Perfluorinated compounds (PFCs) are environmentally widespread, persistent, and bioaccumulative chemicals with multiple toxicities reported in experimental models and wildlife, including ...immunomodulation. The two most commonly detected compounds, which also generally occur in the highest concentrations in environmentally exposed organisms, are perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). PFOA and PFOS have been reported to alter inflammatory responses, production of cytokines, and adaptive and innate immune responses in rodent models, avian models, reptilian models, and mammalian and nonmammalian wildlife. Mounting evidence suggests that immune effects in laboratory animal models occur at serum concentrations below, within the reported range, or just above those reported for highly exposed humans and wildlife. Thus, the risk of immune effects for humans and wildlife exposed to PFCs cannot be discounted, especially when bioaccumulation and exposure to multiple PFCs are considered. This review contains brief descriptions of current and recently published work exploring immunomodulation by PFOA, PFOS, and other PFCs in rodent models, alternative laboratory models, and wildlife.
The Hypothalamic Pituitary Adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity ...in major depression, a relationship of HPA axis activity to cognitive performance, and a potential role of HPA axis genetic variation in cognition. In schizophrenia differential HPA activity has been found, including higher rates of non-suppression to dexamethasone challenge and higher salivary cortisol levels, which have been a premonitory risk factor for conversion to psychosis in adolescents at risk for developing schizophrenia. The present study investigated the simultaneous roles HPA axis activity and clinical symptomatology play in poor cognitive performance. Patients with major depression with psychosis (PMD) or schizophrenia spectrum disorder (SCZ) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, and overnight hourly blood sampling for cortisol. Cognitive performance did not differ between the clinical groups, though they both performed more poorly than the HC's across a variety of cognitive domains. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher evening cortisol levels than did SCZ and HCs. Cortisol and clinical symptoms, as well as age, sex, and antipsychotic use predicted cognitive performance. Diathesis stress models and their links to symptomatology, cognition, and HPA function are discussed.
Objective:
Depression is the leading cause of disability worldwide, and half of patients with depression have treatment-resistant depression. Intermittent theta-burst stimulation (iTBS) is approved ...by the U.S. Food and Drug Administration for the treatment of treatment-resistant depression but is limited by suboptimal efficacy and a 6-week duration. The authors addressed these limitations by developing a neuroscience-informed accelerated iTBS protocol, Stanford neuromodulation therapy (SNT; previously referred to as Stanford accelerated intelligent neuromodulation therapy, or SAINT). This protocol was associated with a remission rate of ∼90% after 5 days of open-label treatment. Here, the authors report the results of a sham-controlled double-blind trial of SNT for treatment-resistant depression.
Methods:
Participants with treatment-resistant depression currently experiencing moderate to severe depressive episodes were randomly assigned to receive active or sham SNT. Resting-state functional MRI was used to individually target the region of the left dorsolateral prefrontal cortex most functionally anticorrelated with the subgenual anterior cingulate cortex. The primary outcome was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 4 weeks after treatment.
Results:
At the planned interim analysis, 32 participants with treatment-resistant depression had been enrolled, and 29 participants who continued to meet inclusion criteria received either active (N=14) or sham (N=15) SNT. The mean percent reduction from baseline in MADRS score 4 weeks after treatment was 52.5% in the active treatment group and 11.1% in the sham treatment group.
Conclusions:
SNT, a high-dose iTBS protocol with functional-connectivity-guided targeting, was more effective than sham stimulation for treatment-resistant depression. Further trials are needed to determine SNT’s durability and to compare it with other treatments.
Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. ...Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample (n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes ('biotypes') defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82-93%) sensitivity and specificity for depression subtypes in multisite validation (n = 711) and out-of-sample replication (n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy (n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.
Persistent organic pollutants (POPs) are toxic man-made chemicals that bioaccumulate and biomagnify in food webs, making them a ubiquitous threat to the marine environment. Although many studies have ...determined concentrations of POPs in top predators, no studies have quantified POPs in stranded cetaceans within the last 30years around the Hawaiian Islands. A suite of POPs was measured in the blubber of 16 cetacean species that stranded in the tropical Pacific, including Hawai'i from 1997 to 2011. The sample set includes odontocetes (n=39) and mysticetes (n=3). Median (range) contaminant concentrations in ng/g lipid for the most representative species category (delphinids excluding killer whales n=27) are: 9650 (44.4–99,100) for ∑DDTs, 6240 (40.8–50,200) for ∑PCBs, 1380 (6.73–9520) for ∑chlordanes, 1230 (13.4–5510) for ∑toxaphenes, 269 (1.99–10,100) for ∑PBDEs, 280 (2.14–4190) for mirex, 176 (5.43–857) for HCB, 48.1 (<5.42–566) for ∑HCHs, 33.9 (<2.42–990) for ∑HBCDs, 1.65 (<0.435–11.7) for octachlorostyrene and 1.49 (<2.07–13.1) for pentachlorobenzene. ∑PCB concentrations in these Pacific Island cetaceans approach and sometimes exceed proposed toxic threshold values. Backward stepwise multiple regressions indicated the influence of life history parameters on contaminant concentrations when performed with three independent variables (species category, year of stranding, and sex/age class). No temporal trends were noted (p>0.063), but sex/age class influences were evident with adult males exhibiting greater contaminant loads than adult females and juveniles for ∑DDT, ∑PCBs, ∑CHLs, and mirex (p≤0.036). POP concentrations were lower in mysticetes than odontocetes for many compound classes (p≤0.003). p,p′-DDE/∑DDTs ratios were greater than 0.6 for all species except humpback whales, suggesting exposure to an old DDT source. These POP levels are high enough to warrant concern and continued monitoring.
•DDTs, PCBs and chlordanes were predominant in Pacific cetaceans.•POP classes are stable in cetaceans stranded over the last 15years for this region.•Contaminants are compared among cetacean species and to other populations globally.
Background. Physical therapy intervention is the primary treatment for gait ataxia and imbalance in individuals with cerebellar damage. Our aim was to determine if a home balance exercise program is ...feasible for improving locomotor and balance abilities in these individuals. Methods. A total of 14 patients with cerebellar ataxia participated in a 6-week individualized home-based balance exercise program and attended 5 testing sessions (2 pretraining, 1 midtraining, 1 posttraining, and 1 one-month follow-up visit). Pretraining, posttraining, and follow-up testing included a neurological assessment, clinical gait and balance tests, and laboratory assessments of balance and walking. Participants kept logs of the frequency and level of balance challenge during their training. Results. Walking speed improved across visits, as did stride length, percentage double-limb support time, Timed Up and Go (TUG), and Dynamic Gait Index. Post hoc comparisons in these measures revealed that significant rehabilitative improvements occurred over the 6-week training period, and all but TUG gains were retained 1 month later. There were no changes across the other measures for the group. Regression analysis indicated that improvements in walking speed were affected by the level of balance challenge but not by age, ataxia severity, proprioception, or duration of exercise. Conclusions. Improvement in locomotor performance in people with cerebellar ataxia was observable after a 6-week home balance exercise program. The exercise program must be designed to provide a significant challenge to the person’s balance.
Variations in neural circuitry, inherited or acquired, may underlie important individual differences in thought, feeling, and action patterns. Here, we used task-free connectivity analyses to isolate ...and characterize two distinct networks typically coactivated during functional MRI tasks. We identified a "salience network," anchored by dorsal anterior cingulate (dACC) and orbital frontoinsular cortices with robust connectivity to subcortical and limbic structures, and an "executive-control network" that links dorsolateral frontal and parietal neocortices. These intrinsic connectivity networks showed dissociable correlations with functions measured outside the scanner. Prescan anxiety ratings correlated with intrinsic functional connectivity of the dACC node of the salience network, but with no region in the executive-control network, whereas executive task performance correlated with lateral parietal nodes of the executive-control network, but with no region in the salience network. Our findings suggest that task-free analysis of intrinsic connectivity networks may help elucidate the neural architectures that support fundamental aspects of human behavior.
Background and objective. Previous studies suggest that error augmentation may be used as a strategy to achieve longer-term changes in gait deficits after stroke. The purpose of this study was to ...determine whether longer-term improvements in step length asymmetry could be achieved with repeated split-belt treadmill walking practice using an error augmentation strategy. Methods. 13 persons with chronic stroke (>6 months) participated in testing: (1) prior to 12 sessions of split-belt treadmill training, (2) after the training, and (3) in follow-up testing at 1 and 3 months. Step length asymmetry was the target of training, so belt speeds were set to augment step length asymmetry such that aftereffects resulted in reduced step length asymmetry during overground walking practice. Each individual was classified as a “responder” or “nonresponder” based on whether their reduction in step length asymmetry exceeded day-to-day variability. Results. For the group and for the responders (7 individuals), step length asymmetry improved from baseline to posttesting (P < .05) through an increased step length on both legs but a relatively larger change on the shorter step side (P < .05). Other parameters that were not targeted (eg, stance time asymmetry) did not change over the intervention. Conclusions. This study demonstrates that short-term adaptations can be capitalized on through repetitive practice and can lead to longer-term improvements in gait deficits poststroke. The error augmentation strategy, which promotes stride-by-stride adjustment to reduce asymmetry and results in improved asymmetry during overground walking practice, appears to be critical for obtaining the improvements observed.
Adult male and female B6C3F1 mice were exposed to perfluorooctane sulfonate (PFOS) daily via gavage for 28 days (0, 0.005, 0.05, 0.1, 0.5, 1, or 5 mg/kg total administered dose TAD). Following ...exposure, various immune parameters were assessed and serum PFOS concentrations were determined. Lymphocyte proliferation was not altered in either gender. Natural killer cell activity was increased compared with control at 0.5, 1, and 5 mg/kg TAD in male mice but was not altered in female mice. At these treatment levels, splenic T-cell immunophenotypes were minimally altered in females, but all T-cell subpopulations were significantly modulated in males beginning at 0.1 mg/kg TAD. The sheep red blood cell (SRBC) plaque-forming cell (PFC) response was suppressed in male mice beginning at 0.05 mg/kg TAD and in females at 0.5 mg/kg TAD. Serum trinitrophenyl (TNP)–specific IgM titers were also decreased by PFOS after TNP–LPS (TNP conjugated to lipopolysacharide) challenge suggesting that the humoral immune effects may be attributed to the B-cell rather than T-cell because both T-dependent (SRBC) and T-independent (TI) (TNP–LPS) antigens result in suppressed IgM production. Based on the PFC response, the low observed effect level (LOEL) for males was 0.05 mg/kg TAD (ED50 = 0.021 mg/kg TAD) and for females was 0.5 mg/kg TAD (ED50 = 0.59 mg/kg TAD). Measured PFOS serum concentrations at these dose levels were 91.5 ± 22.2 ng/g and 666 ± 108 ng/g (mean ± SD), respectively. The male LOEL serum level was approximately 14-fold lower than reported mean blood levels from occupationally exposed humans and fell in the upper range of concentrations reported for the general population. Overall, this study provides a profile of PFOS immunotoxicity showing effects at levels reported in humans and identifies the B-cells as a potential target.
PDF
