Post-traumatic stress disorder symptoms may explain poor mental health in patients with fibromyalgia

Abstract

Symptoms of post-traumatic stress disorder are common in fibromyalgia patients. This study compared post-traumatic stress disorder symptoms in fibromyalgia patients and healthy controls and determined whether patient-control differences in post-traumatic stress disorder symptoms mediated differences in mental health. In all, 30 patients and 30 healthy controls completed questionnaires assessing symptoms of post-traumatic stress disorder and mental health. Fibromyalgia patients had greater symptoms of post-traumatic stress disorder and mental health than controls. Patient-control differences in mental health symptoms were fully or partially mediated by differences in post-traumatic stress disorder symptoms. Healthcare providers should understand the role of trauma as management of trauma symptoms may be one strategy for improving mental health.

Keywords

anxiety depression pain stress trauma

Fibromyalgia and mental health

Fibromyalgia is a heterogeneous chronic pain disorder with a high degree of psychological comorbidity (Maletic and Raison, 2009; Vincent et al., 2015). Several studies suggest a link between poor psychological health and onset and persistence of fibromyalgia symptoms (Hallberg and Carlsson, 1998; Paras et al., 2009; Weissbecker et al., 2006). Compared to healthy controls, patients with fibromyalgia experience higher levels of stress, anxiety, and depression, and lower positive and higher negative affect (Fietta and Manganelli, 2007; Janssens et al., 2015). A number of possibilities exist for why this might be the case, but some likely explanations include the following: (a) the effect of stress on pain processing pathways (Gonzalez-Ramirez et al., 2011; Low and Schweinhardt, 2012), (b) shared neurobiology between depression, anxiety, and fibromyalgia (Maletic and Raison, 2009), and (c) dysfunctional affect regulation (Hassett et al., 2008). However, another possibility exists. Fibromyalgia and trauma appear to be connected in meaningful ways (Afari et al., 2014; Cohen et al., 2002; Hauser et al., 2015; Waller et al., 2016) and it may be that the profile of poor mental health among fibromyalgia patients may be partially explained by trauma and trauma-related symptoms. This raises the question, “Could patients with fibromyalgia show higher levels of mental health symptoms in large part because they experience more trauma symptoms?”

Fibromyalgia and trauma

Several theoretical and conceptual models exist that explain why trauma, post-traumatic stress disorder (PTSD), and functional somatic syndromes such as fibromyalgia might be connected (Afari et al., 2014). First, the mutual maintenance theory argues that trauma and trauma symptoms and conditions such as fibromyalgia co-occur because of common psychological mechanisms that trigger both PTSD symptoms and fibromyalgia-related symptoms. These mechanisms include things such as attentional focus on threat, anxiety sensitivity, and behavioral avoidance. Second, the shared vulnerability model suggests that anxiety sensitivity and sympathetic dysregulation are common elicitors of both PTSD and conditions such as fibromyalgia. Third, the multiplex model of bodily experience suggests that PTSD symptomology and fibromyalgia share common neurobiological fear-networks. Fourth, the perpetual avoidance model considers the notion that traumatic experiences paired with dysfunctional cognitive processing lead to psychological and physiological arousal that causes behavioral avoidance that perpetuates both PTSD symptoms and fibromyalgia. Undoubtedly, the reasons why PTSD and fibromyalgia are commonly co-occurring are multifarious and interact in complex fashions.

Previous research has demonstrated connections between fibromyalgia and trauma. For instance, Cohen et al. (2002) examined a sample of 87 women and men with fibromyalgia and found a high percentage of patients (57%) had PTSD symptoms. Cohen and colleagues also note there was significant overlap between fibromyalgia and PTSD based on the previous American College of Rheumatology diagnostic criteria for fibromyalgia, published by Wolfe et al. (1990). Alternatively, Amir et al. (1997) surveyed patients with PTSD and healthy controls to determine the prevalence of fibromyalgia in each group. They found that 21 percent of patients with PTSD and 0 percent of healthy controls met criteria for fibromyalgia. Patients with PTSD with concurrent fibromyalgia report more pain, greater tenderness, lower quality of life, greater functional impairment, and more psychological distress as compared to patients with PTSD without concurrent fibromyalgia. Another interesting example of research in this area is the work of Hauser et al. (2013) who have examined the temporal relationships between fibromyalgia and PTSD. They found that in the majority of patients (67%), PTSD symptoms pre-dated fibromyalgia symptoms. In 30 percent of the sample fibromyalgia symptom onset preceded PTSD symptoms, and in about 4 percent of the sample both sets of symptoms co-occurred. PTSD in patients with fibromyalgia also appeared to increase the number of pain sites, symptoms of polysymptomatic distress, psychological distress, disability, and depressive disorder. Similar to the pattern of findings published by Amir et al. (1997), these investigators also show that 45 percent of their sample of patients with fibromyalgia and 3 percent of age- and sex- matched healthy controls met diagnostic criteria for PTSD. To summarize, important connections between trauma and fibromyalgia are apparent, but how trauma is involved in the mental health consequences of fibromyalgia has not been closely studied.

This study

The objective of this study was to evaluate the presence of symptoms of PTSD in patients with fibromyalgia and controls and determine whether differences in PTSD symptoms could partly account for differences in mental health symptoms. Based on a review of the available literature, it is hypothesized that patients with fibromyalgia, as compared to healthy controls, will show increased levels of mental health symptoms including perceived stress, anxiety symptoms, depressive symptoms, and less positive and more negative mood. It is also hypothesized that patients with fibromyalgia, as compared to healthy controls, will show increased levels of trauma symptoms including all three core sub-types of symptoms: re-experiencing, avoidance, and arousal. Furthermore, given the intriguing connections that have been demonstrated between fibromyalgia and trauma in past research, it is also hypothesized that part of the difference between fibromyalgia patients and healthy controls on mental health variables will be explained by differences in trauma symptoms. That is, differences in trauma symptoms are hypothesized to mediate differences between patients with fibromyalgia and healthy controls on mental health symptoms.

Method

Design

We conducted a cross-sectional study of patients with fibromyalgia and healthy controls. Symptoms of trauma and mental health were measured. There is much discussion about dimensional (i.e. symptom-based) and diagnostic methods of measuring mental health (Widiger and Samuel, 2005), but symptom measurement provides some distinct advantages for this study. First, symptoms provide insights into the linear relationships between these variables and offer the opportunity to examine mediating effects of trauma on group differences in mental health symptoms. Second, measuring symptoms also provide the opportunity to consider trauma and mental health on continua that individuals vary on as opposed to rigid dichotomies of health and illness.

Participants

Participants included women identified from a cohort of patients with fibromyalgia in Olmsted County, Minnesota (Vincent et al., 2013). The cohort used in this study is composed of patients who were Olmsted county residents on the reference date (31 December 2009) and had been diagnosed with fibromyalgia by a healthcare provider between 1 January 2005 and 31 December 2009. Individuals in the cohort who met eligibility criteria were sent a letter of invitation to participate. Exclusion criteria included uncontrolled diabetes, congestive heart failure, cardiac arrhythmias, chronic pulmonary disease, serious neurological illness, psychiatric disorders other than anxiety and depression, chronic kidney or liver disease, pregnancy in last 12 months, current anemia, uncontrolled hypo or hyperthyroidism, uncontrolled hypertension, cancer within 5 years other than skin cancer, current chemotherapy, substance abuse problems in the last 2 years, anorexia or bulimia within the last 5 years, body mass index (BMI) ⩾40, or age <18 or >60 years. Inclusion criteria were ability to speak and read English. Healthy, pain-, and fatigue-free controls were identified through the county records linkage system and through local advertising. Potential controls were screened via medical record review to determine eligibility. Those meeting eligibility criteria were invited to participate. This study was approved by the Mayo Clinic Institutional Review Board and all participants provided written informed consent.

Measures

Generalized Anxiety Disorder Questionnaire

The Generalized Anxiety Disorder Questionnaire (GAD-7) is a seven-item clinically validated, self-report questionnaire that assesses the presence and severity of anxiety symptoms (Lowe et al., 2008). Individuals complete the questionnaire by indicating how frequently they have experienced symptoms of anxiety such as “not being able to stop or control worrying” and “becoming easily annoyed or irritable” over the past 2 weeks. Scores range from 0 to 21, with higher scores indicating more severe symptoms. The GAD-7 has been used in multiple samples of patients with fibromyalgia as well as community samples and has an internal consistency of .92 (Nymdelger and Nieber, 2007; Peng et al., 2014).

Center for Epidemiologic Studies Depression Scale

The Center for Epidemiologic Studies Depression Scale (CES-D) is a 20-item clinically validated, self-report questionnaire used in assessing the presence and severity of symptoms of depression (Radloff, 1977). Individuals are asked to how often they have experienced symptoms such as poor appetite, trouble concentrating, feeling depressed, or having restless sleep over the past 2 weeks. Scores on the CES-D range from 0 to 60, with higher scores indicating more severe symptoms. The CES-D has been widely used in patients with fibromyalgia and other samples and is considered a valid and reliable measure of depression. It has an internal consistency of .85 in community samples and .90 in psychiatric samples (Radloff, 1977).

Positive and Negative Affect Scale

The Positive and Negative Affect Scale (PANAS) is a 20-item self-report measure that assesses state and trait perceptions of positive and negative affect (Watson et al., 1988). The scale contains a list of positive (e.g. interested, alert, excited) and negative (e.g. guilty, afraid, irritable) feelings and emotions and individuals are asked to what degree they feel the feeling or emotion. The scale yields two summary scores, positive affect and negative affect. Scores on each summary scale range from 10 to 50, with higher scores indicating greater positive or negative affect. The PANAS has an internal consistency of .84–.90 (Crawford and Henry, 2004).

Post-Traumatic Stress Disorder Checklist—Civilian Version

The Post-Traumatic Stress Disorder Checklist—Civilian Version (PCL-C) is a 17-item self-report questionnaire that assesses Diagnostic and Statistical Manual of Mental Disorders (4th ed.) (DSM-IV) symptoms of PTSD (Ruggiero et al., 2003). To complete this questionnaire, individuals are asked to indicate how frequently they experience symptoms such as “repeated, disturbing memories, thoughts, or images of a stressful experience from the past” and “being super alert or watchful on guard.” The PCL-C yields three subscales scores (re-experiencing, avoidance, and hyperarousal) and a total score. Total scores on the PCL-C range from 17 to 85, with higher scores indicating more significant symptoms of PTSD. The PCL-C has an internal consistency of .94 (Ruggiero et al., 2003).

Fibromyalgia Impact Questionnaire—Revised

The Fibromyalgia Impact Questionnaire—Revised (FIQ-R) is a validated, 21-item self-report questionnaire used to characterize the severity and impact of fibromyalgia symptoms (Bennett et al., 2009b). To complete the FIQ-R, individuals are asked to rate their difficulty performing tasks such as climbing stairs and shopping for groceries, and the severity of key fibromyalgia symptoms including pain, fatigue, stiffness, and memory problems in the past week. The total scores on the FIQ-R range from 0 to 100, with higher scores indicating greater symptom severity. The FIQ-R has an internal consistency of.83 (Bennett, 2005; Bennett et al., 2009b). Only patients with fibromyalgia completed the FIQ-R.

Analyses

Demographic variables (age, race, ethnicity, BMI) were summarized using means and standard deviations (SDs) and counts and percentages. Analyses were conducted using one-way analyses of variance to compare patients with fibromyalgia to healthy controls on mental health symptoms and trauma symptoms. Pearson correlation was used to describe the associations among the primary study variables. Multiple regression (ordinary least squares) was used to assess the association between group (fibromyalgia versus healthy control) and mental health symptoms while controlling confounding influences of age and BMI and considering the mediating effect of trauma symptoms (i.e. total and subscale scores). Analyses were conducted using SPSS 22 and indirect effects were estimated using the PROCESS macro (Hayes, 2013). Multi-collinearity diagnostics were examined for every multiple regression model and no model contained a variance inflation factor (VIF) over 3 which is well within acceptable limits (Tabachnick and Fidell, 2013). Because there were five mental health outcome variables, statistical significance was set a p < .01 according to the Bonferroni correction.

Results

In all, 30 patients and 30 healthy controls were enrolled. On average, patients with fibromyalgia were 47.0 years of age (SD: 10.4), white (96.7%) and non-Hispanic (100%). The mean BMI of patients was 25.8 (SD: 4.6). The mean age of controls was 41.1 years (SD: 8.4 years). The majority were white (93.3%) and non-Hispanic (96.5%). The mean BMI of controls was 26.0 (SD: 4.0). On the FIQ-R, the mean score for patients with fibromyalgia was 43.6 (SD: 14.7), indicating moderate symptom severity (Bennett et al., 2009a). Patients and controls showed no statistically significant differences on any of these variables (ps > .05). To control for even small differences in age and BMI, both variables were included as covariates in the mediation models.

Table 1 shows the comparison of patients with fibromyalgia and healthy controls on mental health symptom variables. Patients with fibromyalgia showed significantly higher levels of anxiety, perceived stress, and depressive symptoms and lower positive and higher negative affect. Effect sizes for these differences were large and ranged from 20 percent to 37 percent of the variability in mental health symptoms that was accounted for by knowing if the participant was in the fibromyalgia or healthy control group.

Table 1.

Differences between patients with fibromyalgia and healthy controls on mental health symptoms.

	Healthy controls			Fibromyalgia			F	η ²
	N	Mean	SD	N	Mean	SD
Anxiety symptoms	30	1.63	3.26	25	5.36	4.38	13.06***	.20
Perceived stress	30	9.73	4.09	27	17.52	7.06	26.60***	.33
Depressive symptoms	30	4.20	5.99	26	14.35	7.60	31.16***	.37
Positive affect	29	39.10	6.42	27	31.74	6.67	17.72***	.25
Negative affect	29	13.55	2.91	27	18.30	6.21	13.72***	.20

SD: standard deviation.

***

p < .001.

Table 2 shows the comparison of patients with fibromyalgia with healthy controls on trauma symptom variables. Again, patients with fibromyalgia showed significantly higher levels of trauma symptoms as compared to healthy controls. But this was true only for the arousal sub-type of trauma symptoms, as well as the overall trauma symptom score. Effect sizes for these differences ranged from 7 percent to 53 percent of the variability in trauma symptoms that was accounted for by knowing if the participant was in the fibromyalgia or healthy control group.

Table 2.

Differences between patients with fibromyalgia and healthy controls on trauma symptoms.

	Healthy controls			Fibromyalgia			F	η ²
	N	Mean	SD	N	Mean	SD
PCL-Re-experiencing	30	5.87	1.48	26	7.00	2.62	4.10	.07
PCL-Avoidance	30	8.10	2.55	27	10.52	4.59	6.20	.10
PCL-Arousal	30	6.27	1.74	27	11.30	2.99	61.88***	.53
PCL-Total Score	30	20.23	5.06	26	28.58	8.32	21.17***	.28

SD: standard deviation; PLC: Post-Traumatic Stress Disorder Checklist.

***

p < .001.

Table 3 shows the bivariate correlations for the study variables. Group (fibromyalgia vs control) was significantly correlated with arousal and total trauma symptoms and with all mental health symptom variables (|rs| = .45–.73, ps < .001). Group was not correlated with re-experiencing or avoidance symptoms. Re-experiencing, avoidance, arousal, and total trauma symptoms were significantly correlated with all mental health symptom variables (|rs| = .35–.87, ps < .01). Re-experiencing, avoidance, arousal, and total trauma symptoms were significantly correlated (rs = .47–.89, ps < .001), and all mental health symptom variables were significantly correlated (|rs| = .37–.81, ps < .01).

Table 3.

Correlations between group (fibromyalgia vs control), trauma symptoms, and mental health symptoms.

	1	2	3	4	5	6	7	8	9
1. Group
2. PCL-Re-experiencing	.27
3. PCL-Avoidance	.32	.72***
4. PCL-Arousal	.73***	.47***	.51***
5. PCL-Total Score	.53***	.82***	.89***	.80***
6. Anxiety symp.	.45***	.58***	.51***	.72***	.70***
7. Perceived stress	.57***	.35**	.49***	.60***	.57***	.59***
8. Depressive symp.	.61***	.72***	.76***	.73***	.87***	.63***	.68***
9. Positive affect	−.50***	−.53***	−.64***	−.51***	−.66***	−.37**	−.69***	−.81***
10. Negative affect	.45***	.60***	.51***	.60***	.65***	.72***	.76***	.66***	−.57***

PLC: Post-Traumatic Stress Disorder Checklist.

p < .01; ***p < .001.

Mediation analyses involved using both total trauma symptoms and the arousal trauma symptom subscale as mediators of the relationship between group (i.e. fibromyalgia vs control) and mental health (i.e. anxiety, stress, depression, affect). First, total trauma symptom score was used in separate models examining the extent to which it mediated group differences in mental health variables. Total trauma symptoms fully mediated group differences in anxiety and positive and negative affect. Partial mediation of group differences in stress (indirect β = .18, p < .01) and depression (indirect β = .38, p < .01) was also statistically significant (see Table 4). Second, the arousal trauma symptom subscale was used in separate models examining the extent to which it mediated group differences in mental health variables. These analyses examine the isolated mediating effects of arousal trauma symptoms and determine whether arousal symptoms account for the overall mediating effect of global trauma symptoms. Re-experiencing and avoidance symptoms were not correlated with group (the initial predictor) and hence cannot be examined further as mediators. The results of our mediation models that included only arousal trauma symptoms showed that group differences in mental health symptoms were entirely accounted for by arousal trauma symptoms (see Table 4). However, arousal trauma symptom itself was only a significant mediator of group differences in anxiety, depression, and negative affect, not stress and positive affect. The arousal trauma symptoms variable added 35 percent, 6 percent, 18 percent, 4 percent, and 16 percent to the prediction equation for anxiety symptoms, stress, depression, positive affect, and negative affect, respectively.

Table 4.

Associations of group status (fibromyalgia vs healthy control) with mental health symptoms (Model 1) and mediating effects of total trauma symptoms (Model 2) and arousal trauma symptoms (Model 2A).

	Anxiety symptoms	Perceived stress	Depressive symptoms	Positive affect	Negative affect
	β	β	β	β	β
Model 1 (R²)	.18	.34***	.37***	.30***	.19**
Age	.01	−.02	.02	−.03	.00
BMI	−.04	.13	.10	−.25	.08
Group	.42**	.58***	.60***	−.49***	.44**
Model 2 (ΔR²)	.32***	.09**	.42***	.20***	.25***
Age	−.03	−.03	.00	−.02	−.02
BMI	−.10	.10	.03	−.20	.02
Group	.06	.39**	.20	−.21	.133
PCL-Total	.68***	.36**	.77***	−.53***	.59***
Model 2A (ΔR²)	.35***	.06	.18***	.04	.16***
Age	.11	.02	.10	−.07	.07
BMI	−.05	.16	.11	−.25	.08
Group	−.22	.30	.12	−.26	.00
PCL-Arousal	.87***	.37	.62***	−.30	.59***

BMI: body mass index; PCL: Post-Traumatic Stress Disorder Checklist.

Models 2 and 2A are separate models that add total trauma symptoms (Model 2) or arousal trauma symptoms (Model 2A) in a second step following entry of age, BMI, and group in Model 1.

p < .01; ***p < .001.

Discussion

As hypothesized, patients with fibromyalgia showed higher levels of mental health symptoms and total and arousal trauma symptoms when compared to healthy controls. This is consistent with previous research showing that patients with fibromyalgia experience more mental health problems (Fietta and Manganelli, 2007; Janssens et al., 2015; Maletic and Raison, 2009). It also extends findings showing that trauma and PTSD are more common in fibromyalgia (Afari et al., 2014; Cohen et al., 2002; Hauser et al., 2015) by showing that the intensity of PTSD symptoms is also elevated. Differences between patients and controls on mental health symptoms were all large in size, but unexpectedly differences across the three core sub-types of trauma symptoms varied substantially. That is, patients with fibromyalgia only differed from healthy controls on the arousal subscale of trauma symptoms. Differences between patients and controls on the other two subscales of trauma symptoms were not statistically significant, as hypothesized. That fibromyalgia patients were so dramatically higher on arousal symptoms of PTSD might suggest that the cognitive-emotional sensitization hypothesis of fibromyalgia may bear some relevance to understanding fibromyalgia and PTSD connections (Brosschot, 2002; English, 2014). Cognitive-emotional sensitization involves cognitive bias or selective attention to symptoms of fibromyalgia. In short, sensitization is excessive vigilance about symptoms. Similarly, arousal symptoms of trauma involve excessive awareness of one’s environment and being overly alert, jumpy, or edgy. Perhaps cognitive-emotional sensitization underlies some important part of fibromyalgia and PTSD symptoms. Future neuro-imaging and psychophysiologic studies could better inform the mechanisms that underlie fibromyalgia, PTSD, and sensitization.

Because of the striking differences between patients and controls on arousal symptoms of PTSD, we felt compelled to examine the arousal subscale separately as a potential mediator of the differences between patients with fibromyalgia and healthy controls on mental health symptoms. It is important to know if arousal plays an important role more so than other types of PTSD symptoms in potentially contributing to patient-control differences in mental health symptoms. As it turns out, the pattern of results is quite nuanced. Indeed, the arousal symptoms subscale is an important solo mediator of the patient-control differences in anxiety and depressive symptoms and negative mood, but not so for perceived stress or positive affect. In both cases, arousal is not even a significant mediator and its contribution of predicted variance is negligible. Because group differences in both perceived stress and positive affect are mediated by total trauma symptoms but not by arousal trauma symptoms, there must be other potential mechanisms involved. Re-experiencing and avoidance trauma symptoms are not good candidates as mediators since they did not show group differences and hence cannot be part of mediation. Perhaps other mediating variables should be considered that are related to trauma but focus either more on changed perceptions (e.g. uncertainty, loss/lack of control) resulting from trauma and may mediate differences in stress or address issues of post-traumatic growth which may be more closely linked to group differences in positive affect.

Trauma symptoms clearly differ between patients with fibromyalgia and healthy controls, but the extent of difference and the degree to which differences in trauma symptoms offer clear explanations for differences in mental health symptoms varies. These data offer an argument for overall trauma symptoms and specifically arousal symptoms as mediating mechanisms of patient-control differences in anxiety and depressive symptoms and overall negative affect. Arousal trauma symptoms may reflect unchecked cognitive and physiological vigilance deriving from central or autonomic neurophysiological or cognitive processes common to both fibromyalgia and PTSD (Brosschot, 2002; English, 2014). In summary, patients with fibromyalgia differ from healthy controls on mental health symptoms and trauma symptoms. Patient-control differences in trauma symptoms, especially arousal symptoms, may explain differences in mental health symptoms.

As with all observational studies, this study contains some important limitations that future work should seek to address. First, this study examined mental health and trauma symptoms. Future work could consider mental health and PTSD diagnoses, as there may be important differences in sub-clinical symptomatology and full-blown PTSD and mental illness. Second, this study was cross-sectional and temporal characteristics of the relationship between fibromyalgia, trauma symptoms, and mental health symptoms could not be deciphered. Future longitudinal studies would offer insight into the degree to which the mediating mechanisms identified in this study are causal. Third, although this study examined patients with fibromyalgia versus healthy control differences in mental health and trauma, the sample size was relatively small. Larger studies would offer more ability to create patient sub-groups for analysis.

Patients with fibromyalgia experience high levels of mental health problems. A few studies have also shown a link between fibromyalgia and increased experiences of trauma. This study is unique in that it examines both mental health and trauma symptoms and considers the extent to which elevated mental health symptoms in patients with fibromyalgia might reflect elevations in trauma symptoms. The findings provide good evidence that this model is viable and that elevations in mental health symptoms can be explained, at least in part, by elevations in trauma symptoms. This has important implications for diagnosis and treatment. Diagnoses carry with them implications for symptomatology and treatment, and in the case of fibromyalgia, many of the mental health symptoms may arise from untreated PTSD. Healthcare providers should, at minimum, consider the likelihood of co-morbid conditions and the possibility that trauma symptoms may explain the effects of fibromyalgia on mental health symptoms and design treatment plans to address symptom management appropriately.

Footnotes

Acknowledgements

Study data were collected and managed using REDCap electronic data capture tools hosted at Mayo Clinic. REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing (1) an intuitive interface for validated data entry, (2) audit trails for tracking data manipulation and export procedures, (3) automated export procedures for seamless data downloads to common statistical packages, and (4) procedures for importing data from external sources. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Center for Translational Science Activities, National Center for Research Resources, or NIH.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported, in part, by the National Institute on Aging of the NIH (award R01AG034676) and the Center for Translational Science Activities at Mayo Clinic. The Center is supported, in part, by a grant from the National Center for Research Resources, a component of the NIH (RR024150).

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