Integrating the Memory Support Intervention into the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C): can improving memory for treatment in midlife and older adults improve patient outcomes? Study protocol for a randomized controlled trial.

BACKGROUND: Poor memory for treatment is associated with poorer treatment adherence and poorer patient outcomes. The memory support intervention (MSI) was developed to improve patient memory for treatment with the goal of improving patient outcomes. The aim of this study protocol is to conduct a confirmatory efficacy trial to test whether a new, streamlined, and potent version of the MSI improves outcomes for midlife and older adults. This streamlined MSI is comprised of constructive memory supports that will be applied to a broader range of treatment content. The platform for this study is the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C). We will focus on midlife and older adults who are low income and experiencing mobility impairments. METHODS: Participants (N = 178) will be randomly allocated to TranS-C + MSI or TranS-C alone. Both intervention arms include eight 50-min weekly sessions. Assessments will be conducted at pre-treatment, post-treatment, 6-, and 12-month follow-up (6FU and 12FU). Aim 1 will compare the effects of TranS-C + MSI versus TranS-C alone on sleep and circadian functioning, daytime functioning, well-being, and patient memory. Aim 2 will test whether patient memory for treatment mediates the relationship between treatment condition and patient outcomes. Aim 3 will evaluate if previously reported poor treatment response subgroups will moderate the relationship between treatment condition and (a) patient memory for treatment and (b) treatment outcome. Exploratory analyses will compare treatment condition on (a) patient adherence, patient-rated treatment credibility, and patient utilization of treatment contents, and (b) provider-rated acceptability, appropriateness, and feasibility. DISCUSSION: This study has the potential to provide evidence for (a) the efficacy of a new simplified version of the MSI for maintaining health, well-being, and functioning, (b) the wider application of the MSI for midlife and older adults and to the treatment of sleep and circadian problems, and (c) the efficacy of the MSI for sub-groups who are likely to benefit from the intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT05986604. Registered on 2 August 2023.

Cognitive Therapy-as-Usual versus Cognitive Therapy plus the Memory Support Intervention for adults with depression: 12-month outcomes and opportunities for improved efficacy in a secondary analysis of a randomized controlled trial.

OBJECTIVE: Patient memory for treatment is emerging as an important transdiagnostic mechanism of treatment outcomes. However, patient memory for treatment is limited. The Memory Support Intervention was developed to improve patient memory for treatment and thereby strengthen treatment outcomes. In this secondary analysis, the primary, preregistered aim was to test the 12-month follow-up outcomes of the Memory Support Intervention when used with cognitive therapy (CT + MS) for major depressive disorder, relative to CT-as-usual. The secondary, exploratory aim was to investigate opportunities to improve efficacy of the Memory Support Intervention. METHOD: Adults (N = 178) with major depressive disorder were randomized to CT-as-usual or CT + MS. Therapist use of memory support and patient memory for treatment, depression symptoms, and overall functioning were measured in blind assessments. RESULTS: Findings did not support differences between treatment conditions at 12-month follow-up. Therapists used memory support strategies with a narrow subset of treatment contents, and similarly, patients recalled a narrow subset of treatment contents. CONCLUSIONS: The findings highlight ways to strengthen the efficacy of the Memory Support Intervention, such as applying memory support strategies across a wider variety of treatment contents, which in turn, may boost patient recall and outcomes.

Therapist training in treating sleep problems: A survey study of clinical practice.

OBJECTIVES: Mental health care clinicians' training in treating sleep problems was investigated. We examined clinicians' (1) prior training in providing treatment for sleep problems, (2) interest in receiving training in treatment for sleep problems, and (3) perceptions of the importance of treating sleep problems and interest in incorporating sleep treatments into their practices. METHODS: An online survey was completed by 137 clinicians. RESULTS: The majority of clinicians (61.31%) reported receiving prior training in treating sleep problems, most commonly in the form of a workshop and after receiving a graduate degree. Most clinicians reported interest in receiving further training in treating sleep problems. Clinicians reported that the majority (66.67%) of their clients experience sleep problems, yet reported that they address sleep with fewer than half of clients. Addressing sleep in treatment was rated as "somewhat" to "very" important and most clinicians indicated further interest in receiving training in treating sleep. CONCLUSIONS: Mental health care clinicians receive limited training in treating sleep problems. As clinicians are interested in gaining further training to address sleep concerns within their clinical practice, training programs and continuing education programs should consider increasing the amount of programming in sleep treatment and assessment.

Serial Mediators of Memory Support Strategies Used With Cognitive Therapy for Depression: Improving Outcomes Through Patient Adherence and Treatment Skills.

Patient memory for treatment is poor. Memory support strategies can be integrated within evidence-based psychological treatments to improve patient memory for treatment, and thereby enhance patient outcomes. The present study evaluated possible mechanisms of these memory support strategies. Specifically, we tested whether therapist use of memory support strategies indirectly predicts improved patient outcomes via serial improvements in (a) patient adherence throughout treatment and (b) patient utilization and competency of treatment skills. Adults with major depressive disorder (N = 178, mean age = 37.93, 63% female, 17% Hispanic or Latino) were randomized to Cognitive Therapy plus a Memory Support Intervention or Cognitive Therapy-as-usual. Because therapists from both treatment groups used memory support strategies, data from conditions were combined. Blind assessments of depression severity and overall impairment were conducted before treatment, immediately posttreatment (POST), at 6-month follow-up (6FU), and at 12-month follow-up (12FU). Patient adherence to treatment was rated by therapists and averaged across treatment sessions. Patients completed measures of treatment mechanisms-namely, utilization and competency in cognitive therapy skills-at POST, 6FU, and 12FU. Results of serial mediation models indicated that more therapist use of memory support predicted lower depression severity at POST, 6FU, and 12FU indirectly and sequentially through (a) increased patient adherence during treatment and (b) more utilization and competency of Cognitive Therapy skills at POST, 6FU, and 12FU. The same patterns were found for serial mediation models predicting lower overall impairment at POST, 6FU, and 12FU. Together, boosting memory for treatment may represent a promising means to enhance pantreatment mechanisms (i.e., adherence and treatment skills) as well as patient outcomes.

Respiratory variability of sinus node activation in humans: insights from ultra-high-density mapping.

PURPOSE: Experimental data suggest that shifts in the site of origin of the sinus node (SN) correlate with changes in heart rate and P wave morphology. The direct visualization of the effect of respiration on SN electrical activation has not yet been reported in humans. We aimed to measure the respiratory shifting of the SN activation using ultra-high-density mapping. METHODS: Sequential right atrial (RA) activation mapping during sinus rhythm (SR) was performed. Three maps were acquired for each patient: basal end-expiratory (Ex), end-inspiratory (Ins), and end-expiratory under isoproterenol (Iso). The earliest activation site (EAS) was defined as the earliest unipolar electrograms (EGM) with a QS pattern and was localized with respect to the ostium of the superior vena cava (SVC; negative values if EAS inside the SVC). RESULTS: In 20 patients, 49 maps in SR were acquired (20 Ex, 19 Ins, and 10 Iso). Expiratory (944 ± 227 ms) and inspiratory (946 ± 227 ms) SR cycle lengths were similar, but shortened under isoproterenol (752 ± 302 ms). Activation was unicentric in 33 maps and multicentric in 16: 4 during Ins, 10 during Ex, and 2 Iso. EAS location was significantly more cranial in expiration than in inspiration (0.27 ± 12.1 vs 5 ± 11.51 mm, p = 0.01). Iso infusion tends to induce a supplemental cranial shift (-4.07 ± 15.83 vs 0.27 ± 12.7 mm, p = 0.21). EAS were found in SVC in 22.7% of maps (30% Ex, 21% Ins, and 8% Iso). CONCLUSION: Inspiration induces a significant caudal shift of the earliest sinus activation. In one-third of the cases, sinus rhythm earliest activation is inside the SVC.

Applying the Science of Habit Formation to Evidence-Based Psychological Treatments for Mental Illness.

Habits affect nearly every aspect of our physical and mental health. Although the science of habit formation has long been of interest to psychological scientists across disciplines, we propose that applications to clinical psychological science have been insufficiently explored. In particular, evidence-based psychological treatments (EBPTs) are interventions targeting psychological processes that cause and/or maintain mental illness and that have been developed and evaluated scientifically. An implicit goal of EBPTs is to disrupt unwanted habits and develop desired habits. However, there has been insufficient attention given to habit-formation principles, theories, and measures in the development and delivery of EBTPs. Herein we consider whether outcomes following an EBPT would greatly improve if the basic science of habit formation were more fully leveraged. We distill six ingredients that are central to habit formation and demonstrate how these ingredients are relevant to EBPTs. We highlight practice points and an agenda for future research. We propose that there is an urgent need for research to guide the application of the science of habit formation and disruption to the complex "real-life" habits that are the essence of EBPTs.

Outcomes of the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) in a community setting: Unpacking comorbidity.

OBJECTIVE: Comorbidity and subdiagnostic symptoms are understudied for sleep and circadian problems. We evaluated 1) impairment associated with (a) number of sleep and circadian problems and (b) diagnostic threshold (full diagnosis vs. subdiagnostic symptoms), and 2) Transdiagnostic Sleep and Circadian Intervention (TranS-C) outcomes for participants with specific sleep and circadian problems. METHOD: Community participants (N = 121) with serious mental illness and sleep and circadian problem(s) were randomized to receive TranS-C plus usual care (TranS-C + UC) or usual care plus delayed TranS-C (UC-DT). Overall impairment, psychiatric symptoms, and sleep and circadian dysfunction were assessed at pre-treatment, post-treatment, and 6-month follow-up. RESULTS: Higher numbers of sleep and circadian problems, versus one problem, were associated with worse overall impairment, psychiatric symptoms, and sleep and circadian dysfunction (ps < 0.05, ω2 = 0.06-0.15). Diagnostic threshold was not associated with baseline functioning (ps > 0.05). TranS-C + UC versus UC-DT was associated with psychosocial and sleep and circadian improvements for specific sleep and circadian problems (insomnia, hypersomnia, parasomnias, periodic limb movement/restless leg syndrome, circadian rhythm disorders), though improvements varied by problem. TranS-C + UC outcomes were not moderated by number of sleep and circadian problems (ps > 0.05). CONCLUSION: Higher numbers of sleep and circadian problems, not diagnostic threshold, were associated with greater impairment. Transdiagnostic utility of TranS-C + UC was supported.

The Development and Validation of the Memory Support Treatment Provider Checklist.

Patient memory for the contents of treatment is staggeringly poor, and poor memory for treatment is associated with worse treatment outcome. Accordingly, the Memory Support Intervention was developed to improve patient memory for treatment as an adjunct to treatment as usual. As plans to disseminate the Memory Support Intervention are developed, it is important to have efficient, accurate methods of measuring fidelity to the intervention. However, the existing method of assessing fidelity to the Memory Support Intervention, the Memory Support Rating Scale (MSRS), is burdensome and requires trained independent-raters to spend multiple hours reviewing session recordings, which is not feasible in many routine mental health care settings. Hence, a provider-rated measure of fidelity to the MSI has been developed. The goal of this study is to examine the reliability and validity of scores on this measure-the Memory Support Treatment Provider Checklist. A sample of Memory Support Treatment Provider Checklists (N = 319) were completed by providers (N = 8) treating adults with depression (N = 84). Three metrics of the Memory Support Treatment Provider Checklist were evaluated: (a) the internal consistency and structural validity using confirmatory factor analysis based on prior research on the MSRS and the Memory Support Intervention, (b) construct validity, and (c) predictive validity. Results indicate that the Memory Support Treatment Provider Checklist yields reliable and valid scores of fidelity to the Memory Support Intervention. Overall, this checklist offers a viable, brief method of evaluating fidelity to the Memory Support Intervention.

Relationship to CBT outcome and dropout of decision support tools of the written case formulation, list of treatment goals and plot of symptom scores.

Many patients who receive cognitive behavior therapy (CBT) for mood and anxiety disorders fail to respond or drop out of treatment. We tested the hypotheses that therapist use of each of three decision support tools, a written case formulation, a list of treatment goals, and a plot of symptom scores, was associated with improved outcome and reduced dropout in naturalistic CBT provided to 845 patients in a private practice setting. We conducted regression analyses to test the hypotheses that the presence of each tool in the clinical record was associated with lower end-of-treatment scores on the Beck Depression Inventory (BDI) and the Burns Anxiety Inventory (BurnsAI), and lower rates of premature and uncollaborative dropout. We found that the presence of a written case formulation in the clinical record was associated with lower rates of both types of dropout. A list of treatment goals was associated with lower end-of-treatment scores on the BDI and the BurnsAI, and a lower rate of uncollaborative but a higher rate of premature dropout. A plot of symptom scores was associated with lower end-of-treatment scores on the BDI, and lower rates of both types of dropout. Results suggest that therapist use of a written case formulation, list of treatment goals, and a plot of symptom scores can contribute to improved outcome and reduced dropout in CBT.

Client memory and learning of treatment contents: An experimental study of intervention strategies and relationship to outcome in a brief treatment for procrastination.

BACKGROUND AND OBJECTIVES: Client memory and learning is limited for psychological treatment contents. This study investigated different approaches to support client memory and learning of treatment contents and the relationship between memory and learning of treatment contents and outcome. METHODS: Adult participants (n = 428) were recruited through Amazon's Mechanical Turk and randomized to complete one of three versions of a one-session procrastination intervention. Two versions of the intervention included different amounts of memory support strategy types from the Memory Support Intervention. A control version did not include any types of memory support. Memory and learning of treatment contents were assessed immediately after the intervention and one week later. Procrastination and two mechanisms of procrastination (impulsiveness and self-efficacy) were assessed at baseline and one week after the intervention. RESULTS: Contrary to the hypotheses, a version of the intervention with multiple types of memory support strategies was not associated with better memory and learning of treatment contents than a version of the intervention with only one type of memory support strategy or the control intervention. Greater memory and learning of treatment contents predicted improvement in mechanisms of procrastination, but not procrastination itself. LIMITATIONS: The mean level of procrastination in this study was lower than in other treatment studies of procrastination. CONCLUSIONS: Results partially support the rationale for the Memory Support Intervention that improving client memory and learning of treatment contents can improve outcome. Findings suggest that the Memory Support Intervention may be simplified to include fewer strategies without compromising efficacy.

Patient constructive learning behavior in cognitive therapy: A pathway for improving patient memory for treatment?

Patient memory for treatment is poor and associated with worse outcome. The Memory Support Intervention was designed to improve outcome by enhancing patient memory for treatment. Half of the strategies comprising the Memory Support Intervention (termed constructive memory support strategies) involve therapists inviting patients to construct new ideas, inferences, or connections related to treatment material that go beyond information already presented by therapists. This study investigated the relationship between patient responses to therapist use of constructive memory support strategies and patient recall of treatment contents. Therapist uses of constructive memory support strategies were coded from sessions recorded during a pilot trial of the Memory Support Intervention in the context of cognitive therapy for depression (n = 44 patients). Patients who successfully constructed new ideas, inferences, or connections (termed patient constructive learning behavior) in response to therapist use of constructive memory support strategies showed greater recall of treatment contents. Mediation analyses provided some evidence that patient constructive learning behavior may be a mechanism through which the Memory Support Intervention results in enhanced patient memory. Results highlight patient constructive learning behavior as a potential pathway for improving patient memory for treatment.

The Relationship Between Dropout and Outcome in Naturalistic Cognitive Behavior Therapy.

Dropout from psychotherapy is frequent and limits the benefits patients can receive from treatment. The study of factors associated with dropout has the potential to yield strategies to reduce it. This study analyzed data from a large sample of adults (N = 1,092) receiving naturalistic cognitive behavioral therapy (CBT) to test the hypotheses that dropouts, as compared to completers, had (1) higher symptom severity at treatment termination, (2) a slower rate of symptom change during treatment, and (3) a higher odds that the therapist rated treatment as ending for reasons related to poor outcome. Results showed that although dropouts ended treatment with higher symptom severity than completers, dropouts and completers did not differ in their rate of symptom change during treatment, suggesting that dropouts had higher symptom severity at termination because they received fewer sessions of treatment, not because their symptoms changed at a slower rate. Dropout was also associated with a higher odds of having a therapist-rated termination reason indicating a poor outcome, suggesting that dropout is more likely if patients are dissatisfied with some aspect of the therapy outcome or process. These findings suggest that strategies for monitoring and enhancing patient satisfaction with the process and outcome of treatment may help patients stay in treatment longer and end treatment with fewer symptoms than if they had dropped out.

Adolescents' Perspectives on Personalized E-Feedback in the Context of Health Risk Behavior Screening for Primary Care: Qualitative Study.

BACKGROUND: Electronic health screening tools for primary care present an opportunity to go beyond data collection to provide education and feedback to adolescents in order to motivate behavior change. However, there is limited research to guide feedback message development. OBJECTIVE: The aim of this study was to explore youth perceptions of and preferences for receiving personalized feedback for multiple health risk behaviors and reinforcement for health promoting behaviors from an electronic health screening tool for primary care settings, using qualitative methodology. METHODS: In total, 31 adolescents aged 13-18 years completed the screening tool, received the electronic feedback, and subsequently participated in individual, semistructured, qualitative interviews lasting approximately 60 min. Participants were queried about their overall impressions of the tool, perceptions regarding various types of feedback messages, and additional features that would help motivate health behavior change. Using thematic analysis, interview transcripts were coded to identify common themes expressed across participants. RESULTS: Overall, the tool was well-received by participants who perceived it as a way to enhance-but not replace-their interactions with providers. They appreciated receiving nonjudgmental feedback from the tool and responded positively to information regarding the consequences of behaviors, comparisons with peer norms and health guidelines, tips for behavior change, and reinforcement of healthy choices. A small but noteworthy minority of participants dismissed the peer norms as not real or relevant and national guidelines as not valid or reasonable. When prompted for possible adaptations to the tool, adolescents expressed interest in receiving follow-up information, setting health-related goals, tracking their behaviors over time, and communicating with providers electronically between appointments. CONCLUSIONS: Adolescents in this qualitative study desired feedback that validates their healthy behavior choices and supports them as independent decision makers by neutrally presenting health information, facilitating goal setting, and offering ongoing technological supports.

Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways.

Oncogenic mutations drive anabolic metabolism, creating a dependency on nutrient influx through transporters, receptors, and macropinocytosis. While sphingolipids suppress tumor growth by downregulating nutrient transporters, macropinocytosis and autophagy still provide cancer cells with fuel. Therapeutics that simultaneously disrupt these parallel nutrient access pathways have potential as powerful starvation agents. Here, we describe a water-soluble, orally bioavailable synthetic sphingolipid, SH-BC-893, that triggers nutrient transporter internalization and also blocks lysosome-dependent nutrient generation pathways. SH-BC-893 activated protein phosphatase 2A (PP2A), leading to mislocalization of the lipid kinase PIKfyve. The concomitant mislocalization of the PIKfyve product PI(3,5)P2 triggered cytosolic vacuolation and blocked lysosomal fusion reactions essential for LDL, autophagosome, and macropinosome degradation. By simultaneously limiting access to both extracellular and intracellular nutrients, SH-BC-893 selectively killed cells expressing an activated form of the anabolic oncogene Ras in vitro and in vivo. However, slower-growing, autochthonous PTEN-deficient prostate tumors that did not exhibit a classic Warburg phenotype were equally sensitive. Remarkably, normal proliferative tissues were unaffected by doses of SH-BC-893 that profoundly inhibited tumor growth. These studies demonstrate that simultaneously blocking parallel nutrient access pathways with sphingolipid-based drugs is broadly effective and cancer selective, suggesting a potential strategy for overcoming the resistance conferred by tumor heterogeneity.

Are Trials of Computerized Therapy Generalizable? A Multidimensional Meta-analysis.

BACKGROUND: Previous meta-analyses have established that computerized cognitive behavioral therapy (cCBT) is an effective, acceptable, and efficient method of delivering treatment for anxiety and depression. However, the potential generalizability of these conclusions to nonresearch settings has not yet been investigated. MATERIALS AND METHODS: We conducted a multidimensional meta-analysis of randomized controlled trials of cCBT for anxiety and/or depressive disorders quantifying generalizability by examining the relationship between participant exclusion and treatment outcome. Thirty-six trials of cCBT were identified through systematic searches in six databases. The number of exclusion criteria and exclusion rate served as indices of participant exclusion. Outcome variables included between- and within-group effect sizes in addition to rates of clinically significant improvement. RESULTS: Analyses were performed for all studies, depression studies (n = 11), and anxiety studies (n = 23). Pooling across all studies, we found a between-group effect size of 0.85 (95% confidence interval, 0.77-0.94). The mean number of exclusionary criteria was 12 (range, 2-24), and the mean exclusion rate was 0.49 (range, 0.08-0.92). Risk for suicide was the most common criterion for exclusion. Correlation analyses revealed a large relationship between number of exclusion criteria and proportion clinically changed in the treatment group for anxiety studies (r = 0.70). Results provide evidence for the limited effectiveness of cCBT for anxiety disorders in nonresearch samples. CONCLUSIONS: As computerized therapy is developed to address barriers to dissemination, future trials should examine the effectiveness of cCBT for anxiety for patients with more complex clinical presentations.

The role of assistive robotics in the lives of persons with disability.

Robotic assistive devices are used increasingly to improve the independence and quality of life of persons with disabilities. Devices as varied as robotic feeders, smart-powered wheelchairs, independent mobile robots, and socially assistive robots are becoming more clinically relevant. There is a growing importance for the rehabilitation professional to be aware of available systems and ongoing research efforts. The aim of this article is to describe the advances in assistive robotics that are relevant to professionals serving persons with disabilities. This review breaks down relevant advances into categories of Assistive Robotic Systems, User Interfaces and Control Systems, Sensory and Feedback Systems, and User Perspectives. An understanding of the direction that assistive robotics is taking is important for the clinician and researcher alike; this review is intended to address this need.

Rab7 activation by growth factor withdrawal contributes to the induction of apoptosis.

The Rab7 GTPase promotes membrane fusion reactions between late endosomes and lysosomes. In previous studies, we demonstrated that Rab7 inactivation blocks growth factor withdrawal-induced cell death. These results led us to hypothesize that growth factor withdrawal activates Rab7. Here, we show that growth factor deprivation increased both the fraction of Rab7 that was associated with cellular membranes and the percentage of Rab7 bound to guanosine triphosphate (GTP). Moreover, expressing a constitutively GTP-bound mutant of Rab7, Rab7-Q67L, was sufficient to trigger cell death even in the presence of growth factors. This activated Rab7 mutant was also able to reverse the growth factor-independent cell survival conferred by protein kinase C (PKC) delta inhibition. PKCdelta is one of the most highly induced proteins after growth factor withdrawal and contributes to the induction of apoptosis. To evaluate whether PKCdelta regulates Rab7, we first examined lysosomal morphology in cells with reduced PKCdelta activity. Consistent with a potential role as a Rab7 activator, blocking PKCdelta function caused profound lysosomal fragmentation comparable to that observed when Rab7 was directly inhibited. Interestingly, PKCdelta inhibition fragmented the lysosome without decreasing Rab7-GTP levels. Taken together, these results suggest that Rab7 activation by growth factor withdrawal contributes to the induction of apoptosis and that Rab7-dependent fusion reactions may be targeted by signaling pathways that limit growth factor-independent cell survival.

A new take on ceramide: starving cells by cutting off the nutrient supply.

Ceramide generation is increased by a broad array of signals. In general, ceramide limits cell survival and proliferation and promotes differentiation and senescence. Despite its role in the pathogenesis of multiple human diseases, ceramide's mechanism of action remains poorly defined. Understanding how this sphingolipid modulates cell physiology is therefore an important goal. Building on prior observations that ceramide induces autophagy, we demonstrate that ceramide kills cells by inducing severe bioenergetic stress secondary to nutrient transporter downregulation. In support of this model, maintaining nutrient access blocks ceramide-induced autophagy and cell death. This bioenergetic mechanism of action may explain the increased sensitivity of cancer cells to ceramide. Starvation induces quiescence in normal cells. Tumor cells, in contrast, carry oncogenic mutations that block the switch to catabolism and prevent a reduction in metabolic demand leading to a bioenergetic crisis when nutrients become scarce. We propose that the non-lethal effects of ceramide might also stem from ceramide-induced starvation. While severe nutrient stress kills cells, mild nutrient limitation slows proliferation and may contribute to the induction of senescence. In sum, our new model for ceramide action suggests that regulated nutrient transporter expression may play a previously unappreciated role in cancer and other diseases where ceramide metabolism is altered.

Ceramide starves cells to death by downregulating nutrient transporter proteins.

Ceramide induces cell death in response to many stimuli. Its mechanism of action, however, is not completely understood. Ceramide induces autophagy in mammalian cells maintained in rich media and nutrient permease downregulation in yeast. These observations suggested to us that ceramide might kill mammalian cells by limiting cellular access to extracellular nutrients. Consistent with this proposal, physiologically relevant concentrations of ceramide produced a profound and specific downregulation of nutrient transporter proteins in mammalian cells. Blocking ceramide-induced nutrient transporter loss or supplementation with the cell-permeable nutrient, methyl pyruvate, reversed ceramide-dependent toxicity. Conversely, cells became more sensitive to ceramide when nutrient stress was increased by acutely limiting extracellular nutrients, inhibiting autophagy, or deleting AMP-activated protein kinase (AMPK). Observations that ceramide can trigger either apoptosis or caspase-independent cell death may be explained by this model. We found that methyl pyruvate (MP) also protected cells from ceramide-induced, nonapoptotic death consistent with the idea that severe bioenergetic stress was responsible. Taken together, these studies suggest that the cellular metabolic state is an important arbiter of the cellular response to ceramide. In fact, increasing nutrient demand by incubating cells in high levels of growth factor sensitized cells to ceramide. On the other hand, gradually adapting cells to tolerate low levels of extracellular nutrients completely blocked ceramide-induced death. In sum, these results support a model where ceramide kills cells by inducing intracellular nutrient limitation subsequent to nutrient transporter downregulation.