Autobiographical memory as a latent vulnerability mechanism following childhood maltreatment: Association with future depression symptoms and prosocial behavior

OBJECTIVES: Childhood maltreatment is associated with altered neural reactivity during autobiographical memory (ABM) recall and a pattern of overgeneral memory (OGM). Altered ABM and OGM have been linked with psychopathology and poorer social functioning. The present study investigated the association between altered ABM and subsequent socio-emotional functioning (measured two years later) in a sample of adolescents with (N = 20; maltreatment group, MT) and without (N = 17; non-MT group) documented childhood maltreatment histories. METHOD: At baseline, adolescents (aged 12.6 ± 1.45 years) were administered the Autobiographical Memory Test to measure OGM. Participants also recalled specific ABMs in response to emotionally valenced cue words during functional MRI. Adolescents in both groups underwent assessments measuring depressive symptoms and prosocial behavior at both timepoints. Regression analyses were carried out to predict outcome measures at follow-up controlling for baseline levels. RESULTS: In the MT group, greater OGM at baseline significantly predicted reduced prosocial behavior at follow-up and showed a trend level association with elevated depressive symptoms. Patterns of altered ABM-related brain activity did not significantly predict future psycho-social functioning. CONCLUSIONS: The current findings highlight the potential value of OGM as a cognitive mechanism that could be targeted to reduce risk of depression in adolescents with prior histories of maltreatment

Functional brain plasticity following childhood maltreatment: A longitudinal fMRI investigation of autobiographical memory processing

Altered autobiographical memory (ABM) processing characterizes some individuals with experiences of childhood maltreatment. This fMRI study of ABM processing evaluated potential developmental plasticity in neural functioning following maltreatment. Adolescents with (N = 19; MT group) and without (N = 18; Non-MT group) documented childhood maltreatment recalled specific ABMs in response to emotionally valenced cue words during fMRI at baseline (age 12.71 ± 1.48) and follow-up (14.88 ± 1.53 years). Psychological assessments were collected at both timepoints. Longitudinal analyses were carried out with BOLD signal changes during ABM recall and psychopathology to investigate change over time. In both groups there was relative stability of the ABM brain network, with some developmental maturational changes observed in cortical midline structures (ventromedial PFC (vmPFC), posterior cingulate cortex (pCC), and retrosplenial cortex (rSC). Significantly increased activation of the right rSC was observed only in the MT group, which was associated with improved psychological functioning. Baseline group differences in relation to hippocampal functioning, were not detected at follow-up. This study provides preliminary empirical evidence of functional developmental plasticity in children with documented maltreatment experience using fMRI. This suggests that altered patterns of brain function, associated with maltreatment experience, are not fixed and may reflect the potential to track a neural basis of resilience

Treatment response classes in major depressive disorder identified by model-based clustering and validated by clinical prediction models

The identification of generalizable treatment response classes (TRC[s]) in major depressive disorder (MDD) would facilitate comparisons across studies and the development of treatment prediction algorithms. Here, we investigated whether such stable TRCs can be identified and predicted by clinical baseline items. We analyzed data from an observational MDD cohort (Munich Antidepressant Response Signature [MARS] study, N = 1017), treated individually by psychopharmacological and psychotherapeutic means, and a multicenter, partially randomized clinical/pharmacogenomic study (Genome-based Therapeutic Drugs for Depression [GENDEP], N = 809). Symptoms were evaluated up to week 16 (or discharge) in MARS and week 12 in GENDEP. Clustering was performed on 809 MARS patients (discovery sample) using a mixed model with the integrated completed likelihood criterion for the assessment of cluster stability, and validated through a distinct MARS validation sample and GENDEP. A random forest algorithm was used to identify prediction patterns based on 50 clinical baseline items. From the clustering of the MARS discovery sample, seven TRCs emerged ranging from fast and complete response (average 4.9 weeks until discharge, 94% remitted patients) to slow and incomplete response (10% remitted patients at week 16). These proved stable representations of treatment response dynamics in both the MARS and the GENDEP validation sample. TRCs were strongly associated with established response markers, particularly the rate of remitted patients at discharge. TRCs were predictable from clinical items, particularly personality items, life events, episode duration, and specific psychopathological features. Prediction accuracy improved significantly when cluster-derived slopes were modelled instead of individual slopes. In conclusion, model-based clustering identified distinct and clinically meaningful treatment response classes in MDD that proved robust with regard to capturing response profiles of differently designed studies. Response classes were predictable from clinical baseline characteristics. Conceptually, model-based clustering is translatable to any outcome measure and could advance the large-scale integration of studies on treatment efficacy or the neurobiology of treatment response

Molecular basis of class III ligand recognition by PDZ3 in murine protein tyrosine phosphatase PTPN13

Protein tyrosine phosphatase PTPN13, also known as PTP-BL in mice, represents a large multi-domain non-transmembrane scaffolding protein that contains five consecutive PDZ domains. Here, we report the solution structures of the extended murine PTPN13 PDZ3 domain in its apo form and in complex with its physiological ligand, the carboxy-terminus of protein kinase C-related kinase-2 (PRK2), determined by multidimensional NMR spectroscopy. Both in its ligand-free state and when complexed to PRK2, PDZ3 of PTPN13 adopts the classical compact, globular D/E fold. PDZ3 of PTPN13 binds five carboxy-terminal amino acids of PRK2 via a groove located between the EB-strand and the DB-helix. The PRK2 peptide resides in the canonical PDZ3 binding cleft in an elongated manner and the amino acid side chains in position P0 and P-2, cysteine and aspartate, of the ligand face the groove between EB-strand and DB-helix, whereas the PRK2 side chains of tryptophan and alanine located in position P-1 and P-3 point away from the binding cleft. These structures are rare examples of selective class III ligand recognition by a PDZ domain and now provide a basis for the detailed structural investigation of the promiscuous interaction between the PDZ domains of PTPN13 and their ligands. They will also lead to a better understanding of the proposed scaffolding function of these domains in multi-protein complexes assembled by PTPN13 and could ultimately contribute to low molecular weight antagonists that might even act on the PRK2 signaling pathway to modulate rearrangements of the actin cytoskeleton

Predicting outcomes after acute reperfusion therapy for basilar artery occlusion

Background and purpose Basilar artery occlusion (BAO) leads to high rates of morbidity and mortality, despite successful recanalization. The discordance between flow restoration and long-term functional status clouds clinical decision-making regarding further aggressive care. We sought to develop and validate a practical, prognostic tool for the prediction of 3-month favorable outcome after acute reperfusion therapy for BAO. Methods This retrospective, multicenter, observational study was conducted at four high-volume stroke centers in the USA and Europe. Multivariate regression analysis was performed to identify predictors of favorable outcome (90-day modified Rankin scale scores 0-2) and derive a clinically applicable prognostic model (the Pittsburgh Outcomes after Stroke Thrombectomy-Vertebrobasilar (POST-VB) score). The POST-VB score was evaluated and internally validated with regard to calibration and discriminatory ability. External validity was assessed in patient cohorts at three separate centers. Results In the derivation cohort of 59 patients, independent predictors of favorable outcome included smaller brainstem infarct volume on post-procedure magnetic resonance imaging (P = 125. Conclusions The POST-VB score effectively predicts 3-month functional outcome following acute reperfusion therapy for BAO and may aid in guiding post-procedural care.Peer reviewe

Endovascular therapy versus no endovascular therapy in patients receiving best medical management for acute isolated occlusion of the posterior cerebral artery : A systematic review and meta-analysis

Background and purpose Endovascular therapy (EVT) is increasingly reported for treatment of isolated posterior cerebral artery (PCA) occlusions although its clinical benefit remains uncertain. This study-level meta-analysis investigated the functional outcomes and safety of EVT and best medical management (BMM) compared to BMM alone for treatment of PCA occlusion stroke. Methods We conducted a literature search in PubMed, Web of Science and Embase for studies in patients with isolated PCA occlusion stroke treated with EVT + BMM or BMM including intravenous thrombolysis. There were no randomized trials and all studies were retrospective. The primary outcome was modified Rankin Scale score of 0-2 at 3 months, while safety outcomes included mortality rate and incidence of symptomatic intracranial hemorrhage (sICH). Results Twelve studies with a total of 679 patients were included in the meta-analysis: 338 patients with EVT + BMM and 341 patients receiving BMM alone. Good functional outcome at 3 months was achieved in 58.0% (95% confidence interval [CI] 43.83-70.95) of patients receiving EVT + BMM and 48.1% (95% CI 40.35-55.92) of patients who received BMM alone, with respective mortality rates of 12.6% (95% CI 7.30-20.93) and 12.3% (95% CI 8.64-17.33). sICH occurred in 4.2% (95% CI 2.47-7.03) of patients treated with EVT + BMM and 3.2% (95% CI 1.75-5.92) of patients treated with BMM alone. Comparative analyses were performed on studies that included both treatments and these demonstrated no significant differences. Conclusions Our results demonstrate that EVT represents a safe treatment for patients with isolated PCA occlusion stroke. There were no differences in clinical or safety outcomes between treatments, supporting randomization of future patients into distal vessel occlusion trials.Peer reviewe

Automated final lesion segmentation in posterior circulation acute ischemic stroke using deep learning

Final lesion volume (FLV) is a surrogate outcome measure in anterior circulation stroke (ACS). In posterior circulation stroke (PCS), this relation is plausibly understudied due to a lack of methods that automatically quantify FLV. The applicability of deep learning approaches to PCS is limited due to its lower incidence compared to ACS. We evaluated strategies to develop a convolutional neural network (CNN) for PCS lesion segmentation by using image data from both ACS and PCS patients. We included follow-up non-contrast computed tomography scans of 1018 patients with ACS and 107 patients with PCS. To assess whether an ACS lesion segmentation generalizes to PCS, a CNN was trained on ACS data (ACS-CNN). Second, to evaluate the performance of only including PCS patients, a CNN was trained on PCS data. Third, to evaluate the performance when combining the datasets, a CNN was trained on both datasets. Finally, to evaluate the performance of transfer learning, the ACS-CNN was fine-tuned using PCS patients. The transfer learning strategy outperformed the other strategies in volume agreement with an intra-class correlation of 0.88 (95% CI: 0.83–0.92) vs. 0.55 to 0.83 and a lesion detection rate of 87% vs. 41–77 for the other strategies. Hence, transfer learning improved the FLV quantification and detection rate of PCS lesions compared to the other strategies

Development and Validity of the Rating-of-Fatigue Scale

Objective: The purpose of these experiments was to develop a rating-of-fatigue (ROF) scale capable of tracking the intensity of perceived fatigue in a variety of contexts. Methods: Four experiments were carried out. The first provided the evidential basis for the construction of the ROF scale. The second tested the face validity of the ROF, and the third tested the convergent and divergent validity of the ROF scale during ramped cycling to exhaustion and 30 min of resting recovery. The final experiment tested the convergent validity of the ROF scale with time of day and physical activity (accelerometer counts) across a whole week. Results: Modal selections of descriptions and diagrams at different levels of exertion and recovery were found during Experiment 1 upon which the ROF scale was constructed and finalised. In Experiment 2, a high level of face validity was indicated, in that ROF was reported to represent fatigue rather than exertion. Descriptor and diagrammatic elements of ROF reportedly added to the coherence and ease of use of the scale. In Experiment 3, high convergence between ROF and various physiological measures were found during exercise and recovery (heart rate, blood lactate concentration, oxygen uptake, carbon dioxide production, respiratory exchange ratio and ventilation rate were all P < 0.001). During ramped cycling to exhaustion ROF and RPE did correspond (P < 0.0001) but not during recovery, demonstrating discriminant validity. Experiment 4 found ROF to correspond with waking time during each day (Mon–Sun all P < 0.0001) and with physical activity (accelerometer count) (Mon–Sun all P < 0.001). Conclusions: The ROF scale has good face validity and high levels of convergent validity during ramped cycling to exhaustion, resting recovery and daily living activities. The ROF scale has both theoretical and applied potential in understanding changes in fatigue in a variety of contexts