Faculty Bibliography

Background:at intron 2, with percent glycosylated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-cholesterol), waist circumference (WC), and body mass index (BMI), in a clinic-based sample of 43 individuals with T2DM. Results: = 0.006, respectively). Conclusions:

Research suggests that many children are exposed to adverse experiences in childhood. Such adverse childhood exposures may result in stress and trauma, which are associated with increased morbidity and mortality into adulthood. In general populations and trauma-exposed adults, mindfulness interventions have demonstrated reduced depression and anxiety, reduced trauma-related symptoms, enhanced coping and mood, and improved quality of life. Studies in children and youth also demonstrate that mindfulness interventions improve mental, behavioral, and physical outcomes. Taken together, this research suggests that high-quality, structured mindfulness instruction may mitigate the negative effects of stress and trauma related to adverse childhood exposures, improving short- and long-term outcomes, and potentially reducing poor health outcomes in adulthood. Future work is needed to optimize implementation of youth-based mindfulness programs and to study long-term outcomes into adulthood.

OBJECTIVES/OBJECTIVE:To examine qualitative responses regarding the use of placebo treatments in medical care in a sample of US patients.Survey studies suggest a deliberate clinical use of placebos by physicians, and prior research has found that although most US patients find placebo use acceptable, the rationale for these beliefs is largely unknown. SETTING/METHODS:Members of the Outpatient Clinic at the Kaiser Permanente Northern California interviewed research participants who had been seen for a chronic health problem at least once in the prior 6 months. PARTICIPANTS/METHODS:853 women (61%) and men, white (58%) and non-white participants aged 18-75 years. PRIMARY AND SECONDARY OUTCOMES/METHODS:Qualitative responses on perceptions of placebo use from one-time telephone surveys were analysed for common themes and associations with demographic variables. RESULTS:Prior results indicated that a majority of respondents felt it acceptable for doctors to recommend placebo treatments. Our study found that a lack of harm (n=291, 46.1%) and potential benefit (n=250, 39.6%) were the most common themes to justify acceptability of placebo use. Responses citing potential benefit were associated with higher education (r=0.787; p<0.024). Of the minority of respondents who judged it never acceptable for doctors to recommend placebo treatments, the most often referenced rationale was obligation of the doctor to do more (n=102, 48.3%). Additional themes emerged around the issue of whether a doctor was transparent about placebo use, including honesty, patient's right to know and power of the mind. Older age was associated with likelihood to cite overall physician, as opposed to treatment, related themes (r=0.753; p<0.002). CONCLUSIONS:Participants seem to appreciate and understand the lack of harm and potential benefit associated with placebo treatments, while valuing the role of the physician and the patient in its implementation.

OBJECTIVES/OBJECTIVE:To quantify the influence of abuse, particularly in childhood, with pain sensitivity and other adverse symptoms experienced by women with fibromyalgia (FM). METHODS:Subjects with FM completed a detailed abuse interview, dolorimetry, and questionnaire-based assessments of fatigue, cognitive self-appraisal, and depression. Student's t- and chi-square tests were used to analyse differences in FM symptoms between those with and without a history of childhood abuse. Linear regression was used to evaluate the relationship between abuse and symptom severity, adjusting for possible confounders. RESULTS:In 111 women with FM, physical abuse during childhood demonstrated a clinically modest, yet statistically significant, association with increased tenderness as measured by pain pressure thresholds (β=-0.25, p=0.011) and tender points (β=0.23, p=.022). Physical child abuse was also associated with cognitive language impairment after adjusting for depression (β=0.27, p=0.001). While emotional child abuse was associated with fatigue, the association did not persist after adjustment for depressive symptoms. CONCLUSIONS:Group differences are of small magnitude and might not directly impact clinical practice, however, the experience of child abuse is associated with FM symptom severity and may shape the biological development of interoception in ways that predispose to pain and polysymptomatic distress.

Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide population-based study showed elevated risk of gout in subjects with bipolar disorder (BD), and a recent meta-analysis and systematic review of placebo-controlled trials of adjuvant purinergic modulators confirmed their benefits in bipolar mania. Uric acid may modulate energy and activity levels, with higher levels associated with higher energy and BD spectrum. Several recent genetic studies suggest that the purinergic system - particularly the modulation of P1 and P2 receptor subtypes - plays a role in mood disorders, lending credence to this model. Nucleotide concentrations can be measured using brain spectroscopy, and ligands for in vivo positron emission tomography (PET) imaging of adenosine (P1) receptors have been developed, thus allowing potential target engagement studies. This review discusses the key role of the purinergic system in the pathophysiology of mood disorders. Focusing on this promising therapeutic target may lead to the development of therapies with antidepressant, mood stabilization, and cognitive effects.

OBJECTIVE:To evaluate sensitization, myofascial trigger points, and quality of life in women with chronic pelvic pain with and without endometriosis. METHODS:A cross-sectional prospective study of women aged 18-50 years with pain suggestive of endometriosis and healthy, pain-free volunteers without a history of endometriosis. Patients underwent a physiatric neuromusculoskeletal assessment of clinical signs of sensitization and myofascial trigger points in the abdominopelvic region. Pain symptoms, psychosocial, and quality-of-life measures were also assessed. All participants with pain underwent laparoscopic excision of suspicious lesions to confirm endometriosis diagnosis by histologic evaluation. RESULTS:Patients included 18 with current, biopsy-proven endometriosis, 11 with pain only, and 20 healthy volunteers. The prevalence of sensitization as measured by regional allodynia and hyperalgesia was similar in both pain groups (83 and 82%) but much lower among healthy volunteers (15%, P<.001). Nearly all women with pain had myofascial trigger points (94 and 91%). Adjusting for study group, those with high anxiety (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.004-1.099, P=.031) and depression (OR 1.06, 95% CI 1.005-1.113, P=.032) scores were more likely to have sensitization. Pain patients with any history of endometriosis had the highest proportion of sensitization compared with the others (87% compared with 67% compared with 15%; P<.001). Adjusting for any history of endometriosis, those with myofascial trigger points were most likely sensitized (OR 9.41, 95% CI 1.77-50.08, P=.009). CONCLUSION/CONCLUSIONS:Sensitization and myofascial trigger points were common in women with pain regardless of whether they had endometriosis at surgery. Those with any history of endometriosis were most likely to have sensitization. Traditional methods of classifying endometriosis-associated pain based on disease, duration, and anatomy are inadequate and should be replaced by a mechanism-based evaluation, as our study illustrates. CLINICAL TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov, www.clinicaltrials.gov, NCT00073801. LEVEL OF EVIDENCE/METHODS:II.

BACKGROUND:Shank3, a post-synaptic density protein involved in N-methyl-d-aspartate (NMDA) receptor tethering and dendritic spine rearrangement, is implicated in the pathophysiology of bipolar disorder. We hypothesized that elevated baseline plasma Shank3 levels might predict antidepressant response to the NMDA receptor antagonist ketamine. METHODS:Twenty-nine subjects with bipolar depression received a double-blind, randomized, subanesthetic dose (.5 mg/kg) ketamine infusion. Of the patients for whom Shank3 levels were collected, 15 completed baseline 3-Tesla MRI and 17 completed post-ketamine [(18)F]-FDG PET. RESULTS:Higher baseline Shank3 levels predicted antidepressant response at Days 1 (r=-.39, p=.047), 2 (r=-.45, p=.02), and 3 (r=-.42, p=.03) and were associated with larger average (r=.58, p=.02) and right amygdala volume (r=.65, p=.009). Greater baseline Shank3 also predicted increased glucose metabolism in the hippocampus (r=.51, p=.04) and amygdala (r=.58, p=.02). LIMITATIONS/CONCLUSIONS:Limitations include the small sample size, inability to assess the source of peripheral Shank3, and the lack of a placebo group for baseline Shank3 levels and comparative structural/functional neuroimaging. CONCLUSIONS:Shank3 is a potential biomarker of antidepressant response to ketamine that correlates with baseline amygdala volume and increased glucose metabolism in the amygdala and hippocampus.

Pain modulation by placebo mechanisms is one of the most robust and best-studied phenomena, yet almost all research investigating the mechanisms and implications of the placebo analgesia are based on adult research. After highlighting crucial aspects that need to be considered in studying pain modulation in children, this comprehensive review examines studies related to pain modulation with an emphasis on factors such as age, neural development and pain measures. We critically discuss psychological mechanisms underlying placebo effects, including (1) verbally induced expectations, (2) conditioning and learning mechanisms, and (3) child-parent-physician interactions. Taken together, research suggests that placebo mechanisms can affect therapeutic outcomes and potentially be exploited clinically to improve clinical outcomes in pediatric population. Recommendations for further investigating the mechanistic bases and harnessing placebo effects for supportive therapeutic applications are given.

Glial cell line-derived neurotrophic factor (GDNF) exerts neurotrophic and neuroprotective effects on substantia nigra (SN) dopamine neurons and has great therapeutic potential for Parkinson's disease (PD). Hindering this potential is the fact that GDNF cannot cross the blood-brain barrier. The aim of this study was to assess the effects of GDNF administered by the intranasal route in normal rats, and in the unilateral 6-hydroxydopamine (6-OHDA) model of PD. In the first study, rats received single intranasal doses of 50-μg GDNF in phosphate-buffered saline (PBS) or cationic liposomes, but no 6-OHDA. In the second study, rats were nasally administered 10, 50 or 150 μg of GDNF in PBS or cationic liposomes 1h before injection of 6-OHDA. All groups were sacrificed 3-4 weeks later. Both intranasal GDNF treatments induced a neurotrophic effect in the SN insofar as the number of tyrosine hydroxylase (TH)-positive neurons was significantly higher than in controls given intranasal PBS liposomes. Dopamine cell counts were also higher in the intact SN of 6-OHDA-lesioned rats compared to controls given PBS liposomes. Most importantly, intranasal GDNF provided significant neuroprotective efficacy indicated by greater TH immunostaining density in the lesioned versus intact SN of rats given single 50-μg doses of GDNF in PBS, or 150-μg doses of liposomal GDNF, compared to lesioned rats given PBS liposomes. Three 50-μg doses given at daily intervals (1 day before, 1h before, and 1 day after 6-OHDA) provided even greater protection than single 150-μg doses. Multiple doses at short intervals may therefore provide greater neuroprotection than single bolus doses. These results demonstrate both a neurotrophic effect of intranasal GDNF in the intact SN as well as neuroprotective efficacy in the unilateral 6-OHDA model, supporting pursuit of this approach as a potential treatment for PD.

Myofascial pain syndrome (MPS) is a common, yet poorly understood, acute and chronic pain condition. MPS is characterized by local and referred pain associated with hyperirritable nodules known as myofascial trigger points (MTrPs) that are stiff, localized spots of exquisite tenderness in a palpable taut band of skeletal muscle. Recently, our research group has developed new ultrasound imaging methods to visualize and characterize MTrPs and their surrounding soft tissue. The goal of this paper was to quantitatively analyze Doppler velocity waveforms in blood vessels in the neighborhood of MTrPs to characterize their vascular environment. A lumped parameter compartment model was then used to understand the physiological origin of the flow velocity waveforms. 16 patients with acute neck pain were recruited for the study and the blood vessels in the upper trapezius muscle in the neighborhood of palpable MTrPs were imaged using Doppler ultrasound. Preliminary findings show that symptomatic MTrPs have significantly higher peak systolic velocities and negative diastolic velocities compared to latent MTrPs and normal muscle sites. Using compartment modeling, we show that a constricted vascular bed and an enlarged vascular volume could explain the observed flow waveforms with retrograde diastolic flow.