Changing stroke rehab and research worldwide now.Time is Brain! trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.

What this blog is for:

My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.

Wednesday, March 27, 2024

Most Post-Stroke Depression Strikes Within 5 Years

It is your doctor's responsibility to ABSOLUTELY INSURE that your mental health post stroke is good.  And that is only possible with 100% recovery protocols. If you don't have those protocols, you don't have a functioning stroke doctor. Depression is a secondary problem that would not exist if you had 100% recovery protocols.

 

Most Post-Stroke Depression Strikes Within 5 Years

Cumulative depression incidence was about 60%, long-term study shows

A computer rendering of a stroke.

The vast majority of post-stroke depression (87.9%) occurred within the first 5 years after a stroke, suggesting a benefit for screening within that timeframe, according to a prospective study from the U.K.

During an 18-year study period, the cumulative incidence of post-stroke depression was 59.4%, with 33.4% of cases occurring within 3 months and 54.6% occurring within 1 year, Lu Liu, PhD, of King's College London, and colleagues reported in Lancet Regional Health – Europeopens in a new tab or window.

Given that the majority of cases occurred within 5 years, the findings suggest that routine screening for depression "should be provided to all stroke survivors within 5 years after stroke," the researchers wrote, noting, however, that depression can begin as early as the first 3 to 6 months following a stroke.

Among stroke patients with depression 3 months later, 46.6% first recovered at 1 year and 20.3% did so at 2 years. However, the cumulative recurrence rate was high, at 66.7% -- of which the majority (94.4%) occurred within 5 years of recovery.

"Depression has a high recurrence in the long-term, which means patients with depression at one time-point are at high risk for remaining depressed," Liu told MedPage Today in an email, noting that the cumulative recurrence rate for depression in the general population is about 42%.

Liu and colleagues noted that there's a dearth of evidence on the long-term course of depression in stroke survivors, and that the natural history has rarely been compared between early- and late-onset depression as well as mild and severe depression.

To fill in those gaps, Liu and colleagues analyzed data from the South London Stroke Register on 3,864 stroke survivors who had any assessment for depression from January 1995 through July 2019. The patient population was 55.4% male, 62.5% white, and the median age was 68. The number of patients assessed for depression ranged from 2,293 at 1 year to 145 at 18 years. Depression was measured on the Hospital Anxiety and Depression Scale.

Liu and colleagues found a similar frequency of mild and severe depression, but severe depression occurred earlier after stroke, had a longer duration, and was quicker to recur than mild depression, they wrote.

For instance, those with severe depression at 3 months post-stroke had a significantly lower likelihood of recovery at 1 year compared with those with mild depression (OR 0.43, 95% CI 0.29-0.63). In addition, the recurrence rate 1 year after recovery was higher in patients with severe depression compared with mild depression (52.9% vs 23.5%, P=0.003), indicating "patients with severe depression had a higher risk of having persistent depression," they wrote.

"Patients with a high level of depression on initial assessment tended to have longer duration and faster recurrence than those with milder symptoms," Liu said. "As such, these patients may be more likely to benefit from closer follow-up and longer-term care of their depressive symptoms."

The study was limited by challenges with patient follow-up, and by the fact that it was more likely to include patients with mild and moderate stroke because those with severe stroke were less likely to participate in the depression assessment. Also, the number of patients included in the analysis beyond 10 years was small due to high mortality in stroke patients.

Jacob Ballon, MD, MPH, of Stanford University in California, who wasn't involved in the study, told MedPage Today that getting data on long-term depression outcomes in stroke survivors is hard, as studies will typically only have a 6- to 24-month follow-up period.

"This paper adds nicely to longer term information; 18 years is a long time," Ballon said, adding that the results can help inform decisions about how mental health resources can be deployed in this patient population.

  • author['full_name']

    Michael DePeau-Wilson is a reporter on MedPage Today’s enterprise & investigative team. He covers psychiatry, long covid, and infectious diseases, among other relevant U.S. clinical news. Follow

Disclosures

The study was funded by the National Institute for Health and Care Research.

The authors declared no financial conflicts of interest.

Primary Source

Lancet Regional Health – Europe

Source Reference: opens in a new tab or windowLiu L, et al "Natural history of depression up to 18 years after stroke: a population-based South London Stroke Register study" Lancet Reg Health Eur 2024; DOI: 10. 1016/j.lanepe.2024. 100882.

Bilingualism May Shield Against Aging Brain Problems

 Darn, late life bilingualism doesn't seem to help. My attempts to learn German in grade school, high school and community ed were all failures. Now I'm working on Spanish just for traveling.

Bilingualism May Shield Against Aging Brain Problems

Summary: Bilingualism may serve as a powerful tool against age-related cognitive decline, particularly in social cognition areas such as the theory of mind. A new study demonstrates that early bilingualism leads to beneficial structural changes in the brain, including increased gray matter volume and cortical thickness, which contribute to a stronger cognitive reserve.

This cognitive reserve is crucial for maintaining social cognitive abilities into older age, highlighting bilingualism’s potential to enhance mental flexibility and attention control. The findings suggest that the earlier a second language is learned, the better the protection against the cognitive impairments associated with aging.

Key Facts:

  1. Early Bilingualism Boosts Brain Structure: Learning a second language early in life is linked to increased gray matter volume and greater cortical thickness, fostering a robust cognitive reserve.
  2. Protection Against Age-Related Decline: This cognitive reserve helps maintain social cognition skills, such as understanding others’ mental states, despite aging.
  3. Lifelong Benefits: The study emphasizes the importance of bilingualism for healthier aging, encouraging early language learning to preserve cognitive function and social cognition in later life.

Source: Singapore University of Technology and Design

As a person ages, changes occur in both the body and the brain. Certain areas of the brain shrink and communication between neurons becomes less effective.

“Such structural and functional changes result in an age-related decline in cognitive function, affecting language, processing speed, memory, and planning abilities,” said Yow Wei Quin, Professor at the Singapore University of Technology and Design (SUTD).

This shows two older men talking.
There is evidence that learning and using a second language results in structural and functional changes in the bilingual brain. Credit: Neuroscience News

Cognitive reserve, the brain’s ability to adapt and compensate for decline or damage, allows an individual to use alternative pathways and brain regions to perform tasks. Naturally related to cognitive reserve is its neural basis, the brain reserve, which is defined by desirable neuroanatomical properties such as larger brain size and more neuronal synapses.

“These reserves highlight the brain’s flexibility and resilience. An individual with greater reserves is likely to maintain good cognitive function in aging,” Prof Yow added.

Among the multiple lifestyle factors that contribute to cognitive reserve is bilingualism. The ability of bilinguals to constantly navigate between languages and communicate with people of different backgrounds could enhance their ability to interpret social cues.

Moreover, knowing multiple languages is associated with stronger mental flexibility, attention control, and working memory—skills important for social cognition and theory of mind, which is the ability to understand other people’s behaviour by attributing mental states like beliefs and emotions to them.

Previous studies on children and young adults have shown that bilingual language experience has a positive impact on theory of mind skills, but would this social cognitive enhancement persist in later life?

This is the question that Prof Yow and her research fellow Dr Li Xiaoqian set to answer. In their paper ‘Brain grey matter morphometry relates to onset age of bilingualism and theory of mind in young and older adults’, the SUTD team and collaborators from National University of Singapore (NUS) showed that early bilingualism may protect theory of mind abilities against normal age-related declines.

There is evidence that learning and using a second language results in structural and functional changes in the bilingual brain. The research team hypothesised that acquiring a second language early may influence brain function and also create more efficient structural properties in the brain, which will provide reserves that fight against age-related social cognition decline.

What kind of changes in the brain would early bilingualism create that allows it to preserve social cognition, specifically theory of mind? Some researchers suggest that the association between bilingualism and social cognition manifests in brain areas involved in mental state inferences, while others suggest areas involved in language or cognitive control processes.

In this paper, Prof Yow and the team found that early bilingualism and better social cognitive performance in both young and old adults were associated with higher gray matter volume, greater cortical thickness, and larger surface area in the above-mentioned brain regions.

Her study suggests that the earlier a second language is learned, the more desirable structural changes occur in the brain and the more cognitive reserve is established to protect social cognitive processes against age-related decline.

These social cognitive abilities, particularly theory of mind, are crucial for understanding the thoughts and emotions of others. The current work provided new evidence of bilingualism having benefits beyond language skills and executive function. It supported the idea that bilingualism preserves social cognition in later life, fends off age-related decline, and contributes to healthier ageing.

Co-first author of the paper, Dr Li Xiaoqian from SUTD added: “Our findings highlight the potential social-cognitive benefits associated with acquiring a second language early in life.”

This could encourage parents and educators in supporting early bilingual education and lifelong bilingualism. While age-related neurocognitive decline is natural and often manageable, delaying the process is important to enable individuals to live independently longer.

Bilingualism can enrich and preserve social cognitive function, allowing a person to partake in activities they enjoy, maintain relationships, and perhaps even lessen the need for care in later life.

This study is part of a bigger project on the age-related psychological and neurological changes in social cognition. Functional magnetic resonance imaging (fMRI) data of individuals completing social-cognitive tasks was also collected alongside this study.

Going forward, the research team plans to use the behavioural and neuroimaging data that they have gathered to further investigate the effect of bilingualism on social cognitive functioning.

About this language and neuroscience research news

Author: Melissa Koh
Source: Singapore University of Technology and Design
Contact: Melissa Koh – Singapore University of Technology and Design
Image: The image is credited to Neuroscience News

 

Transforming Posthospital Stroke Care, Outcomes, and Use of New Innovations Through Implementation Science

 Not one thing discussed here will do a damn bit of good until you finally CREATE EXACT 100% RECOVERY PROTOCOLS! It's that simple! Does no one in stroke have two functioning neurons to rub together?

Transforming Posthospital Stroke Care, Outcomes, and Use of New Innovations Through Implementation Science

Originally publishedhttps://doi.org/10.1161/JAHA.123.031310Journal of the American Heart Association. 2024;0:e031310

Life after an acute stroke hospitalization requires an intentional focus toward ensuring optimal daily functioning, behaviors, support, and well‐being. This could be achieved with an array of posthospital services and supports. Although the availability and use of services after a stroke vary widely by individual and geographic region, posthospital stroke care could include additional inpatient stays, outpatient clinic or home‐based care, and remote monitoring. Services can offer rehabilitation, secondary prevention, behavioral health management, and community programs to support return to work, school or family roles, spiritual and social connections, medication management, and healthy lifestyles.1 Because the global stroke burden remains high, and financial landscape supporting service delivery gets further constrained, there is a need for leaders of poststroke services to incorporate new approaches for addressing quality of care and equity in services offered. Bringing the methods from implementation research to poststroke care can help service leaders optimize resource use, ensure evidence‐based guidelines and new best practices are integrated and routinely used, and design interventions tailored to meet the needs of stroke survivors.

Few poststroke services provide guideline‐recommended, evidence‐based treatments to 100% of their stroke survivor patient population. Implementation science, which systematically aims to improve the uptake of research findings and what we know works into practice or policy,2 focuses on this know–do gap. Implementation research is used to explore factors and develop and test strategies or approaches that better promote the adoption and integration of evidence into clinical and community settings to improve population health for all.3 The methods used in implementation research are useful for several purposes.4, 5 There are frameworks to help identify contextual factors that are preventing full use of effective interventions. There are tools to identify how to address barriers to implementation. There are also models and study designs to guide processes for improved implementation and sustainability. Fully and systematically integrating these methods into poststroke services could help address treatments, programs, and policies so current rates of stroke recurrence and years lived with disability do not persist for another decade unchanged.6, 7 It should not be considered acceptable that, for example, a third of stroke survivors live with untreated or uncontrolled hypertension globally; a third of stroke survivors in the United States do not receive any rehabilitation therapy in the year after their stroke, and significant racial and ethnic disparities in care and outcomes persist.8, 9, 10 This article describes 3 opportunities for applying implementation science in posthospital stroke service settings to improve what is delivered, to whom, how well, and with what resources to achieve better outcomes and equity.

EVALUATING IMPLEMENTATION IN ROUTINE CARE AND POSTSTROKE SERVICE DELIVERY

Poststroke service administrators and community program leaders likely monitor the number of people treated or served and what services are provided for those individuals. These interventions may span a range of specific procedures, include different products, stem from different practices or policies, or come together as a multicomponent program. For any of these interventions with an established evidence base, there is a known expectation for who should receive them and the outcomes that should be achieved as a result. These are foundational measures of implementation and effectiveness, respectively. Implementation can be further evaluated in several ways.

Even specific interventions have multiple levels of implementation. When considering a practice of interest that has evidence demonstrating significant population benefit with widespread implementation (eg, addressing poststroke hypertension and falls risk), service leaders can ask high‐level questions of their data to determine the biggest opportunities for improving uptake (Figure).11 Some degree of this evaluation is common in health departments, government agencies with surveillance functions, and organizations with stroke learning health systems that include an operations staff team and robust data infrastructure.12 The data can help identify at which level of implementation within an organization the voltage drop affecting potential benefit is occurring.13 Depending on resources available, priorities, and timing, further exploration may be needed before working toward an action plan for 1 or more levels.

Figure 1. Evaluative questions to explore implementation concepts at different levels within an organization or agency to identify gaps or potential voltage drops.

*Initial evaluation with these and other related questions can establish baseline measures of implementation. From an established baseline, evaluations of representativeness can begin to explore equity. Evaluations of context may follow.

In some organizations, the processes for evaluating practices that address hypertension, falls risk, tobacco use, and other areas with long‐standing evidence may be well established. However, a deeper dive into these data could help identify inequities. Reading the Figure from the bottom up, and focusing on stroke survivors who are not served (or representativeness of those served), service leaders can identify if differences by race, ethnicity, social need, ability, sex, age, ability, and other characteristics are systematic. Even when adoption at the provider level, for example, appears to be 80% within an organization, there is likely to be variation across stroke survivors that would warrant further attention and action.

IMPROVING ADOPTION AND IMPLEMENTATION IN POSTSTROKE SERVICE DELIVERY

Context: Understanding the context for implementation and improvement is critical to successfully advance any plan of action. Implementation science has dozens of frameworks that can be used to specify barriers and enablers of adoption and implementation.4 The purpose of contextual inquiry is to begin to document and explain things that influence the process and ultimately the outcomes. Three commonly used comprehensive determinant frameworks include the Consolidated Framework for Implementation Research, Theoretical Domains Framework, and Promoting Action on Research Implementation in Health Services. Applying these or other frameworks in the exploration of context in poststroke service delivery can identify specific characteristics of the providers and stroke survivors, internal and external environment, the intervention or evidence‐based practice itself, and the processes used for implementing it. Often several barriers are operating simultaneously, such as discordance between a policy and strength of the evidence, lack of a clinical champion, or fractured communication channels. Mixed and multiple methods are recommended for studying context14; the scientific rigor that is applied may be dependent on resources and methodological expertise.

A pragmatic effectiveness trial example of exploring context in postacute stroke care leveraged a process that integrated data from surveys, group calls, interviews, and field notes.15 This evaluation of the COMPASS (Comprehensive Post‐Acute Stroke Services) cluster‐randomized pragmatic trial of transitional care used the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework to identify individual, organizational and community factors that facilitated system‐level intervention adoption, patient reach, and intervention implementation. Organizational readiness, a shared commitment and belief in the capacity for change, was the factor most highly correlated with successful implementation.

Adaptation: A comprehensive assessment of context can signal that the intervention or program itself needs to be adapted. This is especially common when expanding to be more inclusive or culturally relevant. A scoping review of frameworks for adapting evidence‐based interventions documented more than a dozen frameworks from the past 2 decades16; none originated in stroke research or service delivery, but several have since been applied for the benefit of stroke survivors. The synthesis suggests that adaptation involves input and feedback from topical and front‐line experts, engagement with end users, which could include both stroke survivors and their care partners, iterative refinement, training with expected implementers, and small tests of change. In the literature on posthospital stroke care, codesign has been applied as an approach for active engagement of a broad range of people as partners in the process of refinement. Engaging experts and end‐users can also identify how things are implemented.

Implementation Strategies: How clinical and community providers put evidence‐based interventions into routine practice is specified in implementation science as strategies. Strategies already exist when the intervention is already being used; however, if inequities, voltage drops, or persistent gaps in uptake are identified, the existing strategies need to be revisited, and perhaps others should be explored for use. A 2023 scientific statement for strategies to improve blood pressure control recognized that depending on where the gap lies, multiple levels of interventions will be needed.17

Many methodologies exist for identifying strategies. With data from the exploration of context or process of intervention refinement, teams can select from strategies that were reported as enablers. Strategies can also be matched to specifically target barriers. Teams can use other approaches to vet options available in preexisting lists of strategies categorized to facilitate application.18 An approach for identifying strategies that stems from improvement science and studies of organizations is to understand those with better outcomes (or top performers).19 Although this approach has been applied in the stroke community, results from its use have not yet been disseminated for evidence‐based interventions in posthospital stroke care or community‐based services.

Implementation Intervention Research: Testing the strategies that were identified for implementing an evidence‐based intervention while simultaneously measuring clinical, health service, and person‐centered outcomes can generate new knowledge for larger population health benefit. This is a key distinction from quality improvement, which aims to improve care locally and may not include a comprehensive evaluation of context or factors enabling sustainability.20 Study designs for implementation science examine application and can compare the effectiveness of the strategies hypothesized to facilitate change in an implementation outcome such as greater adoption and uptake of the intervention.21 Protocols for hybrid effectiveness‐implementation study designs that prioritize implementation outcomes (hybrid type III) in posthospital stroke services are available, but these studies are underway with no published findings yet available.

NEW INNOVATIONS

It is not uncommon for a new device, technology, or intervention to be brought directly to the posthospital clinical or community setting for use with stroke survivors. Innovators are eager to work directly in the real world. If efficacy is not yet established, or no real‐world study has been conducted to determine effectiveness among a more heterogeneous population of service providers and stroke survivors, it can be useful to include implementation research questions as part of the efficacy or effectiveness study design. Implementation questions in this phase of research or introduction of new innovations into practice include gathering contextual data, documenting where intervention adaptations are needed, and processes or pathways for its use.22 Designing for implementation as part of a randomized controlled trial for efficacy, or planning an effectiveness‐implementation hybrid study design, can expedite research translation.

CONCLUSIONS

There is a strong evidence base and clear guidelines for stroke secondary prevention, rehabilitation, and recovery. However, an estimated 101 million stroke survivors are alive today globally, living longer with disability and earlier onset of comorbid chronic conditions than in past decades. Although clinical and community‐based organizations may need to establish partnerships to acquire the necessary expertise, it is imperative that service leaders become familiar with and begin integrating implementation science to accelerate uptake of emerging evidence into routine practice and improve use of effective interventions with all eligible stroke survivors.

Sherman Lecture: Are We Aiming at the Correct Targets to Reduce Disparities in Stroke Mortality? Celebration, Reflection, and Redirection

We could probably vastly reduce disability and mortality post stroke if we stopped the 5 causes of the neuronal cascade of death in the first week. But no one in the stroke medical world seems to be working on that. And since there is NO leadership in stroke, there is no one to address this problem.

 

Sherman Lecture: Are We Aiming at the Correct Targets to Reduce Disparities in Stroke Mortality? Celebration, Reflection, and Redirection

Originally publishedJournal of the American Heart Association. 2024;0:e031309

Abstract

Although deaths from stroke have been reduced by 75% in the past 54 years, there has been virtually no reduction in the relative magnitude of Black‐to‐White disparity in stroke deaths, or the heavier burden of stroke deaths in the Stroke Belt region of the United States. Furthermore, although the rural–urban disparity has decreased in the past decade, this reduction is largely attributable to an increased stroke mortality in the urban areas, rather than reduced stroke mortality in rural areas. We need to focus our search for interventions to reduce disparities on those that benefit the disadvantaged populations, and support this review using relatively recently developed statistical approaches to estimate the magnitude of the potential reduction in the disparities.

At the beginning of each decade since 1980, the US Department of Health and Human Services releases a Healthy People guidance document providing goals for the nation's health for the upcoming decade. The goals for Healthy People 2000 (released in 1990) included calls for both the reduction of the burden from major diseases and elimination of health disparities.1 Over the years, the goal of reducing the burden of disease has shifted to the more positive view of improving health; however, the focus on eliminating health disparities remains a guiding principle of Healthy People 2030 (released in 2020).1 Herein, we consider the multidecade progress to reduce the overall burden from stroke and improve cerebrovascular health (discussed in the Celebration section), reduce disparities in stroke (discussed in the Reflection section), and new approaches to potentially improve success in better selecting targets for intervention to reduce stroke disparities (discussed in the Redirection section). Although stroke disparities can be defined by innumerable characteristics, the focus of this report is on 3 stroke disparities: (1) race and ethnicity, (2) geographic region of the nation (ie, the Stroke Belt), and (3) rural or urban. These were selected as being the most studied of the potential stroke disparities, and because the Minority Health and Health Disparities Research and Education Act (US Public Law 106–525; 2000) specifically instructs the National Institutes of Health to have a focus of disparity investigations on minority health and rural health research.2 The focus of this lecture is on disparities in the United States, because a more international discussion substantially complicates both the disparities to be considered and the breadth of the potential contributors to these disparities. In the Redirection section of this work, we encourage an approach where the impact of potential interventions specifically on the magnitude of disparities is considered. Relatively new analytic approaches can be employed to quantify the magnitude of the potential impact. In the section, we use different approaches to hypertension management to reduce racial disparities in stroke as an illustrative example. With the wide breadth of potential interventions (ie, structural racism, lifestyle management, environmental exposures, and traditional risk factors), we need to take approaches that proactively and explicitly seek interventions that will differentially benefit the disadvantaged populations. These approaches need to be analytically supported using methods that formally evaluate the potential impact on the disparities.

CELEBRATION

As we continue to work to reduce the burden of stroke, it is important to take time to reflect on progress and celebrate successes. Figure 1 shows the age‐adjusted stroke mortality rates (for those aged ≥45 years) over the 54‐year period from 1968 to 2021 (from the Centers for Disease Control and Prevention WONDER [Wide‐Ranging Online Data for Epidemiologic Research] study).3 To reduce redundancy for the reader, mortality rates in this report are expressed per 100 000 (ie, a reported mortality of 150 represents mortality of 150 per 100 000). Over this 54‐year period, stroke mortality decreased by a remarkable 75%, from 465.5 to 114.8 between 1968 and 2021. In 2021, there were 158 536 deaths from stroke among the population aged ≥45 years; however, had the 1968 stroke mortality rate persisted there would have been 643 966 deaths among those aged ≥45 years, an increase of 485 153 stroke deaths. This increase in stroke deaths is nearly identical to the entire 2021 population aged ≥45 years in Montana (485 431) and larger than the population aged ≥45 years in Delaware (461 971), South Dakota (366 907), Vermont (307 159), North Dakota (295 293), Alaska (271 202), Wyoming (243 700), or Washington DC (222 743).3 In 1999, the decrease in stroke (and heart disease) mortality was declared 1 of the 10 greatest public health achievements of the 21st century,4 and in 2011 was declared 1 of the 10 greatest public health achievement of the decade from 2000 to 2010.5

Figure 1. Age‐adjusted stroke mortality for the population aged ≥45 years, 1968 through 2021.

Data are from 1968 through 1978 from ICD‐8 (codes 430–438), 1979 through 1998 from ICD‐9 (codes 430–438), and 1999 through 2021 from ICD‐10 (codes I60–I69). ICD‐8, ICD‐9, ICD‐10 indicate International Classification of Diseases, Eighth Revision, Ninth Revision, Tenth Revision, respectively.

 

Tampa doctors fit device that restores arm movement to stroke victims

I think most stroke survivors would rather do the non-invasive approaches. 


Dorset Embarks on Revolutionary Stroke Recovery Trial Utilizing Earpiece Technology

Non-invasive VNS approach could enhance post-stroke recovery outcomes August 2023 

The latest here:

Tampa doctors fit device that restores arm movement to stroke victims 

New procedure offered at Tampa General helps retrain brain to bypass damaged cells and restore movement to patients.
Randy Jackson works with Tampa General Hospital occupational therapist Nicole Goldstein on regaining function in his left arm lost after a stoke. The device in her hands triggers a device implanted in Jackson's chest to send electrical signals to his brain to help him regain full control of his limb.
Randy Jackson works with Tampa General Hospital occupational therapist Nicole Goldstein on regaining function in his left arm lost after a stoke. The device in her hands triggers a device implanted in Jackson's chest to send electrical signals to his brain to help him regain full control of his limb. [ Tampa General Hospital ]
Published Earlier today|Updated 5 hours ago
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TAMPA — The pain roused Randy Jackson from his sleep. He tried to sit up but was too dizzy. His face was numb.

The Tampa resident had suffered mild strokes before but this one in February last year was serious. His left side was paralyzed. He spent two days in intensive care.

He emerged from hospital unable to walk or move his left arm. He was facing a long and uncertain recovery through physical and occupational therapy.

Jackson, 68, learned slowly to walk again, first with a walker and then a cane. But moving his left arm was still a struggle 10 months after his stroke. That was when doctors at Tampa General Hospital convinced him to undergo a new procedure that could help retrain his brain to control his arm.

The procedure requires the insertion of a small pacemaker-like device in the chest that is hooked up to the vagus nerve. The device, known as a Vivistim, is then triggered to send signals back to the brain in sync with the patient to help move impaired limbs.

A Tampa General Hospital surgeon demonstrates a Vivistim device, which can help repair movement to stroke victims. [ Tampa General Hospital ]

When repeated over time, the signals cause the formation of new neural connections within the brain, bypassing areas damaged by lack of oxygen during a stroke.

Known as vagus nerve stimulation, the procedure has proven to restore upper-body movement to a high percentage of patients, allowing them to resume activities that were part of their daily routine, such as buttoning a shirt or cutting their own food during meals.

“It’s an exciting new breakthrough,” said Oliver Flouty, assistant professor in the department of neurosurgery and brain repair at the USF Health Morsani College of Medicine.

Strokes are common in the United States, affecting almost 800,000 annually, according to the Centers for Disease Control and Prevention. The majority are ischemic strokes, often caused by blockages of the middle cerebral artery, which provides blood to the brain’s frontal lobe where movement and speech are controlled.

Vagus nerve stimulation has been used for two-plus decades to treat epilepsy. Using the procedure to help stroke victims was approved by the Food and Drug Administration in 2021. It’s proven effective for patients whose movement, especially their arms, have been slow to respond to physical therapy, said Yarema Bezchlibnyk, associate professor of neurosurgery at USF Health and Tampa General.

Surgery to install the device takes roughly 90 minutes, he said. The device, about the size of a dental floss container, is inserted into the chest. A wire with platinum radium contacts that runs from the device is looped three times around the vagus nerve.

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Once the patient has recovered from surgery, physical and occupational therapy is resumed. Using a remote control, the therapist can trigger the device to start sending pulses to the brain during therapy sessions. Patients can also trigger the device by passing a magnet over it while they do at-home exercises.

During clinical trials, 85% of patients saw significant improvements in movement after three years of treatment, Bezchlibnyk said. Science isn’t quite sure why it works so well but some studies suggest it promotes the release of neurotransmitters that may help repair neurons.

Tampa General has performed the procedure on only a handful of patients so far but hopes to make it more widely available to help those undergoing rehab.

“You’re promoting the brain’s natural learning mechanism,” said Bezchlibnyk. “There really hasn’t been anything out there for these patients before this.”

Randy Jackson, works with Tampa General Hospital physical therapist Nicole Goldstein to restore hand and arm movement. An electronic device installed in Jackson's chest is helping to stimulate brain to regain function that he lost during a stroke. [ Tampa General Hospital ]

The limited movement Jackson had in his left arm made it tough to sleep on his left side. He had to rely on his wife to cut up his steak.

But since his surgery in December, he’s already seen improvement in how high he can raise his arm.

Jackson retired in 2016 after 42 years with the U.S. Air Force, including a stint as airfield manager at MacDill Air Force Base. Before his stroke he liked to play pickleball with his wife. His goal is to return to the pickleball court soon.

“I watch it on TV,” he said, “but I want to be out there doing it.”

Dynamics of hippocampal neurogenesis in adult humans

In 9 years has any research been done to see how to migrate these neurons to where the damaged areas are? Or is stroke leadership so fucking incompetent they can't see the possibilities in that?

What about this?

Identification of the growth cone as a probe and driver of neuronal migration in the injured brain March 2024

Dynamics of hippocampal neurogenesis in adult humans

Abstract

Adult-born hippocampal neurons are important for cognitive plasticity in rodents. There is evidence for hippocampal neurogenesis in adult humans, although whether its extent is sufficient to have functional significance has been questioned. We have assessed the generation of hippocampal cells in humans by measuring the concentration of nuclear bomb test-derived 14C in genomic DNA and we present an integrated model of the cell turnover dynamics. We found that a large subpopulation of hippocampal neurons, constituting one third of the neurons, is subject to exchange. In adult humans, 700 new neurons are added per day, corresponding to an annual turnover of 1.75% of the neurons within the renewing fraction, with a modest decline during aging. We conclude that neurons are generated throughout adulthood and that the rates are comparable in middle aged humans and mice, suggesting that adult hippocampal neurogenesis may contribute to human brain function.

New neurons integrate throughout life in the hippocampus and olfactory bulb of most mammals. The newborn neurons have enhanced synaptic plasticity for a limited time after their differentiation (; ), which is critical for their role in mediating pattern separation in memory formation and cognition in rodents (; ; ). It has been long debated whether adult neurogenesis decreased during primate evolution and if there is sufficient generation of neurons in adult humans to contribute to brain function (; ). A seminal study by Eriksson, Gage and colleagues provided the only direct evidence to date for adult neurogenesis in humans (), although it did not enable assessing the number of new neurons generated or the dynamics of this process.

To estimate the extent of adult neurogenesis in humans, recent studies have quantified the number of cells expressing the neuronal precursor (neuroblast) marker doublecortin in the subventricular zone, which gives rise to olfactory bulb neurons, and in the dentate gyrus of the hippocampus (; ; ). Very similar dynamics have been revealed in these two regions, which contain a large number of neuroblasts shortly after birth that then decreases sharply during the first postnatal year and then declines more moderately through childhood and adult life (; ; ; ). The decrease in neuroblast numbers in the subventricular zone and their migratory path suggested that there is negligible, if any, adult olfactory bulb neurogenesis in humans (; ; ). Retrospective birth dating established that olfactory bulb neurons are as old as the individual, and if there is any addition of neurons in the adult human olfactory bulb, less than 1% of the neurons are exchanged over a century (). It appears unlikely that adult olfactory bulb neurogenesis has any functional significance in humans. The similar decline in neuroblast numbers in the subventricular zone and the hippocampus poses the question of whether there is postnatal hippocampal neurogenesis in humans to an extent that may have an impact on brain function.

Analysis of the number of neuronal progenitor cells gives an indirect indication of the possible extent of neurogenesis. However, it does not provide information on whether the neuroblasts differentiate and integrate as mature neurons. This is evident from the studies of the subventricular zone and olfactory bulb, where the generation of neuroblasts does not result in detectable integration of new neurons in the olfactory bulb (). The strategies used to study the generation of mature neurons in experimental animals are not readily applicable to humans. To be able to study cell turnover dynamics in humans, we have developed a strategy to retrospectively birth date cells (). This strategy takes advantage of the elevated atmospheric 14C levels caused by above ground nuclear bomb testing 1955–63 during the Cold War (; ). After the International Test Ban Treaty in 1963, the atmospheric levels have declined due to uptake by the biotope and diffusion from the atmosphere (; ). 14C in the atmosphere reacts with oxygen to form CO2, which is taken up by plants in photosynthesis. When we eat plants, or animals that live off plants, we take up 14C, making atmospheric 14C levels mirrored in the human body at all times (; ; ). When a cell goes through mitosis and duplicates its chromosomes, it integrates 14C in the synthesized genomic DNA with a concentration corresponding to that in the atmosphere at the time, creating a date mark in the DNA (). The cumulative nature of 14C integration, makes the method especially suited for establishing the kinetics of slowly turning over cell populations. The accuracy of individual datings is approximately ±1.5 years (), but higher accuracy is reached by integrating data from many independent measurements.

We have retrospectively birth dated hippocampal cells and provide an integrated model for adult hippocampal neurogenesis in humans. We report that there is substantial neurogenesis in the human hippocampus throughout life, to an extent comparable to that in the middle aged mouse, supporting that adult hippocampal neurogenesis may contribute to human brain function.

Results

Retrospective birth dating of cells from the human hippocampus

Cell nuclei were isolated by gradient centrifugation from dissected human postmortem hippocampi. The nuclei were incubated with antibodies against the neuron specific nuclear epitope NeuN, and neuronal and non-neuronal nuclei were isolated by flow cytometry (Fig. 1 and Fig. S1) (; ; ). The 14C concentration in genomic DNA from hippocampal neurons (n=55) and non-neuronal cells (n=65) was measured by accelerator mass spectrometry in subjects between 19 and 92 years of age (14C data is given in Table S1).

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Isolation of neuronal and non-neuronal nuclei from the human hippocampus

Cell nuclei were isolated from the human postmortem hippocampus and incubated with an isotype control antibody (A) or with an antibody against the neuron-specific epitope (NeuN) (B), and the neuronal and non-neural populations were isolated by flow cytometry. The sorting gate for neuronal nuclei is indicated.

Standard accelerator mass spectrometry analysis requires samples corresponding to about 1 mg of carbon. The total amount of carbon in genomic DNA samples from hippocampal cell populations, after cell sorting and purifications steps is typically in the range 10–20 μg, necessitating a different approach. Consequently, a new experimental method had to be developed, including a new sample preparation setup and laboratory procedure to address various critical issues including reliability and accuracy ().

To infer the cell turnover dynamics in the adult hippocampus, several mathematical models, or scenarios, with increasing detail were fitted to the 14C data. All scenarios were based on a birth-and-death process, by which cells can die or be added to a cell population. A scenario defines a set of rules for how cells are born, die or renew; i.e. it sets whether there should be more, less or equal birth and death, which cells will die preferentially or renew, etcetera. For each of these scenarios, a set of parameters quantifies the extent of renewal. The mathematical model tracks the chronological age of each cell and the age of the person with a variable n(t, α), with the cell density (units in cells per year) of age α in a person aged t. The evolution of the cell density is given by a biological transport equation, which move cells along age as time progresses, with a loss term accounting for cell death: ∂n(t, α)/∂t + ∂n(t, α)/dα = γ(t, α)n(t, α). An initial condition describing the cell population at birth and a boundary condition describing how new cells are added are supplemented to the transport equation to solve the problem fully (equations are given in the Extended Experimental Procedures). Solving the problem allows the prediction of the 14C level for a sample, by integrating the solution n(t, α) along the atmospheric 14C curve between the birth and death of the individual. By comparing the model prediction to all neuronal or non-neuronal cell data, best parameter sets for each scenario was found. The best scenarios were selected based on Akaike Information Criterion (AIC), i.e. their goodness-of-fit and their level of detail. For Scenario A (constant turnover) and Scenario 2POP (constant turnover in a fraction of cells), individual turnover rates could also be estimated.

Turnover of non-neuronal cells in the adult human hippocampus

We first assessed the turnover dynamics of non-neuronal (NeuN-) cells in the human hippocampus. The 14C concentration in genomic DNA corresponded to time points after the birth of the individuals (Figure 2A, B), establishing turnover of non-neuronal cells in the human hippocampus. Mathematical modeling of 14C data allowed a detailed analysis of the dynamics of cell turnover (; ; ). By fitting the models to the data, we can infer how much cell renewal is needed to reproduce the observed 14C levels and whether the renewal is restricted to a subpopulation (see Fig. S2 and the extended experimental procedures). The best model, based on AIC, was Scenario 2POP, in which a fraction of the population is renewing and the other is not. In this scenario, cells within the renewing fraction are set to turn over at a constant rate throughout life. This scenario indicated that a large proportion of the non-neuronal cells (51%, CI [22%, 88%]) is continuously exchanged. The median turnover rate within the subpopulation of non-neuronal cells undergoing exchange is 3.5%/year (Figure 2C, Table S2). Individual turnover estimates suggest that there is a decline in the turnover of non-neuronal cells during aging (r=−0.35, p=0.04). The average age of non-neuronal cells within the renewing fraction at different ages of an individual is shown in Figure 2D.

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Turnover dynamics of non-neuronal cells

(A) Schematic illustration of the representation of the measured 14C concentration in genomic DNA. The black line indicates the 14C concentration in the atmosphere at different time points in the last century. Individually measured 14C concentrations in genomic DNA of human hippocampal cells are plotted at the time of the subject's birth (vertical lines), before (green dot) or after the 14C bomb spike (orange dot). 14C concentrations above the bomb curve (subjects born before the bomb peak) and data points below the bomb curve (subjects born after the nuclear tests) indicate cellular turnover. (B) The 14C concentrations of genomic DNA from non-neuronal cells demonstrate post-natal cell turnover in subjects born before and after the bomb spike. (C) Individual turnover rates for non-neuronal cells computed based on individual data fitting. Individual turnover rate calculations are sensitive to deviations in measured 14C and values <0.001 or >1.5 were excluded from the plot, but the full data is given in Table S1. (D) Non-neuronal average cell age estimates of cells within the renewing fraction are depicted (red curve). The dashed line represents a no-cell-turnover scenario.

Hippocampal neurogenesis in adult humans

We next analyzed the 14C concentration in neuronal genomic DNA. One can draw several conclusions regarding hippocampal neurogenesis from the raw data (Figure 3). First, the 14C concentration in genomic DNA of hippocampal neurons corresponds to the concentration in the atmosphere after the birth of the individual, confirming postnatal generation of hippocampal neurons in humans (). This finding is in contrast to cortical and olfactory bulb neurons, which are not exchanged postnatally to a detectable degree in humans, with 14C levels corresponding to the time around the birth of the individual (; ; ). Second, the oldest studied subjects had higher 14C concentrations in neuronal DNA than were present in the atmosphere before 1955 (Figure 3). This finding establishes that there has been DNA synthesis after 1955, indicating hippocampal neurogenesis at least into the fifth decade of life (the oldest individual was 42 years old in 1955). Third, the rather uniformly elevated levels of 14C in individuals born before the onset of the nuclear bomb tests indicate that there can be no dramatic decline in hippocampal neurogenesis with age; if there was a substantial decrease in neurogenesis during aging, individuals born longer before the rise in atmospheric 14C would have incorporated less of the elevated 14C levels present after 1955. Fourth, individuals born before the onset of nuclear bomb tests have lower 14C levels in hippocampal neuron DNA than at any time after 1955, establishing that, although some neurons are generated postnatally, the hippocampus is heterogeneous and a large subset of hippocampal neurons is not exchanged postnatally. Thus, it is evident from the raw data that there is substantial generation of hippocampal neurons in humans, restricted to a subpopulation, without any dramatic decline during adulthood.

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Hippocampal neurogenesis in adult humans

14C concentrations in hippocampal neuron genomic DNA correspond to a time after the date of birth of the individual, demonstrating neurogenesis throughout life.

A large proportion of hippocampal neurons is subject to turnover

Adult hippocampal neurogenesis in mammals is restricted to the dentate gyrus (). With the current sensitivity of accelerator mass spectrometry, it is not possible to separately carbon date neurons from subdivisions of the human hippocampus. However, neuroblasts and BrdU-labeled neurons have only been demonstrated in the dentate gyrus in adult humans (; ), indicating that neuronal turnover is restricted to the dentate gyrus also in humans. With the term turnover of neurons, it is not implied that individual neurons that are lost are replaced by new neurons taking over their function, but that there is an exchange of neurons at the population level. It was evident from the raw data (Figure 3) that not all hippocampal neurons are exchanged postnataly in humans. Models that allowed two compartments, one continuously turning over population and one non-renewing, fitted the data much better than any other model (see the supplemental material). Scenario 2POP indicates that the size of the cycling neuronal population constitutes 35% (CI [12%, 63%]) of hippocampal neurons (Figure 4A), corresponding to slightly less than the proportion of hippocampal neurons that constitutes the dentate gyrus in humans (see further below). This finding indicates that the vast majority of dentate gyrus neurons are subject to exchange in humans, differing from the situation in the mouse, in which approximately 10% of the dentate gyrus neurons are subject to exchange (; ). The proportion of hippocampal neurons that are exchanged has not been addressed in other species.

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Subpopulation dynamics of hippocampal neurons and non-neurons

(A) Hill function indicates that the fraction of neurons being exchanged is homogenous and confers to one mode of exchange. (B) In line with a non-neuronal population comprised of several cell types, the Hill function indicates that the nonneuronal cells form a heterogeneous group, with some subpopulations having high turnover rates and some very low. The z-axis indicates different possible solutions compatible with the data. Only solutions with a good fit are shown, with those with the highest probability indicated in red and lower probability in blue.

It is possible that cells in the hippocampus form a heterogeneous population in terms of renewal. A scenario with a continuum of turnover rates was used to assess the heterogeneity of the neuronal and non-neuronal cell populations (Scenario XPOP). The modeling indicates that the neuronal subpopulation that is turning over in the hippocampus is rather homogeneous and confers to one mode of exchange (Figure 4A). The non-neuronal cells form a heterogeneous group of cells, consisting mainly of astrocytes, microglia and oligodendrocyte-lineage cells, but also containing several smaller populations of, for example, leukocytes and blood vessela-ssociated endothelial and perivascular cells. In line with this, models that allowed subpopulations to have different turnover dynamics fitted the non-neuronal data best. The non-neuronal cells appear more heterogeneous than the neurons, with some having high turnover rates and some very low (Figure 4B).

The rate of neuronal turnover in the human hippocampus

As the majority of hippocampal neurons are not exchanged, the average age of hippocampal neurons increases with the age of the individual, which may give the false impression that the turnover rate decreases sharply during aging. However, when taking into account that neurogenesis is restricted to a subpopulation, individual estimates of turnover rates indicate a more modest decline in turnover with aging within this population (Fig. 5A, Fig. S3, Table S3, r=−0.31, p=0.03, Scenario 2POP). The median turnover rate of neurons within the renewing subpopulation is 1.75%/year during adulthood, corresponding to approximately 700 new neurons/day or 0.004% of the dentate gyrus neurons/day in the human hippocampus. The turnover rate of hippocampal neurons is not significantly different between men and women (P=0.41, ANOVA). The average age of neurons within the renewing fraction at different ages of an individual is shown in Figure 5B.

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Neuronal turnover dynamics in the human hippocampus

(A) Individual turnover rates for neuronal cells within the renewing fraction were computed based on individual data fitting. The number of doublecortin (DCX)-positive cells per mm2 in the dentate gyrus (data from ) shows a similar modest decline during adult ages as the computed neuronal turnover rates. Straight lines depict linear regression curves, with the regression line for DCX cell counts being calculated for individuals 10 years and older. Individual turnover rate calculations are sensitive to deviations in measured 14C and values <0.001 or >1.5 were excluded from the plot, but the full data is given in Table S1. (B) The average age of the neurons within the renewing fraction (blue curve). The dashed line represents the no-cell-turnover scenario.

Comparing the turnover rates between the full neuronal and non-neuronal hippocampal populations reveals a significantly higher turnover rate within the non-neuronal compartment (p<2e-5, Wilcoxon signed rank test, Scenario A). This finding is largely explained by a larger subset of cells turning over within the non-neuronal population than within the neuronal population, and when comparing the turnover rates specifically within the respective subpopulations that are subject to cellular exchange, there was no significant difference in turnover rates between the neuronal and non-neuronal populations (p=0.054, Wilcoxon signed rank test, Scenario 2POP). However, as non-neuronal cells are more abundant than neurons in the human hippocampus (Fig. 1A), a larger number of non-neuronal cells in absolute numbers is generated.

There was no correlation between the neuronal and non-neuronal turnover rates within individuals older than 50 years (r=−0.14, p=0.58, Scenario 2POP), suggesting that the generation of these different cell types is regulated independently, as in the mouse (). However there was a correlation in young individuals (<50 years, r=−0.62, p=0.003). The inter-individual variation in the turnover rate of neurons and non-neuronal cells in the hippocampus is similar, with a median absolute deviation of 0.0226 and 0.0158 per year, respectively. The inter-individual variation may appear largest in the younger subjects, but this is a consequence of the shallow slope of the atmospheric 14C levels in recent times, which provides less resolution and therefore introduces higher variability.

An integrated model of neuronal dynamics in the human hippocampus

The determination of the fraction of neurons that is subject to exchange in the human hippocampus and their turnover rate makes it possible to infer the age of the full complement of neurons in individuals of different ages. The hippocampus is a mosaic of neurons of different ages, with a large fraction of cells remaining from development and with neurons generated at different times throughout life. Stereological quantifications have revealed a decrease in the number of hippocampal neurons during aging in humans, with the dentate gyrus being least affected (Fig. S4). A relative increase in the proportion of neurons in the renewing fraction with age fits the 14C data well.

The most detailed model, Scenario 2POPEd, provides a global picture of the dynamics of neuronal turnover. Non-renewing neurons die without being replaced, resulting in a slow decrease during life. Within the renewing neuron population, young cells die faster, leading to a neuron age distribution with less middle-aged cells than would be expected if all neurons were as likely to be replaced. One observation from the modeling is that adult-born neurons are preferentially lost and do not survive as long as the neurons generated during development. The half-life of a neuron in the renewing fraction is 7.1 years, or 10 times shorter than in the non-renewing fraction. Although it is known that adult-born neurons integrate long-term in rodents, whether they last for the remainder of the animal's life has not been studied, although the available data are compatible with a preferential loss of adult-born neurons (; ; ). The integrated model of the dynamics of hippocampal neuron numbers and exchange in humans is shown in Figure 6.

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An integrated model of the number and age of neurons in the human hippocampus

Schematic illustration of the number of neurons in the dentate gyrus (above the white line) and the other subdivisions of the hippocampus (below the white line), and the age of neurons within the dentate gyrus at different ages. The total number of neurons declines with age in the hippocampus, with the dentate gyrus being relatively spared. The dentate gyrus is composed of a declining fraction of cells generated during development (black), which is gradually replaced by postnatally generated cells. For a given age of the person, postnatally generated cells are in different shades of gray, indicating decade intervals, with the lightest gray being cells generated during the last decade, one shade darker being cells generated 10–20 years ago, and so on. This way, at age 15, among postnatally generated cells, only cells generated 0–10 years ago and 10–20 years ago are present. Read vertically, for a fixed age of the person, the cell age distribution goes from oldest cells (black) to the youngest ones (light gray). Read horizontally, the fraction of adult-born cells (non-black) increases with age. The model is based on Scenario 2POPEd. The figure was generated using parameters: initial fraction of renewing neurons: 0.31, death rate of the non-renewing neurons: 0.0035/year, death rate of newborn neurons: 0.11/year, cell age at which the death rate has reduced by half: 19 years. The parameter set was selected among the 3% best out of 3×105 parameter sets explored using a Markov Chain Monte Carlo algorithm, and consistent with Scenario 2POP.

Discussion

Newborn neurons in the adult hippocampus have distinct features for a limited period after their differentiation that give them a key role in pattern separation and cognitive adaptability in rodents. We have birth dated hippocampal cells to assess whether adult neurogenesis occurs to a significant extent in adult humans, and provide a detailed view of the cell turnover dynamics. There is substantial neurogenesis throughout life in the human hippocampus, with only a modest decline during aging. There is a preferential loss of adult-born neurons and a larger proportion of hippocampal neurons is subject to exchange in humans compared to the mouse. Nonneuronal cells have more heterogeneous turnover dynamics than hippocampal neurons.

It is important to consider whether DNA repair may contribute to 14C integration in hippocampal cells. DNA damage and repair are largely restricted to proliferating cells and are believed to be several orders of magnitude lower in postmitotic cells than is detectable by 14C dating (). DNA repair during cell proliferation will not affect the assessment of cell generation, as 14C integrates in DNA at a concentration corresponding to that in the atmosphere during mitosis. We have not found any measurable 14C integration in the DNA of cortical, cerebellar or olfactory bulb neurons over many decades in humans (; ; ). Not even neurons surviving at the perimeter of an ischemic cortical stroke, a situation where there is substantial DNA damage and repair, incorporate sufficient 14C to be detected (our unpublished data). The dynamics of 14C integration in the DNA of hippocampal neurons does not appear to be compatible with any pattern of DNA repair previously described; a large fraction of hippocampal neurons (35%) would have to exchange their entire genome by DNA repair during the lifetime of an individual, whereas there would be no detectable DNA repair in the remaining hippocampal neurons. In contrast, the number of neuroblasts reported in the adult human dentate gyrus () is sufficient to give rise to the number of new neurons indicated by the 14C analysis and the decline in neurogenesis closely parallels the decrease in the number of neuroblasts (Figure 5A). Thus, the 14C concentration in genomic DNA of hippocampal neurons is likely to accurately reflect neurogenesis.

Retrospective birth dating reveals that what appears as small numbers of neuroblasts present in adulthood () give rise to a substantial number of new neurons over time in the hippocampus. It is interesting in this context that the similar density of neuroblasts in the subventricular zone to that in the hippocampal dentate gyrus does not result in any detectable addition of new neurons to the olfactory bulb (; ; ; ; ). The lack of olfactory bulb neurogenesis thus appears to be a consequence of an absence of migration and/or integration of new neurons in the olfactory bulb, rather than a lack of generation of neuroblasts.

There are some distinct differences in the pattern of adult hippocampal neurogenesis in humans compared to rodents, in which this process has been most extensively characterized. First, a much larger proportion of hippocampal neurons are subject to exchange in humans. In mice, 10% of the neurons in the dentate gyrus are added in adulthood and subject to exchange (; ). In humans, approximately one third of the hippocampal neurons turn over, corresponding to the vast majority of the dentate gyrus neurons. Second, although hippocampal neurogenesis declines with age in both rodents and humans, the relative decline during adulthood appears smaller in humans compared to mice. Comparisons of the kinetics of the age-dependent decline in hippocampal neurogenesis between different species have revealed a similar chronology, rather than correlating to developmental milestones (). In line with this, the most dramatic decrease in the number of neuroblasts in the dentate gyrus occurs during the first postnatal months in both mice and humans (; ). An effect of this is that young adult mice are still in the most steeply declining phase of neurogenesis, making the relative decrease in neurogenesis during adult life being much larger in mice than humans. Whereas there is an approximate ten-fold decrease in neurogenesis from 2 to 9 months of age in mice (), there is an approximate four-fold decline during the entire adult lifespan in humans (Fig. 5A). Third, the impact of adult neurogenesis on the total number of neurons in the dentate gyrus differs between rodents and humans. Hippocampal neurogenesis in mice and rats is additive and results in a net increase in the number of dentate gyrus neurons with age (; ; ; ). This is not the case in humans, where there is a net loss of dentate gyrus neurons during adult life. Although the decrease in neuronal numbers is less pronounced in the dentate gyrus than other subdivisions of the human hippocampus, the generation of new neurons does not keep up with the neuronal loss (Fig. 6). Computational models have indicated that addition of new neurons to the circuitry, together with loss of older redundant cells and enhanced synaptic plasticity can maximize the effect of the new neurons, whereas an isolated exchange of neurons would have less influence (). The adult generation of neurons serves to uphold a pool of neurons with specific functional properties, rather than replacing individual neurons that are lost. The continuous generation of new neurons in the adult human hippocampus may therefore have an additive role functionally in the circuitry, although more neurons are lost than generated.

Can the number of new neurons generated in the adult human hippocampus have functional significance? An indication of this may be gained by comparing the extent of adult neurogenesis in humans with that in other species, in particular the mouse, in which most experiments on the function of adult hippocampal neurogenesis have been carried out. It is difficult to make direct comparisons as there are several factors influencing the potential impact of newborn neurons that may vary between species, for example the total number of cells in the circuitry and for how long newborn neurons have distinct features. The best measure of adult neurogenesis when comparing across species may be the relative proportion of newborn to old neurons (). We conclude that 0.004% of the dentate gyrus neurons are exchanged daily in adult humans, which can be compared to 0.03–0.06%/day in 2-month-old mice and 0.004–0.02%/day in 5- to 16-year-old macaque monkeys (; ; ). Hippocampal neurogenesis has been estimated to decrease approximately 10-fold between 2 months and 9 months of age in the mouse (), indicating that the rate of neurogenesis in adult humans may correspond to that of a 9-month-old mouse. Together with the extended period of immature features of the adult-born neurons in non-human primates (), and potentially humans, the relative proportion of adult born neurons with unique functions in the human hippocampus may not be smaller than that in a middle-aged mouse. Thus, the extent of neurogenesis in the adult human hippocampus may be sufficient to convey similar functions as in the mouse, in which adult neurogenesis is important for cognitive adaptability.

Adult-born hippocampal neurons have enhanced synaptic plasticity for a period of time after their differentiation (; ). This, together with the dentate gyrus being a bottleneck in the network, allows a small proportion of neurons to have a substantial influence on the circuitry and hippocampal function. The new neurons are required for efficient pattern separation, the ability to distinguish and store similar experiences as distinct memories, whereas the old granule cells are necessary for pattern completion, which serves to associate similar memories to each other (; ; ). Failing pattern separation may result in generalization, a common feature in anxiety and depression in humans (). There are a number of indications that implicate reduced neurogenesis in psychiatric disease, but it has been difficult to explore whether there is a link in humans (). We find considerable interindividual variation in this study, and assessment of hippocampal neurogenesis together with reconstruction of medical histories may reveal whether reduced neurogenesis is associated with psychiatric disease in humans.

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