👤 Irena Stevanovic

Intermittent theta burst stimulation (iTBS) is increasingly explored as a non-invasive neuromodulatory approach capable of inducing long-lasting plasticity with potential therapeutic value in age-related neurological and psychiatric conditions. However, the cellular and molecular mechanisms underlying iTBS protocols remain largely unknown, limiting its further therapeutic development. Here, we investigated the behavioral, structural, synaptic, and calcium-dependent effects of a 7-day iTBS600 protocol using a combination of Prolonged iTBS did not alter general locomotor activity, anxiety-like behavior, or short-term recognition memory, indicating preserved baseline behavioral function. Despite the absence of behavioral changes, prolonged iTBS induced robust structural plasticity in hippocampal CA1 neurons, increasing total spine density and selectively enhancing the proportion of thin, learning spines. Synaptosomal analysis revealed upregulation of GluN1 and GluN2A, elevated BDNF levels, and activation of downstream Akt, ERK1/2, and mTOR pathways. Prolonged iTBS also enhanced perineuronal net formation around PV Together, these findings indicate that prolonged iTBS drives coordinated structural, synaptic, and Ca Show less

Major depressive disorder (MDD) continues to be a primary cause of disability globally, with a significant number of patients exhibiting resistance to standard pharmacological and psychotherapeutic interventions. In recent years, non-invasive brain stimulation techniques, especially transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have emerged as promising therapies for treatment-resistant MDD. A comprehensive search was performed in PubMed, which included all studies published over the last ten years. Eligible studies encompassed both animal models and clinical investigations. This review provides a comparative overview of transcranial electrical stimulation modalities, with a focus on their mechanisms of action, clinical efficacy, and underlying neurobiological mechanisms. We pay particular attention to the role of the neurotrophin system, specifically brain-derived neurotrophic factor (BDNF), in mediating the treatment effects of transcranial stimulation. Recent findings indicate that neuromodulation could improve neuroplasticity by increasing BDNF levels and associated signaling pathways, which may help stabilize mood and enhance the improvement of individuals with MDD. A more profound understanding of these mechanisms could lead to more precise, biomarker-driven interventions. Further research is essential to elucidating the long-term effects of brain stimulation on neurotrophin levels and to creating more individualized treatment strategies. Show less

Residual cardiovascular risk remains, despite achieving low-density lipoprotein cholesterol targets with high-intensity statins. Traditional risk scores are suboptimal. This study evaluated the prognostic utility of a 9-plex apolipoprotein panel in recent patients with acute coronary syndrome on statins and its role in predicting treatment benefit by alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, enabling precision medicine. Baseline serum samples from 11 843 participants in the ODYSSEY OUTCOMES trial (https://www.clinicaltrials.gov; Unique identifier: NCT01663402) were analyzed using mass spectrometry to measure Apo(a), ApoA-I, ApoA-II, ApoA-IV, ApoB, ApoC-I, ApoC-II, ApoC-III, and ApoE. Using logistic regression, probabilities of major adverse cardiovascular events (MACE) and all-cause death over a median follow-up of 2.9 years were estimated based on baseline apolipoproteins and lipid concentrations. Clinical performance was assessed by comparing the area under the curve (AUC) of 3 models: the apolipoprotein panel, the lipid panel (total cholesterol, high-density lipoprotein cholesterol, and triglycerides), and a combination. In addition, prediction models estimating the treatment benefit of alirocumab by the apolipoprotein panel were developed. The prognostic performance of the apolipoprotein panel for MACE showed an AUC (95% CI) of 0.648 (0.626-0.670), compared with 0.579 (0.557-0.602) for the lipid panel. For all-cause death, the apolipoprotein panel had an AUC of 0.699 (0.664-0.733), while the lipid panel had an AUC of 0.599 (0.564-0.635). Adding the apolipoprotein panel significantly improved the performance of the conventional lipid panel ( A multiplex apolipoprotein panel led to better prediction of MACE and all-cause death, beyond lipids, in patients with postacute coronary syndrome on optimized statin therapy. The panel also predicts the treatment benefit of alirocumab. Further validation of this approach is now needed, and if confirmed and improved, it could lead to better disease prediction and management in the future. Show less

Apolipoprotein (Apo) C3 has been associated with incident coronary heart disease and major adverse cardiovascular events (MACE). Whether ApoC3 levels predict risk in patients with acute coronary syndrome (ACS) on optimized statin treatment is unknown. ApoC3 was measured by mass spectrometry at baseline (n=11,956) and after 4 months' treatment (M4; n=11 176) with alirocumab or placebo in the ODYSSEY OUTCOMES trial. Patients with fasting triglycerides >400 mg/dL were excluded. The association of baseline ApoC3 with risk of MACE or death was assessed in post hoc adjusted Cox regression models and spline analyses adjusted for treatment and ApoB. In adjusted models in the alirocumab group we determined association of ApoC3 change from baseline to M4 with subsequent risk of MACE and death. Median (Q1, Q3) baseline ApoC3 concentration was 85 (65, 113) mg/L. With adjustment for ApoB, baseline ApoC3 showed no clinically meaningful relationship to risk of MACE or death in spline analyses and no association with MACE (P=0.89) or death (P=0.70) in Cox regression analyses. Alirocumab reduced ApoC3 modestly by median -10 (-27, -5) mg/L (P<0.0001) and reduced MACE (10.1% vs 12.1%; P=0.0006) and death (3.5% vs 4.2%; P=0.045) versus placebo. However, the change in ApoC3 on alirocumab did not predict subsequent MACE or death. In patients with recent ACS on optimized statins without severe hypertriglyceridemia, neither baseline ApoC3 (accounting for ApoB) nor ApoC3 change with alirocumab predicted MACE or death. It is uncertain whether targeted therapies producing larger reductions in ApoC3 from higher baseline levels will affect cardiovascular risk. Show less