Tag: Medicine

Researchers from Tel Aviv University and Israel’s Shamir Medical Center were able to successfully relieve the symptoms of post traumatic stress disorder (PTSD) in military combat veterans using a new protocols of hyperbaric oxygen therapy (HBOT). In a controlled clinical trial involving Israeli army veterans who suffered from treatment-resistant PTSD, the approach demonstrated significant improvement in all classes of symptoms.

According to the World Health Organization (WHO), almost 4% of the global population, and 30% of all combat soldiers, develop PTSD. 

Hyperbaric medicine involves treatments in a pressurized chamber where atmospheric pressure is higher than sea-level pressure and the air is rich with oxygen. Considered a safe form of treatment, hyperbaric oxygen therapy is already used for a range of medical conditions. Evidence gathered in recent years indicates that special hyperbaric protocols can improve the supply of oxygen to the brain, thereby enhancing the generation of new blood vessels and neurons. It must be noted that HBOT treatments require the evaluation and supervision of qualified physicians. Moreover, for medical indications it should be given using a certified chamber with appropriate quality assurance using the exact studied treatment protocols. 

The breakthrough research was led by Prof. Shai Efrati, Dr. Keren Doenyas-Barak, and Dr. Amir Hadanny of Tel Aviv University’s Sackler Faculty of Medicine and Sagol School of Neuroscience in cooperation with Shamir Medical Center. The team also included Dr. Ilan Kutz, Dr. Merav Catalogna, Dr. Efrat Sasson, Gabriela Levi and Yarden Shechter of Shamir Medical Center.

Unloading Pain for a Better Future

The study included 35 combat veterans of the Israel Defense Forces (IDF) who suffered from PTSD that was resistant to both psychiatric medications and psychotherapy. 

“The veterans were divided into two groups: one group received hyperbaric oxygen therapy while the other served as a control group,” explains Dr. Keren Doenyas-Barak of Shamir Medical Center. “Following a protocol of 60 treatments improvement was demonstrated in all PTSD symptoms, including hyper-arousal, avoidance, and depression. Moreover, both functional and structural improvement was observed in the non-healing brain wounds that characterize PTSD. We believe that in most patients, improvements will be preserved for years after the completion of the treatment.”

“This study gives real hope to PTSD sufferers. For the first time in years the study’s participants, most of whom had suffered from severe PTSD, were able to leave the horrors behind and look forward to a better future.”

Illustration: Clinical example of functional brain imaging by fMRI.  The reduced brain activity in the frontal lobes of the brain (responsible among others for emotional regulation and executive functions) and in hippocampus (responsible for memories functions) is improved after Hyperbaric Oxygen Therapy (HBOT).

Emotional Trauma Can Cause Physical Damage

“Today we understand that treatment-resistant PTSD is caused by a biological wound in brain tissues, which obstructs attempts at psychological and psychiatric treatments,” explains TAU Prof. Shai Efrati. “With the new hyperbaric oxygen therapy protocols, we can activate mechanisms that repair the wounded brain tissue. The treatment induces reactivation and proliferation of stem cells, as well as generation of new blood vessels and increased brain activity, ultimately restoring the functionality of the wounded tissues. Our study paves the way to a better understanding of the connection between mind and body.”

“Our results indicate that exposure to severe emotional trauma can cause organic damage to the brain,” says Prof. Efrati. “We also demonstrate for the first time that direct biological treatment of brain tissues can serve as a tool for helping PTSD patients. Moreover, our findings may be most significant for diagnosis. To date, no effective diagnostic method has been developed and diagnosis of PTSD is still based on personal reports which are necessarily subjective – leading to many clashes between the suffering veterans and the authorities responsible for treating them. Think of a person who comes to the emergency room with chest pains. The pain might be caused by either a panic attack or a heart attack, and without objective EKG and blood tests, the doctors might miss a heart attack. At present we are conducting continuing research in order to identify the biological fingerprint of PTSD, which can ultimately enable the development of innovative objective diagnostic tools.”

Prof. Shai Efrati

Prof. Efrati is an Associate Professor at TAU and director of the Sagol Center for Hyperbaric Medicine and Research at Shamir Medical Center. He is also the co-founder and Chair of the Medical Advisory Board at Aviv Scientific LTD, a company that applies the hyperbaric oxygen therapy protocols developed from his team’s research to enhance the brain and body performance of aging adults. 

A new study at Tel Aviv University revealed abnormal brain activity that precedes the onset of Alzheimer’s first symptoms by many years: increased activity in the hippocampus, a region of the brain which plays a key role in memory processes, during anesthesia and sleep, resulting from failure in the mechanism that stabilizes the neural network. The researchers believe that the discovery of this abnormal activity during specific brain states may enable early diagnosis of Alzheimer’s, eventually leading to a more effective treatment of a disease that still lacks effective therapies.

The study was published in the prestigious scientific journal Cell Reports, and led by Prof. Inna Slutsky and doctoral students Daniel Zarhin and Refaela Atsmon from the Sackler Faculty of Medicine and the Sagol School of Neuroscience at Tel Aviv University.

According to Prof. Inna Slutsky, innovative imaging technologies developed in recent years have revealed that amyloid deposits, a hallmark of Alzheimer’s disease pathology, are formed in patients’ brains as early as 10-20 years before the onset of typical symptoms such as memory impairment and cognitive decline. Unfortunately, most efforts to treat Alzheimer’s disease have failed. She believes that if we could detect the disease at the pre-symptomatic stage, and keep it in a dormant phase for many years, this would be a tremendous achievement in the field. Identifying a signature of aberrant brain activity in the pre-symptomatic stage of Alzheimer’s and understanding the mechanisms underlying its development she says may be a key to effective treatment.

Additional participants in the study include: Dr. Antonella Ruggiero, Halit Baeloha, Shiri Shoob, Oded Scharf, Leore Heim, Nadav Buchbinder, Ortal Shinikamin, Dr. Ilana Shapira, Dr. Boaz Styr, and Dr. Gabriella Braun, all from Prof. Slutsky’s laboratory. Collaborations with the laboratory teams of Prof. Yaniv Ziv of the Weizmann Institute, and Prof. Yuval Nir of TAU were essential for the project. Prof. Tamar Geiger, Dr. Michal Harel, and Dr. Anton Sheinin of Tel Aviv University, as well as researchers from Japan, also contributed to the study.

The researchers used animal models for Alzheimer’s, focusing on the hippocampal region of the brain, which is known to be impaired in Alzheimer’s patients. At first, they measured cell activity in the hippocampus when the model animal was awake and active. For this, they used advanced methods that measure brain activity at a resolution of single neurons.

High Neuronal Activity – Also During Sleep

“It is known that neuronal activity of the hippocampus decreases during sleep in healthy animals,” explains Refaela Atsmon. However, when she examined model animals in early stages of Alzheimer’s, she found that their hippocampal activity remained high even during sleep. This is due to a failure in the physiological regulation, which she says has never before been observed in the context of Alzheimer’s disease.

Daniel Zarhin found similar dysregulation in model animals under anesthesia: neuronal activity did not decline, the neurons operated in a manner that was too synchronized, and a pathological electrical pattern was formed, similar to ‘quiet’ seizures in epileptic patients.

The researchers found that brain states that block responses to the environment – such as sleep and anesthesia – expose abnormal activity which remains hidden when the animal is awake, and this happens before the symptoms of Alzheimer’s disease are observed.

Prof. Slutsky’s explains that even though this abnormal activity can be detected during sleep, it is much more frequent under anesthesia. Therefore, she says, it would be important to test whether short anesthesia can be used for early diagnosis of Alzheimer’s disease.

Defective Stabilizing Mechanisms

The researchers proceeded to ask what causes the abnormality. To this end, they relied on findings from previous studies from Prof. Slutsky’s laboratory and other researchers on homeostasis of neural networks: each neural circuit has a set point of activity, maintained by numerous stabilizing mechanisms. These mechanisms are activated when the balance is disturbed, restoring neuronal activity to its original set point.  

Is a disruption of these mechanisms the main cause of deviant brain activity during sleep and anesthesia in Alzheimer’s disease animal models? To test this, Dr. Antonella Ruggiero examined the effect of various anesthetics on neurons grown on a chip. She found that they lower the set point of neuronal activity. While in healthy neural networks this activity remained low over time, in neural networks expressing genetic Alzheimer’s mutations, the lowered set point recovered quickly, despite the presence of anesthetics.

The researchers now sought to examine a potential drug for the impaired regulatory mechanism. According to Prof. Slutsky, the instability in neuronal activity found in the study is known from epilepsy. In a previous study Prof. Slutsky’s team discovered that an existing drug for multiple sclerosis may help epilepsy patients by activating a homeostatic mechanism that lowers the set point of neural activity. Doctoral student Shiri Shoob examined the effect of the drug on hippocampal activity in the animal model for Alzheimer’s and found that also in this case the drug stabilizes activity and reduces pathological activity observed during anesthesia.

Proceeding Towards Clinical Trials

“The results of our study may help early diagnosis of Alzheimer’s, and even provide a solution for instability of neuronal activity in Alzheimer’s disease,” says Prof. Slutsky. “Firstly, we discovered that anesthesia and sleep states expose pathological brain activity in the early stages of Alzheimer’s disease, before the onset of cognitive decline. We also proposed the cause of the pathological activity – failure of a very basic homeostatic mechanism that stabilizes electrical activity in brain circuits. Lastly, we showed that a known medication for multiple sclerosis suppresses this type of anesthesia-induced aberrant brain activity,” she concludes.

The researchers now plan to collaborate with medical centers in Israel and worldwide to test whether the mechanisms discovered in animal models can also be identified in patients with early-stage Alzheimer’s disease. For this purpose, they propose to incorporate EEG monitoring into surgical procedures, to measure brain activity of patients under anesthesia. They hope that their findings will promote early diagnosis and drug development for the most common form of late-onset dementia.

Featured image: The Research Team (from left to right): Prof. Inna Slutsky, Daniel Zarhin and Refaela Atsmon (Photo: Dr. Tal Laviv)

Traumatic Brain Injury (TBI) is a leading cause of death and long-term disability in the developed world. It is estimated that every year over 10 million people worldwide suffer from traumatic brain injury as a result of head injuries caused by a hard object, a blow, an explosion, road accidents, sports injuries, etc. Such traumas can lead to physical, cognitive, behavioral and emotional damage and is also a risk factor for diseases such as Alzheimer’s and Parkinson’s.

At this point, despite the high frequency of brain injuries, there is no proven effective treatment that can help those suffering from this injury.

A new international study piloted by the Tel Aviv University determines that a ketogenic diet may reduce the effects of brain damage after traumatic injury. The study indicates that the diet improves spatial memory and visual memory, lowers brain inflammation indices, causes less neuronal death and slows down the rate of cellular aging.

The study was led by Prof. Chaim (Chagi) Pick, Director of the Sylvan Adams Sports Institute and a member of the Sagol School of Neuroscience, and Ph.D. student Meirav Har-Even Kerzhner, a registered dietitian and brain researcher, both from the Sackler Faculty of Medicine at Tel Aviv University. The findings were published in Scientific Reports, a syndicate journal from the publishers of Nature.

What does a ketogenic diet consist of?

A ketogenic diet which involves changes in the consumption of common foods is based on high-fat percentages and aims to mimic a state of fasting. As part of the diet, the intake of foods that contain carbohydrates (e.g., bread, sugar, grains, legumes, snacks, pastries and even fruits) are significantly restricted and, at the expense of this restriction, high-fat products such as meat, fish, eggs, avocado, butter etc. – are eaten.

This is a diet that can be continued for extended periods of time. The diet causes an increased production of ketone bodies in the liver that are used to generate energy. These ketone bodies are transferred via the bloodstream to the brain providing optimal nourishment.

The diet has been used as a treatment in Israel and around the world for almost 100 years, among children with epilepsy, while in recent years, the ketogenic diet has become popular among those who want to lose weight. It is important to note that, due to the significant nutritional restrictions, it is necessary to consult with a professional such as a doctor or a registered dietitian.

Inspiring Hope

In the study, conducted on model animals, the researchers identified that the ketogenic diet greatly improves the patient’s brain function. For this purpose, the researchers used advanced methods that included, among other things, behavioral-cognitive tests, biochemical tests and immunohistochemical cell staining (a technique in biology for the detection and placement of proteins in a cross section of tissue). The mechanism by which a ketogenic diet succeeds in benefiting the results of brain damage has not yet been fully revealed, but studies show that it has an antioxidant and metabolic effect on mitochondria (essential organelles in the cell, the its primary function of which is energy production and respiration), lowers free radical production and raises ATP (a major molecule in cellular biochemical channels). 

“The findings were unequivocal and showed that the ketogenic diet improves spatial memory and visual memory, lowers indices of inflammation in the brain and in addition, also slows the rate of cellular aging,” says Prof. Pick. “These results may open the door to further research that will inspire hope for those suffering from traumatic brain injuries, and their family members.”

Featured image: Prof. Chaim Pick and Ph.D. student Meirav Har-Even Kerzhne

Phages are viruses that attack bacteria. Many phages can exist in one of two states: active (lysis), in which the phages attack and destroy bacteria, or dormant, in which they remain passive within the bacteria, replicating themselves but doing no damage (lysogeny). Phages of this type must decide whether to be active or dormant every time they infect a new host. If they decide to be dormant for a time, they must also decide when to ‘wake up’ and attack. As in all dilemmas, it’s important to base the decision upon solid, reliable information.

Researchers at Tel Aviv University have discovered that just like humans with Game Theory, phages weigh all their options and make an informed decision on whether it is time to exit the dormant state and attack their bacterial host. The study was led by Prof. Avigdor Eldar of The Shmunis School of Biomedicine and Cancer Research at Tel Aviv University, together with his students and partners from the Weizmann Institute of Science. The paper was published in December 2021 in the journal Nature Microbiology.

According to the researchers, it has been assumed for some time that a phage bases its decision to exit the dormant state on information regarding the condition of its bacterial host: when the host shows signs of substantial DNA damage (death throes, so to speak), it is in the phage’s interest to leave it and try to infect other bacteria.

The new study discovered an additional mechanism of communication between bacteria and phages: apparently, some phage families have developed a more complex decision-making strategy, a kind of ‘phage game theory’, in which the phage receives information not only from its own host but also from neighboring bacteria.

What’s Going On in The Neighborhood?

Prof. Eldar explains: “When a phage is dormant within a bacterial cell, it forces its host to constantly produce small communication molecules called arbitrium, to which the phage listens via a special receptor. Thus, the presence of high levels of these molecules indicates that neighboring bacteria also contain phages. When this happens, even if its own host exhibits DNA damage, the phage refrains from becoming active. Since every bacterium can only host one dormant phage, the phage makes an informed decision: it’s better to let the host try to repair itself than to ‘betray’ it, since all neighboring bacteria are already taken.”

Prof. Eldar and his team used a range of genetic and biomolecular methods to track the biochemical communication signals passing between the bacteria and phages. In a former study they used a fluorescent marker to show that communication methods used by phages, as well as a large family of similar communication systems (know generally as ‘quorum sensing’) are used only to get signals from close neighbors. “Essentially, the bacteria have developed two separate communication systems – one for long-range communication, and the other for short distances only, used to sense the state of their immediate neighbors,” says Prof. Eldar. “In the phage’s case, it controls communication, and is only interested to know whether its close neighbors, which it might easily infect, are already occupied.”

Prof. Eldar concludes: “Several years ago, Prof. Rotem Sorek and his team at the Weizmann Institute identified communication between phages for the first time. Such systems had been known to exist between other molecular parasites hosted by bacteria (called plasmids). Our new discovery is the fact that phages use communication even in their dormant state. We have identified components critical for understanding how phages combine information about their host’s condition with information about their neighbors. This is one more important step on the way to deciphering the communication and ‘behavioral economics’ of viruses. Phages have an excellent ability to process information and make the right decision to ensure optimal survival. It will be interesting to see whether viruses residing in more complex organisms but facing similar decisions have also developed comparable systems of communication.”

Our brain has a large amount of G protein-coupled receptors (GPCR). Activation of these proteins causes a chain of chemical reactions within the cell. These proteins are very common in the brain and are involved in almost every brain activity, such as learning and memory. The nerve cells in which GPCRs are common, experience changes in their electrical voltage.

20 years ago, it was unexpectedly discovered that GPCRs are voltage-dependent, meaning that they sense the changes in the electrical voltage of nerve cells and change their function. However, to date, it has not been clarified whether the voltage dependence of GPCR proteins has a physiological significance that affects brain activity, our perception, and behavior. In fact, the scientific mindset was that this voltage dependence has no physiological significance.

The study, published recently in the prestigious journal Nature Communications, was conducted by Dr. Moshe Parnas and his team from the Sackler Faculty of Medicine and the Sagol School of Neuroscience at Tel Aviv University.

The Protein that Influences our Sense of Smell

Dr. Parnas and his team investigated, by means of the olfactory system of the fruit fly, whether the voltage dependence of GPCRs is important for brain function. To this end, the researchers decided to focus on one receptor from the G protein-coupled receptor family called “Muscarinic Type A”. This protein is involved, among other things, in habituation to an odor, a process in which the intensity of the reaction to the odor decreases as a result of continuous exposure to it. Thanks to this mechanism, a few minutes after entering a room containing a distinct odor – we stop smelling it.

Dr. Parnas explains: “Nerve cells are able to communicate with each other and brain flexibility is expressed in the ability of nerve cells to set up new connections with each other and change existing connections – and thus influence behavior. Muscarinic Type A protein is involved in strengthening the bond between nerve cells, and strengthening of this bond causes fruit flies to get used to the odor and indicates normal brain flexibility.”

During the course of the study, the researchers were able to neutralize the voltage sensor of the “Type A” Muscarinic protein by means of genetic editing, and thus eliminate its dependence on the electrical voltage of the nerve cell. The researchers found, by applying molecular, genetic and physiological methods, that disabling the voltage sensor actually causes uncontrolled brain flexibility and consequently the process of excessive and uncontrolled habituating to an odor.

Dr. Moshe Parnas

Control Mechanism Uncovered

Dr. Parnas adds: “We found that the receptor in question is very much involved in strengthening the intercellular bond in the brain, much more than what we thought. When we turned off its voltage sensor, the connection between the nerve cells became too strong.”

According to Dr. Parnas, “These findings change our perception of G-protein-coupled receptors. To date, no reference has been made to the effect of electrical voltage on their function and its implications on brain flexibility and conduct. These receptors are involved in many systems and brain diseases and we have now discovered a control mechanism upon which an attempt at drug treatment can be based.”

“Following this, we are continuing to investigate additional receptors. It is reasonable to assume that their dependence on the electrical voltage is important in other systems and not only in the olfactory system [i.e. the bodily structures that serve the sense of smell].”

This study by Dr. Parnas is a follow-up to a study conducted by his parents about two decades ago, which focused solely on the protein level. The current study by Dr. Parnas and his team advances to the next stage, connecting molecules, brain and conduct and indicating, for the first time, that eliminating their ability to sense electrical voltage affects brain activity and our ability to optimally adapt to the environment.

Autism is a neurodevelopmental disease, and its main symptoms are social deficiencies and compulsive behaviors. Cases range from mild to severe, and causes are both genetic and environmental. Researchers at Tel Aviv University have successfully treated autism in animal models with medical cannabis oil, improving behavioral and biochemical parameters.

Advancing in Reverse Order

In about 1% of all autism cases, a mutation in a single gene, called Shank3, is associated. While testing of medicinal cannabis traditionally begins with humans, in the current study PhD student Shani Poleg and Prof. Daniel Offen of TAU’s Sackler Faculty of Medicine, Felsenstein Medical Research Center and Sagol School of Neuroscience used animal models with a mutation in Shank3 to test the effectiveness of cannabis oil for alleviating symptoms of autism. The results of the surprising study were published in Translational Psychology published by Nature.

“We saw that cannabis oil has a favorable effect on compulsive and anxious behaviors in model animals,” says Shani Poleg. “According to the prevailing theory, autism involves over arousal of the brain which causes compulsive behavior. In the lab, in addition to the behavioral results, we saw a significant decrease in the concentration of the arousing neurotransmitter glutamate in the spinal fluid – which can explain the reduction in behavioral symptoms.”

A Little Euphoria Makes All the Difference

Attempting to determine which components of cannabis oil alleviate symptoms of autism, the researchers found that THC, the main psychoactive compound in cannabis which is responsible for the euphoric sensation associated with its use, is effective in treating autism, possibly even in small quantities.

“Clinical trials testing cannabis treatments for autism usually involve strains containing very large amounts of CBD – due to this substance’s anti-inflammatory properties, and because it does not produce a sense of euphoria,” explains Poleg. “Moreover, the strains used for treating autism usually contain very little THC, due to apprehension regarding both the euphoria and possible long-term effects.”

“In the second stage of our study we inquired which active substance in cannabis causes the behavioral improvement, and were surprised to discover that treatment with cannabis oil that contains THC but does not contain CBD produces equal or even better effects – both behavioral and biochemical. Moreover, our results suggest that CBD alone has no impact on the behavior of model animals.”

Addressing Existing Misinformation

Prof. Daniel Offen says, “Since cannabis is not defined as a medication, trials have already been conducted in children and adolescents with autism – without any preliminary studies addressing issues like the effect of cannabis on biochemical processes in the brain, spinal fluid or blood, and who can benefit from which type of cannabis oil. There is a great deal of misinformation on the subject of medicinal cannabis and autism, and Shani Peleg’s doctoral project represents pioneering basic research with regard to treating autism with cannabis oil.”

“This is an initial study,” concludes Poleg. “But we hope that through our basic research we will be able to improve clinical treatments. Our study shows that when treating autism with medicinal cannabis oil there is no need for high contents of either CBD or THC. We observed significant improvement in behavioral tests following treatments with cannabis oil containing small amounts of THC and observed no long-term effects in cognitive or emotional tests conducted a month and a half after the treatment began.”