Improving HSV-2 Vaccine Efficacy with Combination Strategy

Developing a vaccine against infectious disease isn’t always straightforward. While many injectable vaccinations are highly effective, growing research has identified that targeted vaccination to the primary affected tissues may be both more effective and longer lasting.

Genital herpes, caused by herpes simplex virus 2 (HSV-2), is notoriously difficult to effectively vaccinate against due to the immunosuppressive nature of the vaginal mucosal lining, which reduces the effectiveness of vaccines through reduced immune priming.

Previous research shows that CpG oligodeoxynucleotides (ODNs), a synthetic DNA molecule, is effective at stimulating the immune system and reduce viral loads when delivered intravaginally. While effective, this method often results in significant inflammation of the mucosa.

Researchers at Yale University published a study in Science Immunology in which they explain a new strategy to improving the protective ability of an HSV-2 vaccine while reducing the inflammatory side effects. Their approach combines a vaccine adjuvant to stimulate the immune system by recruiting T cells with ODNs.

“Effective local immunity, mediated in part by tissue-resident memory T cells (TRM cells) and luminal antibodies, provides immediate viral control,” wrote the authors. They tested the ability of chemokines bound to ODNs to improve vaccine specificity and efficiency in vaginal mucosa. Their technique is celled bioactive enhanced adjuvant chemokine oligonucleotide nanoparticles (BEACONs).

“Systemically primed immunity can be leveraged to generate appropriate mucosal responses,” the authors reasoned. “For example, intramuscular priming [can] establish a pool of antigen-specific T and B cells, followed by a mucosal boost to drive their recruitment to and activation at the site of infection.”

Using a mouse model, the team tested the adjuvant which combined the CpG ODNs with CXCL9. The mice were initially dosed with an intramuscular injection of HSV-2 glycoprotein-encoding messenger RNA–lipid nanoparticles, followed by an intravaginal booster containing the cognate recombinant glycoprotein and BEACONs.

While additional chemokines were tested, including CXCL10 and a truncated version of CXCL9, neither was effective. “These data emphasize the structural features of the chemokine component that directly influence particle formation and immunological function,” wrote the authors.

BEACONs were shown to improve uptake of ODNs by antigen presenting cells and promoted the recruitment and retention of HSV-specific CD8 T cells in the vaginal mucosa. However, this effect was only seen in the combination treatment. “This response was not induced by CXCL9 or CpG ODNs alone, nor was it observed after intramuscular boosting, indicating that both local antigen and adjuvant signals are required to establish durable CD8 TRM cell populations,” they wrote.

“Our data support a model in which mucosal boosting primarily leads to recruitment and local reprogramming of systemically primed effectors rather than driving a second systemic expansion.”

These data suggest that not only is this technique effective in vaccinating against HSV-2, but there are broader implications to this technique. They explored the concept of delivering a vaccination dose for systemic priming followed by localized delivery of the vaccine components combined with an adjuvant to amplify relevant effectors at infection sites. Further, they highlighted how use of nanoparticle formulations can help to fine-tune reactogenicity of CpG ODNs to reduce inflammation responses, which would be helpful for clinical translation.

“Our findings offer a generalizable strategy for targeting other sexually transmitted pathogens, including HIV-1, human papillomavirus, and chlamydia, in which mucosal immunity is essential but poorly induced by [other types of] vaccines,” the authors wrote.

While these results are promising, more work is needed to establish the long-term efficacy of the strategy by testing viral shedding and testing in alternate models, and multiple delivery methods to adapt for self-administration or clinical options for dose delivery.

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Local brain connectome parameters across the spectrum of clinical cognitive decline

Neurological disorders such as Alzheimer’s disease, Parkinson’s disease, and autism disrupt the brain’s structural and functional organization, particularly in specific regions, and ultimately lead to cognitive impairments. In Alzheimer’s disease-related dementia, neuronal degeneration impairs structural connectivity between brain regions, which in turn leads to functional breakdowns. This phenomenon, referred to as disconnection syndrome, manifests as connectivity breakdowns in affected regions, with these localized changes indirectly influencing the entire brain network. As the disease progresses, patterns consistent with compensatory-type reorganization have been described in the literature, accompanied by structural and functional changes that have been hypothesized to transiently mitigate cognitive decline during early stages. This study examines the structural and functional reorganization of the brain across the clinical spectrum of Alzheimer’s disease by analyzing local nodal changes using measures such as degree, strength, clustering coefficient, and betweenness centrality. Our findings show that early-stage nodal patterns are consistent with this hypothesized reorganization, whereas later-stage changes are dominated by progressive structural decline alongside persistent functional reorganization. Because the present study is cross-sectional and group-level, the compensatory interpretation should be regarded as a working hypothesis rather than a confirmed mechanism, and these exploratory patterns require validation in independent and longitudinal cohorts before clinical translation.

Evaluation of an open-face 8-channel transmit 64-channel receive 7T head coil for neuroimaging

IntroductionUltra-high field (UHF) 7 tesla (7T) MRI offers unique diagnostic opportunities for clinical neuroimaging. However, broader clinical implementation remains limited because the reduced radiofrequency (RF) wavelength at 7T causes RF transmit field (B1+) inhomogeneity, resulting in spatial variation in image signal and tissue contrast. These effects are particularly pronounced in the skull base, temporal lobes, and posterior fossa, regions frequently implicated in neurological disease. RF parallel transmission (pTx) techniques can improve B1+ homogeneity through optimization of multiple transmit fields, while parallel imaging with multiple receive elements enables accelerated acquisitions. To fully exploit these advantages at UHF, RF coils combining high-performance transmit and high-density receive arrays are required.MethodsAn open-face eight-channel transmit 64-channel receive (8Tx64Rx) 7T head coil was developed with electrical and mechanical ergonomic features designed to improve usability and imaging homogeneity. The coil was evaluated in an in vivo validation study assessing ease of use, participant comfort, diagnostic value, and image quality using questionnaires and structured scoring sheets. Imaging performance of the 8Tx64Rx coil was compared with that of a commercially available regulatory approved 7T head coil featuring single transmit (sTx) and a 32-channel receive array. Diagnostic image quality acquired using circularly polarized (CP) mode and pTx mode was additionally assessed and compared.ResultsThe 8Tx64Rx coil demonstrated image quality that was equivalent or superior to the commercial 7T head coil across evaluated measures. In particular, improved signal homogeneity was achieved within the posterior fossa and temporal lobes. The coil also supported practical clinical use through favorable ergonomic performance and user comfort during scanning. Diagnostic image quality was enhanced when using pTx approaches compared with conventional transmit configurations.DiscussionThe developed 8Tx64Rx 7T head coil demonstrates the potential to advance clinical neuroimaging at UHF by improving B1+ homogeneity in anatomically challenging brain regions while maintaining usability and diagnostic performance. These findings support the integration of combined high-density receive arrays and pTx technology to overcome key limitations of 7T MRI and facilitate broader clinical adoption.

Disrupted glymphatic function and its relationship with sleep and cognitive impairment in ME/CFS assessed via DTI-ALPS

The glymphatic system is a recently discovered brain waste clearance system that is mostly active during sleep and disengaged during wakefulness. Impaired glymphatic function leads to the deposition of metabolic waste products in the brain potentially causing inflammation leading to various symptoms in ME/CFS. While the glymphatic function has been assessed in other neurodegenerative diseases using ‘diffusion tensor imaging along the perivascular space’ (DTI-ALPS), it has not been studied in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). This preliminary study investigates glymphatic function in 58 participants (ME/CFS = 31 and healthy controls = 27) using the DTI-ALPS index derived from DTI data acquired with 3 T MRI. The bilateral hemispheric DTI-ALPS index was estimated to assess glymphatic function, and an asymmetry index was calculated to determine interhemispheric asymmetry in glymphatic function. We found that the global DTI-ALPS index was significantly lower in ME/CFS patients compared to healthy controls (ME/CFS: 1.44 ± 0.086; healthy controls: 1.51 ± 0.11, p = 0.014), indicating reduced glymphatic function in ME/CFS. Examining the hemispheres separately, showed the right hemisphere DTI-ALPS index was lower in ME/CFS than healthy controls (ME/CFS = 1.41 ± 0.097; healthy controls = 1.49 ± 0.12; p = 0.009) but not different on the left. Additionally, we did not find any significant difference in asymmetry index between ME/CFS and healthy controls. We observed an association between the global DTI-ALPS index and severity of ‘sleep disturbance’ (p = 0.013, r = −0.47) and “impaired concentration” (p = 0.026, r = −0.43). This study demonstrated impaired glymphatic function in ME/CFS which may lead to symptoms such as cognitive dysfunction and sleep disturbance experienced by ME/CFS.

A computational pipeline for a neurotransmitter-centric analysis of the effects of psychiatric medication on EEG spectral power

IntroductionTraditional pharmaco-electroencephalography (EEG) studies have mainly examined the effects of psychotropic medications at the level of individual drugs or broad drug classes, limiting biological specificity and clinical translation. This study aimed to determine whether modeling EEG spectral power changes according to the engagement of distinct neurotransmitter systems provides a more mechanistic understanding of psychotropic drug effects in a real-world clinical population.MethodsWe analyzed 4,128 EEG sessions from 2,083 patients in the Temple University Hospital EEG Corpus, a large heterogeneous dataset. EEG data were preprocessed and segmented into canonical frequency bands (delta, theta, alpha, beta, and gamma). Psychotropic medication data were systematically extracted and coded at the receptor level for serotonin, dopamine, norepinephrine, histamine, and acetylcholine systems using the Neuroscience-based Nomenclature framework. Receptor profiles were summarized to represent each patient’s overall neurotransmitter engagement (agonistic, neutral, antagonistic, or mixed). Linear mixed-effects models were applied to assess relationships between neurotransmitter profiles and log-transformed spectral power while controlling for electrode location and patient-level variability.ResultsFrequency- and region-specific EEG patterns were identified across neurotransmitter systems. Dopamine antagonists were associated with higher delta and theta power at central electrode locations and lower alpha power at occipital and temporal locations, whereas dopamine agonists were associated with higher delta activity at occipital locations and increased frontal gamma power. Serotonin antagonists showed associations with elevated slow-wave and alpha power, while serotonin agonists were linked to increased frontal alpha, decreased occipital alpha, and enhanced temporal gamma power. Both norepinephrine antagonists and agonists showed positive relationships with delta power, with a broader topographical pattern for antagonists. Theta power was positively associated with norepinephrine antagonists and negatively associated with norepinephrine agonists. Norepinephrine antagonists were related to lower temporal alpha and higher frontal and parietal gamma power. Histamine antagonists and mixed histaminergic agents were associated with lower delta, theta, and alpha power. Acetylcholine antagonists were linked to higher delta, theta, and alpha power across electrode locations.DiscussionModeling psychotropic medication effects on EEG at the neurotransmitter receptor level offers a biologically grounded and clinically relevant improvement over traditional drug class-based approaches. This neurotransmitter-centric framework enhances mechanistic interpretability and may support the development of EEG biomarkers for personalized, mechanism-based psychiatric care.

Outcomes from the ASPEN intervention program: a randomized clinical trial of a culturally adapted parent-mediated intervention program in low-resource settings

This randomized controlled study examined the efficacy of a culturally adapted parent-mediated intervention for parents and young children with autism (n = 45) from low-resource households (ClinicalTrials.gov Identifier: NCT04505488). Families from these settings are often left out of autism intervention studies and arguably have unique needs not considered in autism intervention work. Parent/child dyads were randomized to the intervention group, which received 12 weekly sessions that included psychoeducation and coaching of evidence-based (EB) strategies with their children, or the comparison group who received all materials and 4 triweekly check-in sessions. We found that parents in the intervention group showed improvement in their self-efficacy (confidence) in using EB strategies, compared to the comparison group, and both groups improved in the use of EB strategies. Parents in the comparison group also improved in feeling more empowered and their children improved in social communication skills. These findings suggest that less intense parent interventions may be just as efficacious as those that require more regular participation for families from low-resource households. More research is needed to find the right balance and active ingredients to benefit these families.Clinical Trial Registrationhttps://clinicaltrials.gov/study/NCT04505488, identifier NCT04505488.

Burnout and perceived health in medical residents after the COVID-19 pandemic: a single-center cross-sectional study

IntroductionResidents have a high risk of burnout during the training period. The COVID-19 pandemic has had a great impact on work conditions and health of medical residents. We therefore estimated the prevalence of post-pandemic burnout and perceived health, and their relationship with psychosocial factors, stress profile, and job satisfaction, as well as the pre-post pandemic changes.MethodsWe carried out a retrospective cross-sectional, online, anonymous survey using the validated FPSICO-4.0 questionnaire in a teaching hospital after the COVID-19 pandemic (2023). We also studied the pre-post changes from an independent pre-pandemic online survey (2018) with the same tool.ResultsOne hundred ninety-seven residents, 64% females, answered the questionnaire (43.5%); 28% had post-pandemic burnout without gender differences, being higher in surgical specialties (p=0.017) and along residency years (p=0.041). Role performance, behavior stress, job satisfaction and residency years were associated with an increase in odds of burnout (p<0.05). Supervision, conflict of role/cognitive stress explained 35% of the variation in perceived general health (adjusted-R2 = 0.356); temporary autonomy, supervision, information/training/promotion, behavior/somatic stress, and job satisfaction did 68% of mental health (adjusted-R2 = 0.683); and take decisions, conflict of role, behavior/somatic/cognitive stress, and male gender did 62% of vitality (adjusted-R2 = 0.624). Pre/post pandemic mean differences, adjusted by gender and residency year, showed deterioration of variety sense of work (p<0.001), effort of attention (p=0.026), behavior stress (p=0.022), and improvement of temporary autonomy (p=0.045).ConclusionsThe identification after pandemic of high prevalence of burnout, stress levels and certain psychosocial risk factors (role performance and supervision), highlights the need of specific health promotion plan.

Diagnosis of prolonged grief disorder among older adults: mapping physicians’ knowledge and practice, and evaluating the effectiveness of a brief targeted training program

BackgroundProlonged Grief Disorder (PGD) is a psychiatric diagnosis with significant implications for individuals and society. Familiarity with its diagnostic criteria and recommended interventions is essential for early detection and effective treatment. As aging naturally involves multiple losses, older adults are at distinct risk of developing PGD, a condition associated with psychological and physical comorbidities and increased mortality. In the Israeli context, this issue holds particular significance following the events of October 7, 2023, and the ensuing war, which have had — and continue to have — a profound impact on the population’s mental health. Given PGD’s recent inclusion in diagnostic manuals, many physicians may lack sufficient knowledge, leading to under-recognition or misdiagnosis. This gap is particularly evident among older adults, for whom the assessment and management of psychological distress are often underassessed and undertreated, highlighting the urgent need for targeted training and broader integration of existing knowledge into clinical practice. Accordingly, the present study has two main objectives: (1) to assess physicians’ knowledge and use of PGD diagnostic criteria with older patients, and (2) to evaluate the effectiveness of a brief informational intervention on their understanding and diagnostic application.MethodsUsing a mixed experimental design, the study will include senior physicians and residents specializing in geriatrics, psychiatry, and family medicine. Data will be collected via an online structured questionnaire containing professional background items and clinical vignettes designed to assess participants’ knowledge and application of PGD diagnostic criteria. Afterwards, participants will be individually randomized (1:1) via a computer-generated sequence in a partially participant-blinded, assessor-blinded controlled trial to either an experimental group viewing an informational PGD video or a control group viewing a structurally equivalent video (matched in length, graphics, and word count) addressing bereavement in older adults without directly referencing PGD. All participants will then complete the vignettes again to evaluate the effects of the intervention. A one-month follow-up assessment will evaluate the retention of intervention effects.DiscussionThis first systematic Israeli study on PGD implementation will provide an empirical basis for policy development, professional training, and prevention programs. Its findings may enhance diagnostic accuracy, improve care efficiency, reduce systemic costs, and support ongoing evaluation and refinement of clinical practices.Clinical trial registrationClinicalTrials.gov, identifier NCT07487233.

A startup claims it broke through a bottleneck that’s holding back LLMs

Miami-based AI startup Subquadratic came out of stealth mode last month with a huge claim. It announced that it had solved a mathematical bottleneck that had been holding back large language models for almost a decade.

The details were thin, and many people were unconvinced. But Subquadratic has started to bring the receipts, sharing the results of an independent evaluation of its new tech. The results suggest that the company’s claims might be worth paying attention to.

According to Subquadratic, it has developed a new kind of LLM, called SubQ, that is faster and cheaper and uses a lot less energy than any other model on the market. The company also claims that SubQ is able to process up to 12 times as much text at once than most other models, allowing it to carry out a range of data-heavy tasks, such as analyzing hundreds of documents or entire code bases.

What’s more, Subquadratic says, SubQ does this while more or less matching the performance of the best models put out by Google DeepMind, OpenAI, and Anthropic on key tasks like coding.

The problem was that the company at first provided little evidence for its claims beyond a handful of self-published test scores. And it has yet to make SubQ widely available for people to try out themselves.

So it’s no surprise that Subquadratic’s claims were met with skepticism. Dan McAteer, an artificial intelligence engineer, captured the overall response on X: “SubQ is either the biggest breakthrough since the Transformer … or it’s AI Theranos.”

A month on, the company has published more information about its model, including the results of additional independent tests run by third-party firm Appen.

“We expected healthy skepticism,” says Subquadratic cofounder and chief technology officer Alex Whedon. “In hindsight, releasing the third-party benchmarks alongside the initial announcement would have preempted much of the skepticism, which is why we’re taking the time to make sure any future results are fully verified before putting them out.”

Subquadratic asked Appen, which evaluates other companies’ models, to run its tests on SubQ. The results seem to back up a lot of Subquadratic’s claims. “That was really exciting to me, it validated their architecture,” says Jeanine Sinanan-Singh, Appen’s director of generative AI research.

“I was like, ‘Wow, this could be a game changer,’ because models struggle with speed and inefficiency,” she adds. “But when you have kind of shocking results, it’s really not as credible when you say it yourself.”

SubQ won’t replace existing top models across the board, but it could offer huge increases in speed at a fraction of the typical cost for certain tasks. Subquadratic insists that in the long run, though, its breakthrough could change how LLMs are built. “We hope we’re kicking off a new age of efficiency,” says Justin Dangel, the firm’s cofounder and CEO. “We don’t think anybody will be building on transformers in a few years.”

Attention!

To understand why Subquadratic’s claims are a big deal, let’s dig into how most LLMs work. The key mechanism inside an LLM is a type of neural network called a transformer, which runs a process known as dense attention. Today’s LLMs typically chain together multiple transformers. (The foundational paper of the LLM era, published by researchers at Google in 2017, was titled “Attention Is All You Need.”)

Dense attention works like this: When a transformer processes a chunk of text, it first encodes each word (or part of a word, known as a token) with a number. To capture the meaning of the full text, it then multiplies each of those numbers with every other number for that text. For example, a piece of text 10,000 words long would kick off almost 50 million individual multiplications. That’s a lot of computation and the main reason that LLMs are notorious power hogs.

“If you want to summarize The Great Gatsby, you have to look at the first word and the last word together, and then you have to look at every other combination,” says Dangel.

As the length of the text increases, the number of computations skyrockets. That’s because each additional number must be multiplied by all other previous numbers. Double the number of words, and you roughly quadruple the number of computations, a rate of increase known as a quadratic expansion.

(You can picture this yourself: Draw a circle and mark dots around its edge. Each dot is a token. Then draw lines between pairs of dots to represent the multiplication of those two tokens. A circle with five dots will have 10 lines crossing it. Make it 10 dots and you will have 45 lines, 20 dots and you will have 190 lines, and so on.)

Slashing costs

Subquadratic’s solution is to ditch dense attention, the core operation of a transformer, in favor of what’s known as sparse attention, which slashes the number of computations needed. Instead of multiplying the number assigned to each token by every other number, sparse attention selects just some of the numbers to multiply. The idea is that not all relationships between words in a piece of text matter.

“Sparse attention says not all of those relationships are important, because they’re not,” says Whedon. “If you’re reading a book, you’re not going to look at the first and second words, first and third—that’s insane.”

It’s a simple approach, and Subquadratic is not the first to try it. “Pretty much everything under the sun has been attempted,” says Will Depue, an independent AI researcher who previously worked at OpenAI. “It’s not impossible, but it’s akin to running a four-minute mile.”

Previous techniques for selecting which numbers to multiply and which to ignore have not produced a mechanism that can capture the meaning of a document as well as dense attention can.

Subquadratic claims to have cracked the problem at last. It pitches SubQ as the first sparse-attention LLM that rivals mainstream dense-attention models in performance.

“Historically, most mechanisms have used fixed patterns, like always comparing the first word to the fifth,” says Whedon. “That’s pretty limiting. Language is too sophisticated for that. And so, one of the things that makes our mechanism unique is that we dynamically select which ones are important.”

The firm won’t say exactly how SubQ chooses which words to focus on, but the selection is calculated on the fly and differs for each piece of text the model is given. “That’s kind of where the secret sauce is,” says Whedon.

Testing, testing

The upshot is that for certain tasks, SubQ may be faster and cheaper to run than most other models. Appen evaluated SubQ on a handful of standard tests. In a straight-up speed test, which sets a baseline for how fast a model can operate in theory rather than assess what a model can actually do, Appen found that SubQ was 56 times faster than models using FlashAttention, a previous sparse-attention technique. 

On LiveCodeBench, a test that looks at how well models perform on competitive coding problems taken from real contests, SubQ scored 89.7%, putting it in the same ballpark as other top coding models. “This model continues to provide frontier-level performance in coding,” says Appen’s Sinanan-Singh.

Subquadratic’s claims about cost are harder to verify because SubQ is not yet widely available. According to Dangel, it costs $2600 to run Anthropic’s LLM Opus 4.6 through RULER 128, a test developed by Nvidia to assess a model’s ability to retrieve information from large data sets. And SubQ? “It cost us eight dollars,” he says.

SubQ does seem to be able to handle very large data sets. The model has a context window (roughly akin to a working memory) up to 12 million tokens long. Most top models today have context windows one million tokens long. In a demo that Whedon ran for me, he asked SubQ to perform a task that required it to reason about information contained in 400 documents. It responded in seconds. When he gave Perplexity—a popular LLM-powered search engine—the same task, it failed to load all 400 documents. 

Appen also ran the needle-in-a-haystack test, which assesses how well a model can retrieve specific information buried in a large amount of data. In its report, Appen states that SubQ scored 98% with context windows six million and 12 million tokens long, “sustaining near-perfect long-context retrieval at scales few models are tested at.”

Too good to be true?

Despite the high scores, benchmarks paint an incomplete picture of what a model can and cannot do. Testing under very specific conditions is not a substitute for running a model on a wide range of real tasks.

Subquadratic is offering SubQ as a model tailored to coding and to searching very large data sets. It says that tens of thousands of potential users have already signed up for early access, including more than 500 enterprise customers. But there’s a long waitlist, and the firm has given very few people access so far. Subquadratic’s response is that it is a new, small company with limited resources and cannot serve too many people at once.

Until more people get their hands on the model and try it out for themselves, some skepticism is justified. One nagging issue is that Subquadratic reused the weights (values set within a model during training that determine how it will behave) from a version of the Chinese open-source model Qwen to bootstrap SubQ, rather than training it from scratch. That’s a common thing for model makers to do, but it cuts across Subquadratic’s claim that it has fully reinvented how LLMs work.  

“They may have built something real and useful,” says Depue. “But the public evidence does not yet justify the stronger claim that they have solved the quadratic attention bottleneck.”

In the meantime, Subquadratic cofounder Whedon insists that making something different was his only option. If you want to build a competitive model, you have to have new ideas, he says: “We’re more up against it than OpenAI is.”

Brain-computer interface trials are taking off

This week, I covered the story of Casey Harrell—a man with ALS who is “the first power user” of a brain implant, according to the researchers who worked with him. Harrell is paralyzed and unable to speak coherently without the device. He has now spent almost three years using a brain-computer interface (BCI) that enables him to “speak,” surf the web, and perform his job as a climate activist, largely independently.

Since Harrell was implanted with the device, in July 2023, a team at the University of California, Davis, has worked with him to adjust and improve its offerings. They’ve refined its accuracy, for example. And they’ve introduced settings including a privacy mode and a “profanity filter” that lets Harrell talk to his daughter without risking accidental swearing.

Harrell told me that, for him, the device is “nothing short of revolutionary!” It has enabled him to maintain an income, reconnect with friends and family, and read to his daughter. 

The team that developed his BCI is one of several working on ways to use technology to allow people with paralysis to communicate, engage with the online world, and regain some independence. And Harrell is one of a growing number of people volunteering their brains to, as he puts it, “pay it forward and do the scientific research … [and] get some personal benefit.”

Over the past couple of years, the number of BCI trial volunteers has soared. This year, China became the first country to approve a BCI for medical use. Advances in technology are allowing engineers to provide more features than ever. BCI research is properly taking off.

I should first point out that BCIs come in different forms. Harrell’s device includes a set of electrodes embedded in his brain that pick up the electrical activity associated with speech. Those electrodes are connected to two docking ports on top of his head that can be plugged into a computer.

That computer is loaded with software trained to decode his brain signals into phonemes (units of sound in speech) and predict what Harrell wants to say. He can then use an eye gaze tracker to make any corrections before the speech is played out loud.

But some BCIs don’t need to be “plugged in”—they’re fully implanted and wireless. Others are less invasive; they might involve placing wired electrodes on the surface of the brain or simply wearing a cap of electrodes, for example. There are trade-offs—the closer you get to the neurons you want to record from, the better your signal will be. But generally speaking, the more invasive the surgery, the higher the risk of complications.

BCIs can also have different functions. Harrell has ALS, but most BCIs in use today are sitting in the brains of people with spinal cord injuries. Typically, these individuals have some degree of paralysis; for example, they may be unable to move their arms and legs, but their face and ability to speak are unaffected. In those cases, BCIs can be used to control other kinds of devices that might help with mobility.

In 2024, Michelle Patrick-Krueger, then at the University of Houston, and her colleagues published a roundup of all trials of BCIs conducted between 1998, which is when they believe the first device was implanted, and the end of 2023. They identified 21 research groups that, among them, had trialed BCIs in a total of 67 volunteers.

“Since then, that number has increased a lot,” says Mariska Vansteensel, a BCI researcher at University Medical Center Utrecht. In January, Neuralink (the BCI company founded by trillionaire Elon Musk) announced that it has implanted 21 people with its device in the past two years.

Synchron, another BCI company, is currently testing its devices in trials in North America and Australia. Shanghai-based Neuracle has been trialing a BCI since November 2024, and it recently obtained approval for the device to be used outside of clinical trials. Precision Neuroscience, cofounded by a former co-creator of rival Neuralink, is also trialing its BCI, which sits on the surface of the brain.

At the same time, academic research has continued. The UC Davis team that worked with Harrell is part of BrainGate—a BCI research effort that has been running for the past two decades. Other academic teams are exploring a variety of devices, from the fully implanted to the minimally invasive.

Since 2024, when Patrick-Krueger’s paper was published, the number of people who have been implanted with a brain electrode has more than doubled, according to Vansteensel. “My current estimation would be around 150 people,” she says.

The technology is improving too. Take the BrainGate trial, for example. The first 17 years of that trial focused on the use of what researchers call “point-and-click” communication—allowing users to control a cursor and “click” with their brain activity. But in recent years the team has pivoted toward decoding speech, says David Brandman, the lead investigator on the team (and the person who implanted Harrell’s electrodes). Today, Harrell’s device uses a voice clone—the speech it produces is based on previous recordings of Harrell’s voice.

But BCIs are still experimental. And plenty of questions remain about who might benefit from them—and how long the devices will last. So far, most BCIs have been implanted in people with spinal cord injuries. We know even less about how they might benefit other people who have ALS, for example. In some cases where the devices initially helped people with ALS—even someone who was completely locked in—the BCIs eventually stopped working. And scientists don’t really know why.

The only way they’ll find out is through more research—and the participation of volunteers like Harrell. So it’s exciting to see trials truly take off. And I promise I’ll update you on where they stand two years from now.

This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.