Cervical non-invasive vagus nerve stimulation (nVNS) has emerged as a practical neuromodulation approach with FDA-cleared indications in primary headache disorders, yet skepticism persists over whether transcutaneous stimulation can reliably engage vagal fibers or whether observed benefits reflect nonspecific cervical activation. Here, we synthesize converging anatomical, biophysical, physiological, and clinical evidence demonstrating that nVNS does, in fact, activate vagal pathways without surgical implantation. We first review cervical vagus anatomy and the biophysical basis for target engagement, including ultrasound-measured nerve depth and multi-scale computational models showing that clinically relevant stimulation can recruit predominantly large myelinated vagal fibers. We then integrate mechanistic evidence across complementary modalities: functional imaging consistently modulates canonical vagal projection sites (including brainstem nuclei), electrophysiology demonstrates peripheral vagal recruitment and centrally transmitted evoked responses, immune studies reveal reproducible suppression of pro-inflammatory cytokines consistent with cholinergic anti-inflammatory reflex engagement, and autonomic biomarkers show shifts toward increased parasympathetic tone. Finally, we contextualize these mechanistic findings with sham-controlled randomized trials in cluster headache and migraine, where nVNS repeatedly outperforms sham for acute and preventive outcomes with a favorable safety profile. Together, these independent lines of evidence form a coherent mechanistic fingerprint that is difficult to reconcile with placebo or superficial muscle stimulation accounts. We conclude that nVNS provides a credible, scalable means of accessing vagal neurophysiology and represents a clinically validated, paradigm-shifting advance in bioelectronic medicine.
Longitudinal changes in MMN and P3 during emotional processing in adolescents who engage in NSSI: a 12-week follow-up study
BackgroundAdolescents with nonsuicidal self-injury (NSSI) often show deficits in negative emotion regulation. Within the dual-process framework of implicit and explicit emotion regulation, these deficits may reflect an automatic bias toward negative information and insufficient later-stage controlled regulation. Whether routine clinical intervention modifies both early automatic detection and later controlled evaluation of negative emotional information remains unclear.MethodsIn a longitudinal sample of 32 adolescents with NSSI, we examined changes in mismatch negativity (MMN) and P3 components elicited during an emotional oddball task before and after a 12-week clinical intervention. At baseline and Week 12, participants completed clinical assessments and a two-choice visual emotional oddball task containing neutral standards and negative, positive, and neutral deviants while EEG was recorded. MMN (Fz, 240–300 ms) and P3 (Pz, 450–650 ms) amplitudes were derived from deviant-minus-standard difference waves, indexing pre-attentive deviance detection and controlled evaluation, respectively.ResultsThe intervention selectively modulated neurocognitive processing of negative deviants. Self-injury ideation days (p = .036) and NSSI episode frequency (p = .007) both significantly decreased. MMN absolute amplitude to negative stimuli decreased significantly (p = .047), suggesting attenuated automatic salience detection, whereas P3 amplitude to negative stimuli increased significantly (p = .027), indicating enhanced controlled evaluation. Responses to positive and neutral conditions and behavioural performance remained stable. No baseline ERP–clinical correlations emerged; post-intervention, NSSI ideation days correlated with positive P3 (r = 0.380, p = .032), and episode frequency with neutral P3 (r = 0.461, p = .008).ConclusionsA 12-week intervention may attenuate automatic negative bias while enhancing controlled evaluative processing in adolescents with NSSI, consistent with the implicit–explicit framework. MMN and P3 may serve as candidate biomarkers and temporally sensitive tools for tracking intervention response when behavioural performance is stable.
<![CDATA[Phase 2 depression trial shows ALTO-203 boosts attention, EEG theta-beta ratio and alertness, pointing to biomarker-guided dosing and precision psychiatry.]]>
Signatera™ as a Pan-Cancer Decision-Making Tool to Illuminate the Care Pathway
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To date, precision oncology has largely focused on selecting therapies based on tumor genomics. One of the most persistent challenges in clinical practice remains knowing what to do next. After surgery, during systemic therapy or in surveillance, clinicians are often navigating uncertainty, balancing overtreatment against the risk of recurrence.
Reshaping patient management
Circulating tumor DNA (ctDNA)–based minimal residual disease (MRD) assessment with tumor-informed Signatera
is reshaping this paradigm by providing a dynamic, patient-specific signal that can illuminate next steps across the continuum of care. Unlike conventional imaging or clinicopathologic risk factors, ctDNA offers a real-time measure of tumor burden at the molecular level. Signatera is designed using the patient’s tumor, enabling highly sensitive and specific detection of residual disease at levels far below radiographic visibility. This creates a new layer of clinical intelligence that is actionable across neoadjuvant, adjuvant, surveillance, metastatic, and treatment response settings.
Neoadjuvant setting: early readouts to adapt therapy
In the neoadjuvant setting, clinicians often need to wait until the time of surgery to determine whether therapy was effective. Assessing ctDNA dynamics during neoadjuvant therapy can provide an early indication of treatment response; ctDNA clearance has been associated with improved outcomes while conversely, persistent ctDNA may signal resistance, prompting consideration of treatment escalation, clinical trial enrollment, or alternative regimens.1 This creates an opportunity to move beyond static endpoints toward adaptive treatment strategies. Clinicians can watch ctDNA trends to refine therapy in real time. This is especially relevant in aggressive tumor types where early response assessment is critical.
Adjuvant setting: refining who may benefit from additional therapy
MRD testing may provide immediate clinical impact in the adjuvant setting. Current decision-making relies heavily on population-level risk factors, often leading to overtreatment in some patients and undertreatment in others. Postoperative ctDNA positivity is a strong, independent predictor of recurrence across multiple tumor types. Signatera data demonstrates that ctDNA-positive patients after surgery can have dramatically higher recurrence risk compared with ctDNA-negative patients.2 More importantly, Signatera ctDNA status can help predict who benefits from adjuvant therapy. Evidence suggests that ctDNA-positive patients derive meaningful benefit from additional systemic treatment, while ctDNA-negative patients may not.3
Surveillance: detecting recurrence earlier
Surveillance after curative-intent therapy remains a gray zone as imaging can often be intermittent and insensitive to early recurrence. While many biomarkers like CEA, CA-19-9, CA-125 generally have limitations in both sensitivity and specificity, Signatera ctDNA testing offers a more sensitive approach to detect molecular relapse earlier than imaging and other blood biomarkers. Studies have shown that Signatera can identify recurrence months before it becomes radiographically apparent with high sensitivity and specificity and substantial lead times.4 Earlier detection opens the door to intervention at a lower disease burden, when therapies may be more effective. It also enables more tailored surveillance strategies to intensify monitoring or imaging when ctDNA becomes positive, provides reassurance, and potentially reduces imaging frequency in persistently negative patients. Rather than a fixed surveillance schedule, ctDNA enables a response-guided follow-up strategy.
Treatment on MRD (TOMR)
TOMR is a new paradigm in precision oncology that is used to guide earlier, more proactive therapy decisions to escalate treatment in MRD-positive patients at high risk of relapse and de-escalate or avoid unnecessary toxicity in MRD-negative patients. For clinicians, this moves decision-making from prognostic to personalized, anchored by the presence of residual disease at an earlier and potentially curable stage.
Metastatic setting: real-time disease monitoring
In metastatic disease, treatment decisions are often based on imaging intervals that may lag behind molecular changes in disease burden. A newer technology like ctDNA introduces a more immediate and dynamic tool. Because ctDNA reflects tumor burden and molecular activity, it can be used to monitor treatment response earlier than imaging and identify emerging resistance to inform timely switches in therapy. In practice, this allows clinicians to avoid prolonged exposure to ineffective therapies and pivot more quickly. Additionally, Signatera is being used to monitor response to immunotherapy across tumor types, providing a pan-cancer application in advanced disease.
Treatment response monitoring: a continuous feedback Loop
Across all stages, one of the most powerful aspects of ctDNA is its ability to create a longitudinal feedback loop. Serial testing enables clinicians to track ctDNA trends over time:
- Clearance means favorable response and improved prognosis
- ctDNA dynamics have been shown to correlate strongly with outcomes. Patients who remain ctDNA negative demonstrate significantly better survival than those who become or remain ctDNA positive which could mean there is a higher risk of disease progression
This transforms monitoring from episodic snapshots into a continuous signal, providing actionable insight at each decision point.
A pan-cancer framework for clinical decision-making
What makes Signatera particularly compelling is its pan-cancer applicability. Its tumor-informed design allows it to be used across multiple solid tumors, including colorectal, breast, lung, bladder, ovarian, and melanoma. This consistency enables a unified framework for integrating MRD into clinical workflows:
- At diagnosis or pre-treatment—establish baseline and design assay
- During neoadjuvant therapy—assess early response
- Post-surgery—evaluate MRD and guide adjuvant decisions
- During surveillance—detect molecular relapse early
- In advanced disease—monitor response and resistance
Rather than being confined to a single decision point, ctDNA becomes a longitudinal biomarker embedded throughout the care pathway.
From uncertainty to actionability
Signatera ctDNA testing bridges the gap from uncertainty to actionability by answering clinically meaningful questions at each stage of the patient’s journey: Is there still disease present, and is it changing? By doing so, ctDNA doesn’t just add another biomarker. It redefines how clinicians navigate the care pathway, moving from reactive to proactive care.
References
- Chakrabarti S, Cohen S, Tin A, et al. Utility of Circulating Tumor DNA to Assess Tumor Response in Patients with Locally Advanced Rectal Cancer Undergoing Neoadjuvant Therapy. Cancers. 2026; 18(4):589.
- Reinert T, Henriksen TV, Christensen E, et al. Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer. JAMA Oncol. 2019.
- Nakamura Y, Watanabe J, et al. ctDNA-based molecular residual disease and survival in resectable colorectal cancer. Nature Medicine. 2024. doi: 10.1038/s41591-024-03254-6.
For additional information: www.natera.com.
The post Signatera™ as a Pan-Cancer Decision-Making Tool to Illuminate the Care Pathway appeared first on Inside Precision Medicine.
Gut microbiome dynamics in autism: a prospective nested case–control study demonstrates microbial-clinical associations following rehabilitation interventions
BackgroundChildren with autism spectrum disorder (ASD) commonly exhibit gut microbiota dysbiosis and metabolic abnormalities, yet the mechanisms linking these changes to clinical symptoms remain unclear.ObjectiveThis study employed a nested case–control design and multi-omics approaches to evaluate the effects of rehabilitation intervention on clinical symptoms and gut microbiota in children with ASD, identify distinct microbial-metabolic signatures, and explore their mechanistic links with sleep disorders and developmental abilities.MethodsWithin a prospectively established pediatric cohort (n = 45), we implemented a nested case–control design including 26 ASD children (18 males, 8 females; mean age 61.79 ± 11.15 months) and 19 age- and sex-matched healthy controls. All ASD participants received standardized rehabilitation therapy (2 h/day, 5 days/week for 6 months) comprising occupational therapy and cognitive-linguistic training. Primary outcomes included comprehensive clinical assessments [Griffiths Development Scales-Chinese (GDS-C), Children’s Sleep Habits Questionnaire (CSHQ), Autism Behavior Checklist (ABC), Childhood Autism Rating Scale (CARS)] and longitudinal multi-omics analysis (metagenomic sequencing and LC–MS-based metabolomics). Association analyses were performed with FDR correction (q < 0.05).ResultsFollowing the 6-month rehabilitation intervention, significant clinical improvements were observed in sleep quality (CSHQ total and subscores) and developmental performance (GDS-C). Multi-omics profiling revealed distinct biological signatures in ASD children compared to healthy controls, characterized by elevated Intestinibacter_bartlettii and reduced levels of ornithine and siderophore nonribosomal peptide biosynthesis. Crucially, correlation analysis demonstrated that, after FDR correction, ornithine levels were significantly positively correlated with multiple GDS-C developmental domains, while tyrosine was associated with parasomnias. These findings establish a potential mechanistic link where amino acid metabolism connects gut microbial shifts to clinical phenotypes.ConclusionThis study demonstrates that rehabilitation intervention synchronously ameliorates clinical symptoms and modulates the gut-metabolic profile in ASD. The identified associations between specific metabolites (ornithine and tyrosine) and clinical outcomes suggest a metabolic mechanism underlying the gut-brain axis, highlighting the potential of these metabolites as biomarkers for therapeutic monitoring. Further large-scale studies are needed to validate these findings.
Integrative mechanisms and intervention targets of the microbiota–gut–brain axis in depressive disorders: advances across immune, endocrine, and central nervous system pathways
Depressive disorders are highly heterogeneous syndromes characterized not only by depressed mood but also by cognitive impairment, sleep–circadian rhythm disturbances, altered appetite, somatic discomfort, and metabolic or gastrointestinal comorbidities. In recent years, the microbiota–gut–brain axis (MGBA) has been increasingly recognized as an integrative biological framework linking abnormalities in mood regulation, immune responses, endocrine function, metabolism, and neuroplasticity. This review provides a systematic synthesis of gut microbial ecology and host phenotypic features associated with depressive disorders, with particular emphasis on the depletion of short-chain fatty acid-producing commensals, the enrichment of potentially pro-inflammatory taxa, and the functional remodeling of key metabolic pathways, including the tryptophan–kynurenine pathway, short-chain fatty acids, bile acids, and trimethylamine N-oxide. We further discuss how bidirectional gut-to-brain and brain-to-gut communication may contribute to the onset and progression of depressive disorders through intestinal barrier disruption, low-grade systemic inflammation, hypothalamic–pituitary–adrenal axis activation, vagal signaling, and dysregulation of neurotransmitter and neurotrophic pathways. Current interventional evidence suggests that dietary and lifestyle modification, psychobiotics, and fecal microbiota transplantation may exert antidepressant potential in selected populations; however, the overall effect sizes remain limited and between-study heterogeneity is substantial. Patients with prominent gastrointestinal symptoms, metabolic abnormalities, or low-grade inflammatory states may represent priority candidates for MGBA-targeted interventions; nevertheless, a putative microbiota-responsive phenotype should not be simply equated with high stress exposure alone, and its definition requires prospective validation integrating stress burden, host responses, and microbial/metabolic readouts. Overall, MGBA research is gradually moving beyond descriptive profiling of microbial composition toward functional integration and clinical translation; however, causal inference, multi-omics standardization, and the identification of stratification biomarkers remain major challenges. Future studies should incorporate phenotype-based stratification, strengthened functional readouts, and precision intervention designs to determine which patients are most likely to benefit from microbiota-targeted therapies.
<![CDATA[AI analyzes wearable data to reveal objective biomarkers for ADHD and anxiety, enabling passive tracking and earlier psychiatric detection.]]>
Mirrored structural symmetry index (VMSSI): a novel approach for diagnosing MR-negative focal cortical dysplasia using structural MRI
BackgroundFocal cortical dysplasia (FCD) is a common cause of drug-resistant epilepsy, yet its diagnosis remains challenging, particularly for magnetic resonance imaging (MRI)-negative FCD. In this study, we propose a novel metric, the Voxel-Mirrored Structural Symmetry Index (VMSSI), to quantify hemispheric structural symmetry using T1-weighted MRI.MethodsA total of 104 patients with suspected FCD and 104 age and sex matched healthy controls from two centers were enrolled, and their brain images were mirrored along the longitudinal axis to create a dataset. The diagnostic discriminatory ability of magnetic resonance signal intensity value symmetry, cortical thickness symmetry and VMSSI was further verified by subject receiver operating characteristic (ROC) curve analysis. The sensitivity and specificity were used to assess the performance of VMSSI at different diagnostic thresholds.ResultsThe cortical thickness symmetry index (MeanThicknessDiff) was significantly different between the two groups (p < 0.001). The values of the combined symmetry index were significantly higher in the MR-negative FCD patient group than in the healthy control group (p < 0.001). The area under the curve (AUC) of VMSSI was 0.80 (95% CI: 0.72–0.88).VMSSI exhibited 77% sensitivity and 85% specificity at the optimal thresholds of 3.4.ConclusionThese results demonstrate that VMSSI is a reliable and effective tool for detecting MR- negative FCD, providing a quantitative structural biomarker that may aid in improving diagnostic accuracy in clinical practice.
Exploring ceramide as a novel biomarker and therapeutic target for Alzheimer’s disease
Metabolic dysregulation is increasingly being recognized as a hallmark across various neurodegenerative diseases. While Alzheimer’s disease (AD) is well-established as a dual proteinopathy characterized by amyloid-beta (Aβ) deposition and tau protein tangles, the specific mechanisms mediating lipid homeostasis imbalance have garnered increasing attention. However, translating these findings into safe clinical therapeutic targets remains a formidable challenge, primarily hindered by the pleiotropic roles of ceramides in maintaining neural and immune homeostasis, as well as the blood–brain barrier (BBB) penetration issues and systemic safety limitations of current sphingolipid-targeting strategies. We conducted a comprehensive search of electronic databases, including PubMed, Web of Science, and Google Scholar, to identify relevant studies published from database inception through March 2026. The search term combinations included: “Alzheimer’s disease,” “AD,” “ceramide,” “sphingolipid metabolism,” “biomarker,” “therapeutic target,” “neuroinflammation,” and “mitochondrial dysfunction.” To ensure the depth and rigor of this review, priority was given to peer-reviewed original research, systematic reviews, and meta-analyses. The search was restricted to English-language literature. Additionally, the reference lists of retrieved articles were manually screened to identify further relevant studies. This narrative review aims to comprehensively elucidate the potential roles of ceramides in AD pathogenesis, exploring their associations with triggering inflammatory responses, mediating apoptosis, interfering with signal transduction, and inducing mitochondrial dysfunction.
Nanotube Sensor Provides Chemical Imaging for Earlier Detection of Bladder Cancer Recurrence
Researchers at the Massachusetts Institute of Technology (MIT) have developed a catheter-based nanosensor that can detect the recurrence of bladder cancer at an earlier stage by identifying a biomarker released by tumors directly within the bladder. The technology, detailed in Nature Nanotechnology, combines carbon nanotube sensors with a rotating optical imaging device to create what researchers describe as a three-dimensional chemical imaging platform capable of locating cancer-associated biomarkers within tissue.
“It’s like a camera for molecules instead of light,” said Michael Strano, PhD, a professor of chemical engineering at MIT and senior author of the study. “If you have a billion nanosensors in an array, you can use them to make a chemical image that helps you locate their source.”
Roughly 85,000 people in the U.S. are diagnosed with bladder cancer each year, and more than half of patients experience recurrence within five years. The disease also carries among the highest lifetime treatment costs because patients require ongoing surveillance.
The new method addresses a major challenge in detecting bladder cancer recurrence, which currently relies on urinalysis to look for signs cancer has returned. Using urine for detection is hindered since biomarkers of cancer recurrence are diluted, degraded, and are often cleared shortly after they are released by the new tumor.
To address this, the MIT researchers targeted the matrix protein 22 (NMP-22), an FDA-approved biomarker for bladder cancer. While it is possible to detect NMP-22 in urine, the shortcomings of that method often mean that the cancer is often only found at a later stage of development.
To overcome this gap, the MIT team looked for a way to develop a sensor that could work inside the bladder. Their device consists of a urinary catheter coated with specialized nanosensors that detect the presence of NMP-22. A miniature rotating ball lens embedded in the catheter tip emits laser light and collects fluorescent signals generated by the nanotubes when they interact with the target biomarker.
Over the past decade, Strano’s laboratory has focused on developing carbon nanotube-based sensors that can identify specific molecules. The team customizes nanotubes for each application by applying different polymer coatings that function as “synthetic antibodies,” enabling them to bind to disease biomarkers. Previous development efforts in the lab have yielded sensors capable of detecting molecules such as hydrogen peroxide, riboflavin, and viral proteins.
For the bladder cancer application, researchers engineered a phospholipid-containing a synthetic polymer that selectively recognizes NMP-22. The project was partly motivated by earlier computational modeling conducted by the team, which suggested that placing sensors near an emerging bladder tumor could produce “a more than 50,000-fold increase in detection limit by minimizing biomarker dilution and degradation.” That finding pointed toward the potential advantages of measuring biomarkers at their source rather than after they enter urine.
In experimental testing, the platform achieved a 182-fold signal enhancement compared with biofluid sampling. The new technology was tested in multiple ways. The researchers first tested the nanosensors against six bladder cancer cell lines and healthy fibroblast cells and found distinct sensor responses associated with cancer-cell apoptosis. The team also used the chemotherapy drug gemcitabine to induce cancer cell death in vitro and monitored the resulting release of biomarkers. siRNA analysis confirmed that NMP-22 was a major contributor to the detected signals.
Researchers then evaluated the platform in porcine bladder models using a catheter coated with the specially designed nanotubes. Using a rotating ball lens system, they generated chemical maps showing the location of biomarker sources and demonstrated detection at distances up to two centimeters from the source. The researchers also reported a simulated tumor resolution of 16 square millimeters.
The chemical imaging capability is a unique attribute of the new method and the information it can provide should be very useful for treating recurrent cancer. “If you are scanning over a region of tissue, you would like to know not just that there is a signal indicating that a tumor is there, but also its location so that you can treat it or perform a biopsy,” Strano said. “Before an early-stage tumor breaks through the urothelium so that it’s visible, it’s under the surface but still emitting chemical signals that can be imaged.”
While the study focused on bladder cancer, the researchers indicated that the underlying platform may have broader applications. By replacing the nanosensors with versions designed to recognize other biomarkers, the system could potentially be adapted for additional cancers or for diseases affecting the cardiovascular or gastrointestinal systems.
“The beauty of polymer chemistry is that if we understand the molecular structures of target biomarkers and the design principles of binding sites, we can develop new sensors tailored to different diseases,” said lead author Wonjun Yim, PhD.
Future work will focus on expanding the range of detectable analytes, developing multiplexed sensor arrays, conducting omics-based biomarker validation studies, and improving optical engineering. The researchers also aim to miniaturize the imaging system and integrate the technology into cystoscopes already used in clinical practice.
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