An experimental drug may provide a new treatment option for some patients with rare incurable brain tumours, according to an analysis published in the Journal of Clinical Oncology.
Diffuse midline gliomas are diagnosed in about 800 people per year in the U.S., according to the Centers for Disease Control and Prevention.
A subset of particularly aggressive diffuse midline gliomas are caused by a H3 K27M mutation and the only effective treatment is radiation, as the location of the tumour in the brain makes surgery difficult. Even with radiation, relapse is virtually inevitable and more than 70% of patients with this subtype of brain tumour die from the cancer, according to the National Institutes of Health.
In the study, investigators analysed the results of five previous clinical trials testing the effectiveness of dordaviprone, an experimental drug which works by blocking a certain protein in tumours with the mutation.
The study included results from 50 patients (including four children) with H3 K27M–mutant diffuse midline gliomas and found that 30% of patients responded well to the drug. The most common side effect reported was fatigue, according to the study.
Now, the researchers are launching a trial at Northwestern Medicine hospitals to investigate the drug’s effectiveness in newly diagnosed patients.
A new study published in Life Science Alliance revealed how aberrant epigenetic regulation contributes to the development of atypical teratoid/rhabdoid (AT/RT) tumours, which mainly affect young children. There is an urgent need for more research in this area as current treatment options are ineffective against these highly malignant tumours.
Most tumours take a long time to develop as harmful mutations gradually accumulate in cells’ DNA over time. AT/RT tumours are a rare exception, because the inactivation of one gene gives rise to this highly aggressive form of brain cancer.
AT/RT tumours are rare central nervous system embryonic tumours that predominantly affect infants and young children.
On average, 73 people are diagnosed with AT/RT in the USA each year. However, AT/RT is the most common central nervous system tumour in children under one years old and accounts for 40-50% of diagnoses in this age group. The prognosis for AT/RT patients is grim, with a postoperative median survival of only 11-24 months.
The collaborative study conducted by Tampere University and Tampere University Hospital examined how aberrant DNA methylation distorts cellular developmental trajectories and thereby contributes to the formation of AT/RT. DNA methylation is a normal process of controlling expression whereby methyl groups are added to the DNA strand, adding epigenetic information.
The new study showed that DNA methylation interferes with the activity of multiple regulators, which usually regulate the differentiation and maturation of central nervous system cells during brain development. Disrupted cell differentiation promotes the abnormal, uncontrolled proliferation of cells that eventually form a tumour.
The study also found several genes that regulate cell differentiation or inhibit tumour development and are silenced in AT/RT together with increased DNA methylation.
“These results will provide deeper insights into the development of AT/RTs and their malignancy. In the future, the results will help to accelerate the discovery of new treatments for this aggressive brain tumour,” says senior author Docent Kirsi Rautajoki from Tampere University.
A drug used to treat children with epilepsy prevents brain tumour formation and growth in two mouse models of neurofibromatosis type 1 (NF1), according to a study by researchers at Washington University School of Medicine in St. Louis. NF1 is a genetic condition that causes tumours to grow on nerves throughout the body.
The findings lay the groundwork for a clinical trial to assess whether the drug, lamotrigine, can prevent or delay brain tumours in children with NF1. The study is published online in the journal Neuro-Oncology.
“Based on these data, the Neurofibromatosis Clinical Trials Consortium is considering launching a first-of-its-kind prevention trial,” said senior author David H. Gutmann, MD, PhD, professor of neurology. “The plan is to enrol kids without symptoms, treat them for a limited time, and then see whether the number of children who develop tumours that require treatment goes down.
“This is a novel idea, so we took it to an NF1 patient focus group,” Gutmann continued. “They said, ‘This is exactly what we’re looking for.’ A short-term treatment with a drug that has been used safely for 30 years was acceptable to them if it reduced the chance their children would develop tumours and need chemotherapy that might have all kinds of side effects.”
Optic gliomas, tumours on the optic nerve are the most serious type that those with NF1 get. Such tumours typically appear between ages 3 to 7. Though rarely fatal, they cause vision loss in up to a third of patients as well as other symptoms, including early puberty. Standard chemotherapy for optic gliomas is only moderately effective at preventing further vision loss and can affect children’s developing brains, resulting in cognitive and behavioural problems.
In a previous study, Gutmann and Corina Anastasaki, PhD, an assistant professor of neurology and the first author on the new paper, showed that lamotrigine stopped optic glioma growth in NF1 mice by suppressing neuronal hyperactivity. Intrigued, the Neurofibromatosis Clinical Trial Consortium asked Gutmann and Anastasaki to clarify the connection between NF1 mutation, neuronal excitability and optic gliomas; assess whether lamotrigine was effective at the doses already proven safe in children with epilepsy; and conduct these studies in more than one strain of NF1 mice.
In humans, NF1 could be caused by any one of thousands of different mutations in the NF1 gene, with different mutations causing different medical problems. Repeating experiments in multiple strains of mice was a way of gauging whether lamotrigine was likely to work in people regardless of the underlying mutation.
Anastasaki and Gutmann not only showed that lamotrigine worked in two strains of NF1 mice, they also showed that the drug worked at lower doses than those used for epilepsy, meaning that it was probably safe. Even better, they found that a short course of the drug had lasting effects, both as a preventive and a treatment. Mice with tumours and that were treated for four weeks starting at 12 weeks of age saw their tumours stop growing and even showed no further damage to the retinas. Mice that received a four-week course of the drug starting at 4 weeks of age, before tumours typically emerge, showed no tumour growth even four months after treatment had ended.
These findings have led Gutmann to suggest that a one-year course of treatment for young children with NF1, maybe between the ages of 2 to 4, might be enough to reduce their risk of brain tumours.
“The idea that we might be able to change the prognosis for these kids by intervening within a short time window is so exciting,” Gutmann said. “If we could just get them past the age when these tumours typically form, past age 7, they may never need treatment. I’d love it if I never again had to discuss chemotherapy for kids who aren’t even in first grade yet.”
A new drug for the treatment of a type of brain tumour that strikes young people could soon receive approval by the U.S. Food and Drug Administration. The drug, vorasidenib, could greatly extend the time before further therapy – and eventual resistance – is needed.
In an editorial in the New England Journal of Medicine, David Schiff, MD, the co-director of UVA Cancer Center’s Neuro-Oncology Center, outlines the potential significance of the drug vorasidenib for patients with most low-grade gliomas. The drug was fast-tracked by the FDA in August 2023 based on the strength of the findings, and filings for regulatory approval were made in February 2024. FDA approval is anticipated in the second half of 2024, and its approval in Europe will likely soon follow.
Adult-type diffuse gliomas represent approximately 81% of primary malignant brain tumours. Of those, approximately 20% harbour an isocitrate dehydrogenase (IDH) mutation, including 100% of grade 2 and grade 3 adult-type diffuse gliomas. Approximately 2500 Americans with a median age of only 40 are diagnosed with grade 2 IDH-mutant gliomas each year. The tumours cause steadily increasing disability, eventually become resistant to treatment options and typically prove fatal.
Because of the limited treatment options available, doctors usually take a “watch and wait” approach to managing the brain tumours, holding off on treatment until after the tumour progresses.
In the randomised controlled INDIGO trial, 331 patients received either vorasidenib or placebo. The trial showed that the drug slowed tumour growth significantly and extended the average time until the tumour started growing from 11.1 months to more than 27 months. Vorasidenib also increased the time to next intervention (TTNI), the timeframe before patients need additional treatment such as radio- or chemotherapy.
Schiff, in his editorial, describes the results as “striking.” Vorasidenib’s success could “put a nail in the coffin” of the watch-and-wait approach for such brain tumours, Schiff believes.
“It used to be that we thought of all gliomas as being on a spectrum,” Schiff said. “We now understand that those with the IDH gene mutation have a markedly different biology, outcome and, as this study shows, vulnerabilities that new therapies can exploit.”
If the drug receives approval from the federal Food and Drug Administration, it would become the first targeted therapy for low-grade gliomas. But Schiff notes that there are also other recent advances that are improving our understanding of such gliomas.
“There are still many unanswered questions about how we can best utilise this new medication if and when it receives FDA approval,” Schiff said. “Nonetheless, considering that existing standard therapies for these tumours [radiation and chemotherapy] are tough on patients, with short- and long-term side effects, it will be wonderful to have a useful and very well-tolerated treatment option.”
A neurosurgeon alleged during his employment tribunal that a “gang culture” exists within the neurosurgery department of an NHS hospital already beset by claims of a toxic culture and investigations into negligence.
As reported by the BBC, Dr Mansoor Foroughi was dismissed from University Hospitals Sussex in 2022 for misconduct. At a separate employment tribunal, Krish Singh, the former clinical director for general surgery, claimed that rota changes reduced the number of “safe” consultants, putting patients at risk.
Four whistleblowers had also told the BBC of a “Mafia-like” culture, where patients had died unnecessarily and others “maimed”. These new allegations came to light as the BBC and The Times fought a nine-month court battle to have the employment tribunal documents unsealed.
Dr Foroughi alleges that one colleague was signed off to do complex spinal procedures despite lacking training, another performed procedures with a “disproportionate” mortality rate, and yet another took on private work while on call to the NHS – a serious breach of conduct.
University Hospital Sussex encompasses several hospitals, which includes Royal Sussex Country Hospital, which has been the source of many complaints, and a history of poor service delivery, which was put into special measures between 2016 and 2019.
At least 105 cases of alleged medical negligence from failings at the hospital’s neurosurgery and general surgery departments are being investigated by police. According to court documents, there was “serious dysfunctionality in the neurosurgery department” with “stark divisions between colleagues”.
An investigation by the Royal College of Surgeons found that “a culture of fear” existed in the hospital’s surgery department, and that senior staff were “dismissive and disrespectful”. Two staff were allegedly assaulted.
In a statement, the trust said: “The trust will vigorously contest these claims at the Employment Tribunals, which we are keen take place at the earliest opportunity so they can be examined properly and fairly.
“Dismissing anyone, or removing someone from a leadership role, is an absolute last resort and we would always seek to avoid this outcome if possible.
“In both of these cases, due process was followed, and we are confident we did the right things, in the right way, for the benefit of our patients, their care and safety.”
Neurons in the brain of an Alzheimer’s patient, with plaques caused by tau proteins. Credit: NIH
In findings published in Cell Reports, researchers discovered that the biological instructions within vesicles that communicate between cells differed significantly in postmortem brain samples donated from patients suffering from Alzheimer’s disease.
Small extracellular vesicles (sEVs) are tiny containers are produced by most cells in the body to ferry a wide variety of proteins, lipids and byproducts of cellular metabolism, as well as RNA nucleic acid codes used by recipient cells to construct new proteins.
Because this biologically active cargo can easily elicit changes in other cells, scientists are interested in brain sEVs as a medium for passing along normal as well as bungled instructions for misfolded proteins that accumulate in the brain as neurodegenerative diseases such as Alzheimer’s disease progress.
To be a potential contributor to the buildup of unwanted proteins, sEVs would have to carry blueprints with sufficient information to enable other cells to produce the problematic proteins. Most previous research had indicated that the messenger RNA (mRNA) carrying plans for proteins were chopped into too many shorter fragments to allow recipient cells to change their construction patterns.
“We found quite the opposite to be true in our study,” says senior author Jerold Chun, MD, PhD, professor in the Center for Genetic Disorders and Aging Research at Sanford Burnham Prebys. “We identified more than 10 000 full-length mRNAs through the use of a relatively newer DNA sequencing technique called PacBio long-read sequencing.”
The team isolated sEVs from the prefrontal cortex of 12 postmortem brain samples donated from patients diagnosed with Alzheimer’s disease and 12 from donors without Alzheimer’s disease (or any other known neurological disease). Nearly 80% of identified mRNAs were full-length, allowing them to be transcribed by recipient cells into viable proteins.
“To corroborate the results of long-read sequencing in the human samples, we also looked at vesicles isolated from mouse cells,” says first author Linnea Ransom, PhD, postdoctoral fellow. “We found similar averages of between 78% and 86% full-length transcripts in three brain cell types: astrocytes, microglia and neurons.”
The researchers also compared the sequence of genes reflected in the sEV mRNA transcriptome. In Alzheimer’s disease samples, 700 genes showed increased expression whereas nearly 1500 were found to have reduced activity.
The scientists determined that the 700 upregulated genes are associated with inflammation and immune system activation, which fits within known patterns of brain inflammation present in neurodegenerative diseases such as Alzheimer’s disease. The researchers also found many genes associated with Alzheimer’s disease in prior genome-wide association studies also were present in Alzheimer’s disease sEVs.
“The changes in gene expression contained in these vesicles reveal an inflammatory signature that may serve as a window into disease processes occurring in the brain as Alzheimer’s disease progresses,” says Chun.
Following this study, Chun and team will dig deeper into how cells package sEVs and how the enclosed mRNA codes lead to functional changes in other brain cells affected in Alzheimer’s disease. Better understanding of sEVs and their mRNA contents may enable the discovery of biomarkers that could be used to improve early detection of Alzheimer’s disease and potentially other neurological conditions, while identifying new disease mechanisms to provide new therapeutic targets.
“Additionally, sEVs naturally occur as a vehicle for transporting biologically active cargo between cells, so it also may be possible to leverage them as a targeted delivery system for future brain therapies” says Chun.
Brain organoids (BOs), though often referred to as “mini brains,” are not truly human brains. But the concerns over these lab-grown brain tissues, especially when they are developed from human foetal tissues, can be very human indeed.
In a paper published in EMBO Reports, researchers from Hiroshima University offer valuable insights into the complexities inherent in brain organoid research, highlighting often-overlooked ethical dilemmas for better decision-making, especially for foetal brain organoids (FeBOs).
Brain organoids are three-dimensional human brain tissues derived from stem cells. They replicate the complexity of the human brain in vitro, allowing researchers to study brain development and diseases.
Traditionally, brain organoids (BOs) are grown from pluripotent stem cells, an especially potent sub-type that is typical of early embryonic development, but new technologies now make it possible to generate these organoids from human foetal brain cells.
The research comes amid increasingly heated debates over human BOs. Central concerns are that lab-grown BOs might achieve consciousness and the ethical implications of transplanting them into animal models. The discourse includes matters of consent, commercialisation, integration with computational technologies, and legal ramifications. In addition, the public perception of BOs, often shaped by inaccurate media depictions.
Issues of consciousness arising and transplantation into animal models are particularly morally sensitive for tissue donors, and so rigorous informed consent is needed. With FeBOs, these become even more important. FeBOs, for example, can grow past the developmental stage of the initial foetal donor tissue.
“Our research seeks to illuminate previously often-overlooked ethical dilemmas and legal complexities that arise at the intersection of advanced organoid research and the use of foetal tissue, which is predominantly obtained through elective abortions,” said Tsutomu Sawai, an associate professor at Hiroshima University and lead author of the study.
The study highlights the urgent need for a sophisticated and globally harmonised regulatory framework tailored to navigate the complex ethical and legal landscape of FeBO research. One example is the 14-day rule used in embryo research, as neurogenesis does not occur in embryos prior to 14 days post-fertilisation. Using FeBOs derived from 12-15 week old foetuses therefore raises significant ethical questions, especially as there is a proposed 20-week ethical boundary.
The paper emphasises the importance of informed consent protocols, ethical considerations surrounding organoid consciousness, transplantation of organoids into animals, integration with computational systems, and broader debates related to embryo research and the ethics of abortion.
“Our plan is to vigorously advocate for the development of thorough ethical and regulatory frameworks for brain organoid research, including FeBO research, at both national and international levels,” said Masanori Kataoka, a fellow researcher at Hiroshima University.
“Rather than being limited to issues of consciousness, it’s imperative, now more than ever, to systematically advance the ethical and regulatory discussion in order to responsibly and ethically advance scientific and medical progress,” Sawai said.
Moving forward, the research duo plans to continue supporting the advancement of ethical and regulatory discussions surrounding brain organoid research. By promoting responsible and ethical progress in science and medicine, they aim to ensure that all research involving brain organoids, including FeBOs, is conducted within a framework that prioritises human dignity and ethical integrity.
People with aphantasia – who cannot visualise an image in their mind’s eye – are less likely to remember the details of important past personal events or to recognise faces, according to a review of nearly ten years of research. People who cannot bring to mind visual imagery are also less likely to experience imagery of other kinds, like imagining music, according to new research by the academic who first discovered the phenomenon.
Professor Adam Zeman, of the University of Exeter, first coined the term aphantasia in 2015, to describe those who can’t visualise. Since then, tens of thousands of people worldwide have identified with the description. Many say they knew they processed information differently to others but were unable to describe how. Some of them expressed shock on discovering that other people can conjure up an image in their mind’s eye.
Now, Professor Zeman has conducted a review of around 50 recent studies, published in Trends in Cognitive Sciences, to summarise findings in a field that has emerged since his first publication. Research indicates that aphantasia is not a single entity but has subtypes. For example, not everyone with aphantasia has a poor autobiographical memory or difficulty in recognising faces, and in a minority of people, aphantasia appeared to be linked to autism. People who cannot visualise are more likely to have scientific occupations. Unexpectedly, although people with aphantasia can’t visualise at will, they often dream visually.
Professor Zeman’s review provides evidence that whether people have aphantasia or hyperphantasia – a particularly vivid visual imagination – is linked to variations in their physiology and neural connectivity in the brain, as well as in behaviour. For example, listening to scary stories alters skin conductance in those with imagery, meaning people sweat – but this does not occur in people with aphantasia.
Aphantasia is thought to affect around 1% of the population, while 3% are hyperphantasic. These figures rise to 5–10% with more generous criteria for inclusion. Both aphantasia and hyperphantasia often run in families, hinting at the possibility of a genetic basis.
Professor Zeman, who now holds honorary contracts at the universities of Exeter and Edinburgh, said: “Coining the term ‘aphantasia’ has unexpectedly opened a window on a neglected aspect of human experience. It is very gratifying that people who lack imagery have found the term helpful, while a substantial surge of research is shedding light on the implications of aphantasia.
“Despite the profound contrast in subjective experience between aphantasia and hyperphantasia, effects on everyday functioning are subtle – lack of imagery does not imply lack of imagination. Indeed, the consensus among researchers is that neither aphantasia nor hyperphantasia is a disorder. These are variations in human experience with roughly balanced advantages and disadvantages. Further work should help to spell these out in greater detail.”
“I struggle to fully immerse myself in role-play with my children”
Solicitor Mary Wathen’s frustration that she struggled to engage in role playing games with her two young children, when she found all other engagement with her children so fulfilling, was her sign that she had aphantasia, meaning she cannot visualise imagery.
The 43-year-old, from Newent near Cheltenham, said: “One of my friends said that he uses the images in his head to enhance role play. When I asked him to explain this in more detail it became clear that he – and everyone else in the room – could easily create an image in their head and use that as the backdrop for the role play. This was totally mind-blowing to me. I just cannot understand what they really mean – where is this image and what does it look like? To me, unless you can see something with your eyes, it’s not there.”
Mary’s shock intensified when she realised her husband, has such vivid visual imagery that he is probably hyperphantasic. “He thinks in moving pictures, like movies – sometimes to the point that he can mistake those thoughts for memories. To me, that’s unfathomable.”
Mary has come to realise that her lack of visual imagery may well account for her difficulties with memory. She said: “I can comprehend and retain concepts and principles really well but I’m unable to recall facts and figures. I can’t recreate something in my head or ‘re see’ something that is not actually there in that moment.
“I’ve found it quite saddening to learn that other people can call to mind an image of their children when they’re not there. I’d love to be able to do that, but I just can’t – but I’ve learned to compensate by taking plenty of photos, so that I can relive those memories through those images.
“Whilst I’m sure there are wonderful advantages to being able to think in pictures, I think it’s important to remind myself that there are advantages to having aphantasia too. I’m a really good written and verbal communicator – I think that’s because I’m not caught up with any pictures, so I just focus on the power of the word. I’m also a deeply emotional person and perhaps that’s my brain’s way of overcompensating; I feel things as a way of experiencing them, rather than seeing them.
“I think it’s really important to raise awareness that some people just don’t have this ability – particularly as using visual imagination is a key way that young children are taught to learn and engage. Primary teachers need to know that some children just won’t be able to visualise and that could be why they’re not engaging in those kinds of activities. We need to ensure we cater for everyone and encourage other ways of learning and engaging.”
Disturbed gut flora during the first years of life is associated with diagnoses such as autism and ADHD later in life. One explanation for this disturbance could be from antibiotic treatment. This is according to a study led by researchers at the University of Florida and Linköping University and published in the journal Cell.
The study is the first prospective study to examine gut flora composition and a large variety of other factors in infants, in relation to the development of the children’s nervous system. The researchers have found many biological markers that seem to be associated with future neurological development disorders, such as autism spectrum disorder, ADHD, communication disorder and intellectual disability.
“The remarkable aspect of the work is that these biomarkers are found at birth in cord blood or in the child’s stool at one year of age over a decade prior to the diagnosis,” says Eric W Triplett, professor at the Department of Microbiology and Cell Science at the University of Florida, USA, one of the study leaders.
Antibiotic treatment could be involved
The study is part of the ABIS (All Babies in Southeast Sweden) study led by Johnny Ludvigsson at Linköping University. More than 16 000 children born in 1997–1999, representing the general population, have been followed from birth into their twenties. Of these, 1197 children (7.3%), have been diagnosed with autism spectrum disorder, ADHD, communication disorder or intellectual disability. Many lifestyle and environmental factors have been identified through surveys conducted on several occasions during the children’s upbringing. For some of the children, the researchers have analysed substances in umbilical cord blood and bacteria in their stool at the age of one.
“We can see in the study that there are clear differences in the intestinal flora already during the first year of life between those who develop autism or ADHD and those who don’t. We’ve found associations with some factors that affect gut bacteria, such as antibiotic treatment during the child’s first year, which is linked to an increased risk of these diseases,” says Johnny Ludvigsson, senior professor at the Department of Biomedical and Clinical Sciences at Linköping University, who led the study together with Eric W. Triplett.
Children who had repeated ear infections before one year of age had a higher risk of a developmental neurological disorder diagnosis later in life. It is probably not the infection itself that is the culprit, but the researchers suspect a link to antibiotic treatment. They found that the presence of Citrobacter bacteria or the absence of Coprococcus bacteria increased the risk of future diagnosis. One possible explanation may be that antibiotic treatment has disturbed the composition of the gut flora in a way that contributes to neurodevelopmental disorders. The risk of antibiotic treatment damaging the gut flora and increasing the risk of diseases linked to the immune system, such as type 1 diabetes and childhood rheumatism, has been shown in previous studies.
“Coprococcus and Akkermansia muciniphila have potential protective effects. These bacteria were correlated with important substances in the stool, such as vitamin B and precursors to neurotransmitters which play vital roles orchestrating signalling in the brain. Overall, we saw deficits in these bacteria in children who later received a developmental neurological diagnosis,” says study first author Angelica Ahrens, Assistant Scientist in Eric Triplett’s research group at the University of Florida.
The present study also confirms that the risk of developmental neurological diagnosis in the child increases if the parents smoke. Conversely, breastfeeding has a protective effect, according to the study.
Differences at birth
In cord blood taken at the birth of children, the researchers measured substances such as fatty acids and amino acids, as well as exogenous ones such as nicotine and environmental toxins. They compared substances in the umbilical cord blood of 27 children diagnosed with autism with the same number of children without a diagnosis.
It turned out that children who were later diagnosed had low levels of several important fats in the umbilical cord blood. One of these was linolenic acid, which is needed for the formation of omega 3 fatty acids with anti-inflammatory properties and other effects in the brain. The same group also had higher levels than the control group of a PFAS substance, used as flame retardants and shown to negatively affect the immune system in several different ways. PFAS substances can enter the body via drinking water, food and the air we breathe.
Opens up new possibilities
As the relationships found in the Swedish children may not be generalisable to other populations, studies in other populations are needed. Another question is whether gut flora imbalance is a triggering factor or whether it has occurred as a result of underlying factors, such as diet or antibiotics. Yet even accounting for risk factors that might affect the gut flora, they found that the link between future diagnosis remained for many of the bacteria.
The research is at an early stage and more studies are needed, but the discovery that many biomarkers for future developmental neurological disorders can be observed at an early age opens up the possibility of developing screening protocols and preventive measures in the long term.
A global collaborative research group has identified brain energy metabolism dysfunction leading to altered pH and lactate levels as common hallmarks in numerous animal models of neuropsychiatric and neurodegenerative disorders. These include models of intellectual disability, autism spectrum disorders, schizophrenia, bipolar disorder, depressive disorders, and Alzheimer’s disease. The findings were published in eLife.
The research group, comprising 131 researchers from 105 laboratories across seven countries, sheds light on altered energy metabolism as a key factor in various neuropsychiatric and neurodegenerative disorders. While considered controversial, an elevated lactate level and the resulting decrease in pH is now also proposed as a potential primary component of these diseases. Unlike previous assumptions associating these changes with external factors like medicationa, the research group’s previous findings suggest that they may be intrinsic to the disorders. This conclusion was drawn from five animal models of schizophrenia/developmental disorders, bipolar disorder, and autism, which are exempt from such confounding factorsb. However, research on brain pH and lactate levels in animal models of other neuropsychiatric and neurological disorders has been limited. Until now, it was unclear whether such changes in the brain were a common phenomenon. Additionally, the relationship between alterations in brain pH and lactate levels and specific behavioural abnormalities had not been clearly established.
This study, encompassing 109 strains/conditions of mice, rats, and chicks, including animal models related to neuropsychiatric conditions, reveals that changes in brain pH and lactate levels are a common feature in a diverse range of animal models of conditions, including schizophrenia/developmental disorders, bipolar disorder, autism, as well as models of depression, epilepsy, and Alzheimer’s disease. This study’s significant insights include:
I. Common Phenomenon Across Disorders: About 30% of the 109 types of animal models exhibited significant changes in brain pH and lactate levels, emphasising the widespread occurrence of energy metabolism changes in the brain across various neuropsychiatric conditions.
II. Environmental Factors as a Cause: Models simulating depression through psychological stress, and those induced to develop diabetes or colitis, which have a high comorbidity risk for depression, showed decreased brain pH and increased lactate levels. Various acquired environmental factors could contribute to these changes.
III. Cognitive Impairment Link: A comprehensive analysis integrating behavioural test data revealed a predominant association between increased brain lactate levels and impaired working memory, illuminating an aspect of cognitive dysfunction.
IV. Confirmation in Independent Cohort: These associations, particularly between higher brain lactate levels and poor working memory performance, were validated in an independent cohort of animal models, reinforcing the initial findings.
V. Autism Spectrum Complexity: Variable responses were noted in autism models, with some showing increased pH and decreased lactate levels, suggesting subpopulations within the autism spectrum with diverse metabolic patterns.
“This is the first and largest systematic study evaluating brain pH and lactate levels across a range of animal models for neuropsychiatric and neurodegenerative disorders. Our findings may lay the groundwork for new approaches to develop the transdiagnostic characterisation of different disorders involving cognitive impairment,” states Dr Hideo Hagihara, the study’s lead author.
Professor Tsuyoshi Miyakawa, the corresponding author, explains, “This research could be a stepping stone towards identifying shared therapeutic targets in various neuropsychiatric disorders. Future studies will centre on uncovering treatment strategies that are effective across diverse animal models with brain pH changes. This could significantly contribute to developing tailored treatments for patient subgroups characterized by specific alterations in brain energy metabolism.”
The exact mechanism behind the reduction in pH and the increase in lactate levels remains elusive. But the authors suggest that, since lactate production increases in response to neural hyperactivity to meet the energy demand, this might be the underlying reason.
