Vitamin D in diet might ease effects of age on memory

If you don’t want to dumb down with age, vitamin D may be the meal ticket.

A boosted daily dosage of the vitamin over several months helped middle-aged rats navigate a difficult water maze better than their lower-dosed cohorts, according to a study published online Monday in the journal Proceedings of the National Academy of Sciences.

The supplement appears to boost the machinery that helps recycle and repackage signaling chemicals that help neurons communicate with one another in a part of the brain that is central to memory and learning.

"This process is like restocking shelves in grocery stores," said study co-author Nada Porter, a biomedical pharmacologist at the University of Kentucky College of Medicine.

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Venturing inside the teenage brain

If you’ve ever tried to warn teenagers of the consequences of risky behavior — only to have them sigh and roll their eyes — don’t blame them.

Blame their brain anatomy.

Sociologists and psychologists have long known that teen brains are predisposed to downplay risk, act impulsively and be undaunted by the threat of punishment. But now scientists are beginning to understand why.

"I think teenage behavior is probably the most misunderstood of any age group — not only by parents but by teenagers themselves," says Pradeep Bhide, a Florida State University College of Medicine neuroscientist and director of the Center for Brain Repair.

"It’s a critical time in life, and a very stressful one, when they are going through so many changes at the same time that their brains are changing. The teen years are actually a very busy time for brain development."

During the past year, Bhide brought together some of the world’s foremost brain researchers in a quest to explain why teenagers — and male teens in particular — often behave erratically. He and two Cornell University colleagues examined 20 of the leading research projects from brain experts around the world and recently published their findings in a special volume of the scientific journal Developmental Neuroscience.

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Selectively Rewiring the Brain’s Circuitry to Treat Depression

On Star Trek, it is easy to take for granted the incredible ability of futuristic doctors to wave small devices over the heads of both humans and aliens, diagnose their problems through evaluating changes in brain activity or chemistry, and then treat behavior problems by selectively stimulating relevant brain circuits.

While that day is a long way off, transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex does treat symptoms of depression in humans by placing a relatively small device on a person’s scalp and stimulating brain circuits. However, relatively little is known about how, exactly, TMS produces these beneficial effects.

Some studies have suggested that TMS may modulate atypical interactions between two large-scale neuronal networks, the frontoparietal central executive network (CEN) and the medial prefrontal-medial parietal default mode network (DMN). These two functional networks play important roles in emotion regulation and cognition.

In order to advance our understanding of the underlying antidepressant mechanisms of TMS, Drs. Conor Liston, Marc Dubin, and their colleagues conducted a longitudinal study to test this hypothesis.

The researchers used functional magnetic resonance imaging in 17 currently depressed patients to measure connectivity in the CEN and DMN networks both before and after a 25-day course of TMS. They also compared the connectivity in the depressed patients with a group of 35 healthy volunteers.

TMS normalized depression-related hyperconnectivity between the subgenual cingulate and medial prefrontal areas of the DMN, but did not alter connectivity in the CEN.

Liston, an Assistant Professor at Weill Cornell Medical College, further details their findings, “We found that connectivity within the DMN and between nodes of the DMN and CEN was elevated in depressed individuals compared to healthy volunteers at baseline and normalized after TMS. Additionally, individuals with greater baseline connectivity with subgenual anterior cingulate cortex – an important target for other antidepressant modalities – were more likely to respond to TMS.”

These findings indicate that TMS may act, in part, by selectively regulating network-level connectivity.

Dr. John Krystal, Editor of Biological Psychiatry, comments, “We are a long way from Star Trek, but even the current ability to link brain stimulation treatments for depression to the activity of particular brain circuits strikes me as incredible progress.”

Dubin, also an Assistant Professor at Weill Cornell Medical College, adds, “Our findings may inform future efforts to develop personalized strategies for treating depression with TMS based on the connectivity of an individual’s default mode network. Further, they may help triage to TMS only those patients most likely to respond.”

Americans Reporting Increased Symptoms of Depression

New learning mechanism for individual nerve cells

“This means a dramatic increase in the brain’s learning capacity. The cells we have studied control the blink reflex, but there are many cells of the same type that control entirely different processes. It is therefore likely that the timing mechanism we have discovered also exists in other parts of the brain”, said Professor of neurophysiology Germund Hesslow.

Professor Hesslow and colleagues Fredrik Johansson and Dan-Anders Jirenhed have used ‘conditioned reflexes’ for the research. The principle comes from the Russian researcher Ivan Pavlov, who, around the turn of the last century, taught dogs to associate a certain sound with food so that they began to drool on hearing the sound.

In the present experiment, the researchers studied animals that learnt to associate a sound with a puff of air in the eye that caused them to blink. If the time between the sound and the puff of air was quarter of a second, the animals blinked after quarter of a second even if the puff of air was removed. If the time was changed to half a second, the animals blinked after half a second, and so on.

The prevalent theories in brain research state that this learnt timing mechanism is a result of strengthening or weakening of the contacts – or synapses – throughout a network of nerve cells. However, using super-thin electrodes, the Lund group have now shown that no networks are needed: one single cell can learn when it is time to react.

The cells which the researchers have studied are called Purkinje cells and are located in the cerebellum. The cerebellum is the part of the brain responsible for posture, balance and movement, and the researchers focused on those cells that control blinking.

This work is basic research, but possible future applications could include rehabilitation following a stroke, which often affects a patient’s movements. The findings could also have a bearing on conditions such as autism, ADHD and language problems, in which the cerebellum is believed to play a part.

“Intelligible speech is dependent on correct timing, so that the pauses between the sounds are right”, explained Germund Hesslow.

The new findings have already attracted attention in the research community: the internationally renowned memory researcher Charles Gallistel came all the way from Rutgers University in the spring to study the group’s work. Work is now continuing to study what transmitter substance and what receptor on the surface of the cell are responsible for the newly discovered timing mechanism.

Improving Babies’ Language Skills Before They’re Even Old Enough to Speak

In the first months of life, when babies begin to distinguish sounds that make up language from all the other sounds in the world, they can be trained to more effectively recognize which sounds “might” be language, accelerating the development of the brain maps which are critical to language acquisition and processing, according to new Rutgers research.

The study by April Benasich and colleagues of Rutgers University-Newark is published in the October 1 issue of the Journal of Neuroscience.

The researchers found that when 4-month-old babies learned to pay attention to increasingly complex non-language audio patterns and were rewarded for correctly shifting their eyes to a video reward when the sound changed slightly, their brain scans at 7 months old showed they were faster and more accurate at detecting other sounds important to language than babies who had not been exposed to the sound patterns. 

“Young babies are constantly scanning the environment to identify sounds that might be language,” says Benasich, who directs the Infancy Studies Laboratory at the University’s Center for Molecular and Behavioral Neuroscience. “This is one of their key jobs – as between 4 and 7 months of age they are setting up their pre-linguistic acoustic maps. We gently guided the babies’ brains to focus on the sensory inputs which are most meaningful to the formation of these maps.” 

Acoustic maps are pools of interconnected brain cells that an infant brain constructs to allow it to decode language both quickly and automatically – and well-formed maps allow faster and more accurate processing of language, a function that is critical to optimal cognitive functioning. Benasich says babies of this particular age may be ideal for this kind of training.

“If you shape something while the baby is actually building it,” she says, “it allows each infant to build the best possible auditory network for his or her particular brain. This provides a stronger foundation for any language (or languages) the infant will be learning. Compare the baby’s reactions to language cues to an adult driving a car. You don’t think about specifics like stepping on the gas or using the turn signal. You just perform them. We want the babies’ recognition of any language-specific sounds they hear to be just that automatic.”

Benasich says she was able to accelerate and optimize the construction of babies’ acoustic maps, as compared to those of infants who either passively listened or received no training, by rewarding the babies with a brief colorful video when they responded to changes in the rapidly varying sound patterns. The sound changes could take just tens of milliseconds, and became more complex as the training progressed.

Looking for lasting improvement in language skills

“While playing this fun game we can convey to the baby, ‘Pay attention to this. This is important. Now pay attention to this. This is important,’” says Benasich, “This process helps the baby to focus tightly on sounds in the environment that ‘may’ have critical information about the language they are learning. Previous research has shown that accurate processing of these tens-of-milliseconds differences in infancy is highly predictive of the child’s language skills at 3, 4 and 5 years.”  

The experiment has the potential to provide lasting benefits. The EEG (electroencephalogram) scans showed the babies’ brains processed sound patterns with increasing efficiency at 7 months of age after six weekly training sessions. The research team will follow these infants through 18 months of age to see whether they retain and build upon these abilities with no further training. That outcome would suggest to Benasich that once the child’s earliest acoustic maps are formed in the most optimal way, the benefits will endure.  

Benasich says this training has the potential to advance the development of typically developing babies as well as children at higher risk for developmental language difficulties. For parents who think this might turn their babies into geniuses, the answer is – not necessarily.  Benasich compares the process of enhancing acoustic maps to some people’s wishes to be taller. “There’s a genetic range to how tall you become – perhaps you have the capacity to be 5’6” to 5’9”,” she explains. “If you get the right amounts and types of food, the right environment, the right exercise, you might get to 5’9” but you wouldn’t be 6 feet. The same principle applies here.”

Benasich says it’s very likely that one day parents at home will be able to use an interactive toy-like device – now under development – to mirror what she accomplished in the baby lab and maximize their babies’ potential. For the 8 to 15 percent of infants at highest risk for poor acoustic processing and subsequent delayed language, this baby-friendly behavioral intervention could have far-reaching implications and may offer the promise of improving or perhaps preventing language difficulties.

Memory loss associated with Alzheimer’s reversed for first time

Since its first description over 100 years ago, Alzheimer’s disease has been without effective treatment. That may finally be about to change: in the first, small study of a novel, personalized and comprehensive program to reverse memory loss, nine of 10 participants, including the ones above, displayed subjective or objective improvement in their memories beginning within 3-to-6 months after the program’s start. Of the six patients who had to discontinue working or were struggling with their jobs at the time they joined the study, all were able to return to work or continue working with improved performance. Improvements have been sustained, and as of this writing the longest patient follow-up is two and one-half years from initial treatment. These first ten included patients with memory loss associated with Alzheimer’s disease (AD), amnestic mild cognitive impairment (aMCI), or subjective cognitive impairment (SCI; when a patient reports cognitive problems). One patient, diagnosed with late stage Alzheimer’s, did not improve.

The study, which comes jointly from the UCLA Mary S. Easton Center for Alzheimer’s Disease Research and the Buck Institute for Research on Aging, is the first to suggest that memory loss in patients may be reversed, and improvement sustained, using a complex, 36-point therapeutic program that involves comprehensive changes in diet, brain stimulation, exercise, optimization of sleep, specific pharmaceuticals and vitamins, and multiple additional steps that affect brain chemistry.

The findings, published in the current online edition of the journal Aging, “are very encouraging. However, at the current time the results are anecdotal, and therefore a more extensive, controlled clinical trial is warranted,” said Dale Bredesen, the Augustus Rose Professor of Neurology and Director of the Easton Center at UCLA, a professor at the Buck Institute, and the author of the paper.

In the case of Alzheimer’s disease, Bredesen notes, there is not one drug that has been developed that stops or even slows the disease’s progression, and drugs have only had modest effects on symptoms. “In the past decade alone, hundreds of clinical trials have been conducted for Alzheimer’s at an aggregate cost of over a billion dollars, without success,” he said.

Other chronic illnesses such as cardiovascular disease, cancer, and HIV, have been improved through the use of combination therapies, he noted. Yet in the case of Alzheimer’s and other memory disorders, comprehensive combination therapies have not been explored. Yet over the past few decades, genetic and biochemical research has revealed an extensive network of molecular interactions involved in AD pathogenesis. “That suggested that a broader-based therapeutics approach, rather than a single drug that aims at a single target, may be feasible and potentially more effective for the treatment of cognitive decline due to Alzheimer’s,” said Bredesen.

While extensive preclinical studies from numerous laboratories have identified single pathogenetic targets for potential intervention, in human studies, such single target therapeutic approaches have not borne out. But, said Bredesen, it’s possible addressing multiple targets within the network underlying AD may be successful even when each target is affected in a relatively modest way. “In other words,” he said, “the effects of the various targets may be additive, or even synergistic.”

The uniform failure of drug trials in Alzheimer’s influenced Bredesen’s research to get a better understanding of the fundamental nature of the disease. His laboratory has found evidence that Alzheimer’s disease stems from an imbalance in nerve cell signaling: in the normal brain, specific signals foster nerve connections and memory making, while balancing signals support memory loss, allowing irrelevant information to be forgotten. But in Alzheimer’s disease, the balance of these opposing signals is disturbed, nerve connections are suppressed, and memories are lost.

The model of multiple targets and an imbalance in signaling runs contrary to the popular dogma that Alzheimer’s is a disease of toxicity, caused by the accumulation of sticky plaques in the brain. Bredesen believes the amyloid beta peptide, the source of the plaques, has a normal function in the brain – as part of a larger set of molecules that promotes signals that cause nerve connections to lapse. Thus the increase in the peptide that occurs in Alzheimer’s disease shifts the memory-making vs. memory-breaking balance in favor of memory loss.

Given all this, Bredesen thought that rather than a single targeted agent, the solution might be a systems type approach, the kind that is in line with the approach taken with other chronic illnesses—a multiple-component system.

“The existing Alzheimer’s drugs affect a single target, but Alzheimer’s disease is more complex. Imagine having a roof with 36 holes in it, and your drug patched one hole very well—the drug may have worked, a single “hole” may have been fixed, but you still have 35 other leaks, and so the underlying process may not be affected much.”

Bredesen’s approach is personalized to the patient, based on extensive testing to determine what is affecting the plasticity signaling network of the brain. As one example, in the case of the patient with the demanding job who was forgetting her way home, her therapeutic program consisted of some, but not all of the components involved with Bredesen’s therapeutic program, and included:

(1) eliminating all simple carbohydrates, leading to a weight loss of 20 pounds; (2) eliminating gluten and processed food from her diet, with increased vegetables, fruits, and non-farmed fish; (3) to reduce stress, she began yoga; (4) as a second measure to reduce the stress of her job, she began to meditate for 20 minutes twice per day; (5) she took melatonin each night; (6) she increased her sleep from 4-5 hours per night to 7-8 hours per night; (7) she took methylcobalamin each day; (8) she took vitamin D3 each day; (9) fish oil each day; (10) CoQ10 each day; (11) she optimized her oral hygiene using an electric flosser and electric toothbrush; (12) following discussion with her primary care provider, she reinstated hormone replacement therapy that had been discontinued; (13) she fasted for a minimum of 12 hours between dinner and breakfast, and for a minimum of three hours between dinner and bedtime; (14) she exercised for a minimum of 30 minutes, 4-6 days per week.

The results for nine of the 10 patients reported in the paper suggest that memory loss may be reversed, and improvement sustained with this therapeutic program, said Bredesen. “This is the first successful demonstration,” he noted, but he cautioned that the results are anecdotal, and therefore a more extensive, controlled clinical trial is needed.

The downside to this program is its complexity. It is not easy to follow, with the burden falling on the patients and caregivers, and none of the patients were able to stick to the entire protocol. The significant diet and lifestyle changes, and multiple pills required each day, were the two most common complaints. The good news, though, said Bredesen, are the side effects: “It is noteworthy that the major side effect of this therapeutic system is improved health and an optimal body mass index, a stark contrast to the side effects of many drugs.”

The results for nine of the 10 patients reported in the paper suggest that memory loss may be reversed, and improvement sustained with this therapeutic program, said Bredesen. “This is the first successful demonstration,” he noted, but he cautioned that the results need to be replicated. “The current, anecdotal results require a larger trial, not only to confirm or refute the results reported here, but also to address key questions raised, such as the degree of improvement that can be achieved routinely, how late in the course of cognitive decline reversal can be effected, whether such an approach may be effective in patients with familial Alzheimer’s disease, and last, how long improvement can be sustained,” he said.

Cognitive decline is a major concern of the aging population. Already, Alzheimer’s disease affects approximately 5.4 million Americans and 30 million people globally. Without effective prevention and treatment, the prospects for the future are bleak. By 2050, it’s estimated that 160 million people globally will have the disease, including 13 million Americans, leading to potential bankruptcy of the Medicare system. Unlike several other chronic illnesses, Alzheimer’s disease is on the rise—recent estimates suggest that AD has become the third leading cause of death in the United States behind cardiovascular disease and cancer.

(Image: Corbis)