Use the labels in the right column to find what you want. Or you can go thru them one by one, there are only 27,612 posts. Searching is done in the search box in upper left corner. I blog on anything to do with stroke.DO NOT DO ANYTHING SUGGESTED HERE AS I AM NOT MEDICALLY TRAINED, YOUR DOCTOR IS, LISTEN TO THEM. BUT I BET THEY DON'T KNOW HOW TO GET YOU 100% RECOVERED. I DON'T EITHER, BUT HAVE PLENTY OF QUESTIONS FOR YOUR DOCTOR TO ANSWER.
Changing stroke rehab and research worldwide now.Time is Brain!trillions and trillions of neuronsthatDIEeach day because there areNOeffective 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.
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.
Cumulative depression incidence was about 60%, long-term study shows
by
Michael DePeau-Wilson, Enterprise & Investigative Writer, MedPage Today
March 27, 2024
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.
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.
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:
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.
Protection Against Age-Related Decline: This cognitive reserve helps maintain social cognition skills, such as understanding others’ mental states, despite aging.
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).
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
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?
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.
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.
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.
Originally published26 Mar 2024Journal 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
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.
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.”
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.”
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?
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 (Ge et al., 2007; Schmidt-Hieber et al., 2004), which is critical for their role in mediating pattern separation in memory formation and cognition in rodents (Clelland et al., 2009; Nakashiba et al., 2012; Sahay et al., 2011).
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 (Kempermann, 2012; Rakic, 1985). A seminal study by Eriksson, Gage and colleagues provided the only direct evidence to date for adult neurogenesis in humans (Eriksson et al., 1998), 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 (Knoth et al., 2010; Sanai et al., 2011; Wang et al., 2011).
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 (Göritz and Frisén, 2012; Knoth et al., 2010; Sanai et al., 2011; Wang et al., 2011).
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 (Arellano and Rakic, 2011; Sanai et al., 2011; Wang et al., 2011).
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 (Bergmann et al., 2012).
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 (Bergmann et al., 2012).
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 (Spalding et al., 2005a). This strategy takes advantage of the elevated atmospheric 14C levels caused by above ground nuclear bomb testing 1955–63 during the Cold War (De Vries, 1958; Nydal and Lovseth, 1965).
After the International Test Ban Treaty in 1963, the atmospheric levels
have declined due to uptake by the biotope and diffusion from the
atmosphere (Levin and Kromer, 2004; Levin et al., 2010). 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 (Harkness, 1972; Libby et al., 1964; Spalding et al., 2005b). 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 (Spalding et al., 2005a). 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 (Spalding et al., 2005b), 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.
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) (Bergmann et al., 2012; Bhardwaj et al., 2006; Spalding et al., 2005a). 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).
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 (Salehpour et al., 2013).
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 (Bergmann et al., 2009; Bergmann et al., 2012; Spalding et al., 2008). 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.
(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 (Eriksson et al., 1998).
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 (Bergmann et al., 2012; Bhardwaj et al., 2006; Spalding et al., 2005a). 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.
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 (Kempermann, 2012).
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 (Eriksson et al., 1998; Knoth et al., 2010),
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 (Imayoshi et al., 2008; Santos et al., 2007). The proportion of hippocampal neurons that are exchanged has not been addressed in other species.
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.
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 Knoth et al, 2010)
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 (Steiner et al., 2004).
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 (Imayoshi et al., 2008; Kempermann et al., 2003; Ninkovic et al., 2007). The integrated model of the dynamics of hippocampal neuron numbers and exchange in humans is shown in Figure 6.
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.
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 (Spalding et al., 2005a). 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 (Bergmann et al., 2012; Bhardwaj et al., 2006; Spalding et al., 2005a).
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 (Knoth et al., 2010) 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 (Knoth et al., 2010)
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 (Bergmann et al., 2012; Göritz and Frisén, 2012; Knoth et al., 2010; Sanai et al., 2011; Wang et al., 2011).
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 (Imayoshi et al., 2008; Ninkovic et al., 2007).
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 (Amrein et al., 2011).
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 (Ben Abdallah et al., 2010; Knoth et al., 2010).
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 (Ben Abdallah et al., 2010), 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 (Bayer, 1985; Imayoshi et al., 2008; Kempermann et al., 2003; Ninkovic et al., 2007).
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 (Appleby et al., 2011).
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 (Kempermann, 2012).
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 (Jabès et al., 2010; Kempermann et al., 1997; Kornack and Rakic, 1999).
Hippocampal neurogenesis has been estimated to decrease approximately
10-fold between 2 months and 9 months of age in the mouse (Ben Abdallah et al., 2010),
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 (Kohler et al., 2011),
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 (Ge et al., 2007; Schmidt-Hieber et al., 2004).
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 (Clelland et al., 2009; Nakashiba et al., 2012; Sahay et al., 2011). Failing pattern separation may result in generalization, a common feature in anxiety and depression in humans (Kheirbek et al., 2012).
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 (Eisch and Petrik, 2012).
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.