Images in the mind image via Shutterstock

The media has widely reported recent research which shows that memory processes start to decline at 45 years of age [2]. With increasing attention paid to the impact of dementia on individuals, families, society and healthcare services, memory research is very much in the spotlight. Although it’s important to understand when memory starts to get worse, it’s also vital to come to grips with what happens to memory processes. This might give us clues to how to improve memory.

Memory is a complex set of processes, which may decrease at different rates or in different ways. Thus, Italian researchers at the University of Padua decided to focus on “working memory” — the part of memory that holds information at the ready so it can be processed (to go into “long-term memory”) or used to complete tasks. A now historical example would be looking up a number in a phone book before dialling it out — the numbers are held in working memory, like planes in a holding pattern, before coming in to land as we dialed the number. In real life, information often changes or gets supplemented. This means we have to update our working memory. This updating needs to remove no longer needed information and to retrieve the still needed information. The process then is rather complex and understanding how it works in people of different ages might provide clues as to what is happening as memory declines.

In the study, scientists aimed to examine any differences between younger and older participants in updating working memory. Data were collected from 26 “younger” adults (average age of 27.81 years) and 26 “older” adults (average age of 68.77 years). Because memory processes can work differently with different types of information, this experiment used verbal and visual tasks. In the verbal task, participants were asked to recall the last 4 letters in a string of letters read out to them. This sounds simple enough, so how does this test out the “updating” process? Participants did not know how long the string of letters would be, so every time another letter was given, they had to update their memory of the last 4 letters. The longer the list, the more updating required. Correct responses and incorrect recall of letters no-longer in the last 4 letters of the string were recorded. For the visual task, participants saw squares on a 5 by 5 table light up and had to recall the position of the last 4 lights in the sequence.

When only 4 items were given (so that no updating was required), older adults performed poorly on both the verbal and the visual task compared to younger adults. Older adults performed even worse on longer lists of items, where more updating was required. Older participants incorrectly updated their memory by stating that letters or light positions given earlier in the sequence were in the last 4 presented. Thus, it appears that older adults hold on to information that isn’t needed anymore.

This subtle finding is potentially very important — older participants aren’t forgetting things, rather they seem to be remembering too many things and therefore overloading the memory system. Additionally, it appears that in some cases, errors in memory did not reflect a failure of updating but sometimes simply that people waited until the end of the task before trying to recall. Older adults seemed to rely more often on the fact that recently provided information is held in the working memory quite well with the absence of great effort.

This research helps us to lift the lid on memory decline and to try to understand what is happening in more detail. Working memory performance is worse in older adults compared to younger adults. This itself is helpful, however the study also suggests that this is because memories are not being updated as efficiently and because older adults used less effort to keep items in the working memory.

Now, at this point, it’s always good to ask “so what?”. Well, first come the limitations of the study. From a single study we can’t infer too much. The study is an experiment and uses abstract tasks, which might not reflect real-life activities and therefore real-life cognitive processes. The researchers have inferred from the errors made to attempt to understand the processes, but that is the challenge of this type of research into processes that can’t be seen and people are not necessarily aware of these processes. Now, the so-what that is potentially very useful — a more in depth understanding of what is happening with older adults memory, we might be able to create training activities to enhance working memory based on updating and effort.

We accept that decline in body and mind is part of normal aging. However, there may be things we can do to slow or lessen these declines. Physical activity, healthy diets and staying active all seem to lessen the impact of aging. For psychological processes, research is required to understand how processes are declining. Although scientists are still exploring interventions to treat memory loss, the study reviewed here helps to understand what processes are active. Using working memory and engaging in updating of information and doing tasks that require effort to remember may be beneficial. So keep your working memory active and be wise by using effort to remember rather than tricks.

References

1. Fiore et al. Age differences in verbal and visuo-spatial working memory updating: Evidence from analysis of serial position curves. Memory. 2012 Jan;20(1):14-27. Epub 2011 Dec 2.
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2. Singh-Manoux et al. Timing of onset of cognitive decline: results from Whitehall II prospective cohort study. BMJ. 2011 Jan 5;344:d7622.
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Schizophrenia is a complex disease, characterized most commonly in the popular imagination by delusions and hallucinations but equally likely to impede sufferer’s abilities to think clearly, exhibit appropriate emotional responses to events, and therefore function normally in a social setting. Although there is a strong heritable, and therefore genetic, component in schizophrenia, not all of the genetic sequences that may contribute to schizophrenia have been identified. Currently, most experts think that interactions between genes and the environment, similar to autism, are necessary for schizophrenia to develop.

Epilepsy is a brain disorder in which a person suffers repeated seizures over time. Seizures are the results of abnormal brain activity, the causes of which are often not easily identifiable. Both epilepsy and psychosis — including schizophrenia — are thus symptoms of an underlying neurological dysfunction, such as may be caused by brain damage or even a mutation in a gene regulating neuronal development or the transmission of neurotransmitters.

In this recent work, Taiwanise researchers analyzed the records from National Health Insurance Research Database of Taiwan to identify people diagnosed with either schizophrenia or epilepsy between 1999 and 2008. Since its institution in 1995, the National Health Insurance system in Taiwan has been contracted with over 90% of health care providers in that country. Thus 99% of the 23 million people in Taiwan are registered in the database. The researchers identified 5,195 people with known schizophrenia but no known epilepsy, and 11,527 people with epilepsy and no known schizophrenia. Control groups four times larger than each experimental group were used for comparison. They then followed the patients to see how many schizophrenics developed epilepsy, and vice versa, compared to controls over approximately five years.

They found that people with schizophrenia were almost six times more likely to develop epilepsy than controls, and epileptics were over seven times more likely to develop schizophrenia than controls. Similar findings have been reported in longitudinal studies done in Denmark and Finland, and bidirectional relationships between epilepsy and other psychiatric disorders, primarily mood and depressive disorders, have also been established [2-7]. These findings provide evidence that neurotransmitters such as serotonin, norepinephrine and/or dopamine play a role in regulating the pathophysiologic relationship between mood/depressive disorders and epilepsy.

The authors note that the cause of the association between schizophrenia and epilepsy remains unclear. Additionally, they cite several limitations to the study, including accuracy of medical coding in the claims data, sampling bias (patients with schizophrenia or epilepsy who have not been diagnosed in the comparison group), and other medical conditions that may also associate with schizophrenia or other psychosis.

Lead author I-Ching Chou, M.D., with China Medical University Hospital and Associate Professor with China Medical University in Taichung, Taiwan, said [8]:

Our research results show a strong bidirectional relation between schizophrenia and epilepsy. This relationship may be due to common pathogenesis in these diseases such as genetic susceptibility and environmental factors, but further investigation of the pathological mechanisms are needed.

References

1. Chang et al. Bidirectional relation between schizophrenia and epilepsy: A population-based retrospective cohort study. Epilepsia. 2011 Sep 19. [Epub ahead of print]
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2. Qin et al. Risk for schizophrenia and schizophrenia-like psychosis among patients with epilepsy: population based cohort study. BMJ. 2005 Jul 2;331(7507):23. Epub 2005 Jun 17.
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3. Makikyro et al. Comorbidity of hospital-treated psychiatric and physical disorders with special reference to schizophrenia: a 28 year follow-up of the 1966 northern Finland general population birth cohort. Public Health. 1998 Jul;112(4):221-8.
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4. Kanner AM. Epilepsy and mood disorders. Epilepsia. 2007;48 Suppl 9:20-2.
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5. Kanner AM. Depression in epilepsy: a complex relation with unexpected consequences. Curr Opin Neurol. 2008 Apr;21(2):190-4.
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6. Kanner AM. (2008b) Mood disorder and epilepsy: a neurobiologic perspective of their relationship. Dialogues Clin Neurosci. 2008;10(1):39-45.
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7. Kanner AM. (2009) Depression and epilepsy: a review of multiple facets of their close relation. Neurol Clin. 2009 Nov;27(4):865-80.
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8. Study finds bidirectional relationship between schizophrenia and epilepsy. EurekAlert! 2011 Sep 19.

New enrollment in the study was stopped in April because early data showed significantly more strokes and deaths occurred among the stented patients at the 30-day mark compared to the group who received the medical management alone.

In addition to the intensive medical program, half of the patients in the study received an intervention of a self-expanding stent that widens a major artery in the brain and facilitates blood flow. One possible explanation for the higher stroke rate in the stented group is that patients who have had recent stroke symptoms sometimes have unstable plaque in their arteries which the stent could have dislodged, the study authors suggest. The study device, the Gateway-Wingspan intracranial angioplasty and stenting system, is the only system currently approved by the U.S. Food and Drug Administration (FDA) for certain high-risk stroke patients. The authors noted that although similar stenting systems that do not have FDA approval are being used in clinical practice, they did not evaluate those devices in this study.

The authors also emphasize that the study participants were in the highest risk category, with blockage or narrowing of arteries of 70 to 99 percent. Stroke patients with moderate cerebral arterial blockage (50-69 percent) were excluded because their risk of stroke is low with usual medical management, and researchers thought this group would be unlikely to benefit from stenting.

Walter Koroshetz, M.D., deputy director of NINDS, said:

This study provides an answer to a longstanding question by physicians — what to do to prevent a devastating second stroke in a high risk population. Although technological advances have brought intracranial stenting into practice, we have now learned that, when tested in a large group, this particular device did not lead to a better health outcome.

Stroke is the fourth leading cause of death in the United States. Stenosis, a blockage or narrowing of brain arteries caused by the build-up of plaque, accounts for more than 50,000 of the 795,000 strokes that occur annually nationwide. Stenosis is particularly common in African-Americans, Hispanics, Asian Americans and people with diabetes.

The NIH Stenting vs. Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study enrolled 451 patients at 50 sites across the United States. The investigators looked at whether patients had a second stroke or died within 30 days of enrollment, or had a stroke in the same area of the brain from 30 days to the end of follow-up. They had hypothesized that compared to intensive medical therapy alone, the addition of an intracranial stenting system would decrease the risk of a stroke or death by 35 percent over two years.

Instead they found that 14.7 percent of patients (33) in the stenting group experienced a stroke or died within the first 30 days after enrollment, compared with 5.8 percent (13) of patients treated with medical therapy alone. There were five stroke-related deaths within 30 days, all in the stenting group, and one non-stroke-related death in the medical management group. During a follow-up period of just less than one year, 20.5 percent of patients in the stenting group and 11.5 percent of patients in the medical group had a stroke or death, or a stroke in the same area of the brain beyond 30 days, a highly significant difference in favor of the patients in the study’s medical group. Based on these data, the Data and Safety Monitoring Board recommended that the NINDS stop new enrollment, and the NIH issued a clinical alert. All patients will continue to be followed for two years to determine the long term effects of both interventions.

SAMMPRIS is the first stroke prevention trial to compare intracranial stenting with medical therapy and to incorporate intensive medical management into the study design. This includes a daily dosage of 325 milligrams of aspirin; 75 milligrams a day of clopidogrel, a medication used to prevent blood clots, for 90 days after enrollment; and aggressive management of key stroke risk factors — high blood pressure and high levels of low density lipoprotein (LDL), the unhealthy form of cholesterol. All patients also participated in a lifestyle modification program which focused on quitting smoking, increasing exercise, and controlling diabetes and cholesterol.

In a previous NIH trial, stroke patients with criteria similar to those enrolled in SAMMPRIS were treated with less intensive medical management. Their comparable 30-day and one year rates were 10.7 percent and 25 percent, respectively. The investigators note that comparisons with historical controls have limitations, but the much lower event rates in the medical group in SAMMPRIS suggest that the intensive medical management was effective in lowering the stroke risk.

Marc Chimowitz, M.B.Ch.B., of the department of neurosciences at the Medical University of South Carolina in Charleston, and first author of the NEJM article, said:

The SAMMPRIS study results have immediate implications for clinical practice. Stroke patients with recent symptoms and intracranial arterial blockage of 70 percent or greater should be treated with aggressive medical therapy alone that follows the regimen used in this trial as closely as possible.

Patients in the study were between 30 and 80 years old and had experienced a recent transient ischemic attack, a type of stroke that resolves within 24 hours, or another type of non-disabling stroke, which was caused by a large degree of stenosis in a cerebral artery.

References

1. Chimowitz et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011 Sep 15;365(11):993-1003. Epub 2011 Sep 7.
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Source: NIH News

Walter Koroshetz, M.D., deputy director of NIH’s National Institute of Neurological Disorders and Stroke (NINDS), said:

There are many traumatic brain injury studies whose value to scientific research and clinical care could be greatly enhanced by transforming the data into a common, easily available format.

In the United States, about 1.7 million people sustain traumatic brain injuries each year from common causes such as falls and auto accidents. In addition, American Service members serving in Iraq, Afghanistan and other parts of the world face unique risks of traumatic brain injury from routine military operations, enemy fire and improvised explosive devices. According to the DoD, in the past 12 years, more than 200,000 service members deployed worldwide have been diagnosed with traumatic brain injury, adding to the urgent need for preventive methods and treatments. Total costs of traumatic brain injury in the U.S., including medical care, lost wages and other expenses, exceed $60 billion.

Colonel Dallas Hack, director of the U.S. Army Combat Casualty Research Program and joint chairperson for the Defense Health Program, said:

Despite the great burden of neurotrauma incidence, developing objective diagnostics and treatments has proven especially challenging for the medical community. Only by combining efforts through initiatives such as the FITBIR database can we hope to make major progress in this field.

Despite improved surgeries and rehabilitation techniques for people with brain injuries, treatments remain limited. Cases of traumatic brain injury are highly variable, involving different causes, locations within the brain and different kinds of damage to brain tissue. Such variability makes it difficult for clinicians to treat patients, predict long-term outcomes and investigate new therapies. Also, studies often report different kinds of data on patients, obtained through various tests and measures, further impeding comparison of data across studies. The FITBIR database will address these challenges by collecting uniform and high-quality data on traumatic brain injury, including brain imaging scans and neurological test results. The data will be obtained with informed consent and stripped of any patient-identifying information.

Matthew McAuliffe, Ph.D., co-director of the FITBIR database and a member of NIH’s Center for Information Technology (CIT), said:

Uniform data makes it much easier to compare intervention results across a broad range of studies, providing innovative and unique insights that are not possible from a single study. This is part of a larger effort by the government to make taxpayer-funded research more broadly available and usable.

The database is expected to aid in the development of:

• A system to classify different types of traumatic brain injury
• More targeted studies to determine which treatments are effective and for whom and under what conditions (comparative effectiveness research)
• Enhanced diagnostic criteria for concussions and milder injuries
• Predictive markers to identify those at risk of developing conditions that have been linked to traumatic brain injury, such as Alzheimer’s disease
• Clearer understanding of the effects of age, sex, and other medical conditions on injury and recovery
• Improved evidence-based guidelines for patient care, from the time of injury through rehabilitation

NIH CIT was chosen to build the database because of its experience and success in developing the National Database on Autism Research. Reusing the database structure is expected to save 35-50 percent of the project costs and significantly reduce the time to achieve meaningful results.

The database builds upon a larger effort to create common data elements for the study of traumatic brain injury — which are essentially definitions and guidelines about the kinds of data that should be collected, and how to collect these data in clinical studies. The Common Data Elements project emerged from a collaborative interagency effort involving over 50 American and European universities and several federal agencies, including the National Institute of Neurological Disorders and Stroke (NINDS), Defense and Veterans Brain Injury Center (DVBIC), Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury (DCoE), Department of Veterans Affairs and the National Institute on Disability and Rehabilitation Research within the Department of Education.

The Defense Health Program, through agreement with the U.S. Army Medical Research and Materiel Command (USAMRMC) is the lead DoD component funding the FITBIR database. The Division of Computational Bioscience within NIH CIT is building the database, and will provide ongoing system administration and hosting services once the database is complete in about two years.

The U.S. Army Medical Research and Materiel Command (USAMRMC) and NINDS will provide programmatic support and foster collaborative research to populate the database. Researchers will be given detailed information about the FITBIR database, and encouraged to participate at the time they submit proposals for new studies.

Source: NIH News

ALS can run in families, but in the majority of cases, it is sporadic, with no known cause. The researchers derived astrocytes from patients who had succumbed to either type of ALS, and found that the cells secrete toxic factors that cause nerve cells to degenerate. A similar mechanism has been found in mouse models of ALS.

Senior author Brian Kaspar, Ph.D., an investigator at the Nationwide Children’s Research Institute (NCRI) in Columbus, Ohio said:

The mouse models capture a type of familial ALS that accounts for only 2 percent of all cases. The field has begged for new disease models that can provide a clear window into sporadic ALS.

His collaborators were Jerry Mendell, M.D., director of NCRI’s Center for Gene Therapy, and Arthur Burghes, Ph.D., a professor of molecular and cellular biochemistry at Ohio State University in Columbus. Drs. Kaspar and Mendell also hold faculty positions at Ohio State.

The research is reported in Nature Biotechnology and was funded in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS), including a $1.7 million stimulus grant made possible by the American Recovery and Reinvestment Act [1].

ALS is characterized by the death of motor neurons, which are muscle-controlling nerve cells in the spinal cord. As these neurons die, the body’s voluntary muscles weaken and waste away. Death within five years of diagnosis is common. The only approved treatment, riluzole, extends life expectancy by just a few months.

About 90 percent of ALS cases are sporadic and 10 percent run in families. Mutations in the superoxide dismutase1 (SOD1) gene are found in about one-fifth of people with familial ALS, and for decades, experts have theorized that the gene holds clues to sporadic ALS. Laboratory mice carrying human SOD1 mutations develop signs of ALS as they age, and have been widely used to investigate the causes and potential treatments for the disease.

Recent NIH-funded studies showed that astrocytes derived from these SOD1 mice are toxic to motor neurons. Astrocytes — lesser known than neurons and usually described as playing a supportive role — became prime suspects for killing neurons in ALS.

At the same time, however, researchers have questioned whether SOD1 mice are useful — and whether SOD1 itself is relevant — for understanding sporadic ALS. Although dozens of potential therapies have shown promise in the mice, so far only riluzole has proven to help patients in clinical trials. Those results raised concerns that SOD1 might not be a factor in the majority of ALS cases after all.

Amelie Gubitz, Ph.D., a program director at NINDS, said:

The Ohio team has developed a useful model for addressing these issues. Their analysis of the cells adds to mounting evidence that astrocytes — and particularly SOD1 function in those cells — contribute to both sporadic and familial ALS.

The investigators obtained post-mortem spinal tissue from ALS patients through the National Disease Research Interchange (NDRI). This is a nonprofit organization supported by NIH, voluntary health organizations and corporate and individual sponsors that enables people to donate their tissues for use in research after death, and then delivers specific tissues to research labs. NDRI performed the autopsies in the ALS patients’ local communities and used couriers to fly the tissue samples to Columbus. By working through weekends and often overnight, the Columbus team was able to process the samples in the current study within two to three days of death.

First, the researchers isolated neural progenitor cells from the tissue and coaxed these cells to become astrocytes. Neural progenitor cells are the parent lineage of neurons and astrocytes. Next, the team combined the patient-derived astrocytes with mouse motor neurons. At first, the motor neurons grew normally, but after four days, they began to degenerate. By five days, the number of motor neurons was reduced by about half, compared to motor neurons that had been grown with control astrocytes. Similar results were seen when the motor neurons were grown with astrocytes from a patient with familial ALS, or with a cell culture broth that had been conditioned by astrocytes from any of the ALS patients. This suggests the astrocytes are releasing one or more unknown substances that are toxic to motor neurons.

The researchers found that inflammatory responses may play a role in this toxicity. They analyzed 84 genes involved in inflammation, and found that 35-60 percent of the genes showed increased activity in ALS astrocytes compared to controls.

Further experiments revealed that the SOD1 plays a critical role in the toxicity. The investigators used a method called RNA interference to silence the SOD1 gene. RNA serves as an intermediary between genes and proteins, but in RNA interference, small RNA fragments are used to block a gene from making proteins. When the researchers used a virus to deliver such small RNAs to astrocytes affected by familial ALS, the astrocytes were no longer toxic to motor neurons. This method also suppressed toxicity in four of six astrocyte lines derived from people with sporadic ALS, supporting the idea that the SOD1 enzyme also has a role in sporadic cases.

The results also suggest the need for further investigation of SOD1 and astrocytes as targets for therapy. For example, drugs or small molecules, such as the RNA fragments tested in this study, might be used to reduce SOD1 function in astrocytes and suppress their toxicity. Drs. Kaspar and Burghes are developing a viral system that would carry these RNA fragments through the bloodstream and into the spinal cord, and deliver them to astrocytes. This work is being done in collaboration with Don Cleveland, Ph.D., at the University of California, San Diego, as part of the Recovery Act grant. Several labs are pursuing cell replacement therapies for ALS, and the current work adds to evidence that replacing astrocytes may be just as important as, and perhaps easier than, replacing motor neurons lost to the disease.

Dr. Kaspar said:

It’s been a long road, but the hard work starts now. We still need to confront fundamental questions about what is happening to astrocytes and how they are killing motor neurons. And the ultimate goal is to identify therapies that will translate into helping humans.

Amanda Haidet-Phillips, Ph.D., Mark Hester, Ph.D., and Carlos Miranda, Ph.D. — all current or former members of Dr. Kaspar’s lab — did much of the work in developing the new cell system and are lead co-authors of the study. Additional funding came from Project A.L.S., the Packard Center for ALS Research at Johns Hopkins, the Helping Link Foundation, and the Swiss National Science Foundation.

For more information about ALS, please visit the ALS information page at the National Institute of Neurological Disorders and Stroke (NINDS).

References

1. Haidet-Phillips et al. Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol. 2011 Aug 10. [Epub ahead of print]
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Source: NIH News

The first study appeared in the journal Nature and describes work performed by scientists in New York and Spain. Their work focuses on insulin-like growth factor II (IGF2), the most abundant of the insulin-like growth factors found in the brain. Its expression in the brain begins during embryonic development, is maintained throughout adulthood and declines with age. Expression of IGF2 is also known to be induced after learning, suggesting that it plays a role in memory consolidation. The scientists showed that injecting IGF2 into the hippocampus of rats within fifteen minutes after inhibitory avoidance training ”significantly and persistently enhanced memory retention at 24 hours and 7 days,” and that this memory enhancement was retained when the rats were tested three weeks later; they deduced from this latter finding that IGF2 also prevents forgetting. The researchers then went on to demonstrate that IGF2 facilitates long-term potentiation in the hippocampus; long-term potentiation is a cellular process thought to correlate with the formation of long-term memories.

The second study, published in the journal Science a week later, was performed by a group of Israeli researchers at the Weizmann Institute of Science. They found that infusing a particular enzyme, protein kinase M zeta (PRKCZ), into the insular cortex of rat brains enhanced the rats’ long-term memories of a conditioned taste aversion. This effect was observed when the enzyme was administered before memory formation but, importantly, it was also seen when the enzyme was given a week afterwards, once the memory has been consolidated and is considered to be long-term. The researchers chose to focus on this particular enzyme because they had previously demonstrated that inhibiting it erases long-term memories in rats [4]. They also ascertained that the enzyme worked not by preventing the normal course of memory fading but rather by enhancing the memory once it had already faded, and that it could enhance two different memories acquired at different times, and not only the most recently acquired memory.

These two proteins — IGF2 and PRKCZ — may serve as new targets for memory enhancement therapies. Such therapies would be beneficial in treating cognitive decline and amnesia.

References

1. A Deep Dive to Retrieve and Fortify Memories. The New York Times. 2011 Mar 7.
2. Chen et al. A critical role for IGF-II in memory consolidation and enhancement. Nature. 2011 Jan 27;469(7331):491-7.
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3. Shema et al. Enhancement of consolidated long-term memory by overexpression of protein kinase Mzeta in the neocortex. Science. 2011 Mar 4;331(6021):1207-10.
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4. Shema et al. Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKM zeta. Science. 2007 Aug 17;317(5840):951-3.
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Whilst this sounds like a rather odd description of a slightly disappointing magic trick, this amazing treatment technique, pioneered by V.S. Ramachandran [2], is based on neuroscience. The brain uses multiple sets of information to process body movements: visual information and “somatosensory feedback”, which is a combination of senses of pressure, heat and proprioception (body position). And who said we only had five senses! When damage occurs to the brain, as in stroke, the ability to move may be impaired — if damage is to motor areas (parts of the brain dealing with movement). Rehabilitation may be possible from a neural perspective, as we now know brain tissue to be capable of being reorganised. However, when a stroke patient first tries to move their hand, they see and feel that it does not move. This has an impact on the brain — the neural circuitry is given the message that the movement is not possible. The parts of the brain which are involved in this movement then become inactive over time as they “learn” from the somatosensory feedback that movement is not possible. This prevents rehabilitation of function through what Ramachandran terms “learned paralysis” [3] (this is not to say that the origins of the paralysis are not very real, but that the persistence of paralysis is down to these neural changes).

The mechanisms by which mirror therapy works are not clear, but the logic of mirror therapy is suggested to be as follows: visual stimuli is powerful in the human brain, with large amounts of brain tissue dedicated to it, so if we “trick” the brain into seeing the limb move, it will override the information the brain is getting from the proprioception system that the arm is not moving. The brain areas dedicated to movement for that arm will then be activated, as the system is receiving visual feedback that movement is possible. This overcomes the neural barrier that allows rehabilitation to begin.

Researchers conducted a study to explore this technique with stroke patients [1]. Patients were allocated to either the mirror therapy or control group. All patients completed a 6-week training program, performing physical exercises with their arms, hands and wrists. All patients attended a rehabilitation centre once a week for a session with the physiotherapist and then were asked to practice at home for one hour, 5 times a week. Participants kept a diary of their exercises and received telephone calls to support them. The only difference between the two groups was that the control group had a normal view of both of their arms, whilst the mirror therapy group saw their unaffected arm reflected where they would normally view their affected arm. Data were collected from all patients relating to movement, including the force of grip, performance on tasks to lift, pinch and move and electro-physiological responses to guage muscle activation. Additionally, a sub-sample underwent fMRI scanning before and after the intervention.

Comparing the movement data, participants in the mirror therapy group performed significantly better than those in the control group. Remember: both groups did the same procedure of exercise, the different was the view they had. These results suggest that mirror therapy works to improve movement in stroke patients. Great, but how? The fMRI data found that in the mirror therapy patients, brain activity was increased in the motor area in the damaged side of the side. Prior to the therapy, the activity in the brain’s motor areas was unbalanced, with high activity in the undamaged side of the brain. The mirror therapy seemed to restore this balance, so the motor areas in both sides of the brain were activated. This suggests that the mirror therapy is causing some reorganisation in the brain tissue.

The study is limited by a relatively small sample size (20 participants in each group). fMIR data was collected from only 9 mirror therapy patients and 7 control group patients. Further research is required to understand the neuronal mechanisms: greater attention to motor task might be increasing the brain activity, “mirror neurons” may be activated and play some role and the precise neural pathways are unknown. More work is also required to understand how much mirror therapy is necessary (how many sessions? For how long?) and whether there are participants for whom this therapy is more or less effective.

Nevertheless, the study provides us with a very concrete example of how research into the brain can have practical applications. Neuroscience is highly complex and can appear quite esoteric and abstract. However, the logic underlying neuroscience studies is often easily understood and the findings may be directly applicable to health care. Research into the brain has shown us that the brain structure remains “plastic” (neuroscience jargon to mean it can be altered) and provides hope for those affected by damage to the brain.

References

1. Michielsen et al. Motor Recovery and Cortical Reorganization After Mirror Therapy in Chronic Stroke Patients: A Phase II Randomized Controlled Trial. Neurorehabil Neural Repair. 2011 Mar;25(3):223-33. Epub 2010 Nov 4.
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2. Ramachandran et al. Touching the phantom limb. Nature. 1995 Oct 12;377(6549):489-90. No abstract available.
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3. Ramachandran VS & Blakeslee S. Phantoms in the Brain: Probing the Mysteries of the Human Mind. William Morrow & Company. 1998

The PISCES study (Pilot Investigation of Stem Cells in Stroke) is the first clinical trial of neural stem cell therapy for stroke patients in the world. In it, twelve moderately to severely disabled stroke patients, all men between 60 and 85 years of age, will receive injections of ReN001 cells into their brains six to twelve months after their stroke. They will be monitored for two years to assess the safety of the technique, to identify any side effects, and to get preliminary data on efficacy. One patient will be treated and evaluated at a time; if all goes smoothly, the next will then be treated. The company plans on treating four cohorts of three men each with increasing doses of cells. The first patient received his injection of 2 million cells this past November [2]. At his three month check up at the beginning of March he had not experienced any adverse reactions or effects [3]. The third patient is slated to receive his injection of 2 million cells in May, and if all goes according to plan the next group will get 5 million cells. The study is being conducted at the Institute of Neurological Sciences at Glasgow University.

Michael Hunt, the Chief Executive Officer of ReNeuron, said [3]:

Both ReNeuron and the clinical team in Glasgow are very encouraged by the progress of the PISCES clinical trial thus far. We are delighted that the two patients treated so far are doing as well as they are and we could not have hoped for a smoother start in terms of the clinical procedure itself and the lack of any apparent short term safety effects from the ReN001 therapy thereafter. We look forward to providing further updates on the clinical trial in due course.

In animal models, ReN001 cells were shown to reverse functional deficits caused by stroke disability even when administered weeks after the stroke [4]. Potential mechanisms for how this might occur are the observed formation of new myelin sheaths around axons that have been stripped of them, formation of new neurons, and formation of new capillaries and arterioles (small branches off of arteries that lead to capillaries). Moreover, the transplanted cells seem to be cleared from the animal, as they are undetectable six months after injection.

ReN001 cell therapy consists of a neural stem cell line that was made from an extant manufactured cell bank and scaled up using ReNeuron’s proprietary cell expansion and selection technologies. The cells are genetically engineered to have a prolonged lifespan, so researchers do not need to continually use new donor cells. Importantly, this means that any cells for subsequent clinical use will come from the same cells being used in this Phase I clinical trial, without the need to re-derive or test a new batch of cells for the market.

ReNeuron is also developing stem cell therapies for peripheral arterial disease, a common and serious side effect of diabetes and diseases of the retina that cause blindness. The company has generated its ReNcell stem cell lines for non-therapeutic academic and commercial research purposes as well. Another company, StemCells of Palo Alto, California, received approval in December to conduct a similar Phase I clinical trial of neural stem cells in chronic spinal cord injury in Switzerland [5].

References

1. ReNeuron receives final regulatory approval to commence landmark stroke clinical trial in UK. ReNeuron. 2010 Feb 10.
2. ReNeuron announces first patient treated in landmark stroke stem cell clinical trial. ReNeuron. 2010 Nov 16.
3. ReNeuron gives update on stroke clinical trial. ReNeuron. 2011 Mar 3.
4. Stroemer et al. Development of a human neural stem cell line for use in recovery from disability after stroke. Front Biosci. 2008 Jan 1;13:2290-2.
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5. StemCells, Inc. Receives Authorization to Conduct World’s First Neural Stem Cell Trial in Spinal Cord Injury. StemCells, Inc. 2010 Dec 7

The study, funded by the National Institutes of Health, also found that patients continued to improve up to one year after stroke, defying conventional wisdom that recovery occurs early and tops out at six months. In fact, even patients who started rehabilitation as late as six months after stroke were able to improve their walking.

The results of the study were announced last month at the American Stroke Association’s International Stroke Conference 2011 in Los Angeles. NIH’s National Institute of Neurological Disorders and Stroke (NINDS) provided primary funding for the study.

“More than 4 million stroke survivors experience difficulty walking. Rigorously comparing available physical therapy treatments is essential to determine which is best,” said Walter Koroshetz, M.D., NINDS deputy director. “The results of this study show that the more expensive, high tech therapy was not superior to intensive home strength and balance training, but both were better than lower intensity physical therapy.”

The walking program involves having a patient walk on a treadmill in a harness that provides partial body weight support. This form of rehabilitation, which is known as locomotor training, has become increasingly popular. After the patients complete their training on the treadmill, they practice walking.

Stroke patients who received intensive physical therapy improved their ability to walk just as well as those treated with a more complex rehabilitation program involving a body weight-supported treadmill. Previous studies suggested that these devices, also called commercial lifts or robot-assisted treadmill steppers, are an effective intervention in helping stroke patients walk. But this walking program had not been tested on a large scale or examined in terms of the most appropriate timing for therapy.

The investigators of the Locomotor Experience Applied Post-Stroke (LEAPS) trial set out to compare the effectiveness of the body-weight supported treadmill training with walking practice started at two different stages — two months post-stroke (early locomotor training) and six months post-stroke (late locomotor training). The locomotor training was also compared against a home exercise program managed by a physical therapist, aimed at enhancing patients’ flexibility, range of motion, strength and balance as a way to improve their walking. The primary measure was each group’s improvement in walking at one year after the stroke.

The investigators had hypothesized that the body-weight supported treadmill and walking program, especially early locomotor training, would be superior to a home exercise program. However, they found that all groups did equally well, achieving similar gains in walking speed, motor recovery, balance, social participation and quality of life.

At the end of one year, 52 percent of all the study participants had made significant improvements in their ability to walk. The timing of the locomotor training program did not seem to matter. At one year, no differences were found in the proportion of patients who improved walking with the early or late treadmill training program, nor did the severity of their stroke affect their ability to make progress by the end of the year.

The patients’ measure of improvement was based on how well they were able to walk independently by the end of the study period. For example, severely impaired stroke patients were considered improved when they were able to walk around inside the house, whereas the patients who were already mobile at home were considered improved when they could progress to walking independently in the community. All groups achieved similar gains in the speed and distance of their walking, their physical mobility, motor recovery and social participation, resulting in an improved quality of life.

All study participants started out with usual care, which involved a variable number of physical therapy sessions of about an hour each, before they were assigned to one of the study groups. The study found that earlier was better when it comes to rehabilitation therapy. The patients who were not assigned to a study group until six months after their stroke recovered only about half as much as the participants who received one of the two therapy programs at two months. This finding suggests that either the treadmill training program or the at-home sessions are effective forms of physical therapy, and both are superior to usual care.

The patients in the body-weight supported treadmill and walking program group that started at six months made significant improvements in walking speed, despite the widely held assumptions and reports that most functional improvements after stroke are complete by six months. The researchers said this suggests that recovery beyond six months can be influenced by further therapy. Individuals in the locomotor training groups were more likely to feel faint and dizzy during the exercise, and those who received early locomotor training experienced more falls. Fifty-seven percent of participants experienced one fall, 34 percent had multiple falls and 6 percent had a fall resulting in injury. Falls are a common problem among stroke survivors, and the investigators say this study builds on evidence that additional research is needed to prevent falls.

The at-home group was the most likely to stick with the program; only 3 percent dropped out of this arm of the study, compared to 13 percent of the locomotor training groups. The authors noted that the physical therapy training programs in the study were progressive, intensive, and repetitive, and were highly effective in improving functional status and levels of walking ability, and quality of life at one year post-stroke.

“We were pleased to see that stroke patients who had a home physical therapy exercise program improved just as well as those who did the locomotor training,” said Pamela W. Duncan, Ph.D., principal investigator of LEAPS, and professor at Duke University School of Medicine in Durham, N.C. “The home physical therapy program is more convenient and pragmatic. Usual care should incorporate more intensive exercise programs that are easily accessible to patients to improve walking, function and quality of life.”

The home exercise programs require less expensive equipment, less training for the therapists and fewer clinical staff members. The LEAPS authors suggest that this intervention may help keep stroke survivors active in their own homes and community environments. More than 400 patients were randomly assigned into the three study groups and participated in 36 90-minute sessions over 12 to 16 weeks. They had either severe or moderate walking impairments. The average age of the patients was 62 years. Fifty-four percent were men and 22 percent were black. The trial took place at six inpatient rehabilitation centers including Brooks Rehabilitation Hospital in Jacksonville, FL; Florida Hospital in Orlando; Long Beach Memorial Hospital in Long Beach, CA; and Sharp Rehabilitation Center in San Diego, CA.

The study was funded primarily by NINDS with additional support by the National Center for Medical Rehabilitation Research. Recruitment for the study began in April 2006 and the study was completed in June 2009.

NINDS (www.ninds.nih.gov) is the nation’s leading funder of research on the brain and nervous system. The NINDS mission is to reduce the burden of neurological disease –- a burden borne by every age group, by every segment of society, by people all over the world.

Source: NIH News

“To our knowledge, this is the first demonstration of potent memory enhancement via a naturally occurring factor that readily passes through the blood-brain barrier — and thus may hold promise for treatment development,” explained Cristina Alberini, Ph.D., of Mount Sinai School of Medicine, New York, a grantee of the NIH’s National Institute of Mental Health (NIMH).

Alberini and colleagues say IGF2 could become a potential drug target for boosting memory. They report on their discovery in the Jan. 27, 2011 issue of Nature [1]. “As we learn more about such mechanisms of fear memory formation and extinction, we hope to apply this knowledge to address clinical problems, including post-traumatic stress disorder,” said NIMH Director Thomas R. Insel, M.D.

The staying power of a memory depends on the synthesis of new proteins and structural changes in the connections between brain cells. These memory-strengthening changes occur within time-limited windows right after learning, when memories undergo consolidation, and also right after a memory is retrieved, a process called reconsolidation.

Hints from other studies led the researchers to suspect that IGF2 plays a role in these processes within the brain’s memory center, the hippocampus, where it is relatively highly concentrated. The little-known growth factor is part of the brain’s machinery for tissue repair and regeneration; it is important during development and declines with age.

To find out how it might work in memory, Alberini’s team employed a standard test of fear memory called inhibitory avoidance training. They tracked the movement of rats in an environment where the animals learned to associate a dark area with mild foot shocks. The more an animal avoided the dark area, the better its fear memory.

This kind of learning boosted the expression of naturally occurring IGF2 in the hippocampus. So the researchers injected synthetic IGF2 directly into the hippocampus during windows of consolidation or reconsolidation, when memories are malleable. Remarkably, the rats’ memory markedly improved — with the effects lasting at least a few weeks. An examination of the animals’ brains revealed that IGF2 had strengthened the cellular connections and mechanisms underlying long-term memory — a process called long-term potentiation.

So IGF2 both strengthened a memory and delayed its normal decay — forgetting, noted Alberini.

The researchers had previously discovered that the fragility induced by memory retrieval requires new protein synthesis in the brain’s fear area, the amygdala — but only if the memory is less than two weeks old. In the new study, they found that memory enhancement triggered by IGF2 during this reconsolidation window depended on new protein synthesis in the hippocampus during the same time period. They suggest that these time-limited effects might be explained by a gradual shift in the site where a memory is stored as it grows older, from the hippocampus to the brain’s outer mantle, or cortex.

The study showed that the growth factor works through its own — also little known — IGF2 receptor and depends on activation of an enzyme called Glycogen synthase kinase-3 (GSK3), and AMPA glutamate receptors (AMPA1, AMPA2, AMPA3 and AMPA4) for the chemical messenger glutamate, both of which are implicated in memory. Evidence suggests that rather than activating new neurons, it appears to work through already activated connections between cells — or synapses — that are regulated by the enzyme and receptor.

Among future directions, researchers could explore whether IGF2 might enhance other types of memory, such as extinction learning, in which a fear memory is replaced by a memory of safety, said Alberini. If so, it might provide clues to new treatments for anxiety disorders like PTSD.

In addition to National Institute of Mental Health (NIMH), the research was also funded by NIH’s National Institute on Drug Abuse (NIDA) and National Institute of General Medical Sciences (NIGMS), among other funders.

The mission of the National Institute of Mental Health (NIMH) is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit www.nimh.nih.gov.

Source: NIH News

References

1. Chen et al. A critical role for IGF-II in memory consolidation and enhancement. Nature. 2011 Jan 27;469(7331):491-497.
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