Participants will be adults aged 30 to 80 who have experienced their first stroke, are between one and six months after onset, have Chinese as their native language and can cooperate with treatment and assessment. Stroke must be confirmed by computed tomography or magnetic resonance imaging and meet Chinese diagnostic criteria for cerebral infarction or hemorrhage. Cognitive impairment will be established under a 2021 expert consensus and confirmed with the Montreal Cognitive Assessment and Mini-Mental State Examination, with thresholds adjusted for education. The MoCA threshold is below 26 points, with one additional point for people with 12 years or fewer of education, while MMSE cutoffs vary by educational level. People with unstable vital signs, severe aphasia, significant visual or hearing impairment, serious carotid disease, implanted devices, certain bleeding or neurological disorders, or pre-existing neurodegenerative cognitive disease will be excluded.

All three groups will follow the same treatment schedule: interventions once daily, five days per week, for four weeks. The synchronous group will receive scalp acupuncture while taVNS is applied during the needle-retention period. Control Group 1 will receive scalp acupuncture first and taVNS afterward, while Control Group 2 will receive taVNS before scalp acupuncture. The two sequential groups will have at least three hours between treatments. Conventional care will include management of blood pressure, blood glucose, lipids and atherosclerotic plaques, as well as therapeutic exercise, occupational therapy, physical-agent modalities and 30-minute sessions of individualized cognitive training. Because all three groups receive both active treatments, the design can compare the temporal sequence of delivery but cannot determine whether the combination is better than either intervention alone.

For taVNS, a single electrode will be placed in the left auricular concha, an area supplied by the auricular branch of the vagus nerve. Stimulation will be continuous at 25 Hz, with a pulse width of 200 microseconds and a current amplitude of 1.0 to 5.0 milliamperes adjusted daily to just below the participant’s pain threshold. Each session will last 30 minutes. Scalp acupuncture will target Baihui, Shenting and Sishencong. Disposable needles measuring 0.35 by 40 millimeters will be inserted obliquely at 15 to 30 degrees to a depth of 20 to 25 millimeters, reaching the subgaleal space. The needles will remain in place for 30 minutes, with two minutes of twirling every 10 minutes at 150 twists per minute. The acupuncture sensation known as de qi, described in the protocol as soreness, numbness, distension or heaviness, will be sought and recorded. A dedicated team of certified acupuncturists and rehabilitation therapists will provide the treatments, and an independent monitor will randomly check about 10% of sessions for adherence.

The primary outcome will be the change in MoCA score between baseline and the end of treatment at week 4. The MoCA covers visuospatial skills, executive function, memory, language, attention and concentration, calculation, abstract thinking and orientation, with a maximum score of 30. To reduce practice effects from repeated testing, alternate validated equivalent Chinese versions will be used at the assessment time points. Secondary outcomes include the MMSE for global cognitive status and the Modified Barthel Index for activities of daily living. The Barthel Index measures bowel and bladder control, dressing, toileting, feeding, bathing, grooming, transfers, walking and stair climbing; higher scores indicate greater independence. Assessments will occur before treatment, at the end of the four-week intervention period and at an eight-week follow-up, allowing the protocol to capture both short-term change and a short post-treatment observation period.

Alongside behavioral scales, the study will collect resting-state functional magnetic resonance imaging, auditory event-related potentials and transcranial Doppler ultrasonography. Resting-state fMRI will examine functional connectivity, amplitude of low-frequency fluctuation and regional homogeneity, providing exploratory measures of brain-network activity. Event-related potentials will record the P300 component during a target-tone counting task, with amplitude and latency extracted from a predefined 250-to-500-millisecond window. The protocol will require at least 30 valid target trials after artifact rejection and will maintain electrode impedance below 5 kilohms. Transcranial Doppler ultrasound will measure systolic, end-diastolic and mean flow velocities in the bilateral middle cerebral arteries. The researchers describe these imaging, electrophysiological and hemodynamic measures as exploratory mechanistic endpoints, whereas the trial is powered specifically for the clinical MoCA comparison.

The statistical plan will use mixed-effects models for repeated measurements as the primary confirmatory analysis, following the intention-to-treat principle. Models will include group, time and their interaction as fixed effects, with baseline MoCA score as a covariate. The principal contrasts are adjusted differences at week 4 between the synchronous group and each sequential group, with Holm correction for the two comparisons. The likelihood-based model will handle incomplete data under a missing-at-random assumption, while multiple imputation by chained equations will be used as a sensitivity analysis. Baseline neurological severity and affected hemisphere will also be examined in additional sensitivity analyses. The sample-size calculation was based on an expected MoCA change of 4.9 points in the synchronous group and 1.5 points in each sequential group, a difference of 3.4 points; the trial is planned for 32 participants per group to retain at least 29 completers per group after an assumed 10% attrition rate. These figures are hypotheses for powering the study, not observed treatment effects.

Multimodal machine learning will be used only for hypothesis generation. After normalizing the MoCA and MMSE scores, investigators plan to build an initial pool of roughly 250 candidate features derived principally from regional fMRI measures, P300 parameters and cerebral blood-flow velocities. Support vector machine and random forest models will use the magnitude of cognitive improvement as the prediction target. To reduce the risk of overfitting in a cohort of 96, the complete analytical pipeline will be nested within five-fold cross-validation. Missing-value models will be fitted only on training folds, principal component analysis and recursive feature elimination will remain inside those folds, and hyperparameter tuning will occur exclusively in inner loops. Performance will be evaluated in held-out outer folds using root mean square error and mean absolute error. The authors explicitly state that the machine-learning component is not intended to produce a deployable or fully generalizable clinical prediction system.

Several design limitations could constrain the conclusions. The trial is open-label, and the distinctive nature of acupuncture and electrical stimulation makes participant and practitioner blinding impossible, leaving potential expectation effects despite blinded outcome assessors, imaging staff and statisticians. Recruitment from one hospital and a relatively homogeneous Chinese-speaking population may limit generalizability. The absence of a sham or single-intervention group prevents the trial from separating the effects of combination, the physiological action of each treatment and natural recovery after stroke. Four weeks of treatment also cannot establish long-term benefit, and the multimodal model will need validation in larger, multicenter cohorts. Safety will nevertheless be monitored closely: potential acupuncture events include syncope, hematoma, a stuck or broken needle and subcutaneous bleeding, while taVNS may cause skin irritation, headache or bradycardia. Serious events will be reported immediately to the ethics committee, and affected participants will be withdrawn. The study was approved by the hospital’s ethics committee and prospectively registered with the Chinese Clinical Trial Registry, but its clinical and mechanistic benefits remain untested until the planned outcomes are reported.

Subject of Research: A randomized trial protocol comparing concurrent and sequential neuromodulation timing for post-stroke cognitive impairment.

Article Title: Effects of synchronous versus sequential scalp acupuncture and transcutaneous auricular vagus nerve stimulation on post-stroke cognitive impairment based on multimodal assessments: a single-center randomized controlled trial protocol

Article References: Wei, J., Liu, X., Pan, Z., Wei, C., Wang, R., Wang, X., & Ma, S. (2026). Effects of synchronous versus sequential scalp acupuncture and transcutaneous auricular vagus nerve stimulation on post-stroke cognitive impairment based on multimodal assessments: a single-center randomized controlled trial protocol. Frontiers in Neurology, 17, Article 1931213. https://doi.org/10.3389/fneur.2026.1931213

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1931213

Keywords: post-stroke cognitive impairment, scalp acupuncture, auricular vagus nerve stimulation, neuromodulation, randomized controlled trial, resting-state fMRI, event-related potentials, cerebral blood flow, multimodal data, Effects, synchronous, versus

Idiopathic generalized epilepsies are epileptic syndromes characterized by seizures involving widespread networks without a localized seizure onset on neuroimaging and a presumed genetic etiology. They account for approximately 20% of all epilepsies, according to the study’s background, but remain underrepresented in research. Unlike focal epilepsy, which is associated with discrete seizure foci, idiopathic generalized epilepsies are linked to dysfunction in thalamocortical networks. The thalamus and anterior cingulate cortex, or ACC, are central components of this circuitry and participate in functions including cognitive control, attention and error detection, making them important regions for investigating physiological features of idiopathic generalized epilepsies.

The study was conducted at the University of Alabama at Birmingham using baseline data from two related projects: a blinded randomized controlled trial of combined endurance and resistance exercise training in patients with idiopathic generalized epilepsies and an endurance-training pilot study in healthy controls. The analysis did not test whether exercise changed brain measures. Adults with a clinician-confirmed diagnosis of idiopathic generalized epilepsy and healthy controls underwent the same general procedures, including a physical examination, maximal graded exercise test and magnetic resonance imaging on the same 3T scanner. Most patients were taking one or more antiseizure medications, with leviracetam, lamotrigine and sodium valproate among the most frequently prescribed drugs. This medication heterogeneity was not controlled statistically and could influence exercise capacity, cerebral perfusion or metabolite measurements.

During the cycling test, work began at 25 watts and increased by 25 watts every two minutes while investigators monitored respiratory exchange, blood pressure, heart rate and perceived exertion. Peak oxygen uptake, calculated from the final two 30-second measurements, served as the primary measure of cardiorespiratory fitness. Two participants did not complete the test, leaving 44 people in the fitness analysis: 14 healthy controls, 16 seizure-free patients and 14 patients with active seizures. After adjustment for age and sex, estimated mean peak oxygen uptake was 20.41 millilitres per kilogram per minute in the idiopathic generalized epilepsy group and 22.85 millilitres per kilogram per minute in controls. The difference was not statistically significant, with a p-value of 0.203 and a partial eta-squared of 0.04. Seizure-control status also produced no significant overall difference in fitness, although the estimated mean was lowest among participants with active seizures, at 18.72 millilitres per kilogram per minute, compared with 21.85 among seizure-free patients and 22.88 in controls.

That null result should be interpreted in light of how the comparison group was selected. Both patients and healthy controls had low leisure-time physical activity, with the study requiring activity below the American Heart Association recommendation of 150 minutes per week of moderate-intensity endurance exercise. Their self-reported activity did not significantly differ: estimated marginal means were 2.31 in controls and 2.18 in the idiopathic generalized epilepsy group, with a p-value of 0.696. No objective activity tracker was used. The authors said this similarity may have reduced variation in fitness, potentially masking differences associated with the disorder, although the cross-sectional design cannot establish that explanation. Antiseizure medications may also have influenced exercise capacity. The result therefore indicates no detectable difference in this selected sample, not that cardiorespiratory fitness is unaffected in all people with idiopathic generalized epilepsy.

For cerebral blood flow, researchers used a five-delay pseudo-continuous arterial spin-labeling sequence with post-labeling delays of 500, 1,000, 1,500, 2,000 and 2,500 milliseconds. A multi-delay kinetic model estimated blood flow and arterial transit time, while calibration produced absolute perfusion values in millilitres per 100 grams of tissue per minute. Investigators extracted atlas-based regional values from the ACC and thalamus. Eight participants were excluded because of ghosting artifacts or perfusion variance above the predefined threshold, leaving 38 people for the comparison. After adjustment for age and sex, the idiopathic generalized epilepsy group had significantly higher ACC blood flow than controls: estimated means were 59.61 and 52.72 millilitres per 100 grams per minute, respectively. The difference was 6.89 millilitres per 100 grams per minute, with a p-value of 0.039 and a partial eta-squared of 0.12. Thalamic blood flow did not differ significantly between groups, and seizure-control status was not associated with a significant perfusion difference in either region.

The researchers also used proton magnetic resonance spectroscopy to measure concentrations of N-acetylaspartate, or NAA, and the combined glutamate-glutamine signal, Glx, relative to total creatine in the ACC and thalamus. NAA is considered a marker of neuronal integrity, while Glx reflects aspects of excitatory neurotransmission and cognitive processing. Point-resolved spectroscopy used separate voxels over the bilateral ACC and thalamus, and the resulting spectra were corrected for tissue composition. Seven participants were excluded under predefined spectral-quality criteria, leaving 39 participants in the metabolite analysis. In the thalamus, NAA relative to total creatine was lower in patients with idiopathic generalized epilepsies than in controls, with estimated means of 1.35 and 1.49, respectively. The difference was 0.14, with a p-value of 0.012 and a partial eta-squared of 0.16. Neither ACC metabolite ratio nor the overall thalamic Glx ratio differed significantly between the main study groups.

Seizure-control status was associated with specific thalamic differences. Patients with active seizures had a lower thalamic NAA-to-total-creatine ratio than healthy controls, with an estimated mean of 1.29 compared with 1.49 in controls and a post-hoc p-value of 0.017. Patients who had been seizure-free for the preceding six months did not differ significantly from controls in post-hoc comparisons. The active-seizure group also had a lower thalamic Glx-to-total-creatine ratio than the seizure-free group, with estimated means of 0.57 and 0.81 and a difference of 0.24. The post-hoc p-value was 0.004, while the overall seizure-status effect had a p-value of 0.005 and a partial eta-squared of 0.26. The authors described this pattern as consistent with altered thalamocortical network physiology, but the measurement is not a direct readout of extracellular glutamate or acute seizure activity. Single-voxel spectroscopy has limited spatial and temporal resolution, cannot separate glutamate from glutamine, and could not detect GABA peaks. Medication effects are also plausible because the participants’ drug regimens varied substantially, including both monotherapy and polytherapy.

Several limitations constrain how far the results can be generalized. The sample was relatively small, particularly for the spectroscopy subgroup comparisons, and the investigators used atlas-based regions that averaged across distinct thalamic nuclei and ACC subregions. Such averaging may obscure localized perfusion effects and could contribute to the absence of a significant thalamic blood-flow difference. Seizure control was reduced to a binary classification based on whether any seizures had occurred during six months, without incorporating seizure frequency, severity or type, and the investigators noted that definitions of seizure freedom vary across epilepsy research. Medication effects were not analyzed directly, physical activity was not measured objectively, and the deliberately inactive healthy controls could not establish whether more active people would show different results. The findings are observational associations from a selected cohort, not evidence that altered blood flow or metabolite ratios cause seizures, that exercise can correct them, or that these measurements can predict clinical outcomes. Nevertheless, the combined measurements show that idiopathic generalized epilepsies are associated in this sample with region-specific differences in thalamocortical perfusion and metabolism, while the role of cardiorespiratory fitness remains unresolved.

Subject of Research: Cardiorespiratory fitness, cerebral perfusion and thalamic metabolism in adults with idiopathic generalized epilepsies

Article Title: Investigating cardiorespiratory fitness, cerebral blood flow, and brain metabolism in epilepsy

Article References: Lien, Y., Mitchell, B. S., Szaflarski, J. P., Ver Hoef, L., Buford, T. W., Goodman, A. M., Willoughby, W. R., Morgan, C. J., Moyana, A., Pilkington, J., August, A. R., Bennett, J. T., & Allendorfer, J. B. (2026). Investigating cardiorespiratory fitness, cerebral blood flow, and brain metabolism in epilepsy. Frontiers in Network Physiology, 6, Article 1894335. https://doi.org/10.3389/fnetp.2026.1894335

Image Credits: AI Generated

DOI: 10.3389/fnetp.2026.1894335

Keywords: idiopathic generalized epilepsies, cerebral blood flow, brain metabolism, cardiorespiratory fitness, thalamocortical network, magnetic resonance spectroscopy, arterial spin labeling, seizure control, anterior cingulate cortex, thalamic metabolism, Investigating, cardiorespiratory

The original article, published in January 2019 in the same journal under the title Effects of Mandibular Extension on Pial Arteriolar Diameter Changes in Glucocorticoid-Induced Hypertensive Rats, was authored by a team of Italian researchers including Lapi, Varanini, Galasso, Di Maro, Federighi, Del Seppia, Colantuoni and Scuri. The work appeared in the journal’s Vascular Physiology section and carried the article number 10:3, reflecting its position as the third paper published in that volume of the journal. The study’s stated aim was to examine how mechanical manipulation of the jaw might affect cerebral microvascular tone in an animal model of hypertension induced by glucocorticoids, a class of steroid hormones that includes cortisol and its synthetic analogues.

According to the retraction notice, the trouble began after publication, when concerns were raised regarding the integrity of the images in the published figures. In experimental physiology, figures often contain photomicrographs, fluorescence images, or other visual records of biological preparations, and these images serve as primary evidence for the paper’s claims. When questions arise about whether images have been duplicated, manipulated, or otherwise altered, the evidentiary foundation of the entire study comes into question. That is precisely the situation the journal confronted here.

Frontiers, the publisher, launched an investigation conducted in accordance with its own research integrity policies. The outcome, as stated in the notice, was stark: the authors failed to provide a satisfactory explanation during the investigation. In the absence of a credible account of how the problematic images came to be, the publisher concluded that the data and conclusions of the article had been deemed unreliable. On that basis, the retraction was issued, formally severing the paper from the scientific record.

The retraction followed the procedural safeguards that have become standard in scholarly publishing. It was approved by the Chief Editors of Frontiers in Physiology together with the Chief Executive Editor at Frontiers, ensuring that the decision was made at the highest editorial level rather than by a single handling editor. The authors were informed of the retraction and given an opportunity to respond, and that communication has been recorded by the publisher. This documentation matters, because it creates a permanent record of whether the authors contested the decision, cooperated with the investigation, or declined to engage, information that is often of keen interest to the research integrity community.

The timeline of the retraction itself was brisk. The retraction notice was received by the journal on 12 October 2026, accepted on 13 October 2026, and published on 19 October 2026. The notice was approved by Dirk M. Hermann of the University of Duisburg-Essen in Germany, acting in his editorial capacity. The speed of the process, once the investigation had concluded, reflects a growing emphasis among publishers on acting quickly once integrity concerns are substantiated, rather than allowing disputed papers to linger in the literature for years while cases are adjudicated.

For readers unfamiliar with the underlying science, the original study sat at the intersection of several physiological domains. Pial arterioles are the small vessels that run across the surface of the brain beneath the arachnoid membrane, and they play a crucial role in regulating cerebral blood flow. Their diameter can change in response to a wide range of stimuli, including blood pressure, metabolic signals, and neural activity, a property known as vascular reactivity. Hypertension, particularly the form induced experimentally by chronic glucocorticoid administration, is known to alter vascular reactivity and to damage the microvasculature over time, making the glucocorticoid-treated rat a common model for studying how high blood pressure reshapes the cerebral circulation.

The mandibular component of the study was the element that gave the paper its distinctive character. The temporomandibular joint and the muscles of mastication are richly innervated, and altered jaw position has been reported in some lines of research to influence cardiovascular and cerebrovascular parameters, a topic of ongoing interest in fields ranging from dentistry to autonomic physiology. The idea that extending the lower jaw might produce measurable changes in pial arteriolar diameter, and that such changes might differ in hypertensive versus normodynamic animals, represented an attempt to connect orofacial mechanics with cerebral microvascular control. Whether such a connection exists, and by what mechanism, remains a question that the retracted paper can no longer be cited to answer.

The retraction carries practical consequences for the research community. Under the norms of scholarly publishing, a retracted article should not be cited as supporting evidence, and databases such as the paper’s DOI record now flag the article as retracted, directing readers to the retraction notice. The original article remains accessible online, as is standard practice, but it is permanently watermarked by the retraction so that anyone who encounters it will know its status. This approach preserves the transparency of the scientific record while preventing the paper’s findings from quietly circulating as though nothing had happened. Researchers who had drawn on the 2019 study in reviews, meta-analyses, or grant applications will need to revisit those works and remove or contextualize the citation.

The case is also a reminder of how central image integrity has become to the policing of the scientific literature. Modern forensic analysis can detect duplicated regions within a single figure, reuse of the same image across different experiments, and subtle digital manipulations that would have escaped notice in the era of printed journals. Journals including Frontiers have invested in screening tools and editorial workflows designed to catch such problems, but many cases still surface only after publication, when readers or automated checks flag suspicious figures. The present retraction, initiated on the basis of concerns about published figures and closed after the authors could not satisfactorily explain them, follows that now-familiar arc. For the vascular physiology community, the message is that the question of whether mandibular extension influences pial arteriolar diameter in hypertensive rats remains open, and any future answer will have to rest on data that survive scrutiny.

Subject of Research: Retraction of a 2019 Frontiers in Physiology study on mandibular extension and pial arteriolar diameter in glucocorticoid-induced hypertensive rats due to image integrity concerns

Article Title: Retraction: Effects of mandibular extension on pial arteriolar diameter changes in glucocorticoid-induced hypertensive rats

Article References: Frontiers Editorial Office (2026). Retraction: Effects of mandibular extension on pial arteriolar diameter changes in glucocorticoid-induced hypertensive rats. Frontiers in Physiology, 17, Article 2026350. https://doi.org/10.3389/fphys.2026.2026350

Image Credits: AI Generated

DOI: 10.3389/fphys.2026.2026350

Keywords: retraction, Frontiers in Physiology, pial arterioles, cerebral blood flow, hypertension, glucocorticoids, mandibular extension, vascular physiology, research integrity, image manipulation, rat model, microcirculation

The research topic, titled “Tinnitus in relation to auditory processing: unravelling complex relationships,” brings together six investigations spanning philosophy, neuroimaging, psychophysiology, and therapeutic innovation. Together, they paint a picture of tinnitus as a condition that cannot be understood through the ear alone. Instead, the editors argue, it emerges from a tangled web of auditory processing, cognitive load, emotional distress, and even sex-specific differences in brain physiology.

One of the most provocative contributions comes from philosopher-clinician Aazh, who challenges the very definition of tinnitus itself. For decades, tinnitus has been described as a “phantom” perception, a sound heard without an external source. But Aazh argues this framing falls short. It fails to distinguish tinnitus from other internal auditory experiences, such as the sounds we hear in dreams or auditory hallucinations. Drawing on Socratic questioning, he proposes a new working definition: “the consciously recognized experience of a non-semantic, sound or sound-like event in wakeful consciousness that persists beyond fleeting moments and becomes experientially salient.” This shift matters because prevalence estimates for tinnitus swing wildly, from 5 percent to 37 percent depending on the study, suggesting that inconsistent definitions are muddying the science. By treating tinnitus as a hypothesis rather than a fixed category, researchers hope to avoid forcing a deeply personal and heterogeneous experience into a one-size-fits-all box.

But if defining tinnitus is tricky, understanding its neural roots is even harder. One study by Barker and colleagues turned to a curious auditory illusion called the Zwicker tone to shed light on the problem. The Zwicker tone is a faint, quickly fading pure tone that about 42 percent of people with normal hearing perceive after listening to “notched noise,” a sound signal with a specific frequency band removed. Remarkably, around 95 percent of tinnitus patients also experience this illusion. Both tinnitus and the Zwicker tone are illusory sounds tied to a spectral contrast, a gap or absence in the auditory signal, and both percepts arise in the frequency region that was not stimulated. Because the Zwicker tone can be reliably triggered in the laboratory, the researchers argue it offers a controllable model for studying the neural mechanisms behind chronic tinnitus, a condition that has long resisted direct experimental manipulation.

Meanwhile, Zhang and colleagues took a different tack, using a sophisticated brain imaging technique called arterial spin labeling to measure cerebral blood flow in chronic tinnitus patients. Cerebral blood flow serves as a direct proxy for neuronal activity, reflecting the metabolic demands of active brain tissue. Their findings were striking. Tinnitus patients showed reduced perfusion in regions tied to auditory and cognitive processing, including the inferior frontal gyrus, superior temporal gyrus, insula, and opercular areas. At the same time, they showed increased perfusion in parietal regions associated with attention and spatial awareness, such as the post-central gyrus, inferior parietal lobule, angular gyrus, supramarginal gyrus, and superior parietal lobule. Notably, blood flow in the opercular inferior frontal gyrus correlated positively with how loud patients perceived their tinnitus to be.

Even more intriguing were the sex differences the team uncovered. Male tinnitus patients showed greater hyperperfusion in frontal and precentral cortices, while female patients showed stronger increases in parietal regions. In healthy controls, the pattern was also dimorphic, with males showing greater perfusion in medial prefrontal regions and females showing stronger activity in sensorimotor and associative cortices. These findings suggest that chronic tinnitus is associated with widespread alterations across auditory, cognitive-emotional, and attentional networks, and that the underlying neuropathology may differ between men and women. The results bolster the case for arterial spin labeling as a non-invasive, radiation-free tool for assessing tinnitus patients and potentially tailoring treatments to individual brain signatures.

The emotional and cognitive toll of tinnitus took center stage in a study by Giliberto and colleagues, who put 24 tinnitus patients and 23 controls through a listening task using audiobook excerpts at different signal-to-noise ratios. They combined subjective questionnaires, including the Tinnitus Handicap Inventory, the Tinnitus Questionnaire, the State-Trait Anxiety Inventory, and a hyperacusis questionnaire, with objective measures such as electroencephalography, heart rate, skin conductance, and salivary stress hormones. The results were revealing. Tinnitus patients showed diminished speech comprehension in quiet environments and at moderate noise levels, a finding that aligns with the idea that tinnitus interferes with central auditory processing. Curiously, this deficit disappeared under high-noise conditions, hinting that environmental noise may actually mask the tinnitus percept and free up cognitive resources.

The stress data added another layer of complexity. Salivary alpha-amylase levels were elevated in all tinnitus patients regardless of their hearing status, pointing to an acute stress response triggered by noise exposure through activation of the sympathetic nervous system. Female participants reported more tinnitus perception and greater difficulty in moderate and high-noise environments than males, suggesting higher susceptibility and increased emotional distress. The researchers caution that social and cultural expectations may shape how individuals report their symptoms, with women potentially underreporting negative experiences or overstating positive ones to align with perceived norms. The intricate interplay between anxiety scores, questionnaire responses, salivary biomarkers, and heart rate across experimental phases underscores the need for multimodal, personalized, and gender-sensitive approaches to tinnitus assessment and management.

On the treatment front, two studies offered cautious optimism. He and colleagues conducted a meta-analysis of randomized controlled trials examining repetitive transcranial magnetic stimulation, a non-invasive technique that uses magnetic pulses to modulate neural activity. They found that rTMS reduced tinnitus loudness immediately after treatment and for up to one month, as measured by the Tinnitus Handicap Inventory and Visual Analog Scale. However, the benefit faded gradually, becoming uncertain by six months. The authors conclude that the duration and frequency of rTMS protocols need refinement to achieve more lasting relief, a finding that tempers enthusiasm while pointing the way toward optimized treatment schedules.

Music therapy emerged as another promising avenue. Ni and colleagues studied 515 chronic tinnitus patients using extended high-frequency audiometry, psychophysical assessment of tinnitus frequency and intensity, and standardized questionnaires. Participants first underwent a short-course acoustic test involving a 15-minute session of Tinnitus Multielement Integration Sound Therapy, a blend of narrowband noise, music, and natural environment sounds designed to mask the tinnitus. Based on immediate changes in their tinnitus loudness ratings, patients were sorted into three groups: those whose tinnitus disappeared, those who experienced noticeable relief, and those who felt no change. Using an artificial intelligence application called Tinnitus Assistant, the team then generated personalized sound profiles for each patient, with the music edited to be 180 degrees out of phase with the patient’s tinnitus frequency, a technique intended to reduce cortical perception of the phantom sound. Patients listened for more than two hours daily over ten months. The treatment efficacy rate was highest in the group whose tinnitus had initially disappeared during the acoustic test, suggesting that customized music therapy can be effective for chronic subjective tinnitus and may serve as a valuable clinical guide.

Looking ahead, the editors of the research topic emphasize that the future of tinnitus care lies in customization. They call for greater attention to sex-based differences in brain perfusion and neural network organization, deeper investigation into the connection between tinnitus and cognition using advanced imaging, and more research into the comorbidity between tinnitus and functional impairment in the central nervous system. The message is clear: tinnitus is not a single disorder with a single cause or cure. It is a constellation of experiences shaped by biology, psychology, and environment. By understanding the unique neural signatures and cognitive burdens of each patient, whether influenced by sex, stress response, or physiological reaction to sound, clinicians can move away from standardized solutions and toward truly personalized medicine. The relationships between tinnitus and auditory processing are undeniably complex, but through this integrated body of research, the threads are finally beginning to untangle.

Subject of Research: Neuroscience research on tinnitus and auditory processing

Article Title: Editorial: Tinnitus in relation to auditory processing: unravelling complex relationships

Article References: Gabr, T., Prabhu, P., & Haider, H. (2026). Editorial: Tinnitus in relation to auditory processing: unravelling complex relationships. Frontiers in Neuroscience, 20, 1814945. https://doi.org/10.3389/fnins.2026.1814945

Image Credits: AI Generated

DOI: 10.3389/fnins.2026.1814945

Keywords: tinnitus, auditory processing, Zwicker tone, arterial spin labeling, cerebral blood flow, transcranial magnetic stimulation, music therapy, listening effort, stress hormones, sex differences, neuroimaging, phantom perception

The turning point, as Sunwoo has described it, came from seeing neuromodulation in action. Deep brain stimulation, in which implanted electrodes deliver carefully timed electrical pulses to targeted nuclei such as the subthalamic region, can dramatically reduce the tremors, rigidity, and motor fluctuations that define advanced Parkinson’s disease. For a young student watching patients regain control of their own bodies, the implication was electrifying: if electricity delivered to a precise brain target could restore function, then perhaps the circuitry of the brain itself could be mapped, understood, and ultimately reconstructed. It was a question that would define the first major decision of his scientific life.

That decision was to switch majors and pursue a doctorate in biomedical engineering, training at Cornell University and then the University of Southern California. His doctoral work concentrated on noninvasive physiologic monitoring, brain oxygenation, and the autonomic nervous system, with a strong emphasis on studies involving actual patients rather than isolated laboratory models. This clinical orientation would prove decisive. Working with human subjects teaches a particular kind of humility, Sunwoo has noted, because the brain in all its complexity resists the tidy reverse-engineering fantasy that first drew him to neuroscience. Understanding even a small slice of neural function, he realized, demands starting from the foundational elements — the measurable physiological signals that reveal how the body, and the brain within it, is actually behaving.

So instead of abandoning the dream, Sunwoo scaled it down and grounded it. Noninvasive physiologic monitoring became his new mission, and the brain remained very much at its center. After completing his PhD, he joined the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital, one of the world’s leading facilities for advanced imaging and optical monitoring of human physiology. There he trained in diffuse correlation spectroscopy, a technique that has quietly become one of the most promising tools for measuring cerebral blood flow without needles, radiation, or surgery.

Diffuse correlation spectroscopy, or DCS, belongs to the broader family of near-infrared spectroscopy methods, but it does something distinct. Near-infrared light, at wavelengths between roughly 650 and 900 nanometers, penetrates several centimeters through scalp, skull, and other tissue. Conventional near-infrared spectroscopy measures changes in the absorption of that light to estimate the balance of oxygenated and deoxygenated hemoglobin — in other words, oxygenation. DCS goes a step further by exploiting a quantum optical phenomenon: when coherent laser light scatters off moving red blood cells, the reflected light fluctuates in a pattern that encodes the speed of those cells. By analyzing these intensity fluctuations with a correlation algorithm, researchers can derive an index of blood flow in the microvasculature beneath the sensor. The result is a continuous, bedside measurement of perfusion in tissue that would otherwise require CT perfusion scans, MRI, or invasive probes to assess.

For Sunwoo, the appeal of this technology found its natural application in one of medicine’s most vulnerable populations: preterm infants in the neonatal intensive care unit. These patients are non-verbal, their physiology is extraordinarily labile, and their brains are in a period of explosive development that makes them exquisitely sensitive to disturbances in blood flow and oxygen delivery. Continuous monitoring is not a luxury in this setting; it is a clinical necessity. Yet standard NICU monitoring focuses heavily on heart rate, oxygen saturation, and blood pressure — systemic signals that may not reflect what is actually happening inside the cerebral circulation. A bedside optical sensor that tracks cerebral blood flow directly offers a way to close that gap, and Sunwoo’s work at the Martinos Center placed him at the intersection of optical engineering and neonatal critical care.

His published research illustrates the promise concretely. In a 2022 study in Scientific Reports, Sunwoo and colleagues applied DCS blood flow monitoring to extremely low gestational age newborns, examining how cerebral perfusion patterns relate to the vulnerability of these infants to intraventricular hemorrhage. Intraventricular hemorrhage, bleeding into the brain’s ventricular system, remains one of the most feared complications of extreme prematurity, and its onset has long been linked to unstable fluctuations in cerebral blood flow. By measuring flow continuously at the bedside, the study sought to identify which infants are most at risk and when that risk peaks — information that could eventually guide interventions to stabilize perfusion before injury occurs.

More recently, Sunwoo has turned his attention to another dimension of neonatal brain protection: the autonomic nervous system. In a 2026 study published in Pediatric Research, he and his collaborators assessed parasympathetic tone in infants undergoing therapeutic hypothermia for brain injury following neonatal encephalopathy. Therapeutic hypothermia, the deliberate cooling of the body to around 33.5 degrees Celsius, is the standard of care for infants with hypoxic-ischemic encephalopathy, a condition in which oxygen deprivation around the time of birth damages the brain. Cooling slows the cascade of metabolic injury, but it also profoundly alters autonomic regulation, including the vagal control of heart rate. By quantifying parasympathetic tone during cooling and rewarming, the research aims to understand how the autonomic nervous system responds to this therapy and whether those responses carry prognostic information about which infants will recover and which will sustain lasting damage.

Today, as a faculty member in Pediatrics at Harvard Medical School and an investigator at Mass General Brigham for Children, Sunwoo’s laboratory focuses on using physiologic signals to better understand and protect infants at risk of brain injury. His work is supported by the National Institutes of Health, including grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke, along with funding from the Harvard Medical School Office for Faculty Affairs. The trajectory that began with a dream of reverse-engineering the brain has matured into something arguably more achievable and more immediately humane: reading the physiological signals of patients who cannot report their own symptoms, and translating those signals into clinical protection.

There is a broader lesson in this career arc that resonates well beyond one researcher’s story. Big scientific dreams rarely survive first contact with the brain’s staggering complexity in their original form, but they can be redirected into productive channels. The student who wanted to rebuild the brain became the scientist who measures its blood flow, one photon at a time, in infants weighing less than a kilogram. The humility that Sunwoo describes — learning firsthand what it takes to understand the brain — did not extinguish the original ambition. It refined it, grounding a grand vision in the quiet, continuous work of monitoring, measuring, and protecting the most fragile patients in medicine. In neonatal intensive care, where every bit of continuous monitoring matters, that grounded vision may ultimately prove as transformative as the dream that started it all.

Subject of Research: Noninvasive optical monitoring of cerebral blood flow and autonomic function in newborns at risk of brain injury

Article Title: ECI biocommentary: John Sunwoo

Article References: Sunwoo, J. (2026). ECI biocommentary: John Sunwoo. Pediatric Research. https://doi.org/10.1038/s41390-026-05426-1

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05426-1

Keywords: diffuse correlation spectroscopy, near-infrared spectroscopy, cerebral blood flow, neonatal intensive care, preterm infants, intraventricular hemorrhage, therapeutic hypothermia, neonatal encephalopathy, autonomic nervous system, parasympathetic tone, brain injury, biomedical engineering

The study enrolled 52 volunteers aged 23 to 33 years, of whom four were excluded because of contraindications to MRI or dobutamine administration. From the remaining 48 eligible participants, only 21 ultimately completed all required acquisitions. The reason for the substantial drop-out is telling: 27 volunteers could not finish the second of the study’s two arterial spin labeling acquisitions because of discomfort during the prolonged dobutamine stress examination. Dobutamine, a synthetic catecholamine-like drug, is a mainstay of cardiac stress testing, but lying still inside a noisy MRI scanner while a drug pushes your heart rate and blood pressure upward is far from pleasant. The attrition underscores a practical reality of stress physiology research: the human body under pharmacological strain does not always cooperate with the demands of high-resolution imaging.

The technical heart of the study lies in a parameter known as the post-labeling delay, or PLD. In pseudo-continuous arterial spin labeling, or pCASL, blood water in the neck arteries is magnetically labeled, and after a waiting period, images are acquired. The labeled water has by then exchanged with tissue water, and the resulting signal difference can be converted into an estimate of cerebral blood flow in milliliters per 100 grams of tissue per minute. The choice of PLD is critical. If the delay is too short, the labeled blood may not yet have reached the imaging slices, particularly in regions with long arterial transit times, leading to underestimated flow. If it is too long, the label decays away. The researchers used two sequential single-PLD three-dimensional pCASL acquisitions at delays of 1500 milliseconds and 2500 milliseconds, always in the same fixed order, at 3.0 Tesla during both rest and dobutamine stress.

Dobutamine did exactly what it was expected to do to the body. The infusion significantly increased heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, and respiratory rate, while oxygen saturation remained stable. This constellation of changes defines the hyperdynamic state the investigators sought to create, one in which cardiac output rises and the entire circulatory system operates under heightened drive. The question was whether the brain, which is famously protected by cerebral autoregulation, a mechanism that keeps perfusion remarkably constant across swings in systemic blood pressure, would show measurable changes in its blood flow estimates at all, and if so, where and under which imaging timing.

The answer, at the shorter delay, was essentially no. At PLD equal to 1500 milliseconds, none of the twelve region-of-interest comparisons between rest and stress reached even the nominal unadjusted threshold of P less than 0.05. In other words, when the labeled blood was sampled relatively soon after labeling, the ASL-derived cerebral blood flow estimates looked statistically indistinguishable between the resting and hyperdynamic states across the whole brain, tissue masks, lobes, and vascular territories. This is consistent with the classical view of cerebral autoregulation holding the line, but it may also reflect the physics of the measurement itself, since a shorter delay is more vulnerable to errors when arterial transit times change, as they plausibly do when cardiac output and blood pressure surge.

At the longer delay of 2500 milliseconds, a different picture emerged. Nominal unadjusted increases in ASL-derived cerebral blood flow estimates were observed in three regions: the temporal lobe, the territory supplied by the posterior cerebral artery, and the vertebrobasilar territory, which encompasses the posterior circulation fed by the vertebral and basilar arteries. Only the temporal lobe showed a nominal condition-by-PLD interaction, meaning its response differed between the two delays, while the posterior cerebral artery and vertebrobasilar territories did not reach that level of interaction. The authors were careful to frame these as exploratory observations, noting that the fixed sequential acquisition order and the absence of statistical correction for multiple comparisons mean these regional patterns cannot be taken as established evidence of tissue-specific or delay-dependent responses.

Beyond the regional maps, the team explored whether the change in whole-brain cerebral blood flow, expressed as delta CBF, correlated with the physiological shifts induced by dobutamine. At the 1500-millisecond delay, delta CBF showed a nominal correlation with the change in heart rate. At 2500 milliseconds, nominal correlations appeared with both heart-rate change and diastolic-pressure change. These relationships hint at a coupling between the magnitude of the cardiovascular challenge and the perfusion signal captured by ASL, but the authors emphasize that such exploratory correlations require confirmation with properly powered, counterbalanced designs before any physiological interpretation can be considered firm.

The methodological caveats deserve attention because they shape what the study can and cannot claim. The tissue-mask cerebral blood flow values were derived without individual structural segmentation or partial-volume correction and were treated as purely descriptive. The two PLD acquisitions were always performed in the same order, so any systematic drift in physiology, drug effect, or scanner stability over time is confounded with the delay itself. The authors explicitly state that the findings do not establish PLD-dependent or tissue-specific responses, nor the superiority of a longer post-labeling delay. What the study does establish is a feasible, if demanding, protocol for acquiring ASL data during pharmacological stress, along with a set of hypothesis-generating observations about posterior circulation and temporal lobe perfusion under hyperdynamic conditions.

Why does this matter beyond the laboratory? Arterial spin labeling is increasingly used to study cerebrovascular reactivity, the brain’s capacity to adjust its blood supply, which is relevant to conditions ranging from hypertension and diabetes to dementia and, intriguingly, spaceflight. The study was supported in part by the Space Medical Experiment Project of China’s Manned Space Program, reflecting a growing interest in how the cardiovascular and cerebrovascular systems behave under altered physiological loads. A validated non-contrast method for probing brain perfusion during cardiovascular stress could eventually complement established tools such as blood-oxygenation-level-dependent cerebrovascular reactivity mapping, transcranial Doppler ultrasound, and dynamic susceptibility contrast MRI, each of which has its own limitations in stress settings.

The authors call for further studies using counterbalanced multi-PLD imaging, direct assessment of arterial transit time, and synchronized physiological monitoring to clarify how much of the observed change reflects true perfusion shifts versus sampling timing artifacts. Until then, the study stands as a careful, honest first step: a demonstration that ASL can be attempted during dobutamine stress in humans, that the brain’s perfusion estimates largely hold steady under autoregulation at shorter sampling delays, and that longer delays may reveal regional changes in the posterior circulation that merit rigorous follow-up. For a field where the brain and the heart are usually studied separately, work that watches them interact in real time, inside the magnet, points toward a more integrated physiology of the circulation under stress.

Subject of Research: ASL-derived cerebral blood flow measurement during dobutamine stress in healthy adults

Article Title: ASL-derived cerebral blood flow estimates during dobutamine stress in healthy subjects: an exploratory study using two sequential single-PLD acquisitions

Article References: Zhang, T., Cheng, X., Cai, L., Zhang, S., Niu, H., Yang, Z., Wang, Z., Ren, P., & Liu, Y. (2026). ASL-derived cerebral blood flow estimates during dobutamine stress in healthy subjects: an exploratory study using two sequential single-PLD acquisitions. BMC Medical Imaging. https://doi.org/10.1186/s12880-026-02898-9

Image Credits: AI Generated

DOI: 10.1186/s12880-026-02898-9

Keywords: arterial spin labeling, cerebral blood flow, dobutamine stress, post-labeling delay, pCASL, cerebral autoregulation, hyperdynamic circulation, posterior circulation, MRI, arterial transit time, cerebrovascular reactivity, BMC Medical Imaging

The enzyme at the center of the story, soluble epoxide hydrolase, or sEH, has been attracting growing attention from geneticists and vascular biologists alike. Genome-wide association studies have linked variants in the gene encoding sEH to Alzheimer’s disease and related dementias, and the enzyme is expressed widely throughout the central nervous system, in neurons, endothelial cells, vascular smooth muscle cells, astrocytes, and microglia. Its biochemical role is deceptively simple: it rapidly converts epoxy fatty acids, including the anti-inflammatory and vasodilatory epoxyeicosatrienoic acids produced by cytochrome P450 enzymes, into far less active dihydroxyeicosatrienoic acids. When sEH levels rise, the brain loses access to these protective lipid mediators precisely when it needs them most. The researchers found that sEH protein expression was significantly elevated in the brains of elderly diabetic rats, reaching roughly 1.6-fold the levels seen in age-matched controls, and that nine weeks of chronic TPPU treatment brought those levels back down to a range indistinguishable from healthy animals.

The behavioral consequences of this intervention were striking. In the novel object recognition test, which probes long-term non-spatial memory dependent on both cortical and hippocampal networks, untreated diabetic rats performed poorly, with a recognition index of just 0.34 compared with 0.61 in healthy controls, and a negative discrimination index indicating they actually preferred familiar objects over new ones. Chronic TPPU treatment lifted the recognition index to 0.53 and pushed the discrimination index back into positive territory, indicating a genuine restoration of memory rather than a marginal improvement. Notably, the drug did not rescue the animals’ locomotor deficits, as measured in the open field test, which the authors interpret as evidence that the cognitive gains reflect true neural protection rather than simply more movement or exploration. Intriguingly, treated animals did venture more frequently into the center of the open arena, a sign of reduced anxiety-like behavior that aligns with the drug’s anti-inflammatory effects on frontal cortical and amygdala circuitry.

To understand how an enzyme inhibitor could produce such broad cognitive benefits, the team turned to the cerebral vasculature, where the earliest damage in both Alzheimer’s disease and diabetes-related dementia is thought to occur. Using ex vivo pressure myography, they isolated middle cerebral arteries and penetrating arterioles from the rats and measured their ability to constrict in response to pressure, the myogenic response that underpins cerebral blood flow autoregulation. Diabetic vessels showed a characteristic pattern of dysfunction: elevated basal tone at low pressures but an inability to sustain constriction at high pressures, with autoregulatory breakthrough occurring around 120 mmHg instead of the normal 140 to 150 mmHg. TPPU treatment stabilized the myogenic response across the entire pressure spectrum, preventing the forced dilation that transmits dangerous pressure surges to the fragile microcirculation. Laser speckle contrast imaging in living animals confirmed the functional significance of these findings, showing that treated diabetic rats maintained stable cortical perfusion profiles even at elevated systemic pressures, while untreated animals displayed hot spots of hyperperfusion that signal vascular stress.

Perhaps the most dramatic vascular rescue involved neurovascular coupling, the elegant mechanism by which active neurons recruit local increases in blood flow. When the researchers mechanically deflected the rats’ whiskers at 10 hertz, control animals responded with a robust 31 percent increase in cortical blood flow within the somatosensory cortex. In untreated diabetic rats, this response was nearly abolished, reaching only about 6 percent. After chronic TPPU treatment, the hyperemic response rebounded to 30 percent, statistically indistinguishable from healthy controls. The team traced this rescue, at least in part, to the inward-rectifier potassium channel Kir2.1, which sits on capillary endothelial cells and conducts retrograde electrical signals from active brain tissue back to upstream arterioles. In isolated pressurized capillary-arteriole preparations, local application of potassium chloride to capillary terminals normally dilates the feeding arteriole by about 23 percent, but the response was halved in diabetic vessels. Immunohistochemistry revealed that TPPU significantly increased the coverage of Kir2.1 channels along the capillary basement membrane, providing a concrete molecular mechanism for the restored electrical signaling.

The protective effects extended deep into the architecture of the blood-brain barrier itself. Western blot analysis showed that the tight junction proteins zonula occludens-1 and occludin, which seal the gaps between endothelial cells and prevent leakage of blood-borne toxins into brain tissue, were reduced to roughly half of normal levels in the diabetic brain. Chronic TPPU treatment restored both proteins to near-control levels. Equally important, the drug counteracted capillary rarefaction, the wholesale loss of microvessels that starves brain tissue of oxygen and nutrients. Quantitative analysis of lectin-stained tissue revealed that capillary density in the hippocampal CA1, CA3, and dentate gyrus subfields, as well as in the cortex, had fallen by roughly half in untreated diabetic rats, and that TPPU treatment restored density to values matching or even exceeding those of healthy controls across all four regions.

Downstream of the vascular rescue, the researchers documented a profound calming of the brain’s inflammatory environment. The hippocampus of untreated diabetic rats was riddled with activated astrocytes and microglia, the resident immune cells whose chronic reactivity is a hallmark of neurodegenerative disease. Activated astrocyte counts in the CA1 region, for example, soared from about 4 per field in controls to nearly 31 in diabetic animals, and activated microglia climbed from fewer than 2 to more than 12. TPPU treatment cut both counts substantially, though not entirely to baseline, and correspondingly reduced hippocampal levels of the astrocytic marker GFAP and the microglial marker Iba1. Multiplex ELISA profiling added a revealing nuance: while classical proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1beta remained unchanged, the chemokines MCP-1, RANTES, and MIP-1alpha, which recruit and activate glial cells, were significantly elevated in diabetic hippocampus and normalized by TPPU. The authors suggest this chemokine-selective effect reflects the ability of stabilized epoxy fatty acids to block nuclear factor-kappa B signaling in endothelial cells, silencing the focal chemoattractant signals that drive glial recruitment without altering systemic immune status.

The cellular payoff of all this vascular and inflammatory protection was visible in the neurons themselves. Untreated diabetic rats lost significant numbers of neurons in the hippocampal CA1 and CA3 subfields, regions critically vulnerable to metabolic and hypoxic injury, and showed marked downregulation of the postsynaptic scaffold protein PSD95 and the presynaptic marker synaptophysin, twin indicators of eroding synaptic integrity. Chronic TPPU treatment preserved neuronal survival in both subfields and restored expression of both synaptic proteins to near-control levels. The authors argue that this cascade, from stabilized autoregulation to preserved tight junctions to reduced gliosis to intact synapses, represents a coherent mechanistic chain linking vascular health to cognitive function, and that intervening at the vascular level may be the most effective way to protect the diabetic brain before irreversible neurodegeneration takes hold.

Important caveats remain before this science can translate to the clinic. The study was conducted exclusively in male rats, even though Alzheimer’s disease and diabetes-related dementia disproportionately affect women, and sex differences in sEH expression and oxylipin metabolism are well documented. The authors also note that neurovascular coupling depends on multiple mediators beyond Kir2.1, including nitric oxide, prostaglandins, and epoxyeicosatrienoic acids themselves, so the full mechanism of TPPU’s benefit likely involves several converging pathways. Questions about long-term safety, oxylipin profiles, and whether the drug enhances glymphatic clearance of amyloid and tau in the diabetic brain remain open. Still, with more than 830 million adults worldwide living with diabetes and no approved therapy to slow the cognitive decline it accelerates, the demonstration that a brain-penetrant sEH inhibitor can preserve memory, perfusion, and neurons despite persistent hyperglycemia marks a compelling proof of concept. Human clinical trials of sEH inhibitors are already underway for other indications, and this work provides a strong rationale for extending them to the growing population at risk of diabetes-related dementia.

Subject of Research: Soluble epoxide hydrolase inhibition as a therapy for cerebrovascular dysfunction and cognitive decline in diabetes-related dementia

Article Title: Inhibition of soluble epoxide hydrolase rescues cognitive deficits by preserving neurovascular integrity and attenuating glial and neuropathology in diabetic-related dementia

Article References: Fang, X., Border, J. J., Zhang, H., Morgan, G. C., Gregory, A., Hanscom-Trofy, Y., Dong, R., Yang, J., Hwang, S. H., Morisseau, C., Hammock, B. D., Fan, F., & Roman, R. J. (2026). Inhibition of soluble epoxide hydrolase rescues cognitive deficits by preserving neurovascular integrity and attenuating glial and neuropathology in diabetic-related dementia. GeroScience. https://doi.org/10.1007/s11357-026-02591-3

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02591-3

Keywords: soluble epoxide hydrolase, TPPU, diabetes-related dementia, neurovascular coupling, blood-brain barrier, Kir2.1, capillary rarefaction, neuroinflammation, hippocampus, cerebral blood flow, Alzheimer's disease, GeroScience

The measurement at the heart of the study is called the oxygen extraction fraction, or OEF. In simple terms, OEF is the proportion of oxygen carried by the blood that is actually captured by tissue to keep cells functioning. In healthy brains, this value is remarkably stable across gray and white matter and varies little from person to person, which makes deviations potentially meaningful. When cerebral blood flow drops, the brain typically compensates by extracting a larger fraction of the oxygen that does arrive, a relationship governed by basic physiology and Fick’s principle, which links oxygen consumption to the product of blood flow and extraction. A rising OEF can therefore be read as a warning light on the dashboard: the plumbing may be struggling even if total energy use, measured as the cerebral metabolic rate of oxygen, has not yet declined.

What makes this study technically notable is that the team measured OEF without contrast agents or radiation, using quantitative susceptibility mapping, an MRI method that converts tiny magnetic field disturbances caused by deoxygenated hemoglobin into quantitative maps of venous oxygenation. The researchers acquired multiecho gradient-recalled echo images on a 3 Tesla Siemens Prisma scanner, unwrapped the phase data with an open-source algorithm, removed background field contributions, and inverted the local field maps into susceptibility values using a morphology-enabled dipole inversion approach. Cerebrospinal fluid in the ventricles served as a zero reference, and a deep learning model based on an attention-gated 3D U-Net segmented cortical veins automatically, achieving a Dice coefficient of about 0.79 in held-out testing. Partial volume effects were corrected with an orientation-aware cylindrical fitting method, and subject-specific hematocrit values from blood draws were plugged into the biophysical equation linking susceptibility to oxygen saturation.

The study enrolled 32 participants aged 55 to 85, split into 14 older adults with type 2 diabetes and obesity and 18 age- and sex-matched controls. The diabetes group had a body mass index between 30 and 45 kilograms per square meter and hemoglobin A1c values between 6.0 and 10 percent, while controls had normal-range BMI and HbA1c below 5.7 percent. Anyone with prior stroke, major neurological or psychiatric illness, heart disease, or uncontrolled hypertension was excluded, and the two groups were statistically indistinguishable in age, sex, and education. On average, the participants with diabetes had been diagnosed about 5.7 years earlier and were, by clinical standards, fairly well controlled, with a mean HbA1c of 6.7 percent. Their insulin resistance, however, measured by the HOMA-IR index, was markedly elevated at 5.6 compared with 2.2 in controls, well above a commonly cited metabolic syndrome threshold.

The headline result was striking in its consistency. Whole-brain OEF averaged 29.5 percent in the diabetes and obesity group versus 27.3 percent in controls, a relative increase of about 8 percent that survived statistical correction for multiple comparisons. Every lobar region examined, including the frontal, temporal, parietal, occipital, and insular cortices, showed the same elevation. The largest gap appeared in the occipital lobe, where OEF reached 37.0 percent in the metabolic group against 33.3 percent in controls, an 11 percent relative difference. Crucially, cerebral blood flow measured with arterial spin labeling was mostly similar between groups, and the cerebral metabolic rate of oxygen, calculated by combining flow and extraction, did not differ in any region. That combination, higher extraction with preserved consumption, is exactly the signature expected when the brain is compensating for vascular stress rather than suffering outright metabolic failure.

The cognitive testing added a sobering dimension. Although all scores fell within clinically normal ranges, the diabetes and obesity group performed significantly worse on the Repeatable Battery for the Assessment of Neuropsychological Status, with lower scores in list learning, coding, attention, and the global cognition index. They also scored markedly lower on the Color-Word Switching condition of the Delis-Kaplan Executive Function System, a demanding test of inhibitory control and mental flexibility, where the difference was the largest observed. Depression scores on the Geriatric Depression Scale were equivalent between groups, arguing against mood as a confound. The pattern, spanning attention, processing speed, and executive function rather than a single domain, overlaps with what clinicians see in early vascular cognitive impairment, the spectrum of thinking difficulties caused by compromised brain blood supply.

Even more intriguing were the correlations between brain physiology and behavior. Across all participants, higher regional OEF was consistently associated with poorer cognitive performance, with the strongest relationships appearing in the temporal lobe, where OEF correlated at minus 0.62 with executive switching performance, and minus 0.41 with attention. The direction was uniformly negative across every region tested. On the metabolic side, whole-brain OEF rose with blood leptin levels, a hormone produced by fat tissue that is elevated in obesity and linked to adipose dysfunction and neuroinflammation, and fell with higher HDL cholesterol, the lipoprotein widely regarded as cardioprotective. HbA1c and fasting insulin showed positive trends that approached significance. These associations are exploratory and were not corrected for multiple comparisons, so the authors are careful to frame them as hypothesis-generating rather than definitive.

The interpretation favored by the researchers is that elevated OEF represents an early compensatory response to metabolic and vascular stress, a kind of cerebral overdrive that precedes measurable declines in resting brain metabolism. This fits with prior work showing that OEF is elevated in people with heavy vascular risk burdens, particularly those with cognitive impairment, and with evidence that the occipital lobe is a common site of reduced perfusion in type 2 diabetes. It also echoes findings in other conditions, from asymptomatic carotid artery disease to sickle cell anemia and obstructive sleep apnea, where altered oxygen extraction tracks with cognitive difficulty. If confirmed, OEF could serve as a sensitive, quantitative, and entirely noninvasive marker of cerebrovascular vulnerability, potentially distinguishing vascular contributions to dementia risk from purely neurodegenerative ones, something that visually rated markers like white matter hyperintensities cannot do with the same objectivity.

The caveats are real and the authors state them plainly. This was a small, single-center, cross-sectional pilot study, so it cannot establish causation, cannot disentangle the independent effects of diabetes from those of obesity, and cannot rule out that differences in medication use, including higher rates of antihypertensive treatment in the metabolic group, contributed to the imaging findings. The exploratory statistical analyses carry an elevated risk of false positives. What the study does establish is a plausible and testable physiological link: older adults with type 2 diabetes and obesity show diffusely elevated cerebral oxygen extraction, and that elevation tracks with both adverse metabolic markers and weaker attention and executive performance. The next step, the researchers say, is larger longitudinal cohorts that follow OEF, blood flow, and cognition over time to determine whether this compensatory signature predicts who will decline, and whether interventions that improve metabolic health can normalize the brain’s oxygen economy before damage becomes permanent.

Subject of Research: Cerebral oxygen extraction fraction measured by quantitative susceptibility mapping in older adults with type 2 diabetes and obesity and its associations with cognition and metabolic markers

Article Title: Regional oxygen extraction fraction is higher in older adults with type 2 diabetes and obesity: associations with cognition and metabolic markers

Article References: Elsharydah, M. N., Al-Khoury, Y., Ragunatha Rao, S., Schaffert, J., Saha, A., Kaufman, J., Rezaei, A., Leary, J., Jin, A., Almandoz, J. P., Gauthier, C. J., & Thomas, B. P. (2026). Regional oxygen extraction fraction is higher in older adults with type 2 diabetes and obesity: associations with cognition and metabolic markers. GeroScience. https://doi.org/10.1007/s11357-026-02590-4

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02590-4

Keywords: type 2 diabetes, obesity, oxygen extraction fraction, quantitative susceptibility mapping, cerebral blood flow, cognitive impairment, dementia risk, GeroScience, MRI biomarker, insulin resistance, leptin, vascular cognitive impairment

The central molecular player is the serotonin 2A receptor, or 5-HT2AR, long suspected to be the key gateway to psychedelic experience. To visualize it, the researchers used the radioligand [11C]Cimbi-36, a PET tracer that binds to the same receptor. Seven healthy volunteers, blinded to the dose of LSD they received, underwent baseline PET-MRI scans and then returned for scans after oral doses of LSD ranging from 25 to 200 micrograms. By comparing tracer binding before and after the drug, the team could calculate receptor occupancy — the fraction of 5-HT2AR sites actually commandeered by LSD at each dose. This dose-occupancy relationship, now established in humans for the first time for LSD, gives clinical developers a quantitative anchor for choosing doses in therapeutic trials.

The hemodynamic findings were equally striking. LSD increased global cerebral blood flow, measured with pseudo-continuous arterial spin labeling, and also increased flow through the internal carotid arteries, the main pipelines supplying the brain, measured with phase-contrast mapping MRI. The two measures tracked each other closely across participants: changes in global cerebral blood flow and changes in carotid artery flow showed a strong positive correlation, indicating that the drug’s effect on brain perfusion is driven, at least in part, by increased supply from the great vessels rather than by a purely local redistribution of flow within the brain. This matters because serotonin receptors are abundant on systemic blood vessels, and psychedelics have long been known to interact with the vascular system in complex ways.

Perhaps the most provocative result concerns functional connectivity. Using resting-state BOLD fMRI, the team computed a global measure of brain-wide correlation, often called GCOR, and found that LSD decreased it — a reduction in the overall synchrony of activity across the cortex. Intriguingly, this drop in global connectivity was negatively associated with the rise in cerebral blood flow: the more blood flow increased, the more global connectivity fell. The authors contrasted this with a separate cohort of 25 participants who received psilocybin, where the relationship ran in the opposite direction, with LSD and psilocybin producing opposing effects on global correlation. The finding suggests that although both drugs act primarily at the 5-HT2AR, they are not interchangeable pharmacologically, and that their distinct neurophysiological signatures may have been masked in earlier studies that relied on a single modality.

That distinction carries a methodological warning for the entire field. The BOLD signal that dominates human psychedelic neuroimaging is not a pure readout of neural activity; it entangles neural drive with blood flow, blood volume and oxygenation. If LSD raises cerebral blood flow globally while dampening global connectivity, then some of the connectivity changes reported in prior fMRI studies may reflect vascular confounds rather than altered neural communication. By measuring perfusion, arterial inflow and connectivity simultaneously in the same individuals, the Copenhagen team could begin to disentangle these threads — and their data suggest the entanglement is real and drug-specific, differing between LSD and psilocybin in ways that single-modality designs would miss entirely.

The pharmacokinetics added another layer of intrigue. When the researchers plotted subjective drug intensity against plasma LSD concentrations over time, they observed an anticlockwise hysteresis loop: subjective effects lagged behind and outlasted what plasma levels alone would predict. This temporal dissociation between drug concentration in the blood and the intensity of the experience points to atypical pharmacodynamic mechanisms — perhaps slow receptor kinetics, active metabolites, or downstream signaling cascades that persist after the parent compound has cleared. Notably, the team’s extended analyses showed that psilocybin, converted to psilocin in the body, did not display a comparable hysteresis pattern, with subjective intensity tracking plasma psilocin levels without a consistent temporal offset. The two psychedelics, it seems, operate on different clocks.

The road to these results was not smooth, and the study’s transparency about its difficulties is itself informative. Of 53 volunteers assessed for eligibility, 16 attended in-person screening and 12 were randomized, with 11 completing baseline assessment and receiving LSD. Only seven had complete peak-scan data included in the final analysis; two participants could not complete post-drug scans because of adverse effects, and two scans were lost to scanner failure. Psychedelic research of this intensity — hours inside a PET-MRI scanner at the peak of a drug experience — is logistically brutal, and the attrition underscores how rare and valuable complete multimodal datasets of this kind are. Two of the seven completers also returned for late-effect scans, offering a preliminary glimpse of how the drug’s cerebral effects evolve as the acute experience subsides.

Why does receptor occupancy matter so much for the clinical pipeline? Psychedelic-assisted therapies are advancing through late-stage trials for depression, anxiety and other conditions, yet dosing has remained largely empirical, guided by subjective intensity rather than by molecular target engagement. The new dose-occupancy curve allows researchers to connect the pharmacological dose, the fraction of receptors engaged, the cerebral blood flow response and the reported experience within a single quantitative framework. That framework can inform the design of safer trials, help interpret why different psychedelics produce different durations and qualities of effect, and support the development of compounds engineered to retain therapeutic benefit while minimizing cardiovascular and perceptual side effects.

The comparison with psilocybin also carries a broader scientific message: the class of drugs we call psychedelics is pharmacologically heterogeneous. LSD is an ergoline with a long duration of action and affinity for a wider panel of receptors, while psilocybin’s active metabolite is a tryptamine with a shorter, cleaner profile. The opposing effects on global connectivity observed here, together with the divergent hysteresis patterns and the distinct relationships between blood flow and connectivity, suggest that results from one compound cannot simply be generalized to the other. For a field racing toward regulatory approval, that nuance is not academic; it shapes expectations about which patients may benefit from which compound, and what physiological monitoring each requires.

What remains to be resolved is how these molecular and vascular effects translate into the therapeutic outcomes that matter. The study involved healthy volunteers at a range of doses, not patients, and its sample size — seven completers — is small by any standard, with some correlations reported without correction for multiple comparisons. The raw neuroimaging data have been deposited in the Cimbi database for qualified researchers, and the analysis code has been released publicly, inviting independent scrutiny and reanalysis. As psychedelic medicine matures, studies of this kind — direct, multimodal, and honest about their limitations — will be essential for converting a cultural renaissance into a rigorous clinical science, one receptor and one milliliter of blood at a time.

Subject of Research: In vivo PET-MRI measurement of LSD receptor occupancy, cerebral blood flow and brain connectivity in humans

Article Title: Investigating molecular and hemodynamic effects of LSD in the human brain

Article References: McCulloch, D. E.-W., Larsen, K., Johansen, A., Reveles Jensen, K. H., Nykjær, C. H., Holze, F., Falck, N., Neufeld, V., Steenstrup, E., Skov-Andersen, P., Spanggård, A., Geisler, M., Randrup, P. P., Jensen, P. S., Shalgunov, V., Johansen, S. S., Nielsen, M. K. K., Andersen, T. L., Stenbæk, D. S., … Knudsen, G. M. (2026). Investigating molecular and hemodynamic effects of LSD in the human brain. Nature Neuroscience. https://doi.org/10.1038/s41593-026-02462-2

Image Credits: AI Generated

DOI: 10.1038/s41593-026-02462-2

Keywords: LSD, psychedelics, serotonin 2A receptor, PET-MRI, cerebral blood flow, functional connectivity, psilocybin, receptor occupancy, pharmacokinetics, neuroimaging, 5-HT2AR, Nature Neuroscience

The study recruited 30 healthy, experienced breathwork practitioners who performed high-ventilation breathwork while lying inside a magnetic resonance imaging scanner. This design allowed the researchers to capture both physiological and subjective changes in real time, combining continuous measurement of cerebral blood flow with retrospective reports of the participants’ conscious experiences. Such a combination is rare in consciousness research, where altered states are often studied either through pharmacological manipulation with controlled substances or through meditation and sensory deprivation protocols that produce subtler shifts in awareness. Breathwork, by contrast, is legal, inexpensive, and free of the regulatory constraints that complicate psychedelic research, making it an attractive model system for scientists seeking to understand how consciousness can be systematically altered without drugs.

Participants reported experiencing strong altered states of consciousness during the scanning sessions. The dominant quality of these experiences was what the researchers describe as an oceanic state, a deep and pervasive feeling of connection to the universe and to other people. Many participants also reported altered perception, vivid mental imagery, a diminished or transformed sense of self, and a subjective sense of unity. When these reports were compared against established characterizations of psychedelic experiences, the researchers found that they resembled those produced by a moderate to high dose of LSD or psilocybin, although the breathwork-induced states involved less pronounced visual effects than are typically associated with classical psychedelics. This convergence between a breathing practice and a serotonergic drug state is one of the most intriguing aspects of the work, because the two interventions reach the brain through entirely different physiological pathways.

The imaging data revealed a substantial physiological effect. Global grey-matter cerebral blood flow fell by approximately 45 percent during the breathwork sessions, dropping on average from 16.24 to 9.81 milliliters per 100 grams of tissue per minute, a difference that was highly statistically significant across the 30 participants. This magnitude of reduction is remarkable for a voluntary behavioral intervention and reflects the intense hyperventilation that characterizes high-ventilation breathwork, which alters blood carbon dioxide levels and thereby constricts cerebral vessels. Yet the researchers emphasize that this dramatic reduction in blood supply does not by itself explain the intensity of the experiences participants reported. The brain, it appears, continues to function and to generate extraordinary states of consciousness even while its overall blood supply is sharply curtailed.

Instead, the key to understanding the altered states may lie in how the brain’s networks communicate with one another during the practice. The researchers found that participants who reported stronger and more profound altered states also showed greater changes in the default mode network, a set of interconnected brain regions involved in self-reflection, autobiographical thinking, and the construction of the sense of self. The default mode network has long been a focal point of psychedelic research, because drugs such as psilocybin and LSD are known to disrupt its normally synchronized activity, and the degree of this disruption correlates with experiences of ego dissolution. The new findings suggest that intensive breathing may converge on the same neural target through a fundamentally different mechanism, one driven by blood gas changes and vascular dynamics rather than by receptor pharmacology.

Lead researcher Dr Christian Schmitz of the Central Institute of Mental Health in Mannheim noted that although many practitioners of intensive breathwork report profound changes in perception and self-experience, the underlying brain mechanisms have remained poorly understood. According to Schmitz, the study indicates that these experiences are linked not only to marked changes in cerebral blood flow but also to alterations in how key brain networks communicate. This distinction matters because it reframes the question of how breathwork works. If reduced blood flow alone were responsible, one might expect any condition that lowers cerebral perfusion to produce similar states, which does not appear to be the case. The specificity of the network-level changes suggests that the pattern of reorganization, not the reduction in supply, carries the experiential signature.

Hana Adolphi, co-coordinator of the research, highlighted the practical implications of the work. Breathwork, she noted, is a legal, inexpensive, and non-pharmacological intervention that may provide a valuable tool for studying altered states of consciousness in laboratory settings. Understanding the mechanisms through which voluntary breathing patterns reshape brain communication could also inform future research into novel approaches for mental health treatment. This is a significant point given the current surge of interest in psychedelic-assisted therapies for depression, anxiety, and post-traumatic stress disorder. If breathwork can reliably induce states that overlap with those produced by psychedelics, and if those states can be harnessed therapeutically, an accessible and drug-free route to similar benefits may become available to a much broader population than psychedelic medicine can currently reach.

Independent commentators welcomed the study while cautioning that its conclusions remain preliminary. Dr Guy Fincham of Brighton and Sussex Medical School in the United Kingdom, who was not involved in the research, described the work as intriguing because it extends recent breathwork research suggesting that intensive breathing practices can yield altered states of consciousness that individuals describe in ways analogous to psychedelic compounds, and it does so under controlled brain-imaging conditions. He emphasized that such altered subjective experiences may be harnessed for the improvement of mental health, and that an accessible non-pharmacological route such as breathwork could prove invaluable for many people. At the same time, he pointed out that the study was uncontrolled and that its sample consisted entirely of experienced practitioners, so replication in breathwork-naive participants using a randomized controlled design will be needed to determine whether the findings translate more widely and produce genuine therapeutic benefit.

Professor David Nutt of Imperial College London, also commenting independently, framed the work in the context of the broader psychedelic research program. Breathwork, in his view, represents a non-pharmacological bridge to research into psychedelics, and studies that help clarify how it functions are a welcome addition to the field. The bridge metaphor captures an important scientific opportunity: because breathwork does not require controlled substances, special licensing, or supervised dosing of psychoactive drugs, it allows researchers to probe altered states of consciousness in settings that would otherwise be difficult to approve. Comparing the neural signatures of breathwork-induced states with those of psychedelic states could help isolate which aspects of network reorganization are essential to the therapeutic and experiential effects, and which are incidental to a particular method of induction.

The researchers themselves acknowledge the limitations of the current work. With 30 participants, all of them experienced practitioners, and no control condition, the study cannot yet establish whether the observed brain changes have clinical relevance or whether they would appear in people attempting intensive breathwork for the first time. Larger studies with controlled designs will be required to answer those questions. Nevertheless, the study marks a meaningful step forward in the science of consciousness. It demonstrates that a voluntary, drug-free behavioral practice can produce measurable reductions in cerebral blood flow alongside network-level reorganization that tracks with the intensity of subjective experience, and it points researchers toward a specific neural mechanism, altered communication within the default mode network, as the likely key to understanding how breathwork transforms the mind. For a field increasingly interested in non-pharmacological routes to altered states and mental health, the message is clear: the breath may be a more powerful instrument for probing and shaping consciousness than previously appreciated.

Subject of Research: Effects of intensive breathwork on cerebral blood flow, brain network communication, and altered states of consciousness

Article Title: Intensive breathing alters consciousness by changing brain communication

Article References: Intensive breathing alters consciousness by changing brain communication. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: breathwork, consciousness, default mode network, cerebral blood flow, psychedelics, MRI, altered states, mental health, ECNP Congress, neuroscience, non-pharmacological intervention, self-experience