Tag: neurology

Cardiac Arrest Survivors have Better Outcomes if Cerebrovascular Regulation Kicks in

Source: CC0

A study of out-of-hospital cardiac arrest patients has shown that they have better neurological outcomes if a protective cerebrovascular regulation system reasserts itself. The research, published in the Journal of Cerebral Blood Flow and Metabolism, shows that this information can be used to assign more intensive rehabilitation, and also can be used to develop new interventions to improve cerebral perfusion.

Despite advances in treatment for out-of-hospital cardiopulmonary arrest and efforts to improve outcomes, many patients still suffer neurological sequelae (hypoxic-ischaemic brain injury, HIBI) even after return of spontaneous circulation. It is known that if brain function is maintained normally, there is a mechanism, cerebrovascular autoregulation (CVAR), that tries to maintain cerebral blood flow at a constant level even with changes in systemic blood pressure, but until now, it was unclear whether such a reaction occurs in the brain after resuscitation. Cerebral regional oxygen saturation (crSO2), a measure of oxygen supply and demand balance in the brain, is affected by blood pressure, and we focused on a method to evaluate the presence or absence of CVAR using this correlation. The researchers used this correlation to evaluate the presence or absence of CVAR in the post-resuscitated brain and assessed its relationship to life expectancy.

In this study, the research group analysed 100 patients with out-of-hospital cardiac arrest who were transported to the trauma and acute critical care centre of the Osaka University Graduate School of Medicine. CVAR was determined by calculating the moving Pearson correlation coefficient and by continuously monitoring crSO2 and mean blood pressure for 96 hours after return of spontaneous circulation. Assuming undetected CVAR time as a bad exposure for the organism (time-dependent covariate), the researchers evaluated the association of life prognosis using Cox proportional hazards model. CVAR was detected in all 24 patients with good neuroprognosis (Cerebral Performance Scale5: CPC 1-2) out of 100 analysed subjects and in 65 (88%) of 76 patients with poor neuroprognosis (CPC 3-5). The analysis using the Cox proportional hazards model showed that the survival rate decreased significantly as the undetected time of CVAR increased.

The results of this study have two major implications. First, the ability to identify subgroups with high mortality from early post-resuscitation clinical data can help identify populations that should receive enhanced therapeutic intervention. In addition, it may help to avoid early withdrawal of treatment from those who may recover. Secondly, we believe that intensive therapeutic management that maintains proper cerebral perfusion suggests improved life outcomes, and that developing a systemic management approach based on cerebral perfusion may be a breakthrough in reducing post-resuscitation neurological sequelae.

Source: EurekAlert!

Intermittent Fasting May Aid Nerve Repair

A healthy neuron.
A healthy neuron. Credit: NIH

A new mouse study published in Nature showed that intermittent fasting changes gut bacteria, and increases the ability to recover from nerve damage. The fasting led to gut bacteria increasing production of 3-Indolepropionic acid (IPA), a metabolite which is required for regenerating axons.

The bacteria that produces IPA, Clostridium sporogenesis, is found naturally in the guts of humans as well as mice and IPA is found in human bloodstreams too, the researchers said. 

“There is currently no treatment for people with nerve damage beyond surgical reconstruction, which is only effective in a small percentage of cases, prompting us to investigate whether changes in lifestyle could aid recovery,” said study author Professor Simone Di Giovanni at Imperial College London.

“Intermittent fasting has previously been linked by other studies to wound repair and the growth of new neurons – but our study is the first to explain exactly how fasting might help heal nerves.”

The study assessed nerve regeneration of mice where the sciatic nerve, the longest nerve running from the spine down the leg, was crushed. Half of the mice underwent intermittent fasting (one day with food, one day without), while the other half ate freely. These diets continued for a period of 10 days or 30 days before their operation, and the mice’s recovery was monitored 24 to 72 hours after the nerve was severed. The regrown axons were about 50% greater in mice that had been fasting.

Prof Di Giovanni said, “I think the power of this is that opens up a whole new field where we have to wonder: is this the tip of an iceberg? Are there going to be other bacteria or bacteria metabolites that can promote repair?”

The researchers also studied how fasting led to this nerve regeneration. They found that there were significantly higher levels of specific metabolites, including IPA, in the blood of diet-restricted mice.

To confirm whether IPA led to nerve repair, the mice were treated with antibiotics to remove gut bacteria. They were then given gene-edited of Clostridium sporogenesis that could or could not produce IPA.

“When IPA cannot be produced by these bacteria and it was almost absent in the serum, regeneration was impaired. This suggests that the IPA generated by these bacteria has an ability to heal and regenerate damaged nerves,” Prof Di Giovanni said. 

Importantly, when IPA was administered to the mice orally after a sciatic nerve injury, regeneration and increased recovery was observed between two and three weeks after injury.

The next step is investigating spinal cord injuries in mice, along with seeing if more frequent IPA administrations increase its efficacy.

“One of our goals now is to systematically investigate the role of bacteria metabolite therapy.” Prof Di Giovanni said.

More studies will need to investigate whether IPA increases after fasting in humans and the efficacy of IPA and intermittent fasting as a potential treatment in people.

He said: “One of the questions that we haven’t explored fully is that, since IPA lasts in blood for four to six hours in high concentration, would administering it repeatedly throughout the day or adding it to a normal diet help maximise its therapeutic effects?”

Source: Imperial College

Little to No Link Between Glaucoma and Cognitive Function

Older woman smiling
Photo by Ravi Patel on Unsplasj

Previous studies looking for an association between the neurodegenerative disorder glaucoma and cognitive function have produced mixed results. Now, findings from a large study recently published in the Journal of the American Geriatrics Society suggest that any association, if it exists, will only be small.

Glaucoma, the leading cause of irreversible blindness, is a progressive optic neuropathy with incompletely understood pathogenesis that results in progressive vision loss, often beginning with peripheral visual field defects. As a neurodegenerative process, glaucoma is associated with trans-synaptic degeneration in the brain, specifically in the lateral geniculate nucleus and visual cortex. Some prior studies have suggested that the pathogenesis of primary open angle glaucoma (POAG) and normal tension glaucoma (NTG), specifically, may be part of a broad neurodegenerative mechanism with ocular and non-ocular manifestations. Evidence also suggests that impaired vision is associated with a significant increase in the risk of accelerated cognitive decline and incident dementia. Therefore, there is interest in measuring an association between glaucoma and dementia.

The study included 7073 US adults aged 51 years and older who were interviewed by phone every two years. Those who developed glaucoma tended to have higher cognitive function scores but steeper rates of cognitive score decline over a maximum follow-up time of 18 years. The observed associations between glaucoma and cognitive function were small and unlikely to be clinically meaningful. 

“In this large longitudinal study, a diagnosis of glaucoma was not associated with steeper rates of cognitive decline; however, this study did not have access to clinical data to determine whether glaucoma-related vision loss is a risk factor for cognitive decline and dementia,” said senior author Joshua R. Ehrlich MD, MP, of the University of Michigan Medical School. “This is an important question for future studies to consider.” 

Source: Wiley

Newly Discovered Neuron Type may Help Explain Memory Formation

A healthy neuron.
A healthy neuron. Credit: NIH

Scientists publishing in Neuron have described how a newly discovered neuron type may be involved with the formation of memory in the hippocampus, which is marked by high-frequency electrical events.

It is known that memory is represented by changes in the hippocampus. One of the well-established changes in the hippocampus that has been associated with memory is the presence of so-called sharp wave ripples (SWR). These are brief, high-frequency electrical events generated in the hippocampus, and they are believed to represent a major event occurring in the brain in the so-called episodic memory, such as recalling a life event or a friend’s phone number.

However, what happens in the hippocampus when SRWs are generated has not been well understood.

Now a new study sheds light on the existence of a neuron type in the mouse hippocampus that might be a key to better understanding of episodic memory.

Professor Marco Capogna and Assistant professor Wen-Hsien Hou have contributed to the discovery of the novel neuron that is associated with sharp wave ripples and memory.

Possible disruption in dementia and Alzheimer’s

The study describes the novel neuron type in the hippocampus.

“We have found that this new type of neuron is maximally active during SWRs when the animal is awake – but quiet – or deeply asleep. In contrast, the neuron is not active at all when there is a slow, synchronized neuronal population activity called “theta” that can occur when an animal is awake and moves or in a particular type of sleep when we usually dream,” Prof Capogna said.

Because of this dichotomic activity, this novel type of neuron is named theta off-ripples on (TORO).

“How come, TORO-neurons are so sensitive to SWRs? The paper tries to answer this question by describing the functional connectivity of TORO-neurons with other neurons and brain areas, an approach called circuit mapping. We find that TOROs are activated by other types of neurons in the hippocampus, namely CA3 pyramidal-neurons and are inhibited by inputs coming from other brain areas, such as the septum,” Prof Capogna explained.

“Furthermore, the study finds that TOROs are inhibitory neurons that release the neurotransmitter GABA. They send their output locally – as most GABAergic neurons do – within the hippocampus, but also project and inhibit other brain areas outside the hippocampus, such as the septum and the cortex. In this way, TORO-neurons propagate the SWR information broadly in the brain and signal that a memory event occurred,” he concluded.

The team has monitored the activity of the neuron by using electrophysiology – a technique that detects activity of the neurons by measuring voltage versus time, and by using imaging that detects activity by measuring changes in calcium signalling inside the neurons.

Demonstrating a causal link between the activity of TORO-nerve cells and memory will be the next step, and exploring whether inhibition of TORO-neurons and sharp wave ripples occurs in dementia and Alzheimer’s diseases. 

Source: Aarhus University

Sarin Gas Likely the Cause of Mysterious Gulf War Illness

Photo by Pablo Stanic on Unsplash

Since the 1990s, scientists have debated the underlying cause of Gulf War illness (GWI), a constellation of unexplained and chronic symptoms affecting veterans of the Persian Gulf War. Now researchers have solved the mystery, showing through a detailed genetic study that the nerve gas sarin was largely responsible for the syndrome. The findings were published in Environmental Health Perspectives.

Dr Haley’s research group not only discovered that veterans with exposure to sarin were more likely to develop GWI, but also found that the risk was modulated by a gene that helps break down the nerve gas. Sarin-exposed Gulf War veterans with a weak variant of the gene were more likely to develop symptoms of GWI than other exposed veterans with the strong form of the gene.

“Quite simply, our findings prove that Gulf War illness was caused by sarin, which was released when we bombed Iraqi chemical weapons storage and production facilities,” said Robert Haley, MD, at UT Southwestern, a medical epidemiologist who had led that study and has been investigating GWI for 28 years. “There are still more than 100 000 Gulf War veterans who are not getting help for this illness and our hope is that these findings will accelerate the search for better treatment.”

Multiple causes of Gulf War illness suggested

After the Gulf War, more than a quarter of the US and coalition veterans began reporting a range of chronic symptoms, including fatigue, fever, night sweats, memory and concentration problems, difficulty finding words, diarrhoea, sexual dysfunction, and chronic body pain. Since then, military and academic researchers have studied a list of possible causes of GWI, ranging from stress, vaccinations, and burning oil wells to exposure to pesticides, nerve gas, anti-nerve gas medication, and depleted uranium used in weapons.

“What makes this new study a game-changer is that it links GWI with a very strong gene-environment interaction that cannot be explained away by errors in recalling the environmental exposure or other biases in the data.”

Study leader Robert Haley, MD, medical epidemiologist

Over the years, these studies have identified statistical associations with several of these, but no cause has been widely accepted. Most recently, Dr Haley and a colleague reported a large study testing veterans’ urine for depleted uranium that would still be present if it had caused GWI and found none.

Studies have shown statistical associations with several of these causes, though none received wide acceptance. Dr Haley and a colleague recently reported a large study that found no depleted uranium in veterans’ urine, which would have still been present if it had caused GWI.

“As far back as 1995, when we first defined Gulf War illness, the evidence was pointing toward nerve agent exposure, but it has taken many years to build an irrefutable case,” said Dr Haley.

Sarin’s effects

Sarin is a toxic nerve agent, production of which was banned in 1997. When people are exposed to either the liquid or gas form, sarin enters the body through the skin or breathing and attacks the nervous system. High-level sarin often results in death, but studies on survivors have revealed that lower-level sarin exposure can lead to long-term impairment of brain function. A large release of this gas occurred when a chemical weapons storage plant was bombed, causing thousands of nerve gas alarms to sound.

Previous studies have found an association between Gulf War veterans who self-reported exposure to sarin and GWI symptoms. However, this has raised criticisms of recall bias. “What makes this new study a game-changer is that it links GWI with a very strong gene-environment interaction that cannot be explained away by errors in recalling the environmental exposure or other biases in the data,” Dr Haley said.

In the new paper, Dr Haley and his colleagues studied 508 deployed veterans with GWI and 508 deployed veterans who did not develop any GWI symptoms. They asked whether the veterans had heard chemical nerve gas alarms, indicating sarin exposure, and also collected blood and DNA samples.

The role of PON1

The researchers tested the samples for variants of a gene called PON1, which has two variants. The Q variant generates a blood enzyme that efficiently breaks down sarin while the R variant helps the body break down other chemicals but is not efficient at destroying sarin. Everyone has either a QQ, RR or QR genotype.

For Gulf War veterans with the QQ genotype, hearing nerve agent alarms — a proxy for chemical exposure — raised their chance of developing GWI by 3.75 times, those with the QR genotype had an a 4.43 fold risk increase. And for those with RR genotype, the chance of GWI increased by 8.91 times. Those soldiers with both the RR genotype and low-level sarin exposure were over seven times more likely to get GWI due to the interaction per se, over and above the increase in risk from both risk factors acting alone. For genetic epidemiologists, this number leads to a high degree of confidence that sarin is a causative agent of GWI.

“Your risk is going up step by step depending on your genotype, because those genes are mediating how well your body inactivates sarin,” said Dr Haley. “It doesn’t mean you can’t get Gulf War illness if you have the QQ genotype, because even the highest-level genetic protection can be overwhelmed by higher intensity exposure.”

This kind of strong gene-environment interaction is considered a gold standard for showing that an illness like GWI was caused by a particular environmental toxic exposure, he added. The research doesn’t rule out that other chemical exposures could be responsible for a small number of cases of Gulf War illness. However, Dr. Haley and his team carried out additional genetic analyses on the new data, testing other factors that could be related, and found no other contributing causes.

“There’s no other risk factor coming anywhere close to having this level of causal evidence for Gulf War illness,” said Dr Haley.

The team is continuing research on GWI’s impacts on the body, particularly the immune system, whether any of its effects are reversible, and whether there are biomarkers to detect prior sarin exposure or GWI.

Source: UT Southwestern Medical Center

Scientists Discover the Neurological Basis of Food Cravings in Pregnancy

Photo by Andriyko Podilnyk on Unsplash

By examining mice, which get pregnancy cravings similar to humans, scientists have identified the neurological basis of food craving during pregnancy.

During pregnancy, the mother’s body undergoes a series of physiological and behavioural changes to create an environment facilitating the embryo’s development. Frequent consumption of tasty, high calorie foods driven by the cravings contributes to weight gain and obesity in pregnancy, with possible negative consequences for the baby’s health.

“There are many myths and popular beliefs regarding these cravings, although the neuronal mechanisms that cause them are not widely known,” noted study leader March Claret, at the University of Barcelona and leader of the study published in the journal Nature Metabolism.

The researchers found that the brains of pregnant female mice undergoes changes in the functional connections of the brain reward circuits, as well as the taste and sensorimotor centres. Mice, like pregnant women, are also more sensitive to sweet food, and develop binge-eating behaviours towards high calorie foods. “The alteration of these structures made us explore the mesolimbic pathway, one of the signal transmission pathways of dopaminergic neurons. Dopamine is a key neurotransmitter in motivational behaviours,” notes Claret, member of the Department of Medicine of the UB and the Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM).

The team saw that dopamine levels and dopamine receptor (D2R) activity increased in the nucleus accumbens, a brain region involved in the reward circuit. “This finding suggests that the pregnancy induces a full reorganisation of the mesolimbic neural circuits through the D2R neurons,” noted study leader Roberta Haddad-Tóvolli. “These neuronal cells – and their alteration – would be responsible for the cravings, since food anxiety, typical during pregnancy, disappeared after blocking their activity.”

The team demonstrated that persistent cravings have consequences for the offspring, affecting the metabolism and development of neural circuits that regulate food intake, leading to weight gain, anxiety and eating disorders. “These results are shocking, since many of the studies are focused on the analysis of how the mother’s permanent habits – such as obesity, malnutrition, or chronic stress – affect the health of the baby. However, this study indicates that short but recurrent behaviours, such as cravings, are enough to increase the psychological and metabolic vulnerability of the offspring,” concluded Claret.

The conclusions of the study could contribute to the improvement of nutritional guidelines for pregnant women in order to ensure a proper prenatal nutrition and prevent the development of diseases.

Source: University of Barcelona

Mental Processing of Autistic and Non-autistic People is Similar

Source: Pixabay

Findings published in Journal of Psychopathology and Clinical Science reveal there are fundamental similarities between autistic and non-autistic people in mental processing. The study findings were made available online ahead of ahead of World Autism Day on the 2nd of April.

The brain uses two systems to process information: System 1 for quicker intuitive judgements, and System 2 for slower rational thinking. In autistic people, these systems are thought to work differently ad underlie difficulties they may have in daily life and the workplace.

Yet, this landmark study reports that these fundamental psychological systems are not impaired in autistic people as once thought. The study, involving more than 1000 people, tested the link between autism and ‘quick’ intuitive and ‘slow’ rational thinking.

In three experiments, they analysed the link between autistic personality traits and thinking style. In the fourth, they compared 200 autistic and over 200 non-autistic people. Overall, their results showed that autistic people think as quickly and as rationally as non-autistic people.

Based on these findings, the researchers conclude that certain, fundamental mental processes are more similar between autistic and non-autistic people than prior belief. In light of these findings, they call for a shift in the way that society thinks about autism as a mental processing disorder.

They also recommend that it might be important to redesign educational, clinical, and workplace support for autistic people and their families. Support should be much more targeted, instead of assuming that autistic people all have mental processing difficulties, they say.

The research team argue that the requirement to make ‘reasonable adjustments’ such as allowing extra time in exams and extending deadlines, is not an evidence-based way to support neurodivergent people.

Instead, more fundamental changes could be necessary – for example, changing social and sensory environments, making them more equitable autistic people.

Source: University of Bath

The Claustrum: A Mysterious Brain Region Involved with Pain

Man wearing mask with headache
Source: Usman Yousaf on Unsplash

A new review paper, published in the journal Brain, has shown that a mysterious brain region called the claustrum may play an important role in the experience of pain. This densely interconnected, but difficult to access area of the brain may be the next frontier in improving outcomes for brain damage patients.

The claustrum is a brain region that has been investigated for over 200 years, yet its precise function remains unknown. A 2005 article suggested it to be critically linked to consciousness, which spurred a renewed interest in this region, with recent research revealing its high level of interconnectedness.

Credit: Oxford University

Oxford University researchers reviewed studies of patients with rare cases of lesions in the claustrum, which show cognitive impairments and seizures. There may be many more cases to be uncovered due to the lack of clinical focus on the claustrum.

They also uncovered an underappreciated link between the claustrum and pain. It is already known that there are links between the claustrum and perception, salience and the sleep-wake cycle, but this is the first time a research team has shown how the claustrum might be more involved in the debilitating experience of pain.

Dr. Adam Packer, the lead author of the study, says that “The problem with understanding how the claustrum works is that it is deep inside the brain, and damage that is specific to it is a very rare occurrence. What makes it more difficult to work out what the claustrum actually does is that these rare occurrences are also linked to such a broad range of symptoms.”

“Clearly, when the claustrum is damaged the effects are severe and better therapies are urgently needed. It is possible that claustrum damage is more common than we currently realise, and it may be a crucial component in many more brain damage cases.”

“This work is important because it gives us some insight into the cognitive and neurological processes in which the claustrum may be involved, and gives us targets to pursue in basic research in the lab.”

The researchers found several recorded instances of either infection, autoimmune, or other process that attacked the claustrum in particular, and by analysing the results of these studies and others the most common symptoms in patients were cognitive impairment and seizures.

Additional research is needed for a better understanding of the claustrum and the impact of damage to the claustrum, which could eventually change clinical guidelines.

Source: University of Oxford

Invasive Mechanical Ventilation in PICU has Lasting Neurocognitive Impacts

Photo by Margaret Weir on Unsplash

Children in paediatric ICUs (PICUs) that undergo invasive mechanical ventilation for acute respiratory failure are left with lasting neurocognitive effects, according to a study published in JAMA.

Little is known about whether children undergoing invasive mechanical ventilation worse long-term neurocognitive function than children who do not undergo such procedures. There are concerns about neurotoxic effects of critical illness and its treatment on the developing brain. Therefore, infants and young children may be uniquely susceptible to adverse neurocognitive outcomes after invasive mechanical ventilation.

Researchers conducted a four-year sibling-matched cohort study conducted at 31 PICUs and associated neuropsychology testing centres. Children who survived PICU hospitalisation for respiratory failure and were discharged without severe cognitive dysfunction were found to have significantly lower subsequent IQ scores than their matched siblings.

“While the difference in IQ scores between patients and unexposed siblings was small, the data provide strong evidence of the existence and epidemiology of paediatric post-intensive care syndrome (PICS-p) after a single typical episode of acute respiratory failure necessitating invasive ventilation among generally healthy children,” said Martha A.Q. Curley, PhD, RN, FAAN, Professor of Nursing at the University of Pennsylvania School of Nursing (Penn Nursing) and the study’s lead researcher.

The study reaffirms the importance of assessing long-term outcomes as part of any trial evaluating acute interventions in pediatric critical care. It also underscores the importance of further study to understand which children may be at highest risk, what modifiable factors could cause it, and how it can be prevented.

Source: University of Pennsylvania

Peptide Discovery Could Halt Nerve Degeneration

A healthy neuron.
A healthy neuron. Credit: NIH

Promising results have been found in the quest for a treatment to halt nerve cell degeneration in disorders like Parkinson’s disease, by preventing their mitochondria from breaking apart with a particular peptide.

The research, published in Brain, examined how the long axons that carry messages between nerve cells in the brain can break down, which causes increasingly worse tightening of the leg muscles, leading to imbalance and eventually paralysis, in addition to other symptoms.

Animal studies have shown it may be a problem with the mitochondria that leads to the axons breaking down or not growing long enough. Since studying human nerve cells is difficult, the researchers made use of human stem cells they modified to become nerve cells with the genetic disorder for a particular type of hereditary spastic paraplegia.

“What we found was that the mitochondria in these cells were breaking apart, what we call mitochondrial fission, and that caused the axons to be shorter and less effective at carrying messages to the brain,” study leader Prof Xue-Jun Li said. “We then looked at whether a particular agent would change the way the nerve cells function — and it did. It inhibited the mitochondrial fission and let the nerve cells grow normally and also stopped further damage.”

What this means for the thousands of people affected by this type of genetic disorder is that this peptide could prove to be useful for a drug or other therapy to stop the nerve cells from becoming damaged or possibly even reverse the course of the damage. Additionally, gene therapy could also prevent mitochondrial damage, the researchers suggested, which would provide another strategy to reverse the nerve damage.

Source: University of Illinois Chicago