaging to examine neural activation in the basal ganglia to a reward-processing (monetary gambling) task in a community sample of 59 male and female subjects, including 18 patients diagnosed with CFS according to 1994 CDC criteria and 41 non-fatigued healthy controls. For each subject, the average effect of winning vs. losing during the gambling task in regions of interest (ROI) corresponding to the caudate nucleus, putamen, and globus pallidus was extracted for group comparisons and correlational analyses. Compared to non-fatigued controls, patients with CFS exhibited significantly decreased activation in the right caudate (p = 0.01) and right globus pallidus (p = 0.02). Decreased activation in the right globus pallidus was significantly correlated with increased mental fatigue (r2 = 0.49, p = 0.001), general fatigue (r2 = 0.34, p = 0.01) and reduced activity (r2 = 0.29, p = 0.02) as measured by the Multidimensional Fatigue Inventory. No such relationships were found in control subjects. These data suggest that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks.
Combined increases in peripheral inflammation and brain glutamate may identify a subtype of depression with distinct neuroimaging signatures. Two contrasting subgroups of depressed subjects—with and without combined elevations in plasma C-reactive protein (CRP) and basal ganglia glutamate (high and low CRP-Glu, respectively) were identified by hierarchical clustering using plasma CRP (indexing peripheral inflammation) and magnetic resonance spectroscopy (MRS)-based measurement of left basal ganglia glutamate. High CRP-Glu group status was associated with greater severity of anhedonia and cognitive and motor slowing. Local- and network-level measures of functional integrity were determined using brain oxygen level-dependent (BOLD)-oscillatory activity and graph theory. Greater decreases in concordance of oscillatory activity between neighboring voxels (Regional Homogeneity ‘ReHo’, p < 0.01) within the MRS volume-of-interest was associated with the High CRP-Glu subgroup. Using brain-wide, CRP-Glu ReHo contrast maps, a covariance network of 41 regions-of-interest (ROIs) with similar ReHo decreases was identified in the High CRP-Glu group and was located to brain structures previously implicated in depression. The 41-ROI network was further decomposed into four subnetworks. ReHo decreases within Subnetwork4—comprised of reward processing regions —was associated with anhedonia. Subnetwork4 ReHo also predicted decreased network integrity, which mediated the link between local ReHo and anhedonia in the Low but not High CRP-Glu group. These findings suggest that decreased ReHo and related disruptions in network integrity may reflect toxic effects of inflammation-induced increases in extrasynaptic glutamate signaling. Moreover, local BOLD oscillatory activity as reflected in ReHo might be a useful measure of target-engagement in the brain for treatment of inflammation-induced behaviors.
Background:
The distress thermometer and problem list (DT&PL) is a recommended screening measure but the utility of the physical problem list (PPL) has not been evaluated in patients with metastatic lung cancer who typically have high rates of both physical and psychological symptoms. We hypothesized that the PPL will provide an accurate representation of lung cancer symptoms and be associated with concomitant distress, anxiety, depression, and worsened survival.
Methods:
Stage IV lung cancer patients (n = 116) reported physical symptoms from 22 PPL variables and completed the DT&PL for distress, general anxiety disorder-7 for anxiety, and Patient Health Questionnaire 9 for depression. Inferential analyses were controlled for demographic and clinical characteristics.
Results:
The average number of physical problems was 4.7 (SD = 3.8) while the median was 3.0. Fatigue, sleep, pain, and breathing problems were most common. Physical symptom burden was associated with nonmarried/partnered status (P = .003) and depression (P < .001) on multivariate analysis accounting for 43% of physical symptom burden variance. Greater number of physical symptoms and lower BMI were associated with worsened survival. Individual physical symptoms were most often associated with depression.
Conclusion:
The PPL of the DT&PL appears to have clinical utility given its associations with the most common lung cancer symptoms, depression, and worsened survival. In addition to its potential role in clinics worldwide already using the DT&PL, physical symptom burden on the DT&PL should trigger a concomitant psychological assessment.
Psychological stress can have devastating and lasting effects on a variety of behaviors, especially those associated with mental illnesses such as anxiety and depression. Animal models of chronic stress are frequently used to elucidate the mechanisms underlying the relationship between stress and mental health disorders and to develop improved treatment options. The current study expands upon a novel chronic stress paradigm for mice: predatory stress. The predatory stress model incorporates the natural predator-prey relationship that exists among rats and mice and allows for greater interaction between the animals, in turn increasing the extent of the stressful experience. In this study, we evaluated the behavioral effects of exposure to 15 days of predatory stress on an array of behavioral indices. Up to 2 weeks after the end of stress, adult male mice showed an increase of anxiety-like behaviors as measured by the open field and social interaction tests. Animals also expressed an increase in depressive-like behavior in the sucrose preference test. Notably, performance on the novel object recognition task, a memory test, improved after predatory stress. Taken as a whole, our results indicate that 15 exposures to this innovative predatory stress paradigm are sufficient to elicit robust anxiety-like behaviors with evidence of co-morbid depressive-like behavior, as well as changes in cognitive behavior in male mice.
Inflammatory cytokines have been shown to have a direct effect on mesolimbic dopamine (DA)that is associated with a reduced willingness to expend effort for reward. To date, however, the broader implications of this communication between inflammation and mesolimbic DA have yet to be explored. Here, we suggest that the metabolic demands of chronic low-grade inflammation induce a reduction of striatal DA that in turn leads to a steeper effort-discounting curve because of reduced perceived ability (can't)versus preference (won't)for reward. This theoretical framework can inform how the mesolimbic DA system responds to increased immunometabolic demands during chronic inflammation, ultimately contributing to motivational impairments in psychiatric and other medical disorders.
Background: The direction of the association between inflammation and depressive symptoms remains inconsistent. The objective of this study was to evaluate the temporal relationship between inflammation and depressive symptoms, and to assess the role of genetic factors on this association.
Methods: In this longitudinal cross-lagged twin difference study, we examined 166 (83 pairs) middle-aged male twins recruited from the Vietnam Era Twin Registry, who were assessed at baseline and after 7 years of follow-up. We assayed plasma levels of two inflammatory biomarkers, interleukin-6 (IL-6) and high sensitivity C-reactive protein (CRP) and measured depressive symptoms using the Beck Depression Inventory-II (BDI). To evaluate the direction of the association, we constructed multivariable mixed-effects regression models and calculated standardized beta-coefficients to compare the strength of the within-pair association for both pathways. We then conducted a stratified analysis by zygosity and assessed the associations in monozygotic and dizygotic twin pairs separately.
Results: The 166 twins were 95% white and had a mean (SD) age of 54 (3) years at baseline. The cross-lagged analysis showed significant and positive associations from visit 1 IL-6 to visit 2 BDI across all models (beta-coefficients ranging from 0.18 to 0.22). However, the opposite pathway (visit 1 BDI to visit 2 IL-6) was not significant after adjusting for confounding factors. In contrast, visit 1 BDI was significantly associated with visit 2 CRP in all models (beta-coefficients ranging from 0.23 to 0.33), while the opposite pathway (visit 1 CRP to visit 2 BDI) showed no significant association. When stratifying by zygosity, significant associations from IL-6 to depression were only seen in monozygotic twins, but associations from depression to CRP were more robust in dizygotic twins, which implies that genetic factors may play a role in this association.
Conclusions: The association between inflammation and depression may be bidirectional. Elevated IL-6 levels are more likely to be a risk factor of depression rather than a consequence, while the opposite may be true for elevated CRP. The biological underpinnings of these bidirectional pathways need further evaluation.
Major medical illnesses are associated with increased risk for depression and alterations in hypothalamic–pituitary–adrenal (HPA) axis function. Pathophysiological processes such as inflammation that occur as a part of medical illnesses and their treatments have been shown to cause depressive symptoms, and may also affect the HPA axis. We previously reported that patients with hepatitis C virus chronically administered interferon (IFN)-alpha develop increased evening plasma cortisol concentrations and a flattened diurnal cortisol slope, which correlated with increased tumor necrosis factor (TNF) and its soluble receptor 2 (sTNFR2). Increased TNF and sTNFR2 were further correlated with depression and fatigue scores. The current study examined whether flattened cortisol slope might be secondary to reduced glucocorticoid receptor (GR) sensitivity, by measuring glucocorticoid negative feedback to dexamethasone (DEX) administration followed by corticotropin releasing hormone (CRH) challenge. In an exploratory analysis, 28 male and female patients with hepatitis C virus were studied at baseline (Visit 1) and after 12 weeks (Visit 2) of either IFN-alpha plus ribavirin (n = 17) or no treatment (n = 11). Patients underwent dexamethasone DEX–CRH challenge, neuropsychiatric assessments, and measurement of plasma TNF and sTNFR2 during each visit. IFN-alpha did not affect neuroendocrine responses following CRH but did increase post-DEX cortisol, which was correlated with flattening of the diurnal cortisol slope (r = 0.57, p = 0.002) and with increased depression scores (r = 0.38, p = 0.047). Furthermore, the change in post-DEX cortisol was associated with IFN-alpha-induced increase in sTNFR2 (r = 0.51, p = 006), which was in turn correlated with depression (r = 0.63, p < 0.001) and fatigue (r = 0.51, p = 0.005) scores. Whereas the relationship between sTNFR2 and depression scores were independent of the change in post-DEX cortisol, the correlation between post-DEX cortisol and depression scores was not significant when controlling for sTNFR2. These findings suggest that inflammation induced in patients with hepatitis C virus during IFN-alpha therapy precipitates decreased GR sensitivity to lead to a flattened diurnal cortisol slope. Decreased GR sensitivity may in turn further increase inflammation and its ultimate effects on behavior. Treatments that target inflammation and/or GR sensitivity may reduce depressive symptoms associated with medical illnesses.