Serum amyloid A and mitochondrial DNA in extracellular vesicles are novel markers for detecting traumatic brain injury in a mouse model.

This study investigates the potential use of circulating extracellular vesicles' (EVs) DNA and protein content as biomarkers for traumatic brain injury (TBI) in a mouse model. Despite an overall decrease in EVs count during the acute phase, there was an increased presence of exosomes (CD63+ EVs) during acute and an increase in microvesicles derived from microglia/macrophages (CD11b+ EVs) and astrocytes (ACSA-2+ EVs) in post-acute TBI phases, respectively. Notably, mtDNA exhibited an immediate elevation post-injury. Neuronal (NFL) and microglial (Iba1) markers increased in the acute, while the astrocyte marker (GFAP) increased in post-acute TBI phases. Novel protein biomarkers (SAA, Hp, VWF, CFD, CBG) specific to different TBI phases were also identified. Biostatistical modeling and machine learning identified mtDNA and SAA as decisive markers for TBI detection. These findings emphasize the importance of profiling EVs' content and their dynamic release as an innovative diagnostic approach for TBI in liquid biopsies.

Therapy Processes Associated With Sudden Gains in Cognitive Therapy for Depression: Exploring Therapeutic Changes in the Sessions Surrounding the Gains.

Background: The frequency and clinical impact of Sudden Gains-large symptom improvements during a single between-session interval-in psychotherapy for depression have been well established. However, there have been relatively few efforts to identify the processes that lead to sudden gains. Aim: To explore therapy processes associated with sudden gains in cognitive therapy for depression by examining changes in the sessions surrounding the gains, and the session preceding the gain in particular. Methods: Using ratings of video-recordings (n = 36), we assessed the content, frequency and magnitude of within-session cognitive-, behavioral-, and interpersonal change, as well as the quality of the therapeutic alliance in the session prior to the gain (pre-gain session), the session after the gain (post-gain session) and a control session. After that, we contrasted scores in the pre-gain session with those in the control session. In addition, we examined changes that occurred between the pre- and post-gain session (between-session changes) and explored patients' attributions of change. Results: Although not statistically significant, within-session changes were more frequent and stronger in the pre-gain session compared to the control session. The largest difference between the pre-gain and control session was found in the behavioral domain, and reached the level of trend-significance. There were more, and more impactful between-session changes in the interval during which the gain occurred as compared to a control interval. Exploratory analysis of attributions of change revealed eight subcategories, all corresponding with the cognitive-, behavioral- and interpersonal- domain. The quality of the therapeutic alliance was high and almost identical in all sessions. Conclusion: In spite of its small sample size, our study provides relevant descriptive information about potential precipitants of, themes related to, and attributions given for sudden gains. Furthermore, our study provides clear suggestions for future research. A better understanding of session content in the sessions surrounding sudden gains may provide insight into the mechanisms of change in psychotherapy, hereby suggesting treatment-enhancing strategies. We encourage researchers to conduct research that could clarify the nature of these mechanisms, and believe the methods used in this study could serve as a framework for further work in this area.

Role of zinc transporter ZIP12 in susceptibility-weighted brain magnetic resonance imaging (MRI) phenotypes and mitochondrial function.

Brain zinc dysregulation is linked to many neurological disorders. However, the mechanisms regulating brain zinc homeostasis are poorly understood. We performed secondary analyses of brain MRI GWAS and exome sequencing data from adults in the UK Biobank. Coding ZIP12 polymorphisms in zinc transporter ZIP12 (SLC39A12) were associated with altered brain susceptibility weighted MRI (swMRI). Conditional and joint association analyses revealed independent GWAS signals in linkage disequilibrium with 2 missense ZIP12 polymorphisms, rs10764176 and rs72778328, with reduced zinc transport activity. ZIP12 rare coding variants predicted to be deleterious were associated with similar impacts on brain swMRI. In Neuro-2a cells, ZIP12 deficiency by short hairpin RNA (shRNA) depletion or CRISPR/Cas9 genome editing resulted in impaired mitochondrial function, increased superoxide presence, and detectable protein carbonylation. Inhibition of Complexes I and IV of the electron transport chain reduced neurite outgrowth in ZIP12 deficient cells. Transcriptional coactivator PGC-1α, mitochondrial superoxide dismutase (SOD2), and chemical antioxidants α-tocopherol, MitoTEMPO, and MitoQ restored neurite extension impaired by ZIP12 deficiency. Mutant forms of α-synuclein and tau linked to familial Parkinson's disease and frontotemporal dementia, respectively, reduced neurite outgrowth in cells deficient in ZIP12. Zinc and ZIP12 may confer resilience against neurological diseases or premature aging of the brain.

Specific Pharmacological Effects of Paroxetine Comprise Psychological but Not Somatic Symptoms of Depression.

BACKGROUND: Meta-analyses of placebo-controlled trials of SSRIs suggest that only a small portion of the observable change in depression may be attributed to "true" pharmacological effects. But depression is a multidimensional construct, so treatment effects may differ by symptom cluster. We tested the hypothesis that SSRIs uniquely alter psychological rather than somatic symptoms of depression and anxiety. METHOD: Outpatients with moderate to severe MDD were randomly assigned to receive paroxetine (n = 120) or placebo (n = 60). RESULTS: Paroxetine significantly outperformed placebo on all psychological subscales of the syndrome measures, but not on any of the somatic subscales. The difference in score reduction between paroxetine and placebo was more than twice as great for the psychological symptoms compared to the somatic symptoms. CONCLUSIONS: Paroxetine appears to have a "true" pharmacological effect on the psychological but not on the somatic symptoms of depression and anxiety. Paroxetine's influence on somatic symptoms appears to be mostly duplicated by placebo.

Personality change during depression treatment: a placebo-controlled trial.

CONTEXT: High neuroticism is a personality risk factor that reflects much of the genetic vulnerability to major depressive disorder (MDD), and low extraversion may increase risk as well. Both have been linked to the serotonin system. OBJECTIVES: To test whether patients with MDD taking selective serotonin reuptake inhibitors (SSRIs) report greater changes in neuroticism and extraversion than patients receiving inert placebo, and to examine the state effect hypothesis that self-reported personality change during SSRI treatment is merely a change of depression-related measurement bias. DESIGN: A placebo-controlled trial. SETTING: Research clinics. Patients Adult patients with moderate to severe MDD randomized to receive paroxetine (n = 120), placebo (n = 60), or cognitive therapy (n = 60). OUTCOME MEASURES: NEO Five-Factor Inventory and Hamilton Rating Scale for Depression. RESULTS: Patients who took paroxetine reported greater personality change than placebo patients, even after controlling for depression improvement (neuroticism, P < .001; extraversion, P = .002). The advantage of paroxetine over placebo in antidepressant efficacy was no longer significant after controlling for change in neuroticism (P = .46) or extraversion (P = .14). Patients taking paroxetine reported 6.8 times as much change on neuroticism and 3.5 times as much change on extraversion as placebo patients matched for depression improvement. Although placebo patients exhibited substantial depression improvement (Hamilton Rating Scale for Depression score, -1.2 SD, P < .001), they reported little change on neuroticism (-0.18 SD, P = .08) or extraversion (0.08 SD, P = .50). Cognitive therapy produced greater personality change than placebo (P

Sudden gains in cognitive therapy of depression and depression relapse/recurrence.

Cognitive therapy (CT) may have significant advantages over antidepressants in preventing depression relapses. Many CT patients experience sudden gains: large symptom improvement in 1 between-session interval. Past studies have associated CT sudden gains with in-session cognitive changes but not with life events. This study examined sudden gains and depression relapse/recurrence among 60 CT clinical-trial patients. Survival analyses showed that only one third of sudden-gain-responders relapsed in 2 years, and they had 74% lower relapse risks than did non-sudden-gain-responders. Among patients with sustained responses, 73% experienced sudden gains. The authors also replicated J. R. Vittengl, L. A. Clark, and R. B. Jarrett's finding that sudden gains identified with their unique criteria did not predict relapse. The current authors' findings suggest that CT sudden gains are not measurement artifacts, and that sudden gains and their causes and consequences might be important in preventing relapses.

Cognitive changes, critical sessions, and sudden gains in cognitive-behavioral therapy for depression.

Using an independent cognitive-behavioral therapy (CBT) data set, the authors replicated T. Z. Tang and R. J. DeRubeis' (1999) discovery of sudden gains--sudden and large decreases in depression severity in a single between-session interval. By incorporating therapy session transcripts, the authors of this study improved the reliability of the Patient Cognitive Change Scale to .75 and found that these CBT sudden gains were also preceded by substantial cognitive changes in the pregain sessions.

Sudden gains in recovering from depression: are they also found in psychotherapies other than cognitive-behavioral therapy?

Following T. Z. Tang and R. J. DeRubeis's (1999) report of sudden gains (a sudden and substantial improvement in depression symptoms in one between-session interval) in cognitive-behavioral therapy (CBT) for depression, this study explored sudden gains in supportive-expressive (SE) psychotherapy. Studies suggested that CBT sudden gains are caused by cognitive changes, which is a factor specific to CBT. Thus, sudden gains might not be expected in SE psychotherapy. Contrary to that expectation, sudden gains in SE psychotherapy were found, and they showed similar magnitude, affected a similar percentage of patients, and occurred at about the same time in treatment as CBT sudden gains. However, the symptom gains from the SE psychotherapy sudden gains were much less stable than the CBT sudden gains and showed a much higher rate of reversal before treatment ended. The long-term benefits of SE psychotherapy sudden gains also appear less robust than CBT sudden gains.