Exercise promotes neurogenesis and enhances memory consolidation while reducing the retention of aversive memories and anxiety-like behaviors. While our previous work found that acute exercise alters neurotransmitter concentrations, including dopamine and serotonin, in a time-of-day-dependent manner, the long-term effects of chronically timed exercise on neurotransmitter dynamics and behavioral phenotypes remain unclear. To examine whether the daily timing of a chronic exercise intervention modulates its impact on neurotransmitter profiles and fear responses, male rats were conditioned using a Pavlovian contextual fear approach, then assigned to a 4-week treadmill exercise intervention performed during the early (ZT14) or late (ZT22) active phase or a time-matched sham-exercise control group. One day after completing training, rats underwent a context retrieval test in the middle of active phase (ZT18), and hippocampal neurotransmitters were quantified using UPLC–MRM/MS. Rats subjected to sham-exercise at ZT22 exhibited higher freezing than sham-exercised rats at ZT14, whereas exercise interventions at ZT22 selectively attenuated freezing. Histamine, acetylcholine, and GABA exhibited significant exercise × time interactions. Direct neurotransmitter–freezing correlations were weak after false discovery rate control, consistent with a network-level reorganization rather than a single transmitter driver. These findings suggest that vulnerability to aversive memory expression can be buffered by exercise, if timed appropriately, and that exercise reshapes hippocampal neuromodulatory tone in a circadian–phase–dependent manner, supporting the potential of exercise timing as a chronotherapeutic strategy to enhance stress resilience and mental wellbeing.
Research trends and knowledge mapping of transcranial direct current stimulation in depression: a bibliometric study based on web of science, Scopus, and PubMed (2000-2025)
BackgroundDepressive disorders are clinically heterogeneous and mechanistically complex psychiatric conditions. Transcranial direct current stimulation (tDCS), a key non-invasive neuromodulation technique, has expanded rapidly in both therapeutic application and mechanistic research. However, the field is marked by rapid publication growth, thematic diversity, and variability in evidence quality. A systematic quantitative synthesis is therefore needed to map the research landscape, identify hotspots, and inform future directions.MethodsA systematic search was conducted for English-language publications in the Web of Science Core Collection (WoSCC), Scopus, and PubMed using the terms (“Transcranial direct current stimulation” OR “tDCS”) AND (“depression” OR “major depressive disorder” OR “depressive disorder” OR “MDD”). Only articles and reviews were included. Records from 2026 and non-research publications, including conference abstracts, editorials, letters, news items, and errata, were excluded. Deduplication was performed using DOI-based matching followed by title-assisted matching. Bibliometrix (R), VOSviewer, and CiteSpace were used to analyze publication trends, contributions by countries/regions, institutions, authors, and journals, collaboration networks, keyword co-occurrence, thematic clustering, and burst terms. Citation analysis was based on WoSCC data only.ResultsResearch on tDCS for depression showed sustained growth, with marked acceleration after 2020 and a peak in 2024. The United States, Germany, and Brazil occupied central positions in both productivity and international collaboration, with the United States ranking first in publication volume. Major research hubs included the Universidade de São Paulo, the University of Toronto, and Harvard University, while Brain Stimulation, Journal of Affective Disorders, and Frontiers in Psychiatry were the leading publication venues. Highly cited studies mainly focused on neurophysiological mechanisms, pivotal randomized controlled trials, and evidence-based guidelines. Keyword analyses indicated a shift from early attention to cortical excitability, safety, and short-term efficacy toward a more integrated framework involving prefrontal-targeted stimulation, cognitive function, functional connectivity, treatment outcomes, and cross-disorder applications.ConclusiontDCS research in depression is entering a multidimensional and interdisciplinary phase, with increasing emphasis on network-level mechanisms and precision intervention. Functional connectivity is emerging as a potential biomarker for patient stratification and outcome prediction. Further progress depends on multicenter standardization, reproducible analytic pipelines, and high-quality comparative effectiveness research.
Facilitating Thought Progression: A Neurocognitive Framework Linking Thought Dynamics and Mood Disorders
Mood and thought are tightly coupled, but the mechanisms linking them are not understood. This link is particularly important when considering mood disorders such as depression. We propose the Facilitating Thought Progression (FTP) framework, which characterizes depression as a disorder of thought dynamics, encompassing both the temporal evolution and semantic expanse of mental activity. Five parameters jointly determine the fluency of thought progression: breadth, speed, flexibility, novelty, and scope.
Implications of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) for Mood Disorders and Suicide Risk
A strategic imperative in mood disorders is to identify innovative mechanisms that translate into improved therapeutics when compared to the extant options. More specifically, there is a need for treatments with greater efficacy, shorter time-to-peak efficacy, greater durability of effect as well as improved tolerability profiles. Moreover, priority has also shifted towards identifying mood disorder therapeutics capable of targeting domains of psychopathology that are most pervasive, debilitating and inadequately treated by conventional pharmacology (e.g., anhedonia, cognitive impairment).
<![CDATA[A multicenter study tests SAINT TMS for postpartum depression.]]>
A novel music-based real-time fMRI neurofeedback interface modulates interhemispheric connectivity and enhances mood
IntroductionMusic is a universal language that transcends cultures and is deeply rooted in human evolutionary history. Its creation and appreciation recruit the limbic and reward systems, leading to the evocation of emotions ranging from happiness and sadness to tenderness and grief. Here, we investigate the potential of music as an interventional tool in a novel neurofeedback connectivity-based experiment. MethodsThis study proposes a musical interface for real-time functional magnetic resonance imaging neurofeedback that is adaptable to diverse experimental paradigms, namely the ones aiming at improving mood and other affective dimensions. Using a previously developed motor imagery connectivity-based approach, we evaluate its feasibility and efficacy by comparing the modulation of bilateral premotor cortex activity during functional runs with real versus sham (random) feedback in 22 healthy adults. We also assess its performance against a visual feedback interface. The experiment involves a 50-minute MRI session, including anatomical scans, a premotor cortex functional localizer run, and four neurofeedback runs (two with active feedback and two with sham feedback). Pre- and post-session questionnaires assess the neurobehavioral impact on mood, musical background (as a potential predictor of neurofeedback success), and subjective feedback experiences. During neurofeedback, participants perform motor imagery of finger-tapping, with feedback delivered as a dynamic, pre-validated chord progression that evolves or regresses based on the functional connectivity between left and right premotor cortex.ResultsWe found that our implementation of music-based feedback was successful, with participants managing to modulate their own connectivity using the proposed interface. The modulation performance was similar for active and sham runs, possibly due to the power of music to boost neuromodulation, but the network recruitment was stronger for active neurofeedback, including in the insula, putamen, and target regions of interest. Behaviorally, we found a decrease in tension and an improvement in the overall mood of the participants after the session. DiscussionWhen comparing our results to previous neurofeedback data with a visual interface, we found stronger brain activations, in particular in neurofeedback-relevant regions such as the insula and the putamen. This work shows that it is possible to directly modulate interhemispheric connectivity using a real-time functional magnetic resonance imaging musical interface with potential effects on mood and recruitment of saliency and learning networks.
Combinatorial effects of multi-site stimulation on depression-related brain regions: clinical data analysis and predictive modeling
BackgroundDespite growing evidence supporting deep brain stimulation (DBS) for treatment- resistant depression (TRD), how stimulation delivered across hemispheres or across multiple targets interact to shape large-scale network activity remains poorly characterized.ObjectiveUsing a unique opportunity to simultaneously stimulate the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VC/VS) in subjects with TRD while recording neural activity across putative prefrontal networks underlying depression via intracranial electrodes, we investigated whether bilateral or multi-target stimulation has additive, synergistic/super-additive, or antagonistic/sub-additive effects on power modulation across depression-related brain networks.MethodsFour DBS leads, and ten stereo-electroencephalography (sEEG) leads were implanted in depression-related prefrontal brain regions in three subjects with TRD. Power modulation in response to unilateral and bilateral stimulation, as well as interaction classes of combinatorial stimulations, were evaluated across various combinations of frequency bands and region of interests (ROI) using marginal predictions from a linear mixed-effects model which were then used as input for machine learning classifiers to predict the additive interaction class of combinatorial stimulations.ResultsBilateral and multi-target stimulation produced additive or sub-additive interactions in most cases. A decision tree classifier identified ROI as the most important feature for predicting interaction class, followed by stimulation target and spectral frequency band.
A Scalable Trans Diagnostic Intervention Targeting Adolescent Agency Supported by Conversational AI (AGENCIA)
Conditions: Irritability; Neurodevelopmental Disorders; Impulsivity; Emotional Dysregulation; Distress, Emotional; Distress, Psychological
Interventions: Behavioral: AGENCIA Digital Self-Guided; Behavioral: AGENCIA In-person With Digital Assistant
Sponsors: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla; Hospital Universitario Virgen del Rocio; Instituto de Salud Carlos III
Not yet recruiting
Interventions: Behavioral: AGENCIA Digital Self-Guided; Behavioral: AGENCIA In-person With Digital Assistant
Sponsors: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla; Hospital Universitario Virgen del Rocio; Instituto de Salud Carlos III
Not yet recruiting
Milk Exosomes Transform Therapeutic Bioprocessing
Breast milk has long been understood as more than infant nutrition. It is a biologically active system packed with molecular signals that help shape immune development, metabolism, and even brain function. Among its most intriguing components are milk-derived extracellular vesicles—tiny lipid-bound particles often called milk exosomes—that are rapidly becoming one of bioprocessing’s most promising therapeutic tools.
These nanoscale carriers are naturally designed for transport. They can survive digestion, move into circulation, and distribute cargo throughout the body, with studies suggesting they may even reach the brain during early development. Researchers have shown that these vesicles can influence central nervous system communication, particularly through interactions with microglia, which are crucial to the brain’s immune cells. The ability of milk exosomes to carry microRNAs and regulate epigenetic pathways, including DNA methyltransferase 1 (DNMT1), points to a sophisticated biological delivery system that the industry is now learning to harness.
That potential is especially compelling in drug manufacturing, where delivery often determines whether a therapy succeeds or fails. Traditional nanoparticles can trigger toxicity, instability, or poor absorption. Milk exosomes offer a more elegant alternative: they are biocompatible, naturally abundant, and scalable for pharmaceutical development.
Huiming Tu, MD, a researcher and clinician in the department of gastroenterology at the Affiliated Hospital of Jiangnan University in Wuxi, China, and his colleagues recently demonstrated this with ulcerative colitis. Their team developed an oral delivery platform called mEXOs@TOF, which loads the pan-JAK inhibitor tofacitinib into milk-derived exosomes. The resulting formulation showed strong pharmaceutical performance, including consistent particle size, high drug-loading efficiency, and strong stability during delivery.
More importantly, the therapy improved anti-inflammatory outcomes through multiple mechanisms. It lowered inflammatory mediators such as IL-6, IFN-γ, and nitric oxide, while increasing anti-inflammatory IL-10. It also reduced oxidative stress and suppressed activation of the JAK-STAT3 signaling pathway. In both laboratory and animal studies, the system delivered strong therapeutic benefits without detectable toxicity—an ideal benchmark for translational bioprocessing.
Cancer therapy is seeing similar innovation. Min Suk Shim, PhD, professor of nano-bioengineering at Incheon National University in the Republic of Korea, and colleagues focused on sonodynamic therapy, in which ultrasound activates a sensitizing drug to destroy tumors. Their challenge was improving intracellular delivery of chlorin e6 (Ce6), a common sonosensitizer.
The team engineered glutathione-responsive milk exosomes by incorporating a diselenide bond-bearing fatty amine derivative. This allowed the vesicles to remain stable during circulation but release Ce6 inside breast cancer cells, where glutathione concentrations are higher. Once ultrasound was applied, reactive oxygen species production increased dramatically, leading to significant cancer cell death in MCF-7 breast cancer models. The work shows how responsive bioprocess design can turn natural vesicles into precision-triggered therapeutics.
Meanwhile, scientists from Hong Kong and China have reviewed the broader landscape of milk exosomes in breast cancer treatment. Beyond acting as delivery vehicles for drugs like doxorubicin, paclitaxel, and 5-fluorouracil, milk exosomes may also have direct anti-tumor effects. They can promote apoptosis, interrupt the cell cycle, and regulate pathways such as NF-κB and STAT3. Combined with plant-derived compounds like curcumin and resveratrol, they form hybrid nanoparticles with enhanced therapeutic power.
For bioprocessing, the message is clear: milk exosomes are no longer a niche curiosity. They represent a scalable, safe, and highly adaptable platform for next-generation therapeutics—one that begins with biology’s oldest delivery system and may define medicine’s next one.
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Loss of Smell Therapies Informed by Olfactory Receptor Spatial Mapping
A new study published in Cell titled, “A spatial code governs olfactory receptor choice and aligns sensory maps in the nose and brain,” led by researchers from Harvard Medical School (HMS) has created the first detailed map of the spatial distribution of over 1,000 olfactory receptors in the epithelium. The study informs the development of therapies for loss of smell, where treatment options are limited.
The researchers examined approximately 5.5 million neurons in more than 300 individual mice using single-cell sequencing and spatial transcriptomics. Results showed that neurons are organized into tight, overlapping, horizontal stripes from the top to the bottom of the nose based on the type of smell receptor expressed. This highly organized receptor map was consistent across mouse models and mirrored the organization of smell maps in the brain. Similar maps have been observed in vision, hearing, and touch.
Notably, the olfactory map was informed by a gradient of retinoic acid in the nose, which allowed each neuron to express the correct type of smell receptor based on its spatial location.
“Our results bring order to a system that was previously thought to lack order, which changes conceptually how we think this works,” said Sandeep (Robert) Datta, PhD, professor of neurobiology at HMS and senior author and corresponding author of the study. “We show that development can achieve this feat of organizing a thousand different smell receptors into an incredibly precise map that’s consistent across animals.”
The authors also found that the receptor map in the nose matches up with smell maps in the olfactory bulb of the brain, shedding insight into how information moves from the nose to the brain.
While sensory maps that describe how receptors in the eye, ear, and skin are organized to capture and interpret auditory, visual, and touch information, mapping olfactory receptors has been a longstanding challenge due to high receptor diversity. As an example, mice have approximately 20 million olfactory neurons that express more than a thousand types of smell receptors, compared with only three main types of visual receptors for color vision. Each type of smell receptor detects a unique subset of odor molecules.
The team is also studying smell receptors in human tissue to understand to what degree the smell map is consistent across species to inform treatments, such as stem cell therapies and loss of smell and its consequences, such as an increased risk of depression.
“Smell has a really profound and pervasive effect on human health, so restoring it is not just for pleasure and safety but also for psychological well-being,” Datta said. “Without understanding this map, we’re doomed to fail in developing new treatments.”
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