Caregiving-related experiences associated with depression severity and its symptomatology among caregivers of individuals with a severe mental disorder: an online cross-sectional study.

Caring for a relative with a severe mental disorder puts family caregivers to a great risk of depression. While overall caregiving burden is a strong predictor of depression, the contribution of the various dimensions of burden to caregivers' depression as well as their relationships with depressive symptoms has received little attention. 384 family caregivers completed a cross-sectional online survey including the Center for Epidemiological Studies Depression (CES-D) scale, the Zarit Burden Interview (ZBI), and the Brief Experience of Caregiving Inventory (BECI), measuring caregiving burden and experience. We estimated the structure of the relationships between caregiving experiences (i.e., ZBI and BECI subscales) and CES-D symptoms using a network approach. Negative Emotion/Consequences, (lack of) Positive Personal Experience, and Stigma/Effects on Family were the most connected caregiving dimensions to depression. To untangle the role of the Negative Emotion/Consequences component (by far the most central node in estimated networks), a secondary analysis incorporating its composing items was estimated. Losing control over life, feeling strained around the relative and impaired self-perceived health emerged as central nodes. Interestingly, these caregiving-related dimensions or experiences were differentially connected to depressive symptoms. We discuss how these findings might help future research and inform tailored psychoeducational interventions for family caregivers of people with a severe mental disorder.

Leo program, a short multi-family skill-based psychoeducational program for caregivers of relatives living with a severe mental disorder: a retrospective pilot study.

Background: Caring for a relative with a severe mental disorder (SMD) is associated with high levels of burden and poor physical and mental health. There is a dire need for family psychoeducational programs that can be provided as early as possible. This manuscript describes the pilot testing of "Leo" a motivational-based psychoeducational program for caregivers of individuals with a SMD. The Leo program aims to provide caregivers with skills to best support their relative and to adopt self-care behaviors. Methods: We retrospectively analyzed medical records of caregivers who enrolled in a short, multi-family, skill-based psychoeducational program, consisting of eight 3-hour sessions over 8 weeks. Outcomes of interest included: i) adherence to the program, ii) satisfaction and perceived usefulness, and iii) pre-post changes in self-reported levels of depression (CES-D), burden (ZBI), and skills (10 Likert-scaled items). A network analysis was used to investigate the relationships between pre-post changes in self-evaluated skills and pre-post changes in burden and depression levels. Results: Over the 91 enrolled participants, 87 (95.6%) completed the program attending at least 5/8 sessions, 80.5% attending all sessions. Seventy-six caregivers fulfilled the questionnaires at baseline and after the program, and were included in the analysis. Although there was no evidence for significant change in self-reported depression levels (Cohen's d=0.19, p=0.210), burden scores and all evaluated skills were improved post-intervention, with medium to strong effect size (Cohen's ds from 0.47 to 0.87; p<0.001). Network output indicated that increased self-evaluated competence in 5 skills were associated with a global improvement in caregivers' burden and/or depression scores. Post-intervention, 89.7% of caregivers were "very satisfied" and 82.1% found the program "extremely useful". Conclusion: This pilot retrospective study shows high levels of satisfaction, perceived usefulness, and adherence to "Leo", a short, multi-family, skill-based psychoeducational program with promising results in improving caregivers' burden, self-evaluated competence in coping with caregiving demands and in self-care behaviors. This study provides preliminary insights into the mechanisms by which family psychoeducation might alleviate burden of care. A larger-scaled, controlled, randomized study with follow-up assessments is warranted to determine how burden, depression, and skills, as well as their inter-relationships, evolve over time.

T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase.

Skeletal muscle contraction is triggered by the excitation-contraction (E-C) coupling machinery residing at the triad, a membrane structure formed by the juxtaposition of T-tubules and sarcoplasmic reticulum (SR) cisternae. The formation and maintenance of this structure is key for muscle function but is not well characterized. We have investigated the mechanisms leading to X-linked myotubular myopathy (XLMTM), a severe congenital disorder due to loss of function mutations in the MTM1 gene, encoding myotubularin, a phosphoinositide phosphatase thought to have a role in plasma membrane homeostasis and endocytosis. Using a mouse model of the disease, we report that Mtm1-deficient muscle fibers have a decreased number of triads and abnormal longitudinally oriented T-tubules. In addition, SR Ca(2+) release elicited by voltage-clamp depolarizations is strongly depressed in myotubularin-deficient muscle fibers, with myoplasmic Ca(2+) removal and SR Ca(2+) content essentially unaffected. At the molecular level, Mtm1-deficient myofibers exhibit a 3-fold reduction in type 1 ryanodine receptor (RyR1) protein level. These data reveal a critical role of myotubularin in the proper organization and function of the E-C coupling machinery and strongly suggest that defective RyR1-mediated SR Ca(2+) release is responsible for the failure of muscle function in myotubular myopathy.

The anticholinergic burden is not associated with cognitive impairments in patients treated by electroconvulsive therapy for treatment-resistant depression.

BACKGROUND: Electroconvulsive therapy (ECT) is the most effective non-pharmacological treatment for treatment-resistant depression (TRD) but can expose to transient cognitive impairments. Understanding factors underlying these cognitive side effects is important. This study investigated the impact of anticholinergic treatments on cognitive performances after ECT courses for TRD in naturalistic condition. METHODS: Impact of anticholinergic burden (Anticholinergic Impregnation Scale, AIS) on cognitive changes (Montreal Cognitive Assessment, MoCA) adjusted on depression level (Montgomery and Asberg Depression Scale, MADRS) was investigated in 42 patients who received an ECT course between 2017 and 2020 for unipolar or bipolar TRD. Collection of daily treatments given during ECT was carried out via the computerized traceability of treatments validated by nurses. RESULTS: Among the 31 treatments identified with an anticholinergic score, which represent only 38% of total treatments, the three most frequently given treatments were Lorazepam (47%), Venlafaxine (36%) and Cyamemazine (26%). Delayed recall was the most frequently impaired cognitive function after ECT courses. Using logistic regression, we found no association between the anticholinergic burden and the decrease in cognitive scores after ECT courses, adjusted on MADRS score evolution (p > 0.1). Conversely, improvement in MADRS scores were correlated with improvement in attention MoCA subscores. LIMITATIONS: This is a retrospective monocentric study with a moderate sample size using anticholinergic scales to calculate the anticholinergic burden without plasma dosage. CONCLUSION: Anticholinergic treatments did not seem to explain ECT-related cognitive impairments. This warrants further large prospective investigations including different measures of anticholinergic burden.

Transient receptor potential canonical type 1 (TRPC1) operates as a sarcoplasmic reticulum calcium leak channel in skeletal muscle.

Extensive studies performed in nonexcitable cells and expression systems have shown that type 1 transient receptor potential canonical (TRPC1) channels operate mainly in plasma membranes and open through phospholipase C-dependent processes, membrane stretch, or depletion of Ca(2+) stores. In skeletal muscle, it is proposed that TRPC1 channels are involved in plasmalemmal Ca(2+) influx and stimulated by store depletion or membrane stretch, but direct evidence for TRPC1 sarcolemmal channel activity is not available. We investigated here the functional role of TRPC1 using an overexpressing strategy in adult mouse muscle fibers. Immunostaining for endogenous TRPC1 revealed a striated expression pattern that matched sarcoplasmic reticulum (SR) Ca(2+) pump immunolabeling. In cells expressing TRPC1-yellow fluorescent protein (YFP), the same pattern of expression was observed, compatible with a longitudinal SR localization. Resting electric properties, action potentials, and resting divalent cation influx were not altered in TRPC1-YFP-positive cells. Poisoning with the SR Ca(2+) pump blocker cyclopiazonic acid elicited a contracture of the fiber at the level of the overexpression site in presence and absence of external Ca(2+) which was not observed in control cells. Ca(2+) measurements indicated that resting Ca(2+) and the rate of Ca(2+) increase induced by cyclopiazonic acid were higher in the TRPC1-YFP-positive zone than in the TRPC1-YFP-negative zone and control cells. Ca(2+) transients evoked by 200-ms voltage clamp pulses decayed slower in TRPC1-YFP-positive cells. In contrast to previous hypotheses, these data demonstrate that TRPC1 operates as a SR Ca(2+) leak channel in skeletal muscle.

Electrically silent divalent cation entries in resting and active voltage-controlled muscle fibers.

Ca2+ is known to enter skeletal muscle at rest and during activity. Except for the well-characterized Ca2+ entry through L-type channels, pathways involved in these Ca2+ entries remain elusive in adult muscle. This study investigates Ca2+ influx at rest and during activity using the method of Mn2+ quenching of fura-2 fluorescence on voltage-controlled adult skeletal muscle cells. Resting rate of Mn2+ influx depended on external [Mn2+] and membrane potential. At -80 mV, replacement of Mg2+ by Mn2+ gave rise to an outward current associated with an increase in cell input resistance. Calibration of fura-2 response indicated that Mn2+ influx was too small to be resolved as a macroscopic current. Partial depletion of the sarcoplasmic reticulum induced by a train of action potentials in the presence of cyclopiazonic acid led to a slight increase in resting Mn2+ influx but no change in cell input resistance and membrane potential. Trains of action potentials considerably increased Mn2+ entry through an electrically silent pathway independent of L-type channels, which provided 24% of the global Mn2+ influx at +30 mV under voltage-clamp conditions. Within this context, the nature and the physiological role of the Ca2+ pathways involved during muscle excitation still remain open questions.

Overexpression of transient receptor potential canonical type 1 (TRPC1) alters both store operated calcium entry and depolarization-evoked calcium signals in C2C12 cells.

When the intracellular calcium stores are depleted, a Ca(2+) influx is activated to refill these stores. This store-operated Ca(2+) entry (SOCE) depends on the cooperation of several proteins as STIM1, Orai1, and, possibly, TRPC1. To elucidate this role of TRPC1 in skeletal muscle, TRPC1 was overexpressed in C2C12 cells and SOCE was studied by measuring the changes in intracellular Ca(2+) concentration ([Ca(2+)](i)). TRPC1 overexpression significantly increased both the amplitude and the maximal rate-of-rise of SOCE. When YM-58483, an inhibitor of TRPC1 was used, these differences were eliminated, moreover, SOCE was slightly suppressed. A decrease in the expression of STIM1 together with the downregulation of SERCA was confirmed by Western-blot. As a consequence, a reduction in maximal Ca(2+) uptake rate and a higher resting [Ca(2+)](i) following the Ca(2+) transients evoked by 120mM KCl were detected. Morphological changes also accompanied the overexpression of TRPC1. Differentiation of the myoblasts started later, and the myotubes were thinner in TRPC1-overexpressing cultures. For these changes the observed decrease in the nuclear expression of NFAT1 could be responsible. Our results suggest that enhanced expression of TRPC1 increases SOCE and has a negative effect on the STIM1-Orai1 system, indicating an interaction between these proteins.