Brain-generated marijuana, comfort food and focus, and the one workout to de-age your brain
Last week’s NeuroBrief was all about the CNS. This week, we’re focusing on neuro studies with a different—but timely—theme: cravings. Find out how our cravings for comfort food, love and affection, and even “bliss through ignorance” can affect the brain and vice versa by reading this week’s NeuroBrief.
What would you do if one of your patients told you that they were actually dead? Your first instinct might be to question their sanity. But, don’t be so quick to write them off. The false belief that one is dying, dead or non-existent, or that internal or external parts of their body are missing is called walking corpse syndrome—aka Cotard syndrome. Although this neuropsych illness has probably been around for ages, it was first formally described by French neurologist Jules Cotard in 1880 during a lecture, where he presented the case of a female patient. He originally called the syndrome “hypochondriac delusion,” but it was later renamed Cotard syndrome after his death. People with Cotard syndrome may also present with anxious and depressed moods as well as delusions of immortality. Because of this, some affected individuals have been reported to starve themselves due to negation of self. The syndrome is usually more common among women and older folks, rarely occurring in adolescents. Researchers aren’t sure what causes Cotard syndrome, but some studies have suggested that it may be an underlying symptom of another neuro disease like dementia, encephalopathy, epilepsy, migraine, multiple sclerosis, Parkinson disease, or stroke. As far as treatment goes, the use of electroconvulsive therapy, antidepressants, antipsychotics, and any combination of these therapeutics have been reported to work.
In the News
Fatty food = faulty focus? These days, a lot of us are working from home. But, let’s be clear: It’s no picnic. Between dealing with work fires, technology pitfalls—(yes, we’re looking at you, WiFi)—and distractions (read: kids and fur babies), it can get pretty stressful. And what do many of us do when we’re feeling stressed? You guessed it—we hit up our favorite comfort foods. But while those mashed potatoes and gravy-smothered biscuits might make us feel good in the moment, they’re really not doing our brains any favors. In fact, a new study shows that eating just one meal high in saturated fat can negatively impact our focus. Researchers looked at how eating 2 different meals high in dietary fats—a high-saturated fat meal vs the same meal made with sunflower oil (low-saturated fat meal)—affected attention in 51 women. Each woman gave fasting blood samples and completed a test on attention at baseline. Afterward, they ate a high-fat meal that included eggs, biscuits, turkey sausage, and gravy. The meal contained 60 g of fat and 930 calories, and was made either with an oil high in saturated fat or an oil lower in saturated fat (sunflower oil). Five hours after eating, the women took the attention test again. Between 1 and 4 weeks later, they followed the same protocol but ate the opposite meal of what they had on the first visit.
Compared with the low-saturated fat meal, the high-saturated fat meal was associated with worse scores on the attention test. To rule out any confounders, researchers also looked at whether leaky gut could have had any effect on concentration. They found that women with leakier guts did worse on the attention test—regardless of which fatty meal they ate. The researchers also noted that because both meals were high in dietary fats, the high-saturated fat meal’s cognitive impact could be even worse compared with a meal lower in dietary fats. As far as the brain goes, they aren’t sure why or exactly how fatty foods affect cognition. But, based on previous research, they speculated that foods high in saturated fat might drive up inflammation throughout the body and brain. Plus, fatty acids have been shown to cross the blood-brain barrier, meaning they could be directly interacting with the brain. Just goes to show how a single bad meal can ruin your brain health. So, you might want to call on all your willpower to resist those French fries before your next telehealth consult.
Single-best workout for brain health at any age. If you think you’re too old to get moving, think again. A new study shows that just 6 months of aerobic exercise can boost cognition in the areas of thinking and memory. And the best part? Even older, less active folks can reap the benefits. Time to bust out the sneakers and pound some pavement! Researchers wanted to find out whether aerobic exercise improves cognition and cerebrovascular regulation. So, they enrolled 206 healthy, low-active, middle-aged and older adults (mean age: 66 years) in a supervised 6-month aerobic exercise intervention. Participants had no history of heart or memory problems, and were assessed on physical and cognitive tests before and after the intervention. Before the intervention, they worked out ≤ 4 days a week at a moderate intensity for ≤ 30 minutes daily, or ≤ 2 days a week at a high intensity for ≤ 20 minutes a day. The intervention initially consisted of a supervised 20-minute routine—in which participants warmed up, exercised, and cooled down—for 3 days a week. As time went on, though, the intensity and length of the routine grew. As participants progressed through the program, they increased their routines from an average of 20 minutes daily to ≥ 40 minutes. In addition to their supervised schedule, participants completed a self-run session on their own time, once per week.
After 6 months of exercise, participants improved by about 6% on tests of mental flexibility and self-correction and by roughly 2% on verbal fluency, which measures how quickly you can retrieve info. The improvement in verbal fluency might not seem like a big deal, but the researchers remarked that it’s actually what you’d expect to see in someone about 5 years younger. So, how exactly did aerobic exercise essentially de-age the brain? Seems that it not only gets the blood moving through the body, but also jacks up blood to the brain regions responsible for thinking and memory. The researchers noted that before and after 6 months of aerobic exercise, participants’ blood flow rose, on average, from 51.3 cm/sec to 52.7 cm/sec—a nearly 3% uptick. These modest improvements in blood flow, executive function, and verbal fluency are significant, considering that they usually decline with age. While the study didn’t compare results with non-exercisers, the findings are still noteworthy. Learning that something as simple as aerobic exercise can turn back the clock is huge news—especially for older folks at risk for Alzheimer disease and other neurodegenerative disease.
Craving company? Blame your brain. They say that absence makes the heart grow fonder. But, why is that? Turns out, the answer may lie with the brain—the mastermind behind it all. Researchers of a new brain imaging study have shown that our brains may actually be engineered for longing. Essentially, it craves physical comfort—especially in times of distress—through close relationships. This new insight could help explain why some people are having a hard time coping with social distancing. Researchers used tiny cameras and in-vivo-calcium imaging to study the brain activities of dozens of prairie voles (a kind of rodent) at three different times: when they’d just met another vole, 3 days after the voles mated, and 20 days after they “moved in together.” The researchers also studied animals interacting with voles that were not their mates. Why prairie voles, you ask? Good question. It’s because prairie voles are part of a small, exclusive group of mammalian species (including humans) that mate for life.
Unlike previous brain imaging research findings in humans—which showed altered brain activity in the nucleus accumbens (the brain’s reward center) of people who held the hand of a lover vs a stranger—voles’ brains activities were no different when they were in the company of their partner vs a stranger. Surprisingly, it was only when voles ran to meet their partners after an absence did the cells in the nucleus accumbens light up. The researchers aren’t entirely sure how it all works, but they suspect that certain neurochemicals that have been shown to play a role in building trust and closeness in human and animal studies—like oxytocin, dopamine, and vasopressin—may be involved in the process. And while more research is needed to find out whether the desire to reunite in voles is the same in humans, it’s clear that the need to be with others is a trait unique to monogamous mammals. In the future, the researchers’ findings could be used to help create new treatments for people with emotional connection disorders like autism and major depression.
The body’s self-made marijuana and memory. By now, everyone pretty much knows about marijuana and its stereotypical side effects: the munchies and memory loss. But, did you know that the body actually produces its own kind of marijuana called anandamide? (Not to be confused with adamantium from Marvel comics. Though, it’s just as cool, if you ask us.) Dubbed the “bliss molecule,” anandamide is an endogenous compound that’s part of the endocannabinoid system, which helps regulate a range of processes from pain to memory. But, much isn’t known about anandamide’s specific biological role. And if you’re wondering whether anandamide has effects similar to marijuana, you’re not alone. To answer this question, an international team of researchers began digging into anandamide’s physiological effects on the brain about 5 years ago. Now, in a first-in-kind study, they’ve discovered that the compound may play a role in helping us forget traumatic memories as well as reducing anxiety and stress. Their breakthrough findings could lead to new treatments for anxiety disorders and PTSD in the near future.
So, how’d they figure this out? Well, their first step was to isolate the protein responsible for making anandamide in the brain: NAPE-PLD. Once they did that, their next task was finding a compound that would stop the protein from working. The researchers hypothesized that if they stopped anandamide’s production, it would allow them to study its biological role. After long months of intensive lab work, they were finally able to identify an anandamide-blocking molecule. They then spent the next 2 years synthesizing over 100 analogues, eventually identifying one (LE-401) able to reduce levels of anandamide in the brain. Moving on to animal models, the researchers found the answers they were looking for: LEI-401 stopped traumatic memories from being erased. This reaction also increased corticosteroid levels and activated the brain region responsible for stress response. With these new revelations, drug makers may now be able to focus on a new therapeutic target by looking for molecules that either drive or inhibit anandamide production.
Which neurological disease is characterized as an “electrical brainstorm”?
We admit—this one might’ve been a little too easy. (But, hey, what’s wrong with a little “easy” here and there? It sure seems like we could all use it right about now.) If you guessed “epilepsy,” you’re absolutely right. In people with epilepsy, seizures occur when the brain’s electrical system goes haywire. This phenomenon has been described as an electrical brainstorm. Instead of releasing controlled electrical energy, brain cells keep firing in uncontrolled bursts, like lightning during a storm. Hence, “electrical brainstorm.”
Tattoo electrodes for your brain. Yep, you read that right. And, yes, it’s just as awesome as it sounds. Scientists previously created “tattoo electrodes” that could be printed using an inkjet printer on standard tattoo paper and then placed on the skin, like transfers, to measure heart and muscle activities. They’re inconspicuous, razor-thin (100 times thinner than a human hair!), adapt to uneven skin texture, work without the use of gels, and don’t dry out. And it gets even better: Building on this tech, researchers have now modified the tattoo electrodes so that they can be used to measure brain activity, or EEG. To do this, they followed the same protocol for the development of the heart and muscle electrodes—inkjet printing of conductive polymer on tattoo paper. But, because brain waves are in the low-frequency range and hard to detect with EEG signals, they had to change the composition and thickness of the transfer paper for a better connection between the tattoo electrode and the skin to record EEG signals with optimal quality. When they tested the tattoos under real-world clinical conditions, the researchers found that they were just as good as conventional EEG electrodes. So, if they’re just as good as regular EEG electrodes, what’s the big deal? For one, they’re way cheaper than commercially available EEG electrodes. The tattoos are also much more comfortable to wear and can offer long-term EEG measurements. The researchers are now looking at how their tech can be used in clinics, in neuroengineering, and in brain computer interfaces.
MRI-based score predicts dementia risk. We’re starting to wonder if MRIs might just be the “wonder tool” when it comes to diagnostics. In the span of a few weeks, studies have shown that MRI can be used to prevent brain surgery and help deliver life-saving drugs directly to the CNS. Now, it looks like MRI could help pinpoint patients at risk for cognitive decline and dementia. Previous studies have linked cerebral small vessel disease (SVD) features on MRI to increased dementia risk. So, researchers set out to determine whether a simple SVD score—obtained from quick, visual assessment of routine clinical MRI scans—could help predict future dementia risk. And—good news—it did. They used three prospective longitudinal cohort studies in patients with SVD—ranging from mild and asymptomatic to severe and symptomatic—to investigate the score’s efficacy and find out whether applying the score to a select a group of patients with more severe SVD would reduce sample sizes for clinical intervention trials. In all three studies, MRI was performed at baseline, cognitive tests were repeated during follow-up, and dementia progression was recorded prospectively. In a pooled analysis of the three cohorts, the SVD score improved the prediction of dementia risk vs clinical risk factors alone. And, predictive ability was stronger in patients with more severe SVD. Another plus? The researchers found that selecting patients with a higher score reduced sample sizes needed for hypothetical clinical trials by 40% to 66% depending on the outcome measure used. This is significant since previous studies including patients with all grades of SVD have failed to pick up on cognitive changes during follow-up. Overall, the results are very promising, and the diagnostic could be a simple, quick way to easily screen for dementia risk in clinical practice.
The eyes are the windows to…Alzheimer disease? A person’s eyes can tell you a lot about them—whether they’re honest, kind, angry, or simply up to no good. Apparently, they can also tell you if someone has Alzheimer disease. Biomedical engineers created a new imaging device that can measure the thickness and texture of the layers of the retina to determine whether a person has Alzheimer disease. Previous studies have shown that patients with Alzheimer disease tend to have thinning of the internal layers of the retina, which scientists are now recognizing as a biomarker of the disease. But other diseases like glaucoma and Parkinson disease can also cause retinal thinning, complicating the accuracy of diagnosis. (Not to mention differences across diagnostic machines, which can yield inconsistent or incompatible results.) So, the biomedical engineers of the current study set out to better understand the link between retinal health and Alzheimer disease. Using a light-scattering imaging technique in a mouse model with Alzheimer disease, they discovered that the retinal nerve fiber layer is rougher and more disordered in those with Alzheimer disease. This technique—called angle-resolved low-coherence interferometry—can be used along with the retinal thickness measurement as a combined imaging modality to identify early signs of Alzheimer disease. With this new insight in mind, the engineers’ long-term goal is to create an easy, cheap screening device available for both clinician and patient use.
Abuse-resistant ADHD drug. The FDA is killing it this year, having already approved twice the number of novel drugs vs this time last year—and we’re only halfway through 2020! Speaking of novel drugs, Arbor Pharmaceuticals recently announced that the FDA accepted its New Drug Application filing for AR19, an investigational attention-deficit/hyperactivity disorder (ADHD) prescription stimulant. It’s an immediate-release, amphetamine capsule indicated for the treatment of ADHD in patients ages 3 and up. AR19’s safety, efficacy, and manipulation-resistant properties have been demonstrated in comprehensive clinical programs and studies including children and adults with ADHD, according to Arbor. One recent study of the pharmacokinetics of AR19 showed that treatment was bioequivalent to Evekeo—a reference racemic amphetamine sulfate drug—and AR19’s bioavailability was not affected by food or by sprinkling the capsule’s contents onto food. If approved, AR19 would be the first FDA-approved ADHD stimulant medication designed to resist manipulation for nonmedical misuse or abuse by intranasal, intravenous, or smoking routes of administration. And this is major news, considering the growing trend in prescription stimulant misuse in the United States. The FDA has set a Prescription Drug User Fee Act target action date of November 15, 2020.
New hope for rare, fatal brain disease. Sanfilippo disease type A is a rare, severe, and often fatal pediatric brain disease caused by defects in the SGSH gene that make the body unable to break down certain complex sugars. The resulting buildup leads to serious problems in the brain and CNS. Sanfilippo disease causes a gradual loss of developmental, motor, and cognitive skills in young children. Symptoms include hearing loss, hyperactivity and behavioral problems, severe cognitive impairment, and seizures. Simply put, it’s an agonizing disease with no known cure. But, a group of scientists is giving back some hope to those afflicted with the disease and their loved ones. The preliminary results of a 2-year-old patient treated under compassionate use with an investigational gene therapy over 10 years in the making have shown promise. The treatment involved stem cell harvesting, gene manufacturing, and transplantation. Sounds like a complicated procedure straight out of a sci-fi horror flick, right? But, actually, it was a pretty straightforward process.
After the scientists harvested the patient’s blood stem cells, they used a lentiviral vector to deliver the patient’s “missing” SGSH gene to the blood stem cells. They then transplanted the modified stem cells back into the patient. The modified stem cells were able to restore the patient’s immune system, providing the body with a functioning copy of the manufactured gene. After a year of follow-up, the scientists reported normalized CSF and SGSH enzyme levels in the patient’s blood—which is great news. The researchers have speculated that adequate levels of SGSH enzymes in the brain could prevent disease progression, but they admit that it’s too early to know for sure. So, they plan to investigate this in an upcoming formal clinical trial, funded by Orchard Therapeutics. The phase 1/2 study of the gene therapy transplant will include a very small group of children under age 2 with severe Sanfilippo disease type A. The safety of the therapy, SGSH enzyme levels, changes in patient behavior, quality of life, and other measures will be assessed on a continual basis over the next 3 years.
Breakthrough therapy for CNS edema. CNS injuries, including stroke, affect about 75 million people around the world every year. These injuries occur across a range of age groups and events—from youth contact sports to strokes and falls among older folks. Unfortunately, current treatment options aren’t that great—medically induced coma and/or high-risk surgery—and are often accompanied by lengthy, challenging rehabilitation. But, that may all soon change, thanks to new research from a team of international scientists. They’ve discovered how to significantly reduce brain swelling after CNS injuries in humans through the manipulation of “cell pores.” The best part? There’s already an FDA-approved drug that can be used to achieve this end.
For the research, the scientists used an anti-psychotic medicine known as trifluoperazine (TFP) to manipulate the behavior of tiny water channel “pores” in cells called aquaporins. In a model of injured rats, those that were given a dose of the drug at the trauma site regained full movement and sensitivity in just 2 weeks vs an untreated group of rats that continued to show motor and sensory problems ≥ 6 weeks after the injury. So, how’s it all work? Good question. Normally, when there’s trauma-induced oxygen loss in the CNS, cells become “saltier” in response to a build-up of ions. This causes a rush of water through the aquaporins, making the cells swell and putting pressure on the CNS. This pressure buildup, in turn, damages brain and spinal cord tissues, which messes up the flow of brain-body electrical signals. Treatment with TFP stops all this from happening. It prevents the protein calmodulin from binding with the aquaporins. (This binding effect is what jets the aquaporins to the cell surface, letting in more water.) By stopping this action, cell permeability is reduced. Because TFP is already FDA-approved (for schizophrenia), it could be quickly repurposed as a treatment for CNS edema. But, the scientists say that, with further research, they could potentially make a better drug for brain injuries.
New in Patient Management
Thinking and walking go hand-in-hand? Ever known someone who couldn’t chew gum and walk at the same time? You may have heard the expression being used in good humor to describe someone who isn’t well-coordinated or just isn’t the brightest crayon in the box. But, new research shows that there may be some merit to the idiom. Researchers have found that cognition and gait speed parallel each other, and could be used to determine a person’s health trajectory—including decline. They looked at data from 370 older adults (ages 65-74) in the San Antonio Longitudinal Study of Aging. Based on the participants’ changes in cognition and gait speed over nearly 10 years of follow-up, the researchers grouped them into 3 categories: stable cognition and gait class (65.4% of the participants), cognitive and physical vulnerability class (22.2%), and physical vulnerability class (12.4%). The researchers found that those participants who started the study with higher scores in cognition and gait speed showed greater resilience to age-related decline in both domains, and they continued to be functionally independent. On the other hand, those with lower scores in both domains at baseline (one-fifth of study participants) showed greater, quicker deterioration in cognition and gait speed during follow-up. Interestingly, participants in the physical vulnerability class showed stable cognition during the study, but their gait speed declined over time. Overall, those in cognitive and physical vulnerability class and the physical vulnerability class had a five- to seven-fold increased risk of mortality vs those in the stable cognition and gait class.
The researchers speculated that cognition and gait speed may both be affected by blood vessel disease, brain tissue insults, hormone regulation, or abnormal deposits of amyloid-beta and tau proteins in the brain. They theorized that abnormal protein deposition causes neurodegeneration and synaptic loss, which might lead to dysfunction in brain regions responsible for cognition and gait. But, they acknowledged that damage to white matter in brain regions vital for cognition and gait coordination might be another explanation for why the two functions mirror each other. Ultimately, more study is needed, but the researchers suggested that preventive strategies should focus on young and middle-aged adults while there’s still time to positively change their health trajectories.
The exercise-sleep link in PD. A lot of patients with Parkinson disease have sleep problems, which can lead to poor quality of life, depression, and debilitating motor symptoms. Even worse, there aren’t many safe and effective therapies that can help. Luckily, researchers have found that something as simple and low-cost as high-intensity exercise training may help remedy these sleep problems—providing a simple nonpharmacological intervention for patients with PD. They carried out a study to find out whether high-intensity exercise rehabilitation plus resistance training and body-weight interval training would improve PD sleep outcomes. Participants included 55 patients with idiopathic PD who were randomized to an exercise intervention group (n = 27) or sleep hygiene control group (n = 28). The primary study outcome was the change in sleep efficiency between both groups, measured by polysomnography, from baseline to the post-16-week intervention. Of note, there weren’t any group differences in sleep parameters at baseline.
The researchers found that participants in the exercise group had a significant improvement in sleep efficiency vs those in the sleep hygiene control group. Because changes in motor symptoms weren’t significant predictors of sleep outcomes, the researchers posited that these changes in sleep were due to the exercise intervention. And, unlike acute exercise, chronic exercise improved sleep efficiency vs baseline. Better yet, the intervention group showed additional improvements in measures of sleep architecture—including total sleep time, wake after sleep onset, and slow-wave sleep—compared with the control group. The exercise group also reduced their use of sleep meds vs the sleep hygiene control group. This is all great news, of course, but it might be wise to take these findings with a grain of salt. After all, the study did have some limitations, including a non-blinded design, lack of non-PD control group, completing polysomnography on a single night without adjusting for the potential influence of the first-night effect, and less in-person contact between participants in the sleep-hygiene control group and study staff. Still, the researchers note that their study findings “have important therapeutic implications and are an exciting step forward in identifying non-pharmacological therapies for this common and disabling nonmotor symptom.” It’s too bad most gyms are still closed.
Type 2 diabetes and post-stroke cognition. Bad news for diabetics (as if being a diabetic weren’t bad enough): A new study shows that people with type 2 diabetes (but not prediabetes) had worse cognitive function 3-6 months after suffering a stroke vs those with normal fasting blood sugar levels. Notably, type 2 diabetes increases stroke risk, has been linked to cognitive impairment, and may also drive up dementia risk. That’s why, researchers say, type 2 diabetes is a key target in dementia prevention, and preventive strategies should focus on early treatment of prediabetes. Previous studies have shown that patients with stroke and a history of type 2 diabetes have worse cognitive function vs stroke survivors without type 2 diabetes. So, researchers wanted to know if stroke patients with prediabetes also have worse cognitive function vs stroke survivors without prediabetes or diabetes.
They combined data from over 1,600 stroke survivors (mean age: 66 years) from 7 international studies across 6 countries, and assessed a range of cognitive functions 3-6 months after a stroke. Patients’ fasting blood sugar levels (measured on admission) and medical history were used to define type 2 diabetes and prediabetes. After adjusting for age, sex, and education, the researchers found that those with type 2 diabetes scored much lower in different domains of cognitive function—including memory, attention, speed of processing information, language, visual ability to copy or draw shapes or figures or lines, mental flexibility, and executive functioning. On the bright side, though, patients with prediabetes didn’t score much lower than those with normal blood sugar in any areas of cognitive function. And the comparisons remained the same after researchers adjusted for other factors like stroke type, ethnicity, hypertension, smoking, previous stroke, abnormal heart rhythm, and BMI. The study findings underscore the critical need for clinicians to assess the capacity for self-care—such as measuring glucose levels, self-administration of medication, and understanding food labels and portion sizes—in stroke survivors with type 2 diabetes. The researchers stressed that while their study focused on cognition after stroke, the evidence linking type 2 diabetes to cognitive impairment is strong. They also emphasized that because their study showed no evidence of an association between prediabetes and worse cognitive function, early diagnosis and treatment of prediabetes is imperative to delay or prevent the progression to type 2 diabetes.
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Upcoming Medical Meetings
Please note that, in the interests of containing the current COVID-19 pandemic, the following meeting has been canceled. Please contact this organization for details and specifics on refunds and rescheduling:
International Conference on Opioids (ICOO2020), in Boston, MA, May 30–June 1, 2020.
The following meeting has been rescheduled:
10th Annual Traumatic Brain Injury Conference, to be held in Arlington, VA, June 1–2, 2020, has been rescheduled for November 2–3, 2020, and will be held in Washington, DC.
The following meetings have been changed to virtual workshops:
17th Annual Penn Neurology Board Review Course, in Philadelphia, PA, June 1–3, 2020.
American Society of Clinical Psychopharmacology (ASCP) 2020 Annual Meeting, to be held in Miami Beach, FL, May 26–29, 2020, has been canceled and will be offered, in part, as a virtual option. Please check the website for up-to-the-minute information.