Nature Neuroscience, Published online: 16 July 2026; doi:10.1038/s41593-026-02396-9
Author Correction: FUS-mediated regulation of acetylcholine receptor transcription at neuromuscular junctions is compromised in amyotrophic lateral sclerosis
Immunotherapy More Effective in Colorectal Tumors with Active DR5 Pathway
Response to cancer therapies is highly variable. While some cancers that have genomic defects, including microsatellite instability (MSI) and deficient DMA mismatch repair (dMMR) are understood to be more likely to activate the immune system, the mechanism underlying this response is still unclear.
Researchers from the Keck School of Medicine of USC have identified a genetic feedback loop in colorectal cancers that may explain one such mechanism. They recently published their work in Gastroenterology.
The team, led by Lin Zhang, PhD, professor and chair of oncology at the Keck School of Medicine, and Heinz-Josef Lenz, MD, associate director for clinical research at the USC Norris Comprehensive Cancer Center, focused on identifying the “role and mechanism of MSI-induced antitumor immunity and immunogenic cell death response.”
To do this, they used a combination of methods including createing a mouse model with transplanted tumor cells, immune cell assays and organoid data to elucidate the mechanism of action for the dMMR derived antitumor immune response.
Mice injected with tumor cells lacking a functional Mlh1, a gene that is involved with DNA repair, showed increased immune response that was tracked for cell signaling, behavior, and gene activity. Researchers identified Death Receptor 5 (DR5) and Ligase 3 (Lig3) as immune response mediators.
“We found that inactivating Mlh1 causes endoplasmic reticulum stress and Dr5–mediated apoptosis in syngeneic colorectal tumors,” the authors wrote. “Sustained immune response against Mlh1-deficient tumors requires nuclear Lig3–mediated release of extrachromosomal circular DNAs from apoptotic cells. A feedback Dr5/Lig3 amplification loop perpetuates apoptosis and immune cell activation in Mlh1-deficient syngeneic tumors.”
This continued immune response to dying tumor cells is critical for effective response to immune checkpoint inhibitor therapy, but it is not the complete story.
“We’ve gathered enough evidence to suggest that this feedback loop is an important piece of the puzzle,” said co-lead author Zhang. “Our hope is that these findings can someday help make cancers more visible to the immune system and more responsive to immunotherapy treatment.”
Validation of these results in humans is a necessary next step to get closer to the clinic. The team analyzed data from human patients, examining gene expression in colorectal cancers. They found that in patients with higher levels of DR5 and Lig3 activity, immune checkpoint inhibitor therapies were move effective at treating the cancer, and those patients were more likely to respond better to treatment.
“One of the most encouraging parts of the study was seeing that the same signals showed up in patient tumors,” Zhang said. “That suggests we’re uncovering a mechanism that could be clinically relevant.”
Moving forward, the team plans to explore the effectiveness of drugs that activate the DR5 pathway and investigate alternative methods for how to incorporate DR5 and Lig3 into personalized colorectal cancer therapies. They also note that, “Our results reveal a functional link between dMMR and antitumor immunity, which may be useful for improving immune checkpoint inhibitor therapy in tumors with different MMR statuses.”
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Sweet Caroline: BCIs That Restore Sensation of Touch Show Long-Term Safety
“Touching hands, reaching out, touching me, touching you.”
The lead up to the chorus of Neil Diamond’s “Sweet Caroline” has become a ritual in stadiums and bars across America, celebrating one of the most universal human experiences: reaching out to touch another person.
For people living with paralysis after a spinal cord injury, that experience often disappears. Damage to the spinal cord not only interrupts movement but also severs the flow of sensory information from much of the body, leaving many unable to feel touch below the site of their injury.
While brain-computer interfaces (BCIs) already restore a measure of independence by translating thoughts into movement, allowing people to control robotic limbs, computers, and other assistive devices, they have long lacked something fundamental: touch. Now researchers report the strongest evidence yet that restoring artificial touch can be done safely over the long term.
In a study published in Science Translational Medicine, scientists followed five people with cervical spinal cord injuries who received tiny electrical pulses directly to the brain’s somatosensory cortex for periods ranging from nearly three years to a decade. Across more than 173 million stimulation pulses delivered over a combined 27 years of implanted use, the researchers found no serious stimulation-related adverse events while consistently restoring sensations of touch to participants’ hands.
One participant in the study described the difference after researchers restored an artificial sense of touch by stimulating his brain.
Instead of merely watching a hand grasp another person’s hand, he said, it felt as though he were shaking it himself. “It’s the difference between ‘I told a robotic arm to shake your hand’ and ‘I am shaking your hand,’” Charles Greenspon, PhD, assistant professor of neurological surgery at the University of Chicago and the study’s lead author, told Inside Precision Medicine. “That degree of embodiment is completely impossible without sensory feedback because you just don’t believe it’s yours.”
Creating touch
That sense of ownership—of a prosthetic becoming part of the body—is one of the biggest remaining challenges in neurotechnology. Companies including Neuralink, Precision Neuroscience, and Paradromics have largely focused on reading signals from the brain. Today’s most advanced BCIs excel at reading neural activity, decoding a person’s intentions to move a robotic arm or computer cursor. But they are largely one-way systems, sending nothing back to the brain.
Without sensory feedback, users must rely almost entirely on vision, making movements slower, less natural, and more mentally demanding. Restoring sensation by writing information back into the nervous system has remained a much greater challenge—not because the concept is new, but because evidence that repeated brain stimulation is safe over many years has been limited.
Although involving only five participants, the study is the largest and longest safety evaluation of intracortical microstimulation in humans. The findings address a major obstacle to the next generation of BCIs: proving that the brain can safely receive artificial sensory information over many years. If confirmed in larger clinical trials, the work could accelerate the development of truly bidirectional BCIs that both decode a person’s intentions and restore the sensory feedback that makes movement feel natural.
The researchers’ approach bypasses the damaged spinal cord entirely. Participants received two tiny microelectrode arrays implanted in the region of the somatosensory cortex responsible for hand sensation. Brief electrical pulses delivered through individual electrodes produced sensations that participants perceived as coming from specific locations on their hands.
“Once that device is in, we deliver tiny electrical pulses to the brain directly, and that creates the sensations,” Greenspon said. “The brain cannot functionally tell the difference between something that occurs at your hand and travels up your arm to the brain or directly stimulates the brain.”
Built to last
The researchers also wanted to know whether the implants would continue working after years of repeated use. Like any implanted medical device, microelectrode arrays gradually degrade.
The results suggest repeated stimulation does not accelerate that process. Detection thresholds increased only gradually, and even after a decade, about 60% of the electrodes in one participant could still reliably evoke touch sensations, while about two-thirds remained functional throughout the study. Researchers also found no relationship between how heavily individual electrodes were used and how quickly they deteriorated. “No company is claiming that these implants last forever,” Greenspon said. “It’s the same as a knee replacement.”
The study’s primary goal was straightforward: determine whether years of repeated stimulation would trigger seizures, damage brain tissue, or accelerate deterioration of the implanted electrodes. Across 623 hours of stimulation, participants experienced no seizures and no serious adverse events related to the stimulation itself.
Researchers also found no evidence that the electrical pulses damaged participants’ remaining natural sensation. The only stimulation-related side effects consisted of 53 brief episodes of lingering tingling or buzzing after stimulation ended, most resolving within seconds. “It’s one of the few times where you want a null result,” Greenspon said. “We just wanted to say, ‘Look, we didn’t find anything bad.’”
That absence of problems may ultimately be the study’s most important finding, providing the evidence regulators and device developers need before sensory feedback can become a standard feature of future BCIs.
Closing the brain’s feedback loop
For people who may eventually rely on BCIs outside the laboratory, restoring touch could prove just as important as restoring movement. Without sensory feedback, every movement requires constant visual attention. Greenspon compares the experience to leaving the dentist after a local anesthetic: “You can speak perfectly… It’s because you don’t know where your tongue is.”
Artificial touch changes something more subtle as well. Rather than operating a machine, users begin to experience a prosthetic as part of themselves. Researchers believe that sense of embodiment could make future prosthetic limbs not only more dexterous but also less mentally exhausting to use.
The next major challenge is restoring proprioception—the internal sense that tells us where our limbs are without looking. Current sensory BCIs cannot reproduce that ability. Researchers also hope future systems will deliver richer sensory information, allowing users to distinguish whether an object is soft or hard, rough or smooth, or beginning to slip from their grasp.
The findings arrive as brain-computer interfaces transition from academic laboratories to commercial development. Before sensory neuroprostheses become routine treatments, researchers will still need to conduct larger clinical studies.
For decades, BCI research has focused on teaching machines to understand the brain. The next generation may depend just as much on teaching the brain to understand the machine. If that happens, the most important advance may not be giving people the ability to control a prosthetic hand. It may be giving them the feeling that the hand is their own.
That is what made the participant’s handshake remarkable. The breakthrough wasn’t that a hand closed around another person’s. It was that, for the first time, it felt like their own handshake.
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Parkinson’s Genetic Drivers Show Greater Variation Across Ancestries
Results from one of the largest and diverse genetic studies of Parkinson’s disease to date reveal that genetics may play a much greater role in the condition than previously recognized, especially in some ancestries that have historically been underrepresented in clinical studies. Published in The Lancet Neurology, the findings highlight the importance of representative genetic data for the development of targeted treatments that are effective across diverse populations.
Parkinson’s disease is a progressive neurodegenerative condition that affects more than 10 million people worldwide. While decades of research have uncovered key genetic drivers, most cases arise from a complex combination of genetic and environmental factors that can vary widely across populations and individuals.
“The genetic architecture of Parkinson’s disease varies considerably across ancestries, yet most previous genetic studies have focused on individuals of European ancestry,” write the authors of the study, led by Christine Klein, MD, professor of neurogenetics at the University of Lübeck. “This large-scale, multi-ancestry genetic study offers crucial insights into the population-specific genetic architecture of Parkinson’s disease.”
Klein’s team analyzed genome and exome sequencing data from nearly 100,000 individuals across 11 ancestries, using retrospective data from the Global Parkinson’s Genetic Program (GP2). In particular, the study focused on 18 genes with a well-established link to Parkinson’s disease, including both causal and risk variants.
While some genetic contributors were shared across ancestries, the analysis revealed that certain ancestry-specific differences are larger than previously thought. For instance, risk variants of GBA1, the most common across all ancestries, were present in just about 4% of individuals with east Asian ancestry, compared to nearly 53% of those with African ancestry.
The study also identified the first carriers of causal variants in the LRRK2 gene of African ancestries, highlighting the need to include underrepresented populations in large-scale genetic studies. Overall, 2% of Parkinson’s patients were found to carry a single causal genetic variant across 16 genes, ranging from 0.4% among individuals from African ancestry to 10.7% for those with Ashkenazi jew ancestry.
These findings have important implications for ongoing clinical trials evaluating targeted therapies aimed at Parkinson’s patients carrying GBA1 and LRRK2 variants. Without representative data accounting for the broad differences seen across ancestries, precision medicine approaches will fail to be effective for the global population.
Standard genetic screening panels are mainly built using data from individuals of European ancestry, meaning certain variants more common in other populations might end up being overlooked. If key genetic drivers go undetected, patients from underrepresented populations are generally more likely to be locked out of targeted clinical trials evaluating the next generation of Parkinson’s therapeutics.
“Whereas clinical trials targeting GBA1 and LRRK2 variant carriers are primarily performed in Europe and the U.S.A., increased ancestral diversity in Parkinson’s disease research will be crucial to improve diagnostic accuracy, enhance our understanding of disease mechanisms across populations, and ensure equitable application of and access to emerging genetically informed therapies,” Klein and colleagues conclude.
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See, Blind Mice: Consortium’s Drugs Restore Sight
A consortium led by scientists at the Institute for Bioengineering of Catalonia (IBEC) has developed a series of light-activated small molecule drugs that in preclinicial tests restored sight in blind mice. The team’s approach is based on photopharmacology, a technique for reversibly control drug activity using light.
The newly developed compounds, called prosthe6, mimic the function of light sensing photoreceptor cells, which degenerate in blinding diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP).
The prosthe6 compounds target ON-bipolar neurons and in tests were found to successfully restore saccadic eye movements (optokinetic reflex) in blinded zebrafish larvae, a widely used model for studying visual acuity. Even more strikingly, the researchers demonstrated recovery of innate light-avoidance behavior in mouse models of age-related macular degeneration and retinitis pigmentosa.
Test results suggest that the prosthe6 compounds may be administered by injecting them in the eye, or administered as eye drops. In animal studies the photoswitchable molecules also showed promising preliminary safety profiles, pointing to the development of potential drug candidates for restoring vision in patients with degenerative retinal diseases, without the need for genetic manipulation or implanted devices. Importantly, these compounds are designed to work under normal lighting conditions and do not require light-enhancing devices as optogenetics. They are small, water-soluble molecules that respond to ordinary visible or white light, such as indoor lighting or daylight, without requiring intense or specialized light sources.
“These molecules do not cure blindness, because they do not address the cause of photoreceptor degeneration,” said study co-lead Pau Gorostiza, PhD, ICREA Research Professor at IBEC, leader of the Nanoprobes and Nanoswitches group, member of CIBER-BBN. “But they are remarkably effective at restoring sight, and they do so using a very simple and potentially patient-friendly approach.”
Rosalba Sortino, former PhD student at the University de Barcelona, and currently post-doctoral researcher at Gorostiza’s group at IBEC, added, “Our goal was to restore vision using a molecular mechanism that is as close as possible to how the healthy retina works … Instead of bypassing retinal processing, we aimed to reactivate it right at the same level of the retinal circuit than the lost photoreceptor cells.”
Sortino is co-first author of the team’s published paper in Journal of the American Chemical Society, titled “Restoration of saccadic eye movements and visually guided behavior in ambient white light with photoswitchable small molecules.”
Diseases such as age-related macular degeneration and retinitis pigmentosa affect 200 million people worldwide and are the leading causes of visual impairment and blindness. Beyond the personal impact on quality of life and independence, vision loss places a global economic burden estimated at over US$400 billion per year in healthcare costs and lost productivity.
![Researchers Rosalba Sortino (left) and Joaquin Martinez Tambella (right) working in the laboratories of the Institute for Bioengineering of Catalonia (IBEC). Sortino is a post-doctoral researcher at the Nanoprobes and Nanoswitches group at IBEC and co-first author of the study. Martinez is a PhD student at the Nanoprobes and Nanoswitches group at IBEC and co-first author of the study. [Institute for Bioengineering of Catalonia (IBEC).]](https://www.genengnews.com/wp-content/uploads/2026/07/RSortino-JMartinez-300x223.jpeg)
In many of these conditions, photoreceptor (PhR) cells—the retina’s light detectors—progressively degenerate and die. Although the downstream retinal neuronal circuitry remains largely intact and functionally viable, it no longer receives the light signals needed to drive visual processing towards the brain. This opportunity has fueled intense research efforts to develop treatments capable of restoring light sensitivity to the eye. Current strategies include gene therapy—effective only for a very small subset of patients with specific mutations—and electronic retinal prostheses, which are invasive, expensive, and require extensive training for effective use.
More recently, optogenetics and light-responsive drugs have entered clinical testing, the latter with encouraging safety results. “Photopharmacology can develop photoswitchable small molecules to restore vision impairment by conferring light sensitivity to ion channels that are widely expressed in the remaining inner retinal neurons, and a first-in-human clinical trial is ongoing,” the team noted. However, achieving high-quality vision at ambient illumination levels remains a major challenge.
The (IBEC)-led consortium has now developed a new class of photoswitchable small-molecule drugs that are capable of restoring key visual functions in animal models of blindness. The team’s photopharmacology-based technique involves modifying a drug’s chemical structure by adding a light-activated molecular switch, enabling control of the pharmacological action using light. “Unlike (opto)genetic manipulation and surgically implanted retinal electronic prostheses, pharmacotherapy is noninvasive, readily reversible, and can be upgraded when new drugs are approved,” the authors noted. “Medicines are preferred by patients, clinicians, and public healthcare systems, they can be developed and manufactured at lower costs than other approaches and assessed by conventional regulatory procedures and clinical assays.”
The reported work builds on more than a decade of research and was carried out in collaboration with the team co-led by Pedro de la Villa at the University of Alcalá (UAH), as well as researchers from the Institut de Química Avançada de Catalunya (IQAC-CSIC), the University of Barcelona (UB), the Institute Ramón y Cajal of Health Research (IRYCIS), the Autonomous University of Barcelona (UAB), and the Fundació Eduard Soler.
![Researcher Joaquin Martinez Tambella working in the laboratories of the Institute for Bioengineering of Catalonia (IBEC). Martinez is a PhD student at the Nanoprobes and Nanoswitches group at IBEC and co-first author of the study. [Institute for Bioengineering of Catalonia (IBEC).]](https://www.genengnews.com/wp-content/uploads/2026/07/JMartinez-300x225.jpeg)
The prosthe6 compounds work by acting on a specific type of retinal cells called ON bipolar cells, which normally receive signals from the photoreceptors. “In healthy vision, ON bipolar cells play a key role in passing on information about the presence of light to the rest of the visual circuit,” explained study co-lead de la Villa. “In degenerative eye diseases, although the photoreceptors are lost, much of this underlying circuitry remains intact but inactive. This creates a major therapeutic opportunity.”
By targeting a protein (mGlu6) in this preserved part of the retina, prosthe6 compounds can take over the role of the missing photoreceptors. “… we have targeted metabotropic glutamate 6 (mGlu6) receptors, which are exclusively expressed in ON bipolar cells (OBCs) and localized postsynaptic to PhR cells, thereby leveraging a privileged position to drive physiological visual circuit,” the investigators explained. When light enters the eye, the molecules respond by changing their shape, triggering signals inside the retina in a way that closely resembles natural vision. In this way, the drugs effectively act as “molecular prostheses,” helping the eye process light again without the need for implants or genetic modifications.
Healthy mice naturally prefer to remain in dark environments and instinctively avoid brightly lit areas, a behavior that relies entirely on a functional visual system. Blind mice, by contrast, lose this preference and move indistinctly between light and dark spaces, as they are unable to perceive light. The team showed that after treatment with prosthe6, blind mice once again showed a clear and spontaneous preference for dark areas, indicating that they could perceive light and use this information to guide their behavior.
This recovery occurred without any training and under light levels comparable to those found indoors or on an overcast day, demonstrating that the treatment restores functional light perception capable of driving natural, visually guided behavior.
Two lead compounds, prosthe6-12 and prosthe6-15, showed particularly promising results. The restored behaviors were observed not only after intraocular injection, but also after topical administration as eye drops. “… at least two compounds (prosthe6-12 and -15) appear to be devoid of adverse effects and restore sight by topical administration, which is linked to higher overall clinical success rate than systemic routes for neurological drugs, and to stronger patient adherence,” the investigators pointed out.
The prosthe6 technology is protected by patent and the researchers are now evaluating its safety and formulation to extend the duration of visual rehabilitation. The team is working with Eyelumina, a spin-off company in formation to secure investments that support translational development and future clinical trials.
“Turning this into a therapy is a long and laborious process,” says Gorostiza. “But the results show that there is a realistic possibility of restoring high-quality vision with drugs, non-invasively, reversibly and with a mechanism that is independent of the specific retinal disorder or genetic mutation to reach a majority of patients.”
If successful in humans, the drug-based approach would offer a widely accessible and affordable alternative to existing vision restoration technologies, especially relevant for patients with advanced retinal degeneration for whom no effective treatments currently exist.
In their paper the team further stated, “From a fundamental perspective, prosthe6 constitute new tools for ophthalmology to study the physiopathology of mGlu6 receptors and retinal circuits in vitro and in vivo and contribute to the medicinal chemistry of allosteric modulators. They also achieve the prediction that upstream targeted photopharmacology can deliver nearly native output signals, taking full advantage of the retinal circuit for high-quality vision restoration.”
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Virus Response Insights Offer MS Treatment Hope
A study has revealed how white blood cells in the body react to the Epstein-Barr virus (EBV) in a way that drives autoimmunity in multiple sclerosis (MS), which could help identify and design effective therapies for the condition.
The findings, in Science Translational Medicine, shine a light on immune mechanisms underlying the well-established link between infection with the virus and MS.
Nearly all MS patients are seropositive for EBV, a widespread virus that commonly causes glandular fever otherwise known as infectious mononucleosis.
The research suggests T helper cells in the immune system—also called CD4+ cells—primarily react to particular EBV viral components.
These responses were reduced by B cell depletion therapy, which has known MS therapeutic benefit, suggesting it may be particularly useful for the disease.
“By identifying a readily measurable, peripherally accessible immune response linked to disease, this work provides a foundation for the rational design and monitoring of EBV-targeted vaccines and antivirals for MS,” added the researchers.
MS is a chronic inflammatory disease in which the central nervous system is attacked by the body’s own immune system, damaging the fatty myelin sheath protecting nerves and causing other harm that can affect vision, movement and cognition.
Kjetil Bjornevik, PhD, from Harvard T. H. Chan School of Public health in Boston, and colleagues examined how the virus could affect immune responses by studying healthy individuals, people with treatment-naive MS, and those with MS receiving disease-modifying therapies.
The team found that the CD4+ T cells in the group with MS predominantly targeted several viral components, in particular the late lytic capsid and glycoprotein antigens that are components of EBV viral particles.
The EBV-specific CD4+ T cell response in untreated MS patients was twice that of healthy control individuals, further implicating this response. Responses to other herpes viruses remained similar, suggesting a specific role for EBV in MS immunopathology.
B cell depletion therapy based on anti-CD20 antibodies reduced CD4+ T cell responses to the virus 2.5-fold in two MS groups comprising a total of 69 patients. It also eliminated detectable viral shedding in saliva, consistent with B cells serving as the primary viral reservoir.
The authors concluded: “Together, our findings establish EBV viral particle antigens as the dominant targets of CD4+ T cell responses in MS and demonstrate that these responses are modifiable by current therapies.”
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Beyond visual inspection: the deep learning revolution in quantitative cerebrovascular imaging
The rising global burden of cerebrovascular disease, propelled by an aging population, highlights the inherent limitations of conventional, labor-intensive diagnostic paradigms. In the context of time-sensitive stroke management, variability in image interpretation and the high rate of misclassification, particularly during the assessment of transient ischemic attack (TIA), underscore the urgent need for more consistent and efficient diagnostic solutions. Artificial intelligence (AI), particularly deep learning (DL), offers a transformative pathway by automating the analysis of complex neurovascular imaging. Here, we conduct a comprehensive examination of how DL is revolutionizing stroke-related image analysis, moving beyond general assertions of potential to discuss specific technical implementations. We systematically detail the evolution from traditional segmentation algorithms to advanced deep learning architectures—such as U-Net, DeepMedic, and their variants—in performing critical tasks. These tasks encompass the automated segmentation of intracranial and extracranial (carotid) arteries, the quantification of stenosis and plaque burden, and the hemodynamic assessment of vascular lesions across modalities including MRA, CTA, and DSA. By synthesizing landmark studies, our analysis delineates three core aspects: the technological trajectory of DL models in achieving expert-level accuracy in vascular feature extraction in controlled studies; the clinical translation of these tools into diagnostic, prognostic, or therapeutic procedural planning workflows; and the persistent challenges and future directions, including data standardization, model generalizability, and multimodal integration. This review posits that DL represents not merely an assistive technology but a foundational cornerstone for the next generation of precision cerebrovascular medicine. It holds the potential to bridge critical gaps in diagnostic speed, objectivity, and accessibility, provided its development and validation are guided by rigorous, interdisciplinary collaboration.
ADHD as a disorder of operational capacity: a buffered-state framework for sustained engagement instability
Attention-deficit/hyperactivity disorder (ADHD) is commonly conceptualized as a disorder of executive dysfunction or impaired motivation. In clinical practice, however, many individuals with ADHD describe a different core difficulty: they can initiate tasks appropriately, understand goals, and exert effort, yet struggle to remain engaged as time-on-task and internal strain accumulate. These failures are often abrupt, ego-dystonic, and strongly context-dependent, posing challenges for models based solely on static deficits or gradual depletion. Building on this phenomenology, we propose a constraint-level framework that conceptualizes ADHD as a disorder of operational capacity—the finite tolerance for sustaining stable mental engagement under cumulative cognitive and emotional demand. Within this framework, sustained engagement is modeled as a buffered state that remains stable while cumulative load is within tolerance but becomes increasingly fragile near saturation and may undergo nonlinear collapse into disengagement. We formalize this governing constraint as Operational Economy (OE)—a regulatory, not energetic, constraint principle—and describe a pre-volitional Global Switching Framework (GSF) that mediates rapid state transitions once engagement stability is exceeded. This formulation integrates and extends cognitive-energetic and state-regulation accounts while explicitly differentiating the OE/GSF framework from these predecessors by its emphasis on threshold-dependent dynamics, bounded tolerance, and asymmetric re-engagement. This framework offers a coherent account of clinical features such as intact initial performance with late-stage disengagement, pronounced time-on-task effects, and context-dependent hyperfocus. The framework generates falsifiable predictions regarding sensitivity to cumulative demand, stress-related acceleration of disengagement, pharmacological effects that preferentially extend engagement endurance rather than normalize peak executive performance, and individual differences across ADHD subtypes and comorbid presentations. These predictions are consistent with existing empirical findings on time-dependent variability in ADHD and provide a basis for future experimental validation.
Altered EEG microstate dynamics in adolescents with non-suicidal self-injury at rest and following acute social exclusion
BackgroundNon-suicidal self-injury (NSSI) is highly prevalent in adolescence, yet the fast dynamics of large-scale brain networks remain poorly understood. We aimed to characterize resting-state EEG microstate dynamics in a clinically recruited adolescent NSSI sample and to examine state-dependent changes following acute social exclusion.MethodsResting-state EEG was recorded in hospitalized, medicated adolescents with NSSI and in healthy controls (HCs). An NSSI subgroup then completed EEG assessments before and after either Cyberball-induced social exclusion or a non-stress control condition. Microstate parameters and transition probabilities were analyzed.ResultsAfter multiple-comparison correction, the core baseline finding was robustly reduced microstate A duration in the NSSI group relative to HCs. In uncorrected exploratory analyses, additional differences included shorter durations of microstates B and F, higher occurrence of microstate D, and increased F→D transition probability. A multivariate pattern analysis suggested group-related information but must be interpreted cautiously given the modest sample size. Within the NSSI group, the exclusion group showed reduced microstate A expression and increased microstate D expression relative to the non-stress subgroup, with a broader transition shift toward microstate D. Several interaction effects survived correction.ConclusionsIn this medicated inpatient sample, resting-state microstate dynamics differed from HCs, most robustly in reduced microstate A duration, and reorganized after social exclusion. Specificity to NSSI remains uncertain given the absence of an MDD-only clinical-control group and healthy Cyberball comparison. These preliminary findings require replication in larger studies including medication-naive MDD-only, MDD+NSSI, and HC groups.
Fragile self, mechanical world: mechanistic delusions and ego fragility in schizotypal–affective spectrum disorder—a CARE case report
Categorical nosological systems frequently fall short when confronted with patients whose presentations cross established diagnostic boundaries. We report M.S., a 44-year-old Brazilian man involuntarily admitted to a psychiatric inpatient unit who presented with systematized persecutory ideation of mechanistic–technological content (chip implantation, satellite-based surveillance), structural ego fragility, absent insight, and progressive social and occupational deterioration. While prior diagnoses of bipolar disorder and provisional schizophrenia had been considered, neither fully captured the clinical complexity. Psychopathological-dimensional analysis, grounded in phenomenological observation and contemporary psychopathological theory, suggests three potentially interacting axes: (1) structural ego fragility (Ich-Schwäche), potentially arising from impaired early attachment and deficient relational learning; (2) a relational causality deficit replaced by concrete–mechanistic reasoning; and (3) limbic hyperactivation that appears to sustain an anxiety–perplexity–paranoia feedback loop. These converge on a schizotypal–affective spectrum formulation. Laboratory investigations identified severe dyslipidemia and marked hyperandrogenism (total testosterone 1,367 ng/dL), the latter potentially associated with limbic hyperactivation, though causality cannot be established from a single cross-sectional measurement. Psychometric assessment (BPRS-18) at admission yielded a total score of 43, with suspiciousness (5) and unusual thought content (5) as dominant items. During a seven-day inpatient course, a multimodal thymic strategy—risperidone, lithium carbonate, and structured psychotherapy—produced attenuation of paranoid reactivity, improved family engagement, and the spontaneous resumption of guitar playing from day 3, as a functional correlate of behavioral stabilization. The patient was discharged with a referral for a three-monthly paliperidone palmitate long-acting injectable. The pharmacological response retrospectively supports the dimensional formulation and illustrates the heuristic value of psychopathological analysis grounded in ego structure, causal reasoning, and affective dysregulation as a complementary approach to categorical nosology in complex psychotic–affective presentations.