Propofol for treatment resistant depression: A randomized controlled trial.

Background: Anesthetic agents including ketamine and nitrous oxide have shown antidepressant properties when appropriately dosed. Our recent open-label trial of propofol, an intravenous anesthetic known to elicit transient positive mood effects, suggested that it may also produce robust and durable antidepressant effects when administered at a high dose that elicits an electroencephalographic (EEG) burst-suppression state. Here we report findings from a randomized controlled trial ( NCT03684447 ) that compared two doses of propofol. We hypothesized greater improvement with a high dose that evoked burst suppression versus a low dose that did not. Methods: Participants with moderate-to-severe, treatment-resistant depression were randomized to a series of 6 treatments at low versus high dose (n=12 per group). Propofol infusions were guided by real-time processed frontal EEG to achieve predetermined pharmacodynamic criteria. The primary and secondary depression outcome measures were the 24-item Hamilton Depression Rating Scale (HDRS-24) and the Patient Health Questionnaire (PHQ-9), respectively. Secondary scales measured suicidal ideation, anxiety, functional impairment, and quality of life. Results: Treatments were well tolerated and blinding procedures were effective. The mean [95%-CI] change in HDRS-24 score was -5.3 [-10.3, -0.2] for the low-dose group and -9.3 [-12.9, -5.6] for the high-dose group (17% versus 33% reduction). The between-group effect size (standardized mean difference) was -0.56 [-1.39, 0.28]. The group difference was not statistically significant (p=0.24, linear model). The mean change in PHQ-9 score was -2.0 [-3.9, -0.1] for the low dose and -4.8 [-7.7, -2.0] for the high dose. The between-group effect size was -0.73 [-1.59, 0.14] (p=0.09). Secondary outcomes favored the high dose (effect sizes magnitudes 0.1 - 0.9) but did not generally reach statistical significance (p>0.05). Conclusions: The medium-sized effects observed between doses in this small, controlled, clinical trial suggest that propofol may have dose-dependent antidepressant effects. The findings also provide guidance for subsequent trials. A larger sample size and additional treatments in series are likely to enhance the ability to detect dose-dependent effects. Future work is warranted to investigate potential antidepressant mechanisms and dose optimization.

Diversity of electroencephalographic patterns during propofol-induced burst suppression.

Burst suppression is a brain state consisting of high-amplitude electrical activity alternating with periods of quieter suppression that can be brought about by disease or by certain anesthetics. Although burst suppression has been studied for decades, few studies have investigated the diverse manifestations of this state within and between human subjects. As part of a clinical trial examining the antidepressant effects of propofol, we gathered burst suppression electroencephalographic (EEG) data from 114 propofol infusions across 21 human subjects with treatment-resistant depression. This data was examined with the objective of describing and quantifying electrical signal diversity. We observed three types of EEG burst activity: canonical broadband bursts (as frequently described in the literature), spindles (narrow-band oscillations reminiscent of sleep spindles), and a new feature that we call low-frequency bursts (LFBs), which are brief deflections of mainly sub-3-Hz power. These three features were distinct in both the time and frequency domains and their occurrence differed significantly across subjects, with some subjects showing many LFBs or spindles and others showing very few. Spectral-power makeup of each feature was also significantly different across subjects. In a subset of nine participants with high-density EEG recordings, we noted that each feature had a unique spatial pattern of amplitude and polarity when measured across the scalp. Finally, we observed that the Bispectral Index Monitor, a commonly used clinical EEG monitor, does not account for the diversity of EEG features when processing the burst suppression state. Overall, this study describes and quantifies variation in the burst suppression EEG state across subjects and repeated infusions of propofol. These findings have implications for the understanding of brain activity under anesthesia and for individualized dosing of anesthetic drugs.

Left Ear Hearing Predicts Functional Activity in the Brains of Patients with Alzheimer's Disease Dementia.

OBJECTIVES: To determine whether central speech processing ability, as measured by hearing in noise, differs between right and left ears in adults with Alzheimer's disease related dementia (AD) as well as whether differences in central speech processing ability correlate with an fMRI-based measurement of global functional brain connectivity. METHODS: This prospective study was carried out at a tertiary referral center. Patients with an AD diagnosis and pure tone averages 40 dB HL or better were included. They were examined using resting-state fMRI and underwent central audiometric testing using the Dichotic Sentence Identification Test (DSI), the Dichotic Digits Test (DD), and the Synthetic Sentence Identification Test (SS), which test hearing in noise. DSI scores were correlated with resting-state fMRI connectivity between 361 distinct gray matter brain regions of interest (ROIs). Average global connectivity was calculated as mean functional connectivity between an ROI and the other 360 regions, a quantitative marker representing overall functional connectivity in the brain. RESULTS: Sixteen subjects had adequate fMRI and hearing data. The average age was 71.5 years old (±6.0). The average DSI score for the left ear was 40% (±34%) compared to 90% (±10%) in the right ear (P < .001). No difference between ears was noted on the DD. SS does not differentiate between ears, but worsening scores were noted with increasing background noise. Of the fMRI ROIs, 269 of the 361 had multiple comparison corrected significant correlations between global connectivity and DSI of the left ear (P = .004, r = .673), and all 269 showed higher functional connectivity for individuals with higher left DSI score. No correlations between DSI of the right ear and functional connectivity were found. CONCLUSIONS: Correlation was noted between left sided DSI and functional connectivity in patients with AD. Auditory input from the left ear was more susceptible to impairment, suggesting that side-specific auditory input may influence central auditory processing.

Sex differences in the human reward system: convergent behavioral, autonomic and neural evidence.

Several studies have suggested that females and males differ in reward behaviors and their underlying neural circuitry. Whether human sex differences extend across neural and behavioral levels for both rewards and punishments remains unclear. We studied a community sample of 221 young women and men who performed a monetary incentive task known to engage the mesoaccumbal pathway and salience network. Both stimulus salience (behavioral relevance) and valence (win vs loss) varied during the task. In response to high- vs low-salience stimuli presented during the monetary incentive task, men showed greater subjective arousal ratings, behavioral accuracy and skin conductance responses (P < 0.006, Hedges' effect size g = 0.38 to 0.46). In a subsample studied with functional magnetic resonance imaging (n = 44), men exhibited greater responsiveness to stimulus salience in the nucleus accumbens, midbrain, anterior insula and dorsal anterior cingulate cortex (P < 0.02, g = 0.86 to 1.7). Behavioral, autonomic and neural sensitivity to the valence of stimuli did not differ by sex, indicating that responses to rewards vs punishments were similar in women and men. These results reveal novel and robust sex differences in reward- and punishment-related traits, behavior, autonomic activity and neural responses. These convergent results suggest a neurobehavioral basis for sexual dimorphism observed in the reward system, including reward-related disorders.

Estrogen receptor-α in female skeletal muscle is not required for regulation of muscle insulin sensitivity and mitochondrial regulation.

OBJECTIVE: Estrogen receptor-α (ERα) is a nuclear receptor family member thought to substantially contribute to the metabolic regulation of skeletal muscle. However, previous mouse models utilized to assess the necessity of ERα signaling in skeletal muscle were confounded by altered developmental programming and/or influenced by secondary effects, making it difficult to assign a causal role for ERα. The objective of this study was to determine the role of skeletal muscle ERα in regulating metabolism in the absence of confounding factors of development. METHODS: A novel mouse model was developed allowing for induced deletion of ERα in adult female skeletal muscle (ERαKOism). ERαshRNA was also used to knockdown ERα (ERαKD) in human myotubes cultured from primary human skeletal muscle cells isolated from muscle biopsies from healthy and obese insulin-resistant women. RESULTS: Twelve weeks of HFD exposure had no differential effects on body composition, VO2, VCO2, RER, energy expenditure, and activity counts across genotypes. Although ERαKOism mice exhibited greater glucose intolerance than wild-type (WT) mice after chronic HFD, ex vivo skeletal muscle glucose uptake was not impaired in the ERαKOism mice. Expression of pro-inflammatory genes was altered in the skeletal muscle of the ERαKOism, but the concentrations of these inflammatory markers in the systemic circulation were either lower or remained similar to the WT mice. Finally, skeletal muscle mitochondrial respiratory capacity, oxidative phosphorylation efficiency, and H2O2 emission potential was not affected in the ERαKOism mice. ERαKD in human skeletal muscle cells neither altered differentiation capacity nor caused severe deficits in mitochondrial respiratory capacity. CONCLUSIONS: Collectively, these results suggest that ERα function is superfluous in protecting against HFD-induced skeletal muscle metabolic derangements after postnatal development is complete.

Neuropeptide Y and representation of salience in human nucleus accumbens.

Neuropeptide Y (NPY) produces anxiolytic effects in rodent models, and naturally occurring low NPY expression in humans has been associated with negative emotional phenotypes. Studies in rodent models have also demonstrated that NPY elicits reward behaviors through its action in the nucleus accumbens (NAc), but the impact of NPY on the human NAc is largely unexplored. We recruited 222 healthy young adults of either sex and genetically selected 53 of these subjects at the extremes of NPY expression (Low-NPY and High-NPY) to participate in functional magnetic resonance imaging. Responses of the NAc and surrounding ventral striatum were quantified during a monetary incentive delay task in which stimuli varied by salience (high versus low) and valence (win versus loss). We found that bilateral NAc responses to high-salience versus low-salience stimuli were greater for Low-NPY subjects relative to High-NPY subjects, regardless of stimulus valence. To our knowledge, these results provide the first evidence in humans linking NPY with salience sensitivity of the NAc, raising the possibility that individual differences in NPY expression moderate the risk for disorders of mesoaccumbal function such as addictions and mood disorders. Additionally, we found that head motion was greater among High-NPY subjects, consistent with previous reports linking NPY with hyperactivity. Future studies in animal models are warranted to elucidate the neural mechanisms through which NPY influences NAc function and related behaviors.

The Use of Trace Eyeblink Classical Conditioning to Assess Hippocampal Dysfunction in a Rat Model of Fetal Alcohol Spectrum Disorders.

Neonatal rats were administered a relatively high concentration of ethyl alcohol (11.9% v/v) during postnatal days 4-9, a time when the fetal brain undergoes rapid organizational change and is similar to accelerated brain changes that occur during the third trimester in humans. This model of fetal alcohol spectrum disorders (FASDs) produces severe brain damage, mimicking the amount and pattern of binge-drinking that occurs in some pregnant alcoholic mothers. We describe the use of trace eyeblink classical conditioning (ECC), a higher-order variant of associative learning, to assess long-term hippocampal dysfunction that is typically seen in alcohol-exposed adult offspring. At 90 days of age, rodents were surgically prepared with recording and stimulating electrodes, which measured electromyographic (EMG) blink activity from the left eyelid muscle and delivered mild shock posterior to the left eye, respectively. After a 5 day recovery period, they underwent 6 sessions of trace ECC to determine associative learning differences between alcohol-exposed and control rats. Trace ECC is one of many possible ECC procedures that can be easily modified using the same equipment and software, so that different neural systems can be assessed. ECC procedures in general, can be used as diagnostic tools for detecting neural pathology in different brain systems and different conditions that insult the brain.

Interobserver Reliability of Three Validated Scoring Systems in the Assessment of Diabetic Foot Ulcers.

Scoring systems for diabetic foot ulcers may be used for clinical purposes, research or audit, to help assess disease severity, plan management, and even predict outcomes. While many have been validated in study populations, little is known about their interobserver reliability. This prospective study aimed to evaluate interobserver reliability of 3 scoring systems for diabetic foot ulceration. After sharp debridement, diabetic foot ulcers were classified by a multidisciplinary pool of trained observers, using the PEDIS (Perfusion, Extent, Depth, Infection, Sensation), SINBAD (Site, Ischemia, Neuropathy, Bacterial infection, Depth), and University of Texas (UT) wound classification systems. Interobserver reliability was assessed using intraclass correlations (0 = no agreement; 1 = complete agreement). Thirty-seven patients (78.4% male) were assessed by a pool of 12 observers. Single observer reliability was slight to moderate for all scoring systems (UT 0.53; SINBAD 0.44; PEDIS 0.23-0.42), but multiple observer reliability was almost perfect (UT 0.94; SINBAD 0.91; PEDIS 0.80-0.90). The worst agreement for single observers was when scoring infection (SINBAD 0.28; PEDIS 0.28), ischemia (SINBAD 0.26; PEDIS 0.23), or both (UT 0.25); however, this improved to almost perfect agreement for multiple observers (infection: 0.83; ischemia: 0.80-0.82; both: 0.81). These classification systems may be reliably used by multiple observers, for example, when conducting research and audit. However, they demonstrate only slight to moderate reliability when used by a single observer on an individual subject and may therefore be less helpful in the clinical setting, when documenting ulcer characteristics or communicating between colleagues.

A Systematic Review and Meta-analysis of Endovascular Popliteal Aneurysm Repair Using the Hemobahn/Viabahn Stent-Graft.

PURPOSE: To perform an evidence synthesis study to assess outcomes of endovascular repair of popliteal artery aneurysms (PAAs) using the Hemobahn or Viabahn stent-graft. METHODS: A systematic literature review was conducted conforming to established standards to identify articles published between 1996 (the date of introduction of the Hemobahn stent-graft) and 2013 reporting stent-graft repair of PAAs in at least 10 patients. The data were pooled for Kaplan-Meier analysis of primary and secondary patency rates [presented with 95% confidence intervals (CIs)] as the primary outcomes. Random effects meta-analysis was performed for secondary outcomes that included rates of reintervention, endoleak, stent-graft fracture, and limb salvage. RESULTS: Fourteen studies reported outcomes for 514 PAAs. There was considerable heterogeneity in reporting standards among studies. Pooled primary and secondary patency rates were 69.4% (95% CI 63.3% to 76.2%) and 77.4% (95% CI 70.1% to 85.3%), respectively, at 5 years. Five studies (including only one randomized controlled trial) compared surgical to endovascular repair; no difference was found in primary patency on evidence synthesis (hazard ratio 1.30, 95% CI 0.79 to 12.14, p=0.189). CONCLUSION: Stent-graft repair provides a feasible treatment option for anatomically suitable PAAs. Further studies are required to optimize both patient selection and follow-up protocols.

Distal bypasses in patients with diabetes and infrapopliteal disease: technical considerations to achieve success.

The combination of diabetes and peripheral arterial disease (PAD) is challenging in many ways. The characteristic and complex distal distribution of PAD often encountered in patients with diabetes means that bypass surgery in this context is technically challenging. In addition, many of these patients have a burden of serious comorbidities that must be optimized and managed concurrently. While the authors acknowledge that "achieving success" in distal bypass relies on much more than technical expertise, there are some technical aspects that should be considered when planning surgery on these patients. This article outlines some important issues in the treatment pathway of a patient with diabetes and PAD requiring distal bypass surgery--from selection and optimization of the patient (in the context of a multidisciplinary team) and preoperative workup, to the operative strategy planning, technical tips, and nonoperative adjuncts. These considerations, as well as sound knowledge of the underlying disease process, confounding medical factors and awareness of the difficulty in predicting treatment outcomes, should help maximize the chances of success.

Influence of foot ulceration on cause-specific mortality in patients with diabetes mellitus.

OBJECTIVE: The purpose of this study was to assess the odds of all-cause mortality in individuals with diabetic foot ulceration (DFU) compared with those with diabetes and no history of DFU. In addition, we sought to determine the strength of association of DFU with cardiovascular and nonvascular mortality. METHODS: We obtained data for a cohort of patients who attended a secondary care diabetic foot clinic or a general diabetes clinic between 2009 and 2010. A clinic cohort of patients with diabetes and no history of DFU provided a control group. Cause-specific mortality was recorded during a median follow-up duration of 3.6 years (interquartile range, 3.3-4.2 years). The association between DFU and all-cause mortality was evaluated by Cox regression. The association between DFU and cardiovascular mortality was determined by competing risk modeling. RESULTS: We recorded 145 events of all-cause mortality and 27 events of cardiovascular mortality among 869 patients with diabetes. After adjustment for potential confounders, DFU was associated with both cardiovascular disease (hazard ratio, 2.53; 95% confidence interval, 0.98-6.49; P = .05) and all-cause mortality (hazard ratio, 3.98; 95% confidence interval, 2.55-6.21; P < .001). The proportion of deaths attributable to cardiovascular disease was similar between the groups (18% with diabetes only and 19% with DFU; P = .91). CONCLUSIONS: DFU is associated with premature death from vascular and nonvascular causes.

Systematic review of screening investigations for peripheral arterial disease in patients with diabetes mellitus.

Diabetes-related foot complications are a major cause of amputation. The presence of peripheral arterial disease (PAD) identifies those at increased risk of ulceration, failure to heal an ulcer, and amputation. This systematic review assesses the ability of noninvasive screening tests to detect PAD in patients with diabetes mellitus. A database search was performed using the OVIDSP Web site, from 1946 to June 30, 2012 (MEDLINE®), and from 1974 to June 30, 2012 (EMBASE), to identify studies assessing the utility of screening tests in detecting PAD or predicting clinical outcomes in patients with diabetes mellitus. Thirteen studies were identified that reported sensitivity and specificity data on screening tests. No single screening test was reliable in identifying or excluding peripheral arterial disease in patients with diabetes. Although the evidence base is limited, transcutaneous oxygen measurements appear to be predictive of ulcer or surgical wound healing. The diagnosis of PAD (and the decision to revascularize) in patients with diabetes is unreliable using screening tests. Therefore, all patients with diabetes-related foot ulceration should be assessed by a multidisciplinary diabetes foot team that has access to a vascular specialist. A low threshold for noninvasive diagnostic imaging seems appropriate in patients with diabetes-related foot ulceration.

Successful use of talc sclerodesis to control a persistent high-output groin seroma following endovascular abdominal aortic aneurysm repair.

Groin wound lymphatic complications after vascular procedures are accompanied by increased risk of infection, prolonged hospital stay, and greater patient morbidity. High-output groin seromas can be difficult to manage and refractory to established interventions. Although subcutaneous talc has been used to prevent seroma accumulation in other high-risk surgical fields, such as after axillary lymph node dissection, it has not been described in the context of vascular surgery. This article presents the first reported case of a persistent high-output groin seroma after endovascular abdominal aortic aneurysm repair managed successfully with intraoperative application of sterile talc.

The BASIL survival prediction model in patients with peripheral arterial disease undergoing revascularization in a university hospital setting and comparison with the FINNVASC and modified PREVENT scores.

BACKGROUND: Critical limb ischemia carries a significant risk of morbidity and mortality. The development of scores to predict risk can aid clinical decision making. The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial investigators developed a model to predict death, which has not been previously validated. METHODS: Data were collected in a prospectively maintained database on all patients who underwent angioplasty or arterial bypass for peripheral artery disease in a university hospital between January 2008 and June 2010. The main outcome measures were all-cause mortality and amputation-free survival at 3, 6, 12, and 24 months after the index intervention. The BASIL survival predictor, Finland National Vascular (FINNVASC) registry, and Edifoligide for the Prevention of Infrainguinal Vein Graft Failure (PREVENT) models were applied and receiver-operating characteristic (ROC) curve analysis was used to evaluate their predictive power. RESULTS: Data on 342 patients were collected. Patients with isolated iliac disease or claudication were excluded. The 6-, 12-, and 24-month all-cause mortality rates were 11.6%, 17.9%, and 26.8%, respectively. The area under the ROC curve (95% confidence interval) using the BASIL score to predict mortality at 6, 12, and 24 months was 0.700 (0.60-0.80; P<.001), 0.651 (0.56-0.74; P<.003), and 0.681 (0.59-0.74; P<.001), respectively. ROC curve analysis indicated that the performance of the BASIL score in this cohort was comparable to other validated predictive scores. CONCLUSIONS: The BASIL survival prediction model can moderately predict short-term and medium-term mortality in patients with limb ischemia and may be a useful adjunct to decision making in everyday clinical practice.