On September 17, 2025, we received an encouraging update from Skyhawk Therapeutics’ Phase 1 study, taking place in Australia. The recent update suggests that SKY-0515 can lower the huntingtin protein as well as PMS1, another protein which is thought might also drive Huntington’s disease (HD). Importantly, the drug also appears to be safe and well tolerated. A larger Phase 2/3 trial called FALCON-HD is already underway. Let’s get into what we learned from this latest update.
What is SKY-0515 and how does it work?
SKY-0515 is a pill, taken by mouth, designed to change which proteins are made in the body. The drug works by targeting message molecules, or RNA, which are copied from the DNA code and have the instructions to make different types of proteins. SKY-0515 changes how cells process RNA messages.
SKY-0515, like PTC Therapeutics’ votoplam, isn’t specific for huntingtin. The pill targets many different messages throughout the body, but huntingtin happens to be one that it targets quite strongly. Because it’s not specific, it also influences the levels of other proteins in the body. Two of the proteins whose levels are changed by the SKY-0515 drug are huntingtin and, perhaps serendipitously, PMS1.
Lowering huntingtin levels is one of the main approaches companies are testing in the clinic to try and treat HD. The idea is that by reducing the levels of the toxic, expanded form of the protein made in people who have the gene for HD, we can target the root cause of the disease. SKY-0515 is actually a “total” huntingtin lowering drug, meaning it lowers both the expanded and regular forms of the huntingtin protein.
With multiple huntingtin-lowering approaches now in clinical trials, the HD community is closer than ever to finding therapies that go beyond symptom management.
PMS1 also seems to be targeted by this drug. PMS1 is a DNA repair protein that, when reduced, is thought to slow the “somatic expansion” of CAG repeats. This is the molecular process that makes CAG repeats longer in some cells in the body over time. By reducing the toxic huntingtin protein and also potentially slowing down another one of the disease drivers, the scientists at Skyhawk think they might get a 2 for 1 effect with this drug.
Testing the waters with SKY-0515
This Phase 1 trial is actually divided into three parts (A, B, and C) and the results we are learning about yesterday come from part C of the trial, which is testing the drug in people with HD. Parts A and B looked at the drug in healthy people without the gene for HD and we already learned about how the drug was working in a previous update from Skyhawk. That update showed the drug appeared safe and working as expected to lower huntingtin in the people in which it was tested.
Part C of this trial tested 2 different doses of the drug, a low (3 mg) and high (9 mg) dose, and also included people who received a placebo sugar pill. Folks in the trial are then monitored and all sorts of measurements are made from samples, like blood, to see how well the drug might be working. Safety is the top priority in Phase 1 trials, but other data is collected too to give insights into designing the next round of trials and see if the drug appears to work as expected.
As with all Phase 1 trials, the primary goal of this trial is safety of SKY-0515. However, at the same time, they’re collecting data from blood samples to measure huntingtin and PMS1 to get an indication if the drug is doing what it’s intended to do.
So what’s new?
In this latest update, we got some interim data about Part C of the trial – where they test this drug in people with HD. Skyhawk reported that the drug appears to be generally safe at the doses tested – great news! SKY-0515 was also reported in this update to get into the brain very effectively, a critical challenge for HD therapies.
We also learned that the drug seems to do a good job of lowering the levels of the huntingtin protein, with data shared up to day 84 (12 weeks) into the study. In fact, the more drug participants got, the more lowering Skyhawk could measure in the blood. This “dose-dependent” lowering is a favourable hallmark researchers look out for when testing a new drug and fine-tuning what dose might work best.
Why is this important?
The results so far suggest that SKY-0515 can lower huntingtin protein in people with HD to a greater extent than has been reported before with a pill. That’s exciting, because until now most huntingtin-lowering approaches have required injections or infusions into the spinal fluid, which are far less convenient and come with additional safety challenges. Having an oral drug that can reach the brain effectively and reduce huntingtin to this degree is a very encouraging step forward.
Another promising feature of SKY-0515 is that it does more than just lower huntingtin. It may also reduce levels of PMS1, a protein involved in the process that makes CAG repeats longer in some cells over time. By targeting both huntingtin and PMS1 at once, SKY-0515 could potentially tackle HD through two different disease mechanisms.
Professor Ed Wild, HDBuzz Editor Emeritus, who is involved in the study, summed it up by saying:
“This is what success looks like at the 3-month timepoint, setting the stage for meaningful impact for people living with HD across the world – for whom an orally administered huntingtin-lowering treatment such as SKY-0515 would be truly transformative.”
What we still don’t know
It’s worth pointing out that this update from Skyhawk is still quite limited in details. While the company shared a graph showing reductions in huntingtin protein levels by dose, they didn’t provide all the details behind some of the claims.
The most recent press release suggests that SKY-0515 lowers PMS1, but we’ve not yet seen this data. This would be fantastic if it lowered PMS1 to a meaningful level! But without the data, we don’t know if the levels to which PMS1 are lowered would be considered significant. So the questions remain: How much is PMS1 being lowered by SKY-0515? Is PMS1 being lowered to a level that would be meaningful? Is the lowering of PMS1 significant enough to influence somatic expansion of the CAG repeat within the huntingtin gene?
This kind of early communication is sometimes called “science by press release.” The full picture, including the more complete results from this trial, won’t be available until mid-2026. So, while these first signs are encouraging, it’s important to keep expectations realistic and remember that there’s still a lot we don’t yet know.
So what happens next?
After the first 3 months, people in the study will keep taking SKY-0515 in a longer follow-up, where everyone stays on treatment at a low or a high dose for up to a year. We should hear the main results from this part of the trial in mid-2026.
At the same time, a bigger Phase 2/3 study called FALCON-HD is already underway across 10 sites in Australia and New Zealand. This trial will involve about 120 people with stage 2 or early stage 3 HD, as per the HD Integrated Staging System or HD-ISS, and will test different doses of SKY-0515 to be compared with placebo. Importantly, this study will not just look at effects beyond safety and levels of huntingtin and PMS1. It will also see if the drug can help with symptoms like movement, thinking, and daily life, and whether it influences how the brain structure changes with HD.
Full results from the ongoing Phase 1 trial are expected by mid-2026. At the same time, a larger Phase 2/3 study called FALCON-HD is underway, testing the ability of SKY-0515 to target both huntingtin and PMS1 while measuring signs and symptoms of Huntington’s disease.
What does this mean for the HD community?
For people affected by HD, these results are both hopeful and cautious news. On the hopeful side, SKY-0515 is the first oral therapy to achieve such strong huntingtin lowering in people with HD that can be fine-tuned by changing the dose of the drug. SKY-0515 also seems to target PMS1, potentially tackling an additional potential driver of HD. Most importantly, the drug appears to be generally safe.
By reducing the toxic huntingtin protein and also potentially slowing down another one of the disease drivers, the scientists at Skyhawk think they might get a 2 for 1 effect with this drug.
That said this is very early data in a small group of people with HD. The trial is also focused on safety and whether the drug is working as expected, but not whether it can slow, halt, or reverse symptoms of HD. It will take larger, longer trials to know if SKY-0515 actually slows or improves the course of HD.
Still, this is a big step forward for the field. With multiple huntingtin-lowering approaches now in clinical trials, the HD community is closer than ever to finding therapies that go beyond symptom management.
Summary
SKY-0515 is an oral drug that alters RNA processing, lowering levels of huntingtin and potentially PMS1, a DNA repair protein linked to CAG repeat expansion in Huntington’s disease (HD).
Phase 1 results show safety and brain penetration, with dose-dependent reductions in huntingtin protein—greater than previously achieved with an oral therapy.
Dual targeting of huntingtin and PMS1 could provide a “two-for-one” therapeutic effect, addressing both toxic protein buildup and CAG repeat expansion, though PMS1 data remain limited.
Next steps: Full Phase 1 results are expected in mid-2026, while the larger Phase 2/3 FALCON-HD trial is already underway to test effects on symptoms, brain changes, and overall disease progression.
People living with Huntington’s disease (HD) experience changes in their thinking, memory, and behaviours. This is anarea of HD that is widely studied and fairly well understood. However, sometimes people with HD don’t realize these changes are happening. This is actually a symptom known as anosognosia. This symptom isn’t the same as being in denial, where a person avoids reality while still being aware of it.
A recent study used MRI to explore why anosognosia happens in people with HD and what parts of the brain are involved. The findings help explain why people with HD don’t see or feel the symptoms that the people around them notice and why that is important for safety and understanding of the disease. Let’s get into what the researchers found, and what this means for the HD community.
Ignorance isn’t always bliss
Anosognosia can be mislabelled as stubbornness or laziness and dismissed as denial of a diagnosis. It can create major challenges for people with HD, their families, and caregivers. If a person does not realise they are sick, they may refuse or delay medical support, make unsafe decisions, or perhaps strain their relationships with family members and caregivers who are trying to help.
This study aimed to understand what is going on physically in the brain when this challenge presents itself. If these scientists can see physical changes that could be linked to anosognosia, they can help physicians, caregivers, and researchers better support people with
HD and understand why they might be unable to recognize their own symptoms. With this knowledge we could reduce the tendency to blame the impacted person and break the “stubbornness” stigma.
A photoshoot for your brain
To investigate anosognosia, researchers looked at MRI (short for magnetic resonance imaging) scans from 570people (males and females). These scans came from two large research projects, the PREDICT-HD and TRACK-HD studies. Many participants were premanifest HD (HD-ISS stage 0), or in early stages of the disease (HD-ISS stage 1).
The MRI scans are essentially detailed pictures of the different structures inside the brain. Think of it like a super high-quality camera that uses magnets and radio waves to take pictures. Getting an MRI can be scary – it’s large, loud,and intimidating. But it is also powerful!
MRIs are intimidating machines, but they are really just like fancy cameras that take super close up pictures. It doesn’t hurt but you do have to stay still so the pictures aren’t blurry!
Here’s how it works: the machine is like the magnets on your fridge, except much larger and stronger. The hydrogen atoms that make up the water in our bodies act like micro magnets that are spinning in every direction (each one like a tiny Earth spinning on its own axis). When you enter the MRI machine, the big magnet makes the spins of the hydrogen atoms align. Then it sends out radio waves that push the hydrogen atoms out of place. Eventually they fall back to their original positions, giving off signals that the computer can detect. The computer takesall those signals and turns them into an image. All the thumping and buzzing sounds you hear are the quick electrical changes happening to the coils of the machine (the wires carrying the
electricity) to get the best images. It causes no damage, emits no radiation, and teaches us a lot about what’s happening inside our bodies – an all-round win!
But how do you measure a symptom someone is unaware of?
Since anosognosia means not being aware of your own symptoms, it can’t be measured directly. They used a questionnaire called the Frontal Systems Behaviour Scale (FrSBe). The person with HD and a companion who knows them well (caregiver or family member) filled out the survey. The questionnaire asked about things like behaviour, thinking and emotions. Comparing how the two responded to questions allowed them to observe the differences in how they view the symptoms (e.g., loss of energy, impulsivity, problems with organization).
Think of it like using two weather apps, where the app you use consistently misreports the temperature. If your weather app says it’s 20°C, and a friend’s app says 0°C for the same location, you may go outside without a sweater because you didn’t get an accurate reading of what the temperature really is. In the same way, a person with HD may think they are fine and rate their symptoms low, while a caregiver who sees what the symptoms truly are will rate their symptoms high. The bigger the gap in scores, the more unaware the person is of their symptoms, potentially impacting the person’s care.
The group used this gap to measure how much anosognosia the person with HD was experiencing. Then they ran the numbers, looking for connections between these score differences and saw is this tallied with what they saw in the MRI scans.
Comparing the outside temperature on two smart phones can lead to a false sense of reality for the temperature. Comparing two sets of answers to a survey ranking behaviours associated with HD allows researchers to see how a person’s view of their symptoms (their sense of reality) is different from an outside perspective.
What did the study find?
The study found that seven brain regions were closely linked to anosognosia in people with HD – the globus pallidus, putamen, caudate, basal forebrain, substantia nigra, angular gyrus, and cingulate cortex. Each of these regionshas a special job, but many of them help with movement, learning, memory and emotion.
Through further investigation, one region in particular stood out: the globus pallidus. This region was thestrongest predictor of anosognosia in the study. This means that people with more globus pallidus atrophy (shrinkage) tended to be less aware of their symptoms.
The globus pallidus helps in controlling movements and makes sure our movements are smooth and efficient. In many HD studies and in the clinic, researchers tend to focus on the caudate and putamen, but this study suggests that changes to the globus pallidus could contribute to some of the symptoms of HD, especially when it comes to anosognosia.
What does this mean for HD families?
This research shows that anosognosia in HD is not about having a bad attitude, it’s linked to real brain changes. Being able to recognize the neurological side of things gives families and caregivers a better understanding of why people might not see their symptoms. It reduces the stigma and blame that is often misunderstood, and empowers safer decision making, and opens doors to new care strategies in the future. When we recognise that someone isn’t ignoring their illness on purpose, we can replace frustration with compassion.
Finally, a huge thank you to all the participants and families who contributed to the data sets used in this study. Your donation of brain data is a generous decision that will continue to provide new information and advance research. The studies you help build, like this one, stress the importance of working with the brain, and not against it and brings us one step closer to fully understanding the HD brain!
TL;DR
People with HD often experience anosognosia (a lack of awareness of their own symptoms).
A recent study used MRI data from over 500 people to explore brain regions linked to anosognosia.
Researchers used a questionnaire to compare perspectives of caregivers and people with HD across different symptoms and used the gap between the two to measure anosognosia.
Seven brain regions were linked to anosognosia, with the globus pallidus standing out as the most significant.
These findings show that anosognosia in HD is linked to biological changes, not behavioral concerns. Knowing this can help families and caregivers respond with more empathy and better care.
Jenna Hanrahan is a PhD student at Memorial University in Newfoundland, Canada, under the supervision of Dr. Lindsay Cahill. Her research focuses on using medical imaging techniques such as MRI and ultrasound to better understand brain changes associated with HD. Jenna hopes her findings will contribute to the development of novel therapies for the disease.
This year, the HDBuzz Prize is brought to you by the Hereditary Disease Foundation (HDF), who are sponsoring this year’s competition.
Pridopidine has been under investigation as a treatment for Huntington’s disease (HD) since the early 2000s. The most recent Phase 3 trial testing to see if pridopidine might improve signs and symptoms of HD, a study called PROOF-HD, did not meet its key goals. Furthermore, this summer we learned that the European Medicines Agency (EMA) did not accept Prilenia’s application to market pridopidine for the treatment of HD in Europe.
While we’ve known about the overall outcome of the PROOF-HD study for quite some time, it’s important to acknowledge a new major research milestone: publication of the trial results in a medical journal. Publishing clinical trial data can take a while – especially in a prestigious journal like Nature Medicine, where the PROOF-HD results appear.
This is an important opportunity for the investigators involved in this clinical trial to lay out all the details, and to share detailed analyses that can help determine next steps for a drug. Let’s get into what the PROOF-HD investigators report.
What the paper adds
Prilenia has publicly shared the data from the PROOF-HD study over the course of the last few years, at HD conferences and other research events. This recent paper reiterates the main points – overall, pridopidine did not improve how people with HD function or move, compared to a placebo.
Like any clinical trial publication, this one examines the nitty-gritty of the data, including instances of safety issues and side effects. Importantly, pridopidine remains safe and is tolerated well by the vast majority of participants.
What’s most notable about this paper is that it places a lot of emphasis on analyses that split up the participants into different groups, depending on the other types of medications they were taking while they participated. As with most HD trials, PROOF-HD allowed people to continue taking drugs to control chorea, like tetrabenazine and deutetrabenazine, and drugs that can help with both chorea and behavioral symptoms, like risperidone and olanzapine – among many others. These anti-dopaminergic medications (ADMs) are commonly used to manage various movement and psychiatric symptoms of HD.
When Prilenia analyzed data only from those who were not taking ADMs (less than half of the participants), they observed some potential trends. Starting at about six months, up until about a year, those taking pridopidine and no ADMs seemed to do slightly better on some clinical tests of function, movement, and thinking than those taking placebo. But by the end of the study (about 18 months), this was no longer the case – the groups had both declined by about the same amount.
This recent paper reiterates the main points – overall, pridopidine did not improve how people with HD function or move, compared to a placebo.
Mining the data for more
This recent paper places strong emphasis on how the data was sliced, diced, and examined from multiple angles to check for any clues that pridopidine could have promise for some people with HD. They used specialized maths and statistics to ask more questions about the full group of participants, as well as only those taking ADMs.
This recent paper places strong emphasis on how the data was sliced and diced to check for any clues that pridopidine could have promise for some people with HD.
For example, looking at performance using a multi-pronged clinical score that combines information from multiple tests across the spectrum of HD symptoms (the cUHDRS), what percentage of people improved by 5% or more? More people in the pridopidine group met this threshold than in the placebo group, but depending on the participants and time points they analyzed, this wasn’t always a clear cut result. From other mathematical angles, individual tests of movement and memory also had quite mixed results.
Some of these analyses were planned from the start (pre-specified), while others were decided upon later (post hoc). The paper contains clear language that the results should be interpreted with caution – and interpretation is in fact challenging. There were some promising trends in a minority of participants who were not taking common medications to manage their HD symptoms. But because the group sizes were small, the authors state that “the findings were not powered to support definitive conclusions,” meaning that the results must be taken with a hefty pinch of salt.
Progress in publication
The PROOF-HD study was designed to ask whether pridopidine is safe and whether it is effective at slowing decline of function and movement symptoms in people with HD. The study unfortunately did not meet its primary or secondary endpoints – its overall goals. Given the positive trends they observe in a portion of the folks in the trial, it’s possible that yet another study in a different segment of the HD population (those not managing their symptoms with ADMs) could have some promise, or that small changes could be more meaningful over time. This hope has buoyed pridopidine through 20 years of study, across trials varying in dosing regimens, HD participant populations, and outcome measures, in pursuit of evidence for benefit. This hope is driving Prilenia and their partner Ferrer to continue development plans.
A clinical trial paper comes to fruition through the efforts of researchers, clinicians, and industry scientists who ran the study, as well as external reviewers and steering committees, which often involve community members.
Even when studies of experimental HD treatments don’t turn out how we’d hoped, publication is the gold standard for responsible sharing of data within the scientific community. The publication process – which can sometimes take years – allows for careful review, analysis, and presentation of all relevant data. A clinical trial paper comes to fruition through the efforts of researchers, clinicians, and industry scientists who ran the study, as well as external reviewers and steering committees, which often involve community members.
Starting at about six months, up until about a year, those taking pridopidine and no ADMs seemed to do slightly better on some clinical tests of function, movement, and thinking than those taking placebo. But by the end of the study (about 18 months), this was no longer the case – the groups had both declined by about the same amount.
Hope and human variability
Publication is also an opportunity to craft a story that fosters momentum, in this case by focusing on a subset of the data. ADMs include quite a few drugs that are helpful for managing a range of HD symptoms, from unwanted movements and behaviors, to sleep disruptions and anxiety. Each individual responds differently to their prescribed medications, especially as a complex disease like HD progresses. This paper emphasizes that ADMs, while important for managing HD, introduce a degree of variability into tests designed to measure changes in movement, motivation, and problem solving. In short – humans and health are complex.
The hope is that a truly effective drug would overcome that variability. Some scientists and doctors think that if certain subgroups of people may benefit from pridopidine, further research should clarify which ones and determine how best to measure meaningful change. Others question whether continued trials are justified. What’s clear is the tremendous contribution of the HD community: the many brave individuals who participated in PROOF-HD and other trials of pridopidine, some of whom felt that the drug made a difference in their lives.
Summary
Pridopidine has been tested for HD for 20+ years; the Phase 3 PROOF-HD trial did not meet its main goals
The drug was safe and well-tolerated, but showed no overall benefit compared to placebo
Subgroup analyses hinted at short-term improvements in participants not taking anti-dopaminergic medications, but these faded by 18 months
Results were exploratory and not definitive, so must be interpreted with caution
Publication in Nature Medicine makes the full data available, ensuring transparency and learning for the HD community
A group of researchers at the University of Pennsylvania, USA, has recently carried out an investigation to explore whether using a type of talking therapy, called Acceptance and Commitment Therapy (ACT), can help improve the mental wellbeing of people affected by Huntington’s disease (HD). The study, published in the Journal of Huntington’s Disease, combines a short review of earlier work on ACT with the detailed report on a person with HD who underwent an online caregiver-assisted ACT programme. The results showed promising effects of ACT on a number of psychological difficulties in both the person with HD and his caregiver.
Psychological Difficulties in HD
HD is associated with a heavy psychological load. Alongside the well-known movement and cognitive problems, people with HD often face psychological difficulties such as depression, anxiety, irritability, apathy, emotional dysregulation, obsessions, and ‘perseverative’ behaviours (i.e., getting stuck on the same thoughts or actions). These issues can be experienced even years before the onset of movement problems (i.e., at the ‘premanifest’ stage, HD-ISS stage 0) and have been linked with a risk of suicide which is two to seven times higher than in the general population. Growing up within an HD family has also been linked to increased experiences of childhood trauma.
In addition, since HD is inherited, taking a predictive genetic test can be exceptionally stressful from a psychological perspective and lead to difficult family dynamics, which may explain why less than one in four persons at risk worldwide choose to get tested. At the same time, caregivers of people with HD – often represented by partners, relatives, or friends – may also experience several psychological difficulties, including burnout, anxiety, depression, as well as social issues such as stigma and isolation.
What Support Can HD Families Get?
Although access to psychological support is often mentioned as a top priority by HD families, the current landscape of psychological interventions for this population is extremely limited, with very few studies carried out so far and no gold-standard recognised approach. In addition, the availability of psychological support tends to vary dramatically both between countries as well as even within the same country, as specific regions may have fewer opportunities and resources.
This limited availability is perhaps unsurprising when we consider how emotional and behavioural difficulties in people with HD have been traditionally seen under a purely biomedical lens, which means that common issues such as high levels of anxiety and low mood are often considered a consequence of brain degeneration, and not a reflection having to adjust to the fact that, you know, having HD really sucks.
What is Acceptance and Commitment Therapy (ACT)?
Acceptance and Commitment Therapy (ACT) is a modern form of psychotherapy which, in a nutshell, aims to help people make room for difficult thoughts and feelings while moving towards what matters most to them. The approach is based on six main principles/skills:
Acceptance: making room for tough feelings instead of fighting them.
Defusion: noticing thoughts and separating oneself from them.
Being Present: paying attention to what is happening right now, without ‘replaying’ the past or jumping to the future.
Self-as-Context: remembering that one may havethoughts and feelings but is not defined by them.
Values: knowing what kind of person one wants to be and what matters to them.
Committed Action: taking small, steady steps that match one’s values, even when feelings are tough.
These skills are often taught and practised through metaphors and short exercises which can be carried out in person or virtually, as well as in one-on-one or group therapy sessions.
Crucially, unlike some other forms of psychotherapy such as traditional Cognitive Behavioural Therapy (CBT), ACT does not ask people to challenge sad or difficult thoughts or to prove them wrong, but rather to change their relationship with them. This is particularly helpful for individuals affected by HD, as it acknowledges and respects the genuine losses, fears, and worries associated with the condition.
Acceptance and Commitment Therapy (ACT) is an approach that promotes acceptance of tough thoughts and feelings, focus on the present, and value-guided actions to lead a meaningful life.
A Review of Earlier ACT Work
ACT was developed in the late 1980s by the American psychologist Steven C. Hayes as an evolution of traditional Cognitive Behavioural Therapy (CBT). Since then, over 900 randomised trials have investigated the efficacy of this approach, including one from the World Health Organisation (WHO), which now formally distributes it as a form of therapy.
ACT has shown benefits in tackling depression, anxiety, suicidality, and substance misuse across several chronic conditions – such as cancer, obesity, hearing loss, and chronic pain – as well as neurodegenerative illnesses more akin to HD, including Parkinson’s, multiple sclerosis, and amyotrophic lateral sclerosis. Despite this, no formal exploration of ACT with people with HD had been published until this study.
The Case Report
A 52-year-old white American man (whom we shall call ‘Alan’ in this article), living with HD as well as bipolar and obsessive-compulsive issues, was invited by the authors’ US clinic to undergo a six-session ACT programme adapted from earlier work in other chronic conditions (e.g., HIV, cystic fibrosis, and cancer). All meetings took place online between May and June 2022. Alan attended these alongside his ex-wife, who was also his main caregiver and close friend. Her presence was found to be especially helpful in calming Alan’s anxiety and facilitating exercises and homework between sessions.
Each session was inspired by one of ACT’s six core principles/skills:
Session 1 helped the pair list their top five values and notice obstacles – what did Alan stand for and what got in his way?
Session 2 introduced acceptance through metaphors showing how struggling to control feelings can make things worse – e.g., how did Alan try to avoid or push away anxiety, depression, and worries about HD?
Session 3 focused on committed actions – what small, yet consistent moves towards values could Alan take even on bad days?
Session 4 taught present-moment awareness and normalised acceptance of painful thoughts – how could Alan allow anxiety, depression, and fears about cognitive decline and life expectancy to be here now?
Session 5 practiced defusion – how could Alan change his mind’s attachment to his thoughts?
Session 6 summarised previous sessions and explored the idea of self-as-context – how could Alan remind himself he was more than his own feelings or a diagnosis and create flexibility by changing his habits?
Before and after therapy, Alan took a series of standardised questionnaires to measure anxiety, depression, defusion, and quality of life.
The presence of Alan’s caregiver was especially helpful in calming his anxiety and facilitating exercises and homework between sessions.
What Changed After Therapy?
At the end of therapy, Alan’s depression score dropped from ‘moderate’ to ‘mild’, showing a clinically significative change. His quality of life scores also improved in physical function, general worries, and mood, and he was overall found to be less ‘hooked’ on troubling thoughts (i.e., higher ‘defusion’). On the other hand, Alan’s anxiety remained ‘moderate’, which may be due to his long history of obsessive-compulsive difficulties. Beyond these scores, Alan also mentioned that the sessions were enjoyable and useful, and his caregiver found them helpful in realising she had been neglecting her own self-care and to start finding some time for herself.
What Does This Mean?
Since this was a single case study without a control group, we need to be careful not to overstate the significance of its results. However, Alan’s decrease in depression, increase in defusion, and improvement in quality of life after only six sessions do suggest that ACT may be a viable and helpful psychotherapy approach for people with HD. Randomised controlled trials (RCTs) are now needed to compare ACT with usual care or other psychotherapies, explore different delivery formats, and monitor efficacy across different HD stages.
TL;DR
HD is associated with significant psychological challenges that can affect both people with HD and caregivers.
Psychological care options for HD are scarce, especially due to biomedical perspectives that overlook the burden of adjusting to HD.
Acceptance and Commitment Therapy (ACT) aims to help people accept difficult thoughts or feelings and unhook from them, stay present, identify values, and take value-guided actions.
A team at the University of Pennsylvania explored the adoption of an online caregiver-assisted ACT program with a 52-year-old man with HD.
The results showed improvements in the man’s depression, quality of life, and feeling ‘hooked’ on thoughts; his caregiver found the sessions helpful for her self-care.
ACT looks promising for people with HD, but evidence is preliminary until more comprehensive trials are carried out.
Dr Nicolò Zarotti is an Academic and Clinical Psychologist working in Neuropsychology. He holds a BSc and an MSc in Psychology from the University of Trieste, a PhD in Health Research from Lancaster University, a Doctorate in Clinical Psychology (ClinPsyD) from the University of East Anglia, and a Postgraduate Diploma (PGDip) in Clinical Neuropsychology from the University of Glasgow. He is a Chartered Psychologist (CPsychol) and Associate Fellow (AFBPsS) of the British Psychological Society, an HCPC-registered Practitioner Psychologist, and a Fellow of the Higher Education Academy (FHEA). Dr Zarotti’s main research and clinical work, carried out between the Manchester Centre for Clinical Neurosciences and the University of Leeds, revolves around developing psychological approaches to mental health and cognitive difficulties in people with neurodegenerative conditions such as Huntington’s disease, Parkinson’s disease, motor neurone disease, and multiple sclerosis.
This year, the HDBuzz Prize is brought to you by the Hereditary Disease Foundation (HDF), who are sponsoring this year’s competition.
We know that HD affects how we move, think, and feel but these symptoms don’t appear overnight. Tiny hidden changes in the brain can begin years before a diagnosis. One way that scientists can detect these early shifts is by measuring brainwaves. This is a painless, non-invasive way to see how the brain is working during rest or while performing simple tasks.
A recent study used this approach to see whether people who carry the HD gene, both before and after symptoms start, show differences in how their brains respond to unexpected noises. The result of this study suggests that even in the “silent” pre-manifest stage of HD (HD-ISS stage 0), the brain’s automatic reactions are already changing. This could open the door to new ways of tracking HD’s earliest effects.
Eavesdropping On The Brain’s Electrical Chatter
You might remember Sherlock Holmes saying, “The world is full of obvious things which nobody by any chance ever observes.” When it comes to HD, that seems to be especially true. While we often notice the louder, more obvious, symptoms of HD like movement difficulties, mood changes or thinking problems, the brain can “whisper” clues for years beforehand. The challenge for researchers is learning how to listen.
Our brains are constantly alive with tiny bursts of electricity zipping along and between neurons. Even when we’re resting or not paying attention, this electrical chatter never stops. Imagine a stadium full of fans. From far away, you can’t hear individual conversations, but you can tell when the crowd gasps at a near goal, bursts into cheers, or suddenly falls silent. That’s how brainwaves work, rhythmic electric signals made by networks of brain cells talking to one another.
To “hear” these brainwaves, researchers use a very fancily named tool called electroencephalography, or EEG, for short. It’s painless, requires no needles, and simply involves placing small sensors on the scalp. EEG doesn’t read our thoughts (sorry, no mind reading here!), but it does detect patterns and timing of brain activity. A bit like noticing when the crowd shifts from calm murmuring to roaring cheers.
The Brain’s Surprise Detector
In this study, researchers were particularly interested in a certain brainwave signal called mismatch negativity (MMN). Think of MMN as your brain’s “surprise detector.” Even if you aren’t paying attention, your brain automatically notices when something changes around you.
Picture yourself on a long train journey, listening to the steady click-clack of the train on the tracks. If one clack sounds different, louder, or higher pitched, your brain reacts instantly, even if you’re daydreaming. That small, automatic reaction is what MMN represents.
Even when you’re daydreaming, your brain notices small changes around you, just like spotting a different click in the rhythm of a train on its tracks.
To test this, researchers invited people with the HD gene (both with and without symptoms) as well as volunteers without the gene. While wearing an EEG cap, participants listened to a series of steady beeps, with the occasional odd “bleep” slipped in. EEG measured how strongly and consistently each person’s brain reacted to the odd sounds.
What the Study Found: Cracking Open The Brain’s Whispering
When the results were compared, one pattern stood out. People with symptoms of HD had smaller MMN signals, especially at the front of the brain. This suggests their automatic “something’s different” response was weaker.
People who carried the gene but had no symptoms yet did not show a reduction in MMN signal size. But their brainwave timing told an interesting story. The researchers looked at something called theta phase coherence, a fancy way to measure precisely how the brain’s rhythm lined up each time a surprise sound occurred.
In people without symptoms but who carry the HD gene, their theta phase coherence was higher than in both people with symptoms and those without the HD gene. This is interesting for us as this finding suggests that perhaps the brain is trying to overcompensate, like a drummer keeping an unusually strict beat to hold the rest of the band together. These brainwave changes may be the brain’s way of coping, helping it keep things working in the early stages of the disease.
Why Does This matter?
Think of your brain like an orchestra. In healthy brains, the instruments (neurons) keep perfect time, adjusting smoothly to new notes (unexpected sounds). In early HD, the orchestra might still sound fine to an outside listener, but behind the scenes, the conductor is working overtime to keep everyone in sync, maybe even counting every beat twice.
In early HD, the brain’s “conductor” may work overtime to keep the orchestra playing in time.
This extra timing consistency in people with the HD gene but without symptoms, could be that overworked conductor. The brain finding clever ways to compensate before symptoms emerge. In people with symptoms, that compensation may no longer be enough, leading to weaker responses.
What This Doesn’t Tell Us (Yet)
Like all early-stage research, this study has limits. It involved a relatively small number of participants (25 people with HD symptoms and 14 people carrying the HD gene without symptoms) , so larger studies will be needed to confirm these patterns. In this study, brainwave changes didn’t directly match the results of the other HD symptoms tests the team used, such as thinking, mood or movement assessments typically used in HD research. That doesn’t mean the signals aren’t important, it just means researchers still need to figure out how, or if, these brainwave changes connect to the real challenges people with HD face in their daily lives, like thinking clearly, managing mood, or moving easily.
A Quiet but Promising signal
One of the best parts of this type of research is how easy it is on participants, no tricky tasks, no needles, just sitting back with headphones on while the EEG listens to your brain’s reactions. In the future, this type of test might even be possible at home. Because it’s so simple, it could be repeated regularly, making it a valuable way to track changes over time. A big thank you goes to the amazing participants who made this research possible.
In HD, where the disease can quietly cause damage for years before symptoms appear, that’s a big deal. The sooner we can detect these changes, the earlier we can respond. For now, this research is a promising step, not a finished tool. But it shows that the brain’s whispers are there if we know how to listen. And just like Sherlock Holme said, the clues are often in plain sight, or in this case, plain sound, waiting for someone to observe them.
Summary
Brainwave changes can appear in people with the HD gene before symptoms show.
EEG detects the brain’s automatic “surprise responses” in a painless, simple test.
Early-stage gene carriers show compensating brain activity, while symptomatic HD shows weaker signals.
EEG could become a home-friendly tool to track HD long before obvious symptoms appear.
Eva Woods is a PhD student at Trinity College Dublin, Ireland. Eva completed her BSc in Biological and Biomedical Sciences at Maynooth University, where she worked with the Department of Electronic Engineering on a final-year project investigating EEG-based Brain-Computer Interfaces. Following this, she progressed directly into her PhD at Trinity. A key focus of Eva’s research is identifying early changes in the brain in people who carry the Huntington’s disease gene but have not yet shown symptoms. Her work combines brain imaging (MRI) with techniques such as electroencephalography (EEG), which records tiny electrical signals from the brain, and transcranial magnetic stimulation (TMS), which uses magnetic pulses to safely stimulate brain activity. Through this research, she aims to improve understanding of early disease mechanisms and contribute to the search for new biomarkers of disease progression. Eva is also passionate about science literacy and engaging Huntington’s disease families in Ireland with research. Each year, she hosts “TCD’s Huntington’s Disease Research Day”, which brings together researchers, clinicians, advocates, and families from across the country. The event is designed to be welcoming and accessible, with talks delivered in clear, easy-to-understand language and plenty of space for families to ask questions and engage with speakers in a supportive environment.
This year, the HDBuzz Prize is brought to you by the Hereditary Disease Foundation (HDF), who are sponsoring this year’s competition.
