Candida albicans selection for human commensalism results in substantial within-host diversity without decreasing fitness for invasive disease.

Candida albicans is a frequent colonizer of human mucosal surfaces as well as an opportunistic pathogen. C. albicans is remarkably versatile in its ability to colonize diverse host sites with differences in oxygen and nutrient availability, pH, immune responses, and resident microbes, among other cues. It is unclear how the genetic background of a commensal colonizing population can influence the shift to pathogenicity. Therefore, we examined 910 commensal isolates from 35 healthy donors to identify host niche-specific adaptations. We demonstrate that healthy people are reservoirs for genotypically and phenotypically diverse C. albicans strains. Using limited diversity exploitation, we identified a single nucleotide change in the uncharacterized ZMS1 transcription factor that was sufficient to drive hyper invasion into agar. We found that SC5314 was significantly different from the majority of both commensal and bloodstream isolates in its ability to induce host cell death. However, our commensal strains retained the capacity to cause disease in the Galleria model of systemic infection, including outcompeting the SC5314 reference strain during systemic competition assays. This study provides a global view of commensal strain variation and within-host strain diversity of C. albicans and suggests that selection for commensalism in humans does not result in a fitness cost for invasive disease.

Histone variant-specific post-translational modifications.

Post-translational modifications (PTMs) of histones play a key role in DNA-based processes and contribute to cell differentiation and gene function by adding an extra layer of regulation. Variations in histone sequences within each family of histones expands the chromatin repertoire and provide further mechanisms for regulation and signaling. While variants are known to be present in certain genomic loci and carry out important functions, much remains unknown about variant-specific PTMs and their role in regulating chromatin. This ambiguity is in part due to the limited technologies and appropriate reagents to identify and quantitate variant-specific PTMs. Nonetheless, histone variants are an integral portion of the chromatin system and the understanding of their modifications and resolving how PTMs function differently on specific variants is paramount to the advancement of the field. Here we review the current knowledge on post-translational modifications specific to histone variants, with an emphasis on well-characterized PTMs of known function. While not every possible PTM is addressed, we present key variant-specific PTMs and what is known about their function and mechanisms in convenient reference tables.

H3K36 dimethylation shapes the epigenetic interaction landscape by directing repressive chromatin modifications in embryonic stem cells.

Epigenetic modifications on the chromatin do not occur in isolation. Chromatin-associated proteins and their modification products form a highly interconnected network, and disturbing one component may rearrange the entire system. We see this increasingly clearly in epigenetically dysregulated cancers. It is important to understand the rules governing epigenetic interactions. Here, we use the mouse embryonic stem cell (mESC) model to describe in detail the relationships within the H3K27-H3K36-DNA methylation subnetwork. In particular, we focus on the major epigenetic reorganization caused by deletion of the histone 3 lysine 36 methyltransferase NSD1, which in mESCs deposits nearly all of the intergenic H3K36me2. Although disturbing the H3K27 and DNA methylation (DNAme) components also affects this network to a certain extent, the removal of H3K36me2 has the most drastic effect on the epigenetic landscape, resulting in full intergenic spread of H3K27me3 and a substantial decrease in DNAme. By profiling DNMT3A and CHH methylation (mCHH), we show that H3K36me2 loss upon Nsd1-KO leads to a massive redistribution of DNMT3A and mCHH away from intergenic regions and toward active gene bodies, suggesting that DNAme reduction is at least in part caused by redistribution of de novo methylation. Additionally, we show that pervasive acetylation of H3K27 is regulated by the interplay of H3K36 and H3K27 methylation. Our analysis highlights the importance of H3K36me2 as a major determinant of the developmental epigenome and provides a framework for further consolidating our knowledge of epigenetic networks.

Associations between CD70 methylation of T cell DNA and age in adults with systemic lupus erythematosus and population controls: The Michigan Lupus Epidemiology & Surveillance (MILES) Program.

BACKGROUND: Environmental factors can influence epigenetic regulation, including DNA methylation, potentially contributing to systemic lupus erythematosus (SLE) development and progression. We compared methylation of the B cell costimulatory CD70 gene, in persons with lupus and controls, and characterized associations with age. RESULTS: In 297 adults with SLE and 92 controls from the Michigan Lupus Epidemiology and Surveillance (MILES) Cohort, average CD70 methylation of CD4+ T cell DNA across 10 CpG sites based on pyrosequencing of the promoter region was higher for persons with SLE compared to controls, accounting for covariates [ß = 2.3, p = 0.011]. Using Infinium MethylationEPIC array data at 18 CD70-annoted loci (CD4+ and CD8+ T cell DNA), sites within the promoter region tended to be hypomethylated in SLE, while those within the gene region were hypermethylated. In SLE but not controls, age was significantly associated with pyrosequencing-based CD70 methylation: for every year increase in age, methylation increased by 0.14 percentage points in SLE, accounting for covariates. Also within SLE, CD70 methylation approached a significantly higher level in Black persons compared to White persons (ß = 1.8, p = 0.051). CONCLUSIONS: We describe altered CD70 methylation patterns in T lymphocyte subsets in adults with SLE relative to controls, and report associations particular to SLE between methylation of this immune-relevant gene and both age and race, possibly a consequence of "weathering" or accelerated aging which may have implications for SLE pathogenesis and potential intervention strategies.

Effect of parenteral micronutrient supplementation at birth on immunity, growth, and health in preweaning dairy heifers.

This randomized clinical trial aimed to determine the extent to which injectable micronutrient supplementation at birth can improve intranasal vaccine response by ameliorating oxidative stress in dairy calves from birth to weaning. For this, 120 Holstein heifer calves were enrolled at birth and randomly allocated into one of 4 groups. The 4 groups included 3 commercially available micronutrient supplements (selenium, copper, zinc, and manganese; selenium and vitamin E; and vitamins E, A, and D) and one control (saline). Calves received an intranasal vaccine against the respiratory viruses parainfluenza 3, bovine herpesvirus type 1 (BHV-1), and bovine respiratory syncytial virus (BRSV) within the first week of life. Body weight and hip height (HH) were recorded, and a blood sample and nasal secretion sample were collected at birth before treatment and vaccine administration, as well as weekly until weaning at 8 wk. Health scores, including thoracic ultrasound assessment, were recorded weekly from wk 1 to wk 8. Farm treatment records were collected after the completion of the study. Serum micronutrient concentrations were determined from birth to weaning to identify micronutrient status, and serum blood metabolites were analyzed as markers of nutrient utilization. Redox balance was determined in serum as a ratio of reactive oxygen and nitrogen species to antioxidant capacity, known as the oxidant status index (OSi). Intranasal vaccine response was quantified as anti-BRSV and anti-BHV-1 IgA concentrations in nasal secretions. Linear mixed models with repeated measures were built for micronutrient concentrations, blood metabolites, redox balance, IgA concentrations, BW, and HH. Pre-planned contrasts of the control and supplemented groups were also built for the primary outcome of IgA concentrations. A logistic regression mixed model was built for health events and treatment of disease. Serum selenium concentrations were greater in calves receiving supplements containing Se throughout the first 4 wk of life. However, we did not observe any consistent differences in the other micronutrients. The metabolic biomarkers indicate that supplemented calves had better energy status, as suggested by lower BHB and nonesterified fatty acids concentrations. Supplemented calves showed improved redox balance, as indicated by lower OSi throughout the first week of life. Calves supplemented with antioxidants at birth had higher anti-BRSV IgA than control calves. Our results indicate an improved immune response to vaccines in calves supplemented with antioxidants at birth. However, this did not translate to growth and health performance, as we did not find any differences in average daily gain or incidence of health events throughout the preweaning period. This study provides evidence that improving the antioxidant capacity might improve vaccine response, and further research is required to investigate the appropriate frequency and dose of supplementation to improve calf growth and health.

Brain-based mechanisms of late-life depression: Implications for novel interventions.

Late-life depression (LLD) is a particularly debilitating illness. Older adults suffering from depression commonly experience poor outcomes in response to antidepressant treatments, medical comorbidities, and declines in daily functioning. This review aims to further our understanding of the brain network dysfunctions underlying LLD that contribute to disrupted cognitive and affective processes and corresponding clinical manifestations. We provide an overview of a network model of LLD that integrates the salience network, the default mode network (DMN) and the executive control network (ECN). We discuss the brain-based structural and functional mechanisms of LLD with an emphasis on their link to clinical subtypes that often fail to respond to available treatments. Understanding the brain networks that underlie these disrupted processes can inform the development of targeted interventions for LLD. We propose behavioral, cognitive, or computational approaches to identifying novel, personalized interventions that may more effectively target the key cognitive and affective symptoms of LLD.

Learning and achievement characteristics of sheltered homeless population subgroups.

BACKGROUND: There is little systematic information about intelligence and academic achievement among sheltered homeless adults. This study adds descriptive data on intelligence and academic achievement, examines discrepancies across these concepts, and explores the associations among demographic and psychosocial characteristics in the context of intelligence categories and discrepancies. METHODS: We studied intelligence, academic achievement, and discrepancies between IQ and academic achievement among 188 individuals experiencing homelessness who were systematically recruited from a large, urban, 24-hour homeless recovery center. Participants completed structured interviews, urine drug testing, the Wechsler Abbreviated Scale of Intelligence, and the Wide Range Achievement Test, 4th edition. RESULTS: Average full-scale intelligence was low average (90) but higher than scores obtained in other studies of homeless populations. Academic achievement was lower than average (82 to 88). Performance/math deficits in the higher intelligence group indicate functional difficulties that could have contributed to homeless risk. CONCLUSIONS: The low-normal intelligence and below-average achievement scores are not extreme enough to warrant immediate attention and intervention for most individuals. Systematic screening during entry into homeless services might identify learning strengths and weaknesses, presenting modifiable factors that could be addressed in focused educational/vocational interventions.

Changes in biomarkers of metabolic stress during late gestation of dairy cows associated with colostrum volume and immunoglobulin content.

The objective of this observational study was to compare the metabolic status of dairy cows during the last 6 wk of gestation based on colostrum volume and immunoglobulin content. For this, healthy Holstein cows were randomly selected from 3 commercial herds in Michigan. In each farm, 4 cohorts of 21 cows (1 per season), stratified by parity, were enrolled (n = 228). Cows were blood sampled weekly during the last 6 wk of gestation, and biomarkers related to nutrient utilization, oxidant status, and inflammation were quantified in serum. Cows were milked within 6 h of calving, and the volume of colostrum produced was recorded and an aliquot collected. Concentration of IgG, IgA, and IgM were measured by radial immunodiffusion. Cows were grouped into high or low colostrum producer, high or low IgG, high or low IgA, and high or low IgM. For volume category, we arbitrarily defined 6 L of colostrum (4 L for first and 2 L for second feeding of calves) as the cutoff point, whereas for IgG we used the industry standard of ≥50 g/L. To create groups of low and high IgM or IgA, we used the median of these immunoglobulin as the cutoff point. Colostrum volume was lowest in winter, but no differences were observed among parity groups. Conversely, colostrum IgG concentration was highest in fall and winter, but colostrum IgM was lowest at these seasons. However, colostrum immunoglobulin content only showed a negative weak correlation with volume (Spearman's correlation coefficient < -0.28). Compared with low colostrum producer, high colostrum producer cows had higher concentrations of antioxidant potential and ß-hydroxybutyrate, and lower cholesterol and oxidant status index. Cows with high IgG showed higher concentrations of glucose compared with low IgG. Cows with high IgA had higher concentrations of cholesterol, reactive oxygen and nitrogen species, oxidant status index, and total protein, whereas ß-hydroxybutyrate and glucose were lower compared with low IgA. Biomarkers of metabolic stress were not significantly different between high IgM and low IgM. Nevertheless, the differences observed did not result in differences in inflammatory status between animals in any of the colostrum variable categories analyzed, suggesting that physiological homeostasis was not disrupted during late gestation in association with the colostrum variables studied. Overall, the great variability observed in colostrum variables suggests that colostrogenesis is a complex and multifactorial process. However, our results suggest that greater availability of antioxidants during late gestation could support the production of higher volumes of colostrum, which needs to be explored in future trials.

Eating disorder risk among college sorority and fraternity members within the United States.

Eating disorder (ED) risk is elevated among college populations in the United States. However, current research assessing the relative risk of ED symptomatology within Greek life has been mixed. We aimed to assess whether Greek Life Affiliation (GA) was associated with a greater risk for ED among college students in the United States as measured on the SCOFF questionnaire. Data were extracted from the Healthy Minds Study, which surveyed 44,785 American college students across 79 schools. The survey asked about GA, Greek life housing, and included the SCOFF questionnaire. This study utilized multiple logistic regressions and chi-square analyses (n = 44785) to analyze the data. GA failed to predict ED-risk in both women (aOR = 0.98 [95% CI = 0.90, 1.06]) and men (aOR = 1.07 [95% CI = 0.92, 1.24]). Similarly, among female [aOR = 1.00 [95% CI = 0.46, 2.12]) and male participants (aOR = 1.06 [95% CI = 0.59, 1.98]), sorority/fraternity housing also failed to predict ED-risk. Greek Life Affiliation is not associated with greater ED-risk among US college students.

Distribution of biomass dynamics in relation to tree size in forests across the world.

Tree size shapes forest carbon dynamics and determines how trees interact with their environment, including a changing climate. Here, we conduct the first global analysis of among-site differences in how aboveground biomass stocks and fluxes are distributed with tree size. We analyzed repeat tree censuses from 25 large-scale (4-52 ha) forest plots spanning a broad climatic range over five continents to characterize how aboveground biomass, woody productivity, and woody mortality vary with tree diameter. We examined how the median, dispersion, and skewness of these size-related distributions vary with mean annual temperature and precipitation. In warmer forests, aboveground biomass, woody productivity, and woody mortality were more broadly distributed with respect to tree size. In warmer and wetter forests, aboveground biomass and woody productivity were more right skewed, with a long tail towards large trees. Small trees (1-10 cm diameter) contributed more to productivity and mortality than to biomass, highlighting the importance of including these trees in analyses of forest dynamics. Our findings provide an improved characterization of climate-driven forest differences in the size structure of aboveground biomass and dynamics of that biomass, as well as refined benchmarks for capturing climate influences in vegetation demographic models.

Modifiable predictors of nonresponse to psychotherapies for late-life depression with executive dysfunction: a machine learning approach.

The study aimed to: (1) Identify distinct trajectories of change in depressive symptoms by mid-treatment during psychotherapy for late-life depression with executive dysfunction; (2) examine if nonresponse by mid-treatment predicted poor response at treatment end; and (3) identify baseline characteristics predicting an early nonresponse trajectory by mid-treatment. A sample of 221 adults 60 years and older with major depression and executive dysfunction were randomized to 12 weeks of either problem-solving therapy or supportive therapy. We used Latent Growth Mixture Models (LGMM) to detect subgroups with distinct trajectories of change in depression by mid-treatment (6th week). We conducted regression analyses with LGMM subgroups as predictors of response at treatment end. We used random forest machine learning algorithms to identify baseline predictors of LGMM trajectories. We found that ~77.5% of participants had a declining trajectory of depression in weeks 0-6, while the remaining 22.5% had a persisting depression trajectory, with no treatment differences. The LGMM trajectories predicted remission and response at treatment end. A random forests model with high prediction accuracy (80%) showed that the strongest modifiable predictors of the persisting depression trajectory were low perceived social support, followed by high neuroticism, low treatment expectancy, and low perception of the therapist as accepting. Our results suggest that modifiable risk factors of early nonresponse to psychotherapy can be identified at the outset of treatment and addressed with targeted personalized interventions. Therapists may focus on increasing meaningful social interactions, addressing concerns related to treatment benefits, and creating a positive working relationship.

Estimated Regional White Matter Hyperintensity Burden, Resting State Functional Connectivity, and Cognitive Functions in Older Adults.

OBJECTIVE: White matter hyperintensities (WMH) are linked to deficits in cognitive functioning, including cognitive control and memory; however, the structural, and functional mechanisms are largely unknown. We investigated the relationship between estimated regional disruptions to white matter fiber tracts from WMH, resting state functional connectivity (RSFC), and cognitive functions in older adults. DESIGN: Cross-sectional study. SETTING: Community. PARTICIPANTS: Fifty-eight cognitively-healthy older adults. MEASUREMENTS: Tasks of cognitive control and memory, structural MRI, and resting state fMRI. We estimated the disruption to white matter fiber tracts from WMH and its impact on gray matter regions in the cortical and subcortical frontoparietal network, default mode network, and ventral attention network by overlaying each subject's WMH mask on a normative tractogram dataset. We calculated RSFC between nodes in those same networks. We evaluated the interaction of regional WMH burden and RSFC in predicting cognitive control and memory. RESULTS: The interaction of estimated regional WMH burden and RSFC in cortico-striatal regions of the default mode network and frontoparietal network was associated with delayed recall. Models predicting working memory, cognitive inhibition, and set-shifting were not significant. CONCLUSION: Findings highlight the role of network-level structural and functional alterations in resting state networks that are related to WMH and impact memory in older adults.

The Structural and Functional Neuroanatomy of Post-Stroke Depression and Executive Dysfunction: A Review of Neuroimaging Findings and Implications for Treatment.

Post-stroke depression and executive dysfunction co-occur and are highly debilitating. Few treatments alleviate both depression and executive dysfunction after stroke. Understanding the brain network changes underlying post-stroke depression with executive dysfunction can inform the development of targeted and efficacious treatment. In this review, we synthesize neuroimaging findings in post-stroke depression and post-stroke executive dysfunction and highlight the network commonalities that may underlie this comorbidity. Structural and functional alterations in the cognitive control network, salience network, and default mode network are associated with depression and executive dysfunction after stroke. Specifically, post-stroke depression and executive dysfunction are both linked to changes in intrinsic functional connectivity within resting state networks, functional over-connectivity between the default mode and salience/cognitive control networks, and reduced cross-hemispheric frontoparietal functional connectivity. Cognitive training and noninvasive brain stimulation targeted at these brain network abnormalities and specific clinical phenotypes may help advance treatment for post-stroke depression with executive dysfunction.

Strategies to Promote Cognitive Health in Aging: Recent Evidence and Innovations.

PURPOSE OF REVIEW: We review recent work on applications of non-pharmacologic strategies to promote cognitive health in older adulthood and discuss potential network mechanisms, limitations, and considerations for improving intervention uptake and efficacy. RECENT FINDINGS: In healthy older adults and patients with mild cognitive impairment, cognitive training produces global and domain-specific cognitive gains, though effect sizes tend to be modest and transfer is variable. Non-invasive brain stimulation has shown moderate success in enhancing cognitive function, though the optimum approach, parameters, and cortical targets require further investigation. Physical activity improves cognitive functions in late life, with emerging trials highlighting key intervention components that may maximize treatment outcomes. Multimodal interventions may be superior to single-component interventions in conferring cognitive gains, although interpretation is limited by modest sample sizes and variability in training components and parameters. Across modalities, individual differences in patient characteristics predict therapeutic response. These interventions may advance cognitive health by modulating functional networks that support core cognitive abilities including the default mode, executive control, and salience networks. Effectiveness of cognitive enhancement strategies may be increased with clinician-led coaching, booster sessions, gamification, integration of multiple intervention modalities, and concrete applications to everyday functioning. Future trials involving rigorous comparisons of training components, parameters, and delivery formats will be essential in establishing the precise approaches needed to maximize cognitive outcomes. Novel studies using patient-level clinical and neuroimaging features to predict individual differences in training gains may inform the development of personalized intervention prescriptions to optimize cognitive health in late life.

Cortical Thickness of the Salience Network and Change in Apathy Following Antidepressant Treatment for Late-Life Depression.

OBJECTIVE: Apathy is common in late-life depression and is associated with poor response to antidepressant drugs. In depressed older adults, apathy may be characterized by neuroanatomical abnormalities of the salience network. The current study examined whether cortical thickness of select salience network structures predicted change in apathy following a 12-week treatment with escitalopram. METHODS: A sample of 46 older adults with major depressive disorder received 12 weeks of escitalopram treatment at a daily target dose of 20 mg. All participants underwent a structural brain MRI scan at baseline, and cortical thickness was estimated in key cortical nodes of the salience network: the caudal anterior cingulate cortex and the insula. We measured baseline and post-treatment symptoms using the Apathy Evaluation Scale and the Hamilton Depression Rating Scale. RESULTS: A thicker insula at baseline predicted reduction in apathy symptoms following 12 weeks of treatment with escitalopram, even when controlling for age, baseline depression severity and change in depressive symptoms. CONCLUSION: Reduced insular thickness predicted residual apathetic symptoms following escitalopram treatment. These results converge with our previous findings of abnormal functional connectivity of the insular cortex in older depressed individuals with apathy. Older depressed adults with apathy may benefit from alternative treatment approaches or augmentative interventions that target abnormalities of the salience network.

Multistep Continuous Flow Synthesis of Stavudine.

Herein, we demonstrate an elegant multistep continuous flow synthesis for stavudine (d4T), a potent nucleoside chemotherapeutic agent for human immunodeficiency virus, acquired immunodeficiency syndrome (AIDS) and AIDS-related conditions. This was accomplished via six chemical transformations in five sequential continuous flow reactors from an affordable starting material, 5-methyluridine. In the first instance, single step continuous flow synthesis was demonstrated with an average of 97% yield, 21.4 g/h throughput per step, and a total of 15.5 min residence time. Finally, multistep continuous flow synthesis of d4T in 87% total yield with a total residence time of 19.9 min and 117 mg/h throughput without intermediate purification was demonstrated.

Longitudinal Transcriptomic, Proteomic, and Metabolomic Analysis of Citrus limon Response to Graft Inoculation by Candidatus Liberibacter asiaticus.

Presymptomatic detection of citrus trees infected with Candidatus Liberibacter asiaticus (CLas), the bacterial pathogen associated with Huanglongbing (HLB; citrus greening disease), is critical to controlling the spread of the disease. To test whether infected citrus trees produce systemic signals that may be used for indirect disease detection, lemon (Citrus limon) plants were graft-inoculated with either CLas-infected or control (CLas-) budwood, and leaf samples were longitudinally collected over 46 weeks and analyzed for plant changes associated with CLas infection. RNA, protein, and metabolite samples extracted from leaves were analyzed using RNA-Seq, mass spectrometry, and 1H NMR spectroscopy, respectively. Significant differences in specific transcripts, proteins, and metabolites were observed between CLas-infected and control plants as early as 2 weeks post graft (wpg). The most dramatic differences between the transcriptome and proteome of CLas-infected and control plants were observed at 10 wpg, including coordinated increases in transcripts and proteins of citrus orthologs of known plant defense genes. This integrated approach to quantifying plant molecular changes in leaves of CLas-infected plants supports the development of diagnostic technology for presymptomatic or early disease detection as part of efforts to control the spread of HLB into uninfected citrus groves.

Differing functional mechanisms underlie cognitive control deficits in psychotic spectrum disorders.

Background: Functional underpinnings of cognitive control deficits in unbiased samples (i.e., all comers) of patients with psychotic spectrum disorders (PSD) remain actively debated. While many studies suggest hypofrontality in the lateral prefrontal cortex (PFC) and greater deficits during proactive relative to reactive control, few have examined the full hemodynamic response. Methods: Patients with PSD (n = 154) and healthy controls (n = 65) performed the AX continuous performance task (AX-CPT) during rapid (460 ms) functional neuroimaging and underwent full clinical characterization. Results: Behavioural results indicated generalized cognitive deficits (slower and less accurate) across proactive and reactive control conditions in patients with PSD relative to healthy controls. We observed a delayed/prolonged neural response in the left dorsolateral PFC, the sensorimotor cortex and the superior parietal lobe during proactive control for patients with PSD. These proactive hemodynamic abnormalities were better explained by negative rather than by positive symptoms or by traditional diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision (DSM-IV-TR), with subsequent simulations unequivocally demonstrating how these abnormalities could be erroneously interpreted as hypoactivation. Conversely, true hypoactivity, unassociated with clinical symptoms or DSM-IV-TR diagnoses, was observed within the ventrolateral PFC during reactive control. Limitations: In spite of guidance for AX-CPT use in neuroimaging studies, one-third of patients with PSD could not perform the task above chance and were more clinically impaired. Conclusion: Current findings question the utility of the AX-CPT for neuroimaging-based appraisal of cognitive control across the full spectrum of patients with PSD. Previously reported lateral PFC "hypoactivity" during proactive control may be more indicative of a delayed/prolonged neural response, important for rehabilitative purposes. Negative symptoms may better explain certain behavioural and hemodynamic abnormalities in patients with PSD relative to DSM-IV-TR diagnoses.

Targeting Cognitive Control Deficits With Neuroplasticity-Based Computerized Cognitive Remediation in Patients With Geriatric Major Depression: A Randomized, Double-Blind, Controlled Trial.

Late life major depression (LLD) is often accompanied by cognitive deficits. When patients have specific deficits in cognitive control functions (CCD), they are not only distressing and debilitating, they often predict poor clinical outcomes such as reduced response to SSRI/SNRI antidepressants, increased disability, suicide and all-cause mortality. We recently reported that in an open label trial, our treatment designed to target these specific CCD with neuroplasticity-based computerized cognitive remediation (nCCR) improved depression and CCD in patients who failed to remit with conventional antidepressant treatment. This study tested the hypothesis that in patients with LLD who have failed at least one trial of an SSRI/SNRI antidepressant at an adequate dose for at least 8 weeks, nCCR will improve both depressive symptoms and the CCD associated with poor antidepressant response (i.e. semantic strategy, inhibition of prepotent responses) more than an active control group. Participants were randomized (1:1) to receive either 30 hours/ 4 weeks of neuroplasticity based computerized cognitive remediation (nCCR) designed to target CCD, or the active control condition matched for duration, engagement, reward, computer presentation, and contact with study staff. All participants and raters were blinded. Mixed effects model analysis the time effect (week) (F(1,71.22)=25.2, p<0.0001) and treatment group X time interaction (F(1,61.8)=11.37, p=.002) reached significance indicating that the slope of decline in MADRS was steeper in the nCCR-GD group. Further, the nCCR group improved their semantic clustering strategy(t(28)=9.5; p=.006), as well as performance on the Stroop interference condition, and cognitive flexibility (Trails B). Further, results transferred to memory performance, which was not a function trained by nCCR. clinicaltrials.gov.

Resting State Functional Connectivity and Outcomes of Psychotherapies for Late-Life Depression.

BACKGROUND: Problem solving therapy (PST) and "Engage," a reward-exposure" based therapy, are important treatment options for late-life depression, given modest efficacy of antidepressants in this disorder. Abnormal function of the reward and default mode networks has been observed during depressive episodes. This study examined whether resting state functional connectivity (rsFC) of reward and DMN circuitries is associated with treatment outcomes. METHODS: Thirty-two older adults with major depression (mean age = 72.7) were randomized to 9-weeks of either PST or "Engage." We assessed rsFC at baseline and week 6. We placed seeds in three a priori regions of interest: subgenual anterior cingulate cortex (sgACC), dorsal anterior cingulate cortex (dACC), and nucleus accumbens (NAcc). Outcome measures included the Hamilton Depression Rating Scale (HAMD) and the Behavioral Activation for Depression Scale (BADS). RESULTS: In both PST and "Engage," higher rsFC between the sgACC and middle temporal gyrus at baseline was associated with greater improvement in depression severity (HAMD). Preliminary findings suggested that in "Engage" treated participants, lower rsFC between the dACC and dorsomedial prefrontal cortex at baseline was associated with HAMD improvement. Finally, in Engage only, increased rsFC from baseline to week 6 between NAcc and Superior Parietal Cortex was associated with increased BADS scores. CONCLUSION: The results suggest that patients who present with higher rsFC between the sgACC and a structure within the DMN may benefit from behavioral psychotherapies for late life depression. "Engage" may lead to increased rsFC within the reward system reflecting a reconditioning of the reward systems by reward exposure.