Brain structural plasticity is an extraordinary tool that allows the mature brain to adapt to environmental changes, to learn, to repair itself after lesions or disease, and to slow aging. A long history of neuroscience research led to fascinating discoveries of different types of plasticity, involving changes in the genetically determined structure of nervous tissue, up to the ultimate dream of neuronal replacement: a stem cell-driven “adult neurogenesis” (AN). Yet, this road does not seem a straight one, since mutable dogmas, conflicting results and conflicting interpretations continue to warm the field. As a result, after more than 10,000 papers published on AN, we still do not know its time course, rate or features with respect to other kinds of structural plasticity in our brain. The solution does not appear to be behind the next curve, as differences among mammals reveal a very complex landscape that cannot be easily understood from rodents models alone. By considering evolutionary aspects, some pitfalls in the interpretation of cell markers, and a novel population of undifferentiated cells that are not newly generated [immature neurons (INs)], we address some conflicting results and controversies in order to find the right road forward. We suggest that considering plasticity in a comparative framework might help assemble the evolutionary, anatomical and functional pieces of a very complex biological process with extraordinary translational potential.
Brief Historical Perspective: Revisiting A Never-Ending Story
The intense research following the “re-discovery” of AN in mammals (starting from the seminal work of Lois and Alvarez-Buylla (1994), but adding to the pioneering studies of Joseph Altman and Fernando Nottebohm) were carried out almost exclusively using mice and rats. These studies were aimed to exploit endogenous and exogenous sources of stem/progenitor cells for therapeutic purposes (Bao and Song, 2018); however, the reparative capacity of mammalian AN was not sufficient, even in rodents (Bonfanti and Peretto, 2011; Lois and Kelsch, 2014). Further studies began to reveal that the main significance of the newborn neurons is linked to physiological roles, related to learning and adaptation to a changing environment (Kempermann, 2019). What appeared interesting is the discovery that AN is highly modulated by the internal/external environment and, ultimately, by lifestyle (Vivar and van Praag, 2017; Kempermann, 2019), which opened the road to prevention of age-related problems. These results also began to highlight the importance of evolutionary aspects (and constraints) revealed by the remarkable differences that exist among mammals (Barker et al., 2011; Amrein, 2015; Feliciano et al., 2015). As stated by Faykoo-Martinez et al. (2017): “Species-specific adaptations in brain and behavior are paramount to survival and reproduction in diverse ecological niches and it is naive to think AN escaped these evolutionary pressures” (see also Amrein, 2015; Lipp and Bonfanti, 2016). Subsequently, several studies addressed the issue of AN in a wider range of species, including wild-living and large-brained mammals that displayed a varied repertoire of anatomical and behavioral features, quite different from those of mice (reviewed in Barker et al., 2011; Amrein, 2015; Lipp and Bonfanti, 2016; Paredes et al., 2016; Parolisi et al., 2018). Though still too fragmentary to support exhaustive conclusions about phylogeny (much less function), this landscape of heterogeneity directs us to re-evaluate, discuss and better contextualize the observations obtained in rodents, especially in the perspective of translation to humans (analyzed in Lipp and Bonfanti, 2016; Paredes et al., 2016; Parolisi et al., 2018; Duque and Spector, 2019; Snyder, 2019). Comparative approaches strongly indicate that there is a decrease in the remarkable plastic events that lead to whole cell changes (i.e., AN) with increasing brain size. In an evolutionary framework, the absence/reduction of neurogenesis should not be viewed as a limit, rather as a requirement linked to increased computational capabilities. Unfortunately, this same fact turns into a “necessary evil” when brain repair is needed: a requirement for stability and a high rate of cell renewal, apparently, cannot coexist (Rakic, 1985; Arellano et al., 2018). Why then do some reports claim the existence of AN in humans? Several scientists in the field warn of high profile papers published on human AN that were technically flawed, their interpretations going well beyond what the data could support; some have never been reproduced (these aspects are thoroughly reviewed in Oppenheim, 2018; Duque and Spector, 2019). Apart from the soundness of data, a strong species bias exists in the neurogenesis literature, due to an overestimation of the universality of laboratory rodents as animal models (Amrein, 2015; Lipp and Bonfanti, 2016; Bolker, 2017; Faykoo-Martinez et al., 2017; Oppenheim, 2019). There is also a common misunderstanding that the putative existence of AN in primates suggests or provides evolutionary proof that the same process exists in humans. In fact, the few existing reports are on non-human primates (common marmosets and macaca), endowed with smaller, less gyrencephalic brains and lower computational capacity, compared to apes (Roth and Dicke, 2005). Systematic, quantitative studies in apes (family Hominidae) are still lacking and most studies carried out in monkeys suggest that very low levels of hippocampal neurogenesis persist during adulthood. In Callithrix jacchus, proliferating doublecortin (DCX)+ neuroblasts were virtually absent in adults and markers of cell proliferation and immaturity declined with age (Amrein et al., 2015). In another study involving Macaca mulatta and Macaca fascicularis, the estimated rate of hippocampal neurogenesis was approximately 10 times lower than in adult rodents (Kornack and Rakic, 1999). These data, along with evidence that AN is virtually absent in cetaceans (Patzke et al., 2015; Parolisi et al., 2017), do provide strong support for declining rates of AN in large-brained mammals (Paredes et al., 2016).
The reasons for some of these misunderstandings are analyzed in the next paragraph.
The birth of neurons from NSC/radial glia cells has been well demonstrated both in embryonic and AN (Lim and Alvarez-Buylla, 2014; Berg et al., 2019). The germinal layers in the embryo and the neurogenic sites in the adult brain (subventricular zone, V-SVZ; subgranular zone, SGZ; hypothalamus) are microenvironments in which the NSCs are regulated so that new neurons can be formed. Hence, an adult neurogenic process, as we now understand it, must be sustained by an active NSC niche (Figure 1A). If we accept this definition, then the biological limits of mammalian AN are clear: it is highly restricted to small neurogenic zones, most cells proliferating outside these regions are glial cells, it is related to physiological needs and species-specific adaptations/behaviors, and it is strictly linked to the different animal species, developmental stages and ages (Bonfanti, 2016; Paredes et al., 2016).[…]
Intermittent fasting (IF) has been suggested to have neuroprotective effects through the activation of multiple signaling pathways. Rodents fasted intermittently exhibit enhanced hippocampal neurogenesis and long‐term potentiation (LTP) at hippocampal synapses compared with sedentary animals fed an ad libitum (AL) diet. However, the underlying mechanisms have not been studied. In this study, we evaluated the mechanistic gap in understanding IF‐induced neurogenesis.
We evaluated the impact of 3 months of IF (12, 16, and 24 hr of food deprivation on a daily basis) on hippocampal neurogenesis in C57BL/6NTac mice using immunoblot analysis.
Three‐month IF significantly increased activation of the Notch signaling pathway (Notch 1, NICD1, and HES5), neurotrophic factor BDNF, and downstream cellular transcription factor, cAMP response element‐binding protein (p‐CREB). The expression of postsynaptic marker, PSD95, and neuronal stem cell marker, Nestin, was also increased in the hippocampus in response to 3‐month IF.
These findings suggest that IF may increase hippocampal neurogenesis involving the Notch 1 pathway.
Dietary restriction (DR) is defined as a decrease in energy consumption without reducing nutritional value. This simple dietary intervention has been shown in a wide range of experimental animals to extend lifespan and decrease the incidence of several age‐related diseases. The definition of DR has been expanded from an alternative description of caloric restriction (CR) to also encompass a broader scope of interventions, including short‐term starvation, periodic fasting, fasting‐mimetic diets, and intermittent fasting (IF; Mattson & Arumugam, 2018). IF has been proven to be advantageous to various organ systems in the body and acts as a mild metabolic stressor. It has been postulated that IF is able to cause powerful changes in the metabolic pathways in the brain via an increase in stress resistance, and breakdown of ketogenic amino acids and fatty acids (Bruce‐Keller, Umberger, McFall, & Mattson, 1999; Kim et al., 2018). Experimental studies have also shown that IF is neuroprotective against acute brain injuries such as stroke, and neurodegenerative diseases (Arumugam et al., 2010; Halagappa et al., 2007; Manzanero et al., 2014). In addition, recent studies have also shown that IF can lead to an increase in neurogenesis levels in the hippocampus (Manzanero et al., 2014).
In the adult brain, the niches of neuronal stem cells (NSCs) are located specifically at the subventricular zone (SVZ) of the lateral ventricles, and in the subgranular zone (SGZ) of the hippocampus. The ability of NSCs to maintain cerebral neurogenesis is controlled by the tight regulation of balanced events commencing from stem cell maintenance, to stem cell division and proliferation, to its differentiation into mature neurons, and finally their survival and functional integration into the brain parenchyma (Lathia, Mattson, & Cheng, 2008; Lledo, Alonso, & Grubb, 2006). The process of adult neurogenesis is highly regulated and is adaptable to environmental, morphological, and physiological cues, whereby cerebral performance is suited to function at optimal levels for a given environment. Studies have demonstrated that the proliferation of neural stem cells can be modified through metabolic perturbations experienced during high temperatures (Matsuzaki et al., 2009), physical activity (Niwa et al., 2016), and a high‐fat diet (Kokoeva, Yin, & Flier, 2005). Experimental studies from our group have also shown that IF increases neurogenesis in the hippocampus as a form of neuroprotection following acute brain injury such as ischemic stroke. Moreover, we established that the number of BrdU‐labeled cells in the dentate gyrus of IF mice was elevated (Manzanero et al., 2014). To measure cell proliferation without the confound availability of an exogenous marker BrdU, we established increases in the number of Ki67‐labeled cells in the dentate gyrus of mice on the IF diet, indicating enhancement of cell proliferation in these mice (Manzanero et al., 2014). In addition to our findings, previous work similarly demonstrated that using the every other day (EOD) IF regimen also increased BrdU‐labeled cell number in the hippocampus (Lee, Duan, & Mattson, 2002).
However, the molecular process involved in IF‐induced neurogenesis is not well understood. The Notch signaling pathway that is intricately involved in the determination of cell fate during brain development and adult neurogenesis may be a possible molecular process involved in IF‐induced neurogenesis (Lathia et al., 2008). In this study, we investigated the expression levels of molecular and cellular components of the hippocampal region, focusing specifically on Notch activation and associated proteins that are known to promote hippocampal neurogenesis such as brain‐derived neurotrophic factor (BDNF) and cAMP response element‐binding protein (CREB).[…]
Imagine the brain could reboot, updating its damaged cells with new, improved units. That may sound like science fiction — but it’s a potential reality scientists are investigating right now. Ralitsa Petrova details the science behind neurogenesis and explains how we might harness it to reverse diseases like Alzheimer’s and Parkinson’s.
The evolutionary history of humans explains why physical activity is important for brain health
It is by now well established that exercise has positive effects on the brain, especially as we age.
Less clear has been why physical activity affects the brain in the first place.
Key events in the evolutionary history of humans may have forged the link between exercise and brain function.
Cognitively challenging exercise may benefit the brain more than physical activity that makes fewer cognitive demands.
In the 1990s researchers announced a series of discoveries that would upend a bedrock tenet of neuroscience. For decades the mature brain was understood to be incapable of growing new neurons. Once an individual reached adulthood, the thinking went, the brain began losing neurons rather than gaining them. But evidence was building that the adult brain could, in fact, generate new neurons. In one particularly striking experiment with mice, scientists found that simply running on a wheel led to the birth of new neurons in the hippocampus, a brain structure that is associated with memory. Since then, other studies have established that exercise also has positive effects on the brains of humans, especially as we age, and that it may even help reduce the risk of Alzheimer’s disease and other neurodegenerative conditions. But the research raised a key question: Why does exercise affect the brain at all?
Physical activity improves the function of many organ systems in the body, but the effects are usually linked to better athletic performance. For example, when you walk or run, your muscles demand more oxygen, and over time your cardiovascular system responds by increasing the size of the heart and building new blood vessels. The cardiovascular changes are primarily a response to the physical challenges of exercise, which can enhance endurance. But what challenge elicits a response from the brain?
Answering this question requires that we rethink our views of exercise. People often consider walking and running to be activities that the body is able to perform on autopilot. But research carried out over the past decade by us and others would indicate that this folk wisdom is wrong. Instead exercise seems to be as much a cognitive activity as a physical one. In fact, this link between physical activity and brain health may trace back millions of years to the origin of hallmark traits of humankind. If we can better understand why and how exercise engages the brain, perhaps we can leverage the relevant physiological pathways to design novel exercise routines that will boost people’s cognition as they age—work that we have begun to undertake.
FLEXING THE BRAIN
To explore why exercise benefits the brain, we need to first consider which aspects of brain structure and cognition seem most responsive to it. When researchers at the Salk Institute for Biological Studies in La Jolla, Calif., led by Fred Gage and Henriette Van Praag, showed in the 1990s that running increased the birth of new hippocampal neurons in mice, they noted that this process appeared to be tied to the production of a protein called brain-derived neurotrophic factor (BDNF). BDNF is produced throughout the body and in the brain, and it promotes both the growth and the survival of nascent neurons. The Salk group and others went on to demonstrate that exercise-induced neurogenesis is associated with improved performance on memory-related tasks in rodents. The results of these studies were striking because atrophy of the hippocampus is widely linked to memory difficulties during healthy human aging and occurs to a greater extent in individuals with neurodegenerative diseases such as Alzheimer’s. The findings in rodents provided an initial glimpse of how exercise could counter this decline.
Following up on this work in animals, researchers carried out a series of investigations that determined that in humans, just like in rodents, aerobic exercise leads to the production of BDNF and augments the structure—that is, the size and connectivity—of key areas of the brain, including the hippocampus. In a randomized trial conducted at the University of Illinois at Urbana-Champaign by Kirk Erickson and Arthur Kramer, 12 months of aerobic exercise led to an increase in BDNF levels, an increase in the size of the hippocampus and improvements in memory in older adults.
Other investigators have found associations between exercise and the hippocampus in a variety of observational studies. In our own study of more than 7,000 middle-aged to older adults in the U.K., published in 2019 in Brain Imaging and Behavior, we demonstrated that people who spent more time engaged in moderate to vigorous physical activity had larger hippocampal volumes. Although it is not yet possible to say whether these effects in humans are related to neurogenesis or other forms of brain plasticity, such as increasing connections among existing neurons, together the results clearly indicate that exercise can benefit the brain’s hippocampus and its cognitive functions.
Researchers have also documented clear links between aerobic exercise and benefits to other parts of the brain, including expansion of the prefrontal cortex, which sits just behind the forehead. Such augmentation of this region has been tied to sharper executive cognitive functions, which involve aspects of planning, decision-making and multitasking—abilities that, like memory, tend to decline with healthy aging and are further degraded in the presence of Alzheimer’s. Scientists suspect that increased connections between existing neurons, rather than the birth of new neurons, are responsible for the beneficial effects of exercise on the prefrontal cortex and other brain regions outside the hippocampus.
UPRIGHT AND ACTIVE
With mounting evidence that aerobic exercise can boost brain health, especially in older adults, the next step was to figure out exactly what cognitive challenges physical activity poses that trigger this adaptive response. We began to think that examining the evolutionary relation between the brain and the body might be a good place to start. Hominins (the group that includes modern humans and our close extinct relatives) split from the lineage leading to our closest living relatives, chimpanzees and bonobos, between six million and seven million years ago. In that time, hominins evolved a number of anatomical and behavioral adaptations that distinguish us from other primates. We think two of these evolutionary changes in particular bound exercise to brain function in ways that people can make use of today.
Researchers used to think that after adolescence, people were pretty well stuck with the brain cells they’d already formed. No so anymore. Discoveries in recent years have shown that neurogenesis—the formation of new neurons—can occur much later than this, well into adulthood. And now, a new study from the University of Illinois at Chicago finds that brain cells can form into one’s nineties, even if one has cognitive decline and Alzheimer’s disease (though at a much decelerated rate). The question is how the late-in-life growth of new neurons fits into what’s already known about degenerative diseases.
The study was published last week in the journal Cell Stem Cell.
The researchers looked at the postmortem brains of people aged 79-99, some of whom had had cognitive decline or Alzheimer’s disease. They targeted markers for two kinds of burgeoning cells—neuroblasts (stem cells that would one day give rise to neurons), and immature neurons—in the hippocampus, the brain area that’s most affected in Alzheimer’s disease.
People who had died without cognitive problems had proliferation of both kinds of cells in their brains. People with cognitive decline and Alzheimer’s also had evidence of the cells, but in much lower numbers.
Lazarov, neurogenesis study
COURTESY, ORLY LAZAROV, ET AL.
“We found that there was active neurogenesis in the hippocampus of older adults well into their 90s,” said study author Orly Lazarov in a statement. “The interesting thing is that we also saw some new neurons in the brains of people with Alzheimer’s disease and cognitive impairment.”
What was interesting was the finding that people who had scored higher on tests of cognition during their later lives had more neuroblasts in their hippocampi, compared to those who’d scored lower—and this was independent of the level of degeneration that was visible in the brain.
“In brains from people with no cognitive decline who scored well on tests of cognitive function, these people tended to have higher levels of new neural development at the time of their death, regardless of their level of pathology,” Lazarov said. “The mix of the effects of pathology and neurogenesis is complex and we don’t understand exactly how the two interconnect, but there is clearly a lot of variation from individual to individual.”
The finding is intriguing since it’s long been known that a person’s level of brain “gunk” (the plaques and tangles associated with Alzheimer’s disease) doesn’t always correlate with their cognitive and behavioral symptoms. So it’s possible that these new findings helps explain why this disconnect exists—perhaps the level of neurogenesis matters as much or more than the amount of plaques and tangles that develop. If that’s true, then the big question would be how to harness this for therapeutic purposes.
“The fact that we found that neural stem cells and new neurons are present in the hippocampus of older adults means that if we can find a way to enhance neurogenesis, through a small molecule, for example, we may be able to slow or prevent cognitive decline in older adults, especially when it starts, which is when interventions can be most effective,” said Lazarov.
More research will obviously be needed to understand all of this, but preventing cognitive decline and dementia is probably the way to go, especially since medications to treat Alzheimer’s after the fact have fallen flat in recent years. In the meantime, the study is encouraging on another level: Certain lifestyle habits—most notably exercise—have consistently been shown to boost neurogenesis. The findings suggest we’d do well to pick up exercise, and other brain-healthy habits, and engage in them for as much of our lives as we can, as regularly as we’re able.
New neurons are generated in the hippocampal dentate gyrus from early development through adulthood. Progenitor cells and immature granule cells in the subgranular zone are responsive to changes in their environment; and indeed, a large body of research indicates that neuronal interactions and the dentate gyrus milieu regulates granule cell proliferation, maturation, and integration. Following traumatic brain injury (TBI), these interactions are dramatically altered. In addition to cell losses from injury and neurotransmitter dysfunction, patients often show electroencephalographic evidence of cortical spreading depolarizations and seizure activity after TBI. Furthermore, treatment for TBI often involves interventions that alter hippocampal function such as sedative medications, neuromodulating agents, and anti-epileptic drugs. Here, we review hippocampal changes after TBI and how they impact the coordinated process of granule cell adult neurogenesis. We also discuss clinical TBI treatments that have the potential to alter neurogenesis. A thorough understanding of the impact that TBI has on neurogenesis will ultimately be needed to begin to design novel therapeutics to promote recovery.
Adult neurogenesis in the hippocampal dentate gyrus is widespread in mammals. Generation of dentate granule cells occurs late in embryonic development, continues after birth, and persists into old age in most mammals examined (Amrein et al., 2011; Amrein, 2015; Ngwenya et al., 2015). Studies in rodents indicate that adult generated granule cells play a role in hippocampal dependent learning (Nakashiba et al., 2012; Danielson et al., 2016; Johnston et al., 2016). Whether neurogenesis continues into old age in humans remains controversial (Danzer, 2018a), with studies finding evidence for (Eriksson et al., 1998; Spalding et al., 2013; Boldrini et al., 2018) and against ongoing neurogenesis (Sorrells et al., 2018). Yet there is general agreement that dentate neurogenesis occurs in childhood and continues throughout young adulthood in humans, and that newly-generated neurons are poised to contribute to hippocampal function. At a minimum, therefore, traumatic brain injuries (TBIs) occurring during adolescence have the potential to disrupt this important process.
The generation, maturation, and integration of new neurons is critical for hippocampal function. This tightly regulated process, however, is easily disrupted by pathological events, such as TBI. In this review, we discuss the coordinated process of adult neurogenesis in the hippocampal subgranular zone (SGZ) and the impact that TBI and TBI treatments have on this process. An understanding of the regulation and dysregulation of neurogenesis is important for determining whether and how therapeutic interventions targeted at adult neurogenesis are useful for TBI treatment.
Neurogenesis Is a Complex, Tightly-Regulated Process
Adult neurogenesis is characterized by multiple “control” points. The number of daughter cells produced by neural stem cells (NSC) located in the SGZ of the dentate gyrus can be modulated by the rate of cell proliferation and survival, while factors regulating fate specification control whether and how the new cells become neurons and integrate into the hippocampal circuitry (see recent review by Song et al., 2016). These control points can be regulated by signals released into the extracellular milieu by both neuronal and non-neuronal cells (Alenina and Klempin, 2015; Egeland et al., 2015), neurotrophic and transcription factors (Faigle and Song, 2013; Goncalves et al., 2016), neuroinflammatory mediators (Belarbi and Rosi, 2013), metabolic and hormonal changes (Cavallucci et al., 2016; Larson, 2018), and direct synaptic input from both glutamatergic and GABAergic neurons (Chancey et al., 2014; Alvarez et al., 2016; Song et al., 2016; Yeh et al., 2018). For additional information, the readers are referred to the excellent reviews cited for each mechanism, and the schematic in Figure 1. Critically, all of these factors can be disrupted by TBI, creating an environment in which immature granule cells and granule cell progenitors no longer receive the proper cues to guide their development.
Figure 1. Generation and integration of adult-born granule cells is a coordinated process that is impacted by TBI. At each stage of adult neurogenesis, the normal process (blue) has potential to be altered by TBI (orange). (1) Quiescent radial neural stem cells (NSCs) in the subgranular zone (SGZ) can be depleted by frequent activation early in life, such as by TBI-induced seizures, leading to deficiencies with age. (2) TBI and its effects, including spreading depolarizations and seizures, cause an increase in proliferation of progenitor cells. (3) Newly-generated neurons migrate from the SGZ to the granule cell layer (GCL), and after TBI abnormal hilar migration is apparent. (4) Parvalbumin interneurons and (5) mossy hilar neurons are susceptible to cell death after TBI. Reduction in their numbers results in decreased GABAergic and glutamatergic (respectively) input to the newly-generated neurons. Newly-generated neurons show additional signs of aberrant neurogenesis such as abnormal connectivity (6), hyperexcitability (7) and inappropriate integration and dendritic maturity (8) which can be caused by changes in the environmental milieu.
You can ask many different experts, and neuroplasticity will be explained in many different ways. The purpose of this website is not to get into technical jargon that overwhelms the stroke patient but rather to educate persons about stroke rehabilitation in simple laymen terms. In stroke recovery, neuroplasticity basically refers to the ability of the brain to rewire or reorganize itself after injury. Various studies over the past decade have shown that the adult brain can “rewire” itself when damaged. Studies have also shown that the adult brain can create new neurons, a phenomenon called neurogenesis. These new neurons require support from neighboring cells, blood supply, and connection with other neurons to survive. Certain requirements must be met during rehabilitation for neurogenesis and plasticity to actually change the brain. Rehabilitation involving neuroplasticity principles requires repetition of task and task specific practice to be effective. What this means for the stroke patient is that going to see your therapist for a one hour visit (or even a 3 hour visit) is not enough to lead to neuroplastic changes in the brain. Patients need to think of physical, occupational, and speech therapy as an adjunct to stroke recovery. It’s up to the patient to make the most of recovery by continuously using the injured parts of the body and mind outside of therapy sessions in everyday life.
A good comparison would be how one learns multiplication. A teacher doesn’t just show a multiplication table a couple of times to her students for the concept to be mastered. Instead, students have to practice over and over to learn and master multiplication. A child doesn’t learn how to walk overnight. It requires much practice. A baseball player doesn’t become elite just by playing a few games of baseball. You must take control of your stroke recovery process and be willing to invest a lot of time and energy if you want to see change especially with moderate to severe stroke. It’s also important to keep using a skill once you have mastered it – use it or lose it as you often hear in rehab.
Please note that plasticity doesn’t mean that one can practice every task over and over and accomplish them all. Stroke is much more complicated than that. Different parts of the brain control different body functions and the brain adapts better to some areas of damage more than others. Scientists have identified certain areas of the brain that yield neurogenesis but have not identified it in all areas of the brain. If you want to learn more about your specific stroke, ask your neurologist specifically what areas of your brain were affected. The neurologist will also be able to tell you what problems you can expect because of that damage (e.g. speech deficits, vision deficits, dizziness, difficulties with balance, etc.) You can further improve your rehabilitation by specifically targeting the weaknesses caused by your stroke.
In my opinion, neuroplasticity doesn’t necessarily change exercise and therapeutic activities done in stroke rehabilitation but rather emphasizes that more repetition and task specific practice is needed. Probably the most commonly used therapy that is based on neuroplasticity is constraint induced therapy. Constraint induced therapy involves limiting the movement of the non-affected or stronger arm and instead using the affected or weaker arm more frequently and intensely. There has been some positive research results with constraint induced therapy, however, it requires much effort and patience from the stroke patient. Some other treatments that may help with brain reorganization include interactive metronome, brain retraining software and websites, mirror box therapy, and robotic and gait devices that assist with movement repetition.
Research is still needed in the area of brain plasticity and stroke rehabilitation. Scientists have demonstrated that brain reorganization can occur, but only limited rehab treatments have been developed that address neuroplasticity. The stroke patient, however, armed with the knowledge that brain rewiring occurs with repetition, can improve their rehabilitation outcomes by application of this concept in their daily lives. Remember, therapy is an adjunct to recovery. You cannot go to therapy sessions and expect positive outcomes without applying what you have learned on a consistent daily basis.
NEURON NURSERY Roughly the same number of new nerve cells (dots) exist in the hippocampus of people in their 20s (three hippocampi shown, top row) as in people in their 70s (bottom). Blue marks the dentate gyrus, where new nerve cells are born. M. BOLDRINI/COLUMBIA UNIV.
Your brain might make new nerve cells well into old age.
The finding contradicts a study published in March, which suggested that neurogenesis in the hippocampus stops in childhood (SN Online: 3/8/18). But the new research fits with a larger pile of evidence showing that adult human brains can, to some extent, make new neurons. While those studies indicate that the process tapers off over time, the new study proposes almost no decline at all.
Understanding how healthy brains change over time is important for researchers untangling the ways that conditions like depression, stress and memory loss affect older brains.
When it comes to studying neurogenesis in humans, “the devil is in the details,” says Jonas Frisén, a neuroscientist at the Karolinska Institute in Stockholm who was not involved in the new research. Small differences in methodology — such as the way brains are preserved or how neurons are counted — can have a big impact on the results, which could explain the conflicting findings. The new paper “is the most rigorous study yet,” he says.
Researchers studied hippocampi from the autopsied brains of 17 men and 11 women ranging in age from 14 to 79. In contrast to past studies that have often relied on donations from patients without a detailed medical history, the researchers knew that none of the donors had a history of psychiatric illness or chronic illness. And none of the brains tested positive for drugs or alcohol, says Maura Boldrini, a psychiatrist at Columbia University. Boldrini and her colleagues also had access to whole hippocampi, rather than just a few slices, allowing the team to make more accurate estimates of the number of neurons, she says.
To look for signs of neurogenesis, the researchers hunted for specific proteins produced by neurons at particular stages of development. Proteins such as GFAP and SOX2, for example, are made in abundance by stem cells that eventually turn into neurons, while newborn neurons make more of proteins such as Ki-67. In all of the brains, the researchers found evidence of newborn neurons in the dentate gyrus, the part of the hippocampus where neurons are born.
Although the number of neural stem cells was a bit lower in people in their 70s compared with people in their 20s, the older brains still had thousands of these cells. The number of young neurons in intermediate to advanced stages of development was the same across people of all ages.
Still, the healthy older brains did show some signs of decline. Researchers found less evidence for the formation of new blood vessels and fewer protein markers that signal neuroplasticity, or the brain’s ability to make new connections between neurons. But it’s too soon to say what these findings mean for brain function, Boldrini says. Studies on autopsied brains can look at structure but not activity.
Not all neuroscientists are convinced by the findings. “We don’t think that what they are identifying as young neurons actually are,” says Arturo Alvarez-Buylla of the University of California, San Francisco, who coauthored the recent paper that found no signs of neurogenesis in adult brains. In his study, some of the cells his team initially flagged as young neurons turned out to be mature cells upon further investigation.
But others say the new findings are sound. “They use very sophisticated methodology,” Frisén says, and control for factors that Alvarez-Buylla’s study didn’t, such as the type of preservative used on the brains.