Sage Journals: Discover world-class research

Abstract

Neural stem cells (NSCs) persist in the subventricular zone lining the ventricles of the adult brain. The resident stem/progenitor cells can be stimulated in vivo by neurotrophic factors, hematopoietic growth factors, magnetic stimulation, and/or physical exercise. In both animals and humans, the differentiation and survival of neurons arising from the subventricular zone may also be regulated by the trophic factors. Since stem/progenitor cells present in the adult brain and the production of new neurons occurs at specific sites, there is a possibility for the treatment of incurable neurological diseases. It might be feasible to induce neurogenesis, which would be particularly efficacious in the treatment of striatal neurodegenerative conditions such as Huntington's disease, as well as cerebrovascular diseases such as ischemic stroke and cerebral palsy, conditions that are widely seen in the clinics. Understanding of the molecular control of endogenous NSC activation and progenitor cell mobilization will likely provide many new opportunities as therapeutic strategies. In this review, we focus on endogenous stem/progenitor cell activation that occurs in response to exogenous factors including neurotrophic factors, hematopoietic growth factors, magnetic stimulation, and an enriched environment. Taken together, these findings suggest the possibility that functional brain repair through induced neurorestoration from endogenous stem cells may soon be a clinical reality.

Keywords

Neural stem cells (NSCs)Neurotrophic factor Hematopoietic growth factor Magnetic stimulation Enriched environment

Introduction

Stem cells have two essential properties: self-renewal and multipotency. Self-renewal is the ability to generate an identical daughter cell, and multipotency is the capacity to generate many cell types (40,130). Because of these abilities, stem cells can continuously generate unaltered cells and also have the ability to produce many different cell types with more restricted properties. Multipotent neural stem cells (NSCs), which are capable of giving rise to both neurons and glia, persist in the subventricular zone (SVZ) lining the ventricles of the adult animal and the human brain. These cells may be mobilized and differentiated into neuronal cells in vivo by stimulating resident stem/progenitor cells with neurotrophic/growth factors via overexpression using viral vectors, chronic infusion using osmotic pumping, paracrine actions by transplanted stem cells, magnetic stimulation, and/or physical exercise.

In the adult mammalian brain, new neurons are continuously generated in the SVZ and dentate gyrus of the hippocampus. If the number of newly generated cells increases, the cells can differentiate toward a neuronal fate (12,114,142,161). The SVZ contains the largest pool of neural stem/progenitor cells, consisting of the following cell types: NSCs (type B cells), transit amplifying progenitor cells (type C cells), and migrating neuronal progenitor cells (type A cells) (5,7,8,10,49). These cells migrate through the rostral migratory stream into the olfactory bulb, where they differentiate into new interneurons (34,80). The proliferation, migration, survival, and differentiation of these cells in vivo and neurons arising from the adult SVZ may be regulated by various growth factors or neurotrophic factors such as brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), hepatocyte growth factor (HGF), stromal cell-derived factor-1 (SDF-1), platelet-derived growth factor (PDGF), erythropoietin (EPO), and granulocyte colony-stimulating factor (G-CSF), among others (5,8–10,16,21, 77,78,85,93,102,127,146,184). Previous studies in animal models have also shown that the SVZ can respond to insults by producing new progenitor cells that can migrate to sites that have been affected by neurodegenerative diseases or brain injury (8,9). Progenitor cell production and migratory proteins are upregulated in the SVZ after a seizure or stroke, leading to an increase in the number of newly generated neurons, whereas there are fewer proliferating cells in the SVZ of Alzheimer's disease (AD) and Parkinson's disease (PD) patients (8,9).

The presence of stem/progenitor cells in the adult brain and the fact that production of new neurons occurs at specific sites suggest the possibility for a treatment of otherwise incurable neurological diseases. The set of circumstances suggests that it may be feasible to induce neurogenesis. This strategy could be particularly efficacious in striatal neurodegenerative conditions such as Huntington's disease (HD), as well as cerebrovascular diseases such as ischemic stroke and cerebral palsy, conditions that are widely seen in the clinics. More broadly, understanding of the molecular control of endogenous NSC activation and progenitor cell mobilization will likely provide many new opportunities for the use of induced neuronal replacement as a therapeutic strategy for neurodegenerative or cerebrovascular diseases (60).

Enhanced neurogenesis has been reported in animal stroke models and even in stroke patients (75,76,134), suggesting a potential avenue for the treatment of ischemic stroke. Previous studies have demonstrated that cerebral ischemia increased neurogenesis both in the hippocampus and SVZ of the adult brain (12,75,178). Neuronal precursors of the SVZ migrate to the ischemic zone of the adjacent striatum and to the ischemic zone of the cerebral cortex where the damaged neurons are differentiated and replaced (12,75,178). However, it is now apparent that endogenous neurogenesis is not a standalone consideration for complete functional recovery from stroke because compensatory neurogenesis induced after brain damage is largely limited (134). Therefore, in this review, we will focus on endogenous stem/progenitor cell activation that occurs in response to exogenous factors including neurotrophic factors, hematopoietic growth factors, magnetic stimulation, and an enriched environment (38,70,74,137).

Neurotrophic Factors

Neurotrophic growth factors have an array of activities in the nervous system that consist of functions in development, plasticity, neurogenesis, disease, and injury (68). Adult neurogenesis may be enhanced by growth factors such as BDNF (16,28,184), EGF (21,93,184), FGF-2 (21,93,107,127,157), VEGF (22,74,179), IGF-1 (62,189), HGF (145,188), SDF-1 (31,100), and PDGF (34,38). Among multiple approaches to exogenous trophic factor delivery, experimental studies have employed injection of viral vectors (16,22) or continuous infusion via an osmotic pump (77,85,93,146,184) (Table 1).

Table 1.

Endogenous Neurorestoration in Response to Neurotrophic Factors in Experimental Studies

Factors	Model	Route of Delivery	Effects	References
BDNF	Normal	Adenovirus in LV	Neurogenesis in the neostriatum and olfactory bulb of adult rat brain	Benraiss et al. (16)
	Normal	In vitro treatment	Autocrine–paracrine regulation of hippocampal neuron survival in primary hippocampal neurons	Lindholm et al. (102)
BDNF/EGF	HD	Osmotic pump in LV	Induction of striatal regeneration and delayed disease progression in a R6/2 transgenic mouse model of HD	Yu et al. (184)
BDNF/Noggin	HD	Adenovirus in LV	Induction of striatal neurogenesis and slowed disease progression in a R6/2 transgenic mouse model of HD	Cho et al. (28)
EGF	Normal	Osmotic pump in LV	Increased proliferation of neural progenitor cells in adult rats	Kuhn et al. (93)
IGF-1	Normal	In vitro treatment	Autocrine–paracrine regulation of hippocampal neuron survival in primary hippocampal neurons	Lindholm et al. (102)
	Stroke	AAV in cortex and caudate nucleus	Neurogenesis and angiogenesis in a mouse model of MCAO	Zhu et al. (189)
FGF-2	Normal	Primary hippocampal neuron treatment	Dose dependence raises cell survival and proliferation in primary hippocampal neurons	Ray et al. (127)
	Normal	Subcutaneous injection	Neuroblast proliferation in hippocampus and the granule layer of the cerebellum in rat pups	Tao et al. (157)
	Normal	Osmotic pump in LV	Increase of neurogenesis in SVZ and migrating neurons from the SVZ to the olfactory bulb in adult rats	Kuhn et al. (93)
	Stroke	Intranasal administration	Neurogenesis in SVZ of a rat model of MCAO	Ma et al. (107)
VEGF	Normal	Osmotic pump in ICV	Neurogenesis in SVZ and SGZ of adult rats	Jin et al. (77)
	Normal	Osmotic pump or AAV in dorsal hippocampus	Neurogenesis and angiogenesis in hippocampus of adult rats	Cao et al. (22)
	Stroke	Intranasal administration	Angiogenesis in ischemic boundary in a rat model of MCAO	Yang et al. (179)
HGF	Stroke	Spongel on the surface of the cerebral cortex	Neurogenesis and angiogenesis in a rat model of MCAO	Shang et al. (145)
SDF-1	TBI	Injection in brain penumbra	Angiogenesis in a rat model of TBI	Li et al. (100)

BDNF, brain-derived neurotrophic factor; EGF, epidermal growth factor; IGF-1, insulin growth factor-1; FGF-2, fibroblast growth factor-2; VEGF, vascular endothelial growth factor; HGF, hepatocyte growth factor; SDF-1, stromal cell-derived factor-1; LV, lateral ventricle; SVZ, subventricular zone; SGZ, subgranular zone; HD, Huntington's disease; MCAO, middle cerebral artery occlusion; TBI, traumatic brain injury; ICV, intracerebroventricular.

Previous animal studies reported the induction of striatal regeneration from the endogenous stem/progenitor cells and functional recovery by the intraventricular administration of BDNF and EGF in hypoxic–ischemic brain injury (72) and HD (184). Infusion of EGF and FGF-2 for 2 weeks into the lateral ventricle of adult rats also increased the proliferation of neural progenitor cells (93). Chronic infusion of FGF-2 into the lateral ventricle of adult rats resulted in an increase in the population of proliferating precursors in the SVZ and a subsequent increase in the number of neurons migrating from the SVZ to the olfactory bulb (93). Likewise, administration of FGF-2 has been shown to promote neurogenesis in both the intact and ischemic brain (62,107). Using a viral delivery system of neurotrophic genes, subependymal overexpression of BDNF induced neuronal recruitment from endogenous neural progenitor cells in the SVZ of the adult mammalian forebrain (16). While BDNF induced neural progenitors to promote neuronal differentiation, the combination of BDNF and noggin potentiated neostriatal neurogenesis, by suppressing progliogenic factor bone morphogenetic protein and astroglial differentiation, expanded neural progenitor pool responsive to BDNF, and slowed disease progression in a transgenic model of HD (28).

The potential to utilize endogenous neurogenesis for the treatment of neurodegenerative diseases has been investigated (63). Neurogenesis often appears in parallel with angiogenesis (3). Indeed, NSCs were found to extend long cytoplasmic processes, with their endfeet contacting nearby striatal vessels (101). Moreover, hippocampal neurogenesis appears to occur in intimate association with angiogenesis, suggesting that VEGF might be involved in both processes (22,77). IGF-1 enhanced endothelial function as well as neurogenesis (62,189). HGF and SDF-1 also participated in angiogenesis and neurogenesis during physiological and pathological processes including brain development and brain injury such as middle cerebral artery occlusion (MCAO) (145,188). Additionally, treatment of stem cells derived from the fetal or adult brain with PDGF induces their differentiation into neuronal cells (78,93). NSCs in the SVZ can also promote angiogenesis by secreting several angiogenic factors such as VEGF, angiopoietin-2, and FGF-2 (104,105,134). Taken together, these findings indicate that neurotrophic factors play an important part in neuron–target interactions in the adult brain. Administration of neurotrophic factors could be a potential therapeutic approach not only to prevent the progression of neurodegenerative diseases, but also to improve behavioral function following induced neurogenesis from endogenous stem/progenitor cells in neurodegenerative diseases or cerebrovascular diseases.

Animal studies seem to indicate a robust response to infusion of neurotrophic factors; however, few mature neurons are actually formed, and appropriate new axonal connections with distant targets are even fewer (63). Several clinical trials have reported that neurotrophic factor treatments exhibit many drawbacks, including side effects, and some beneficial effects in neurodegenerative diseases (159). We have summarized the outcomes of clinical trials on neurotrophic factors, including nerve growth factor (NGF) (48,118,165), ciliary neurotrophic factor (CNTF) (18), glial cell line-derived neurotrophic factor (GDNF) (58,94,116,121), and BDNF (15,117), for common neurodegenerative conditions (68,159) in Table 2. Studies on NGF infusion have shown that intraventricular administration is also associated with significant side effects, such as hypophagia and neuropathic pain, although long-term administration of NGF may offer potentially beneficial effects (48,174). GDNF infusion provided no significant benefits (94,116) or modest improvement in motor function and health-related quality of life score (58,121) to human patients with PD. CNTF can be safely delivered into the brain of HD patients (18). Side effects without significant benefits of treatments were reported with intrathecal infusion of recombinant BDNF in patients with amyotrophic lateral sclerosis (ALS) (15,117). To a great disappointment, previous clinical trials have failed to achieve striking success (159). Nevertheless, the failure to demonstrate clinical efficacy may be due to the models used to predict the actions of a drug in the human system.

Table 2.

Outcomes of Neurotrophic Factor Treatments in Clinical Trials

Factors	Model	Patients and Period	Route of Delivery	Effects	References
NGF	PD	One patient, 17 months	3.3 mg NGF intraputaminal infusion	NGF treatment may be safe in human beings	Olson et al. (118)
	AD	Three patients, 3 months	6.6 mg NGF administered into the LV 3 months in two patients/0.55 mg for three shorter periods in one patient	Two negative side effects occurred with NGF treatment	Eriksdotter Jonhagen et al. (48)
	AD	Eight patients, 3 months	Implanting autologous fibroblasts genetically modified to express hNGF to NBM	No long-term adverse effects of NGF occurred and improvement in the rate of cognitive decline	Tuszynski et al. (165)
CNTF	HD	Six patients, 24 months	Encapsulated genetically modified to express hCNTF. Cells implanted into the right LV	The safety, feasibility, and tolerability of this gene therapy procedure	Bloch et al. (18)
GDNF	PD	50 patients, 8 months/16 subjects, 20 months	25–4,000 μg GDNF implanted ICV	GDNF did not improve Parkinsonism	Nutt et al. (116)
	PD	Five patients, 12 months	10.8–14.4 μg at 2–6 μl/h GDNF intraputamenal infusion	No serious clinical side effects and improvement in UPDRS and the activities of daily living subscore and increase in putamen dopamine storage after 18 months	Gill et al. (58)
	PD	Five patients, 12~18 months	14.4 μg/day at rate of 6 μl/h intraputamenal Infusion	Improvement in UPDRS and health-related quality of life measures	Patel et al. (121)
	PD	34 patients, 6 months	15 μg/day at rate of 6 μl/h intraputamenal infusion	This treatment difference was not significant or similar between groups	Lang et al. (94)
BDNF	ALS	25 patients, 12 weeks	25–1,000 μg/day subcutaneously at the lateral abdominal wall implanted pump	r-metHuBDNF in doses of up to 150 μg/day was well tolerated and appears feasible	Ochs et al. (117)
	ALS	10 patients, 9 months	25 or 150 μg/day BDNF intrathecally administered	Autonomic function tests were not different between patients treated with BDNF and placebo, but norepinephrine levels were higher in the BDNF group	Beck et al. (15)

NGF, nerve growth factor; CNTF, ciliary neurotrophic factor; LV, lateral ventricle; GDNF, glial cell line-derived neurotrophic factor; BDNF, brain-derived neurotrophic factor; PD, Parkinson's disease; UPDR, unified Parkinson's disease rating scale; AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; NBM, nucleus basalis of Meynert; ICV, intracerebroventricular.

Hematopoietic Growth Factors

Hematopoietic growth factors such as EPO and G-CSF are likely to play broad roles not only in the circulatory system but also in the brain because receptors for both are expressed in the brain (12,65,140,183). In neurological diseases, exogenous administration of EPO and/or G-CSF can have effects on experimental studies (Table 3) (36,37,131,167) and clinical trials (Table 4). These beneficial effects have been attributed to multiple neuroprotective mechanisms including antiapoptosis, antioxidant actions, and restoration of blood–brain barrier (BBB) integrity as well as stimulation of neurogenesis and angiogenesis (99,150,171,183). Interestingly, hematopoietic growth factors also influence the proliferation of neural precursor cells. Previous investigators reported on the individual capability of EPO or G-CSF to stimulate proliferation and differentiation of neural stem/progenitor cells in the brain (141,146,172). Furthermore, a combination of G-CSF and EPO could synergistically promote proliferation of the neural progenitor cells residing in the hippocampus and SVZ (103). Exogenous hematopoietic growth factors delivered to the brain can stimulate endogenous neural stem/progenitor cells in the SVZ to promote tissue repair after injury (39,173).

Table 3.

Endogenous Neurorestoration in Response to Hematopoietic Growth Factors in Experimental Studies

Factors	Model	Route of Delivery	Effects	References
EPO	Normal	Osmotic pump deliver of hrEPO (1,000 IU/ml) in LV	EPO appears to act directly on neural stem cells, promoting the production of neuronal progenitors at the expense of multipotent progenitors	Shingo et al. (149)
	Stroke	5,000 U/kg, IP	EPO protects hippocampal neurons against hypoxia-induced neuronal death through activation of extracellular signal-regulated kinases and protein kinase Akt-1/protein kinase B	Siren et al. (150)
	Stroke	5,000 or 10,000 U/kg, IP	EPO significantly increased brain levels of VEGF and BDNF and may be involved in angiogenesis and neurogenesis	Wang et al. (171)
	Stroke	Hydrogel delivery of 1,000 U/ml EPO, IV	EPO increased numbers of both neurons in the peri-infarct region and migratory neuroblasts in SVZ, and decreased apoptosis in both SVZ and the injured cortex	Wang et al. (173)
G-CSF	Normal	Osmotic pumps deliver a total of 1 μg in LV	G-CSF stimulates neurogenesis through reciprocal interaction with VEGF and STAT activation	Jung et al. (79)
	Stoke	15, 50, 60 μg/kg, IV	G-CSF receptor was expressed by adult neural stem cells, and G-CSF induced neuronal differentiation and strong antiapoptotic activity in mature neurons and activates multiple cell survival pathways	Schneider et al. (141)
	Stroke	200 μg/kg, IP	G-CSF treatment might help recovery through induction of bone marrow-derived angiogenesis, thus improving neuronal survival	Toth et al. (162)
EPO + G-CSF	HI brain injury	EPO (5,000 U/kg) + G-CSF (250 μg/kg), SC	Induction of HIF-1α expression by combination therapy with EPO and G-CSF synergistically enhances not only behavioral function but also neurogenesis and angiogenesis, while decreasing the astroglial response in a time-dependent manner	Yu et al. (183)
	Stroke	EPO (5,000 U/kg) + G-CSF (250 μg/kg), G-CSF (250 μg/kg), EPO (10,000 U/kg), SC	G-CSF activates HIF-1α, which then binds to the EPO promoter and enhances EPO expression; expression of the antiapoptotic protein of Bcl-2, augmented neurotrophic factors synthesis and promoted neovascularization	Liu et al. (103)

EPO, erythropoietin; G-CSF, granulocyte colony-stimulating factor; LV, lateral ventricle; SVZ, subventricular zone; IP, intraperitoneal; IV, intravenous; SC, subcutaneous; MCAO, middle cerebral artery occlusion; HI, hypoxic-ischemic.

Table 4.

Outcomes of Hematopoietic Growth Factor Treatments in Clinical Trials

Factors	Model	Patients and Period	Route of Delivery	Effects	References
EPO	Stroke	53 patients, 30 days	3.3 × 10⁴ IU/50 ml/30 min for 3 days, IV	Well tolerated in acute ischemic stroke and associated with an improvement in clinical outcomes at 30 days	Ehrenreich et al. (44)
	Stroke	522 patients, 3 months	40,000 IU each within 6 h of symptom onset, at 24 and 48 h, IV	This is a negative trial that also raises safety concerns, particularly in patients receiving systemic thrombolysis	Ehrenreich et al. (45)
	Stroke	167 patients, 3 months	5,000 IU at 48 h and 72 h, SC	EPO therapy significantly improved circulating EPC level and 90 days MANE	Yip et al. (182)
	Stroke	142 patients, 5 years	5,000 IU at 48 h and 72 h, SC	EPO therapy significantly improved long-term neurological outcomes in patients after acute stroke	Tsai et al. (164)
G-CSF	Stroke	44 patients, 3 months	30–180 μg/kg for 3 days, IV	G-CSF was well tolerated even at high dosages in patients with acute ischemic stroke	Shabitz et al. (138)
	Stroke	328 patients, 3 months	135 μg/kg for 3 days, IV	G-CSF treatment failed to meet the primary and secondary end points of the trial. However, a trend for reduced infarct growth in the G-CSF group was noted	Ringelstein et al. (129)
	Stroke	10 patients, 12 months	15 μg/kg for 5 days, SC	G-CSF as therapy for acute stroke is safe and feasible and leads to improved neurologic outcomes	Shyu et al. (147)
	Stroke	36 patients, 3 months	1 to 10 μg/kg, 1 or 5 daily dose for 5 days, SC	Administration is feasible and appears to be safe and well tolerated. The fate of mobilized cells and their effect on functional outcome remain to be determined	Sprigg et al. (153)
	Stroke	10 patients, 6 months	10 μg/kg for 5 days, SC	This study did not have power to examine efficacy. It provides preliminary evidence of potential safety, feasibility, and tolerability of G-CSF therapy	Prasad et al. (126)
	Stroke	20 patients, 6 months	10 μg/kg for 5 days, SC	G-CSF to acute ischemic stroke therapy is safe; its efficacy remains unproven	Alasheev et al. (4)
	Stroke	41 patients, 38 days	10 μg/kg for 10 days, SC	Safe and reasonably well tolerated, even in elderly chronic stroke patients	Floel et al. (54)
	Stroke	60 patients, 3 months	10 μg/kg for 5 days, SC	G-CSF is safe when administered subacutely	England et al. (46)

SC, subcutaneous; IV, intravenous.

EPO is the major growth regulator of the erythroid cell lineage. Its main biological functions are to regulate proliferation, maturation, and survival of erythroid progenitor cells in bone marrow. These functions result in an oxygen-dependent regulation of red blood cell mass. Additionally, endogenous stem/progenitor cell stimulation with EPO has resulted in proliferation, migration, and maturation as well as promoting regeneration and replacement of cells and tissues lost following stroke (43,171,173). In contrast, infusion of EPO blockers has the opposite effect; there was a decrease in the number of newly generated cells migrating to the olfactory bulb (146). In clinical trials, EPO has demonstrated both safe and beneficial effects in acute stroke patients (44,182). Improvements in outcome scales and reduction in infarct size were shown to be associated with increases in cerebrospinal fluid EPO and S100β (1,44,177). EPO enhances the circulating levels of endothelial progenitor cells, which have been reported to be associated with positive prognostic outcomes in ischemic stroke patients (181,182). However, in the randomized phase II/III German Multicenter EPO Stroke Trial, previous results from preclinical trials were not replicable in over 533 patients (45). The failure of EPO in clinical studies may be due to an inadequate dose, since the receptors responsible for organ protection may require higher concentrations than the receptors responsible for erythropoiesis (122). Meanwhile, recent clinical trials have reported that subcutaneously administered EPO significantly improves long-term neurological outcomes in patients after acute ischemic stroke (164).

G-CSF has been widely used clinically to elicit hematopoietic stem cell mobilization into systemic circulation after life-saving bone marrow transplantation for the prevention and treatment of chemotherapy-induced neutropenia and apheresis (26,81,95,120,162,183). Systemically given G-CSF was able to pass the intact BBB. This property is shared with other hematopoietic factors, such as EPO (19) and granulocyte macrophage colony-stimulating factor (GM-CSF) (109), showing neuroprotective activities in models of focal cerebral ischemia (141). G-CSF has been shown to promote structural and functional regeneration of the central nervous system (CNS) in stroke patients. It can also act as a neurotrophic factor, induce neurogenesis, and counteract apoptosis. These properties suggest a major role for its use in the development of treatments of neurological diseases, such as cerebral ischemia (2,123,141). G-CSF activates intracellular signaling pathways including STAT3 (27) and Akt (42), which are both linked to suppression of apoptosis and proliferation (141). G-CSF-induced STAT activation might operate an autocrine VEGF loop in NSCs and subsequently enhance neurogenesis (79). In clinical trials, G-CSF treatment has demonstrated safety and improvement in neurological outcomes and reduction of infarct size in acute and subacute stroke (4,138,147,153). Recent studies have shown that G-CSF treatment in both subacute and elderly chronic stroke patients is safe and reasonably well tolerated (2,46,54). Of note, G-CSF treatment facilitated CD34⁺ hematopoietic stem cell mobilization and increases in leukocyte counts (51). G-CSF also improved functional results by facilitating the recruitment of CD34⁺ cells to the infarct area, mobilizing them through the BBB, and promoting the generation of neurotrophic factors and VEGF (51). However, other studies reportedly failed to find effects of G-CSF in improving neurological outcomes in patients with acute and subacute stroke (126,129). Despite contrary results, G-CSF might exert its clinical effects by promoting the mobilization of blood CD34⁺ stem cells in stroke patients.

Repetitive Transcranial Magnetic Stimulation

Transcranial magnetic stimulation was introduced in 1985 as a neurological technique for noninvasively inducing motor movement by direct magnetic stimulation of the brain's motor cortex to measure connectivity and excitability (14,33,64,82,133). This procedure depends on the basic principle of mutual induction, whereby magnetic fields can be converted into electrical energy. If the electrical field falls in a conductor, the electrical current will consequently flow into the brain tissue. The nature of repetitive transcranial magnetic stimulation (rTMS) means that the stimulus can be repeated for a few seconds at frequencies up to 50 Hz (55,128,169).

rTMS is a noninvasive therapeutic device that can alter the excitability of the cerebral cortex or neural network. Many studies have reported that rTMS treatment has therapeutic benefits in both experimental studies (Table 5) and clinical trials (Table 6). There is evidence that rTMS causes changes in neuronal circuits as reflected by behavioral changes (55,108,125). Possible mechanisms include the release of neurotransmitters, synaptic efficiency, and alteration of signaling pathways and gene expression (66,73,125). Recent studies have reported that long-term rTMS treatment significantly elevated BDNF in the hippocampus, parietal cortex, and piriform cortex (113). The rTMS also modulated various neurotrophic factors such as BDNF, GDNF, NGF, PDGF, VEGF, cholecystokinin, and neuropeptide tyrosine in ALS (6), depression (57,186), and PD (96). Effects on neurotrophic factors could possibly explain preliminary findings of neuroprotective and neurotrophic effects of rTMS on degenerated dopaminergic neurons of the substantia nigra in 6-OHDA-induced PD rats and mossy fiber sprouting in the hippocampus following chronic rTMS (96).

Table 5.

Endogenous Neurorestoration in Response to Repetitive Transcranial Magnetic Stimulation in Experimental Studies

Frequency and Sessions	Model	Effects	References
0.5 Hz, 15 daily sessions	Normal	Chronic rTMS has a modulatory effect on the glutamate and γ-aminobutyric acid systems. This change in amino acid neurotransmitter may contribute to its beneficial effects	Yue et al. (185)
20 Hz, 20 sessions	Normal	Acute rTMS of frontal brain regions has a differentiated modulatory effect on selected neurotransmitter/neuromodulator systems in distinct brain areas	Keck et al. (83)
5 Hz, 5 daily sessions	Normal	rTMS to cortex facilitates BDNF-TrkB-NMDAR functioning in both the cortex and lymphocytes	Wang et al. (170)
20 Hz, 5 sessions/week for 11 weeks	Normal	BDNF may contribute to the neuroprotective effects of rTMS	Muller et al. (113)
20 Hz, 6 sessions	Normal	Functional modification of neuroanatomic substrates as demonstrated by c-Fos expression may partially differ between rTMS and ECS	Doi et al. (41)
20 Hz, 14 daily sessions	Normal	Chronic rTMS enhances c-Fos in the parietal cortex and hippocampus	Hausmann et al. (66)
25 Hz, 1 session	Normal	rTMS induces different patterns of immediate-early gene c-Fos expression and evokes strong neural responses in the PVT and in other regions involved in the regulation of circadian rhythms	Ji et al. (73)
25 Hz, 4 sessions for 2 weeks	Normal	Chronic rTMS increases hippocampal neurogenesis in rats	Ueyama et al. (166)
15 Hz, 17 daily sessions	Depression	Chronic rTMS significantly increases hippocampus cell proliferation, BDNF protein level, and phosphorylation of ERK1/2	Feng et al. (52)
10 Hz, daily session for 4 weeks	PD	rTMS treatment improved motor functions and survival of DA neurons, suggesting that the neuroprotective effect of rTMS treatment might be induced by upregulation of neurotrophic/growth factors in the PD animal model	Lee et al. (96)

rTMS, repetitive transcranial magnetic stimulation; BDNF, brain-derived neurotrophic factor; ECS, electroconvulsive shock; PVT, paraventricular nucleus of the thalamus; DA, dopamine; PD, Parkinson's disease.

Table 6.

Outcomes of Repetitive Transcranial Magnetic Stimulation in Clinical Trials

Frequency and Region	Model	Patients and Sessions	Effects	References
10 Hz, frontal cortex	AD	Eight patients, five sessions/week for 6 weeks	rTMS may be a promising effective and safe modality for AD	Bentwich et al. (17)
10 Hz, DLPFC	MDD	29 patients, over 10 daily sessions	ECT and rTMS may not exert their clinical effects by altering serum BDNF levels in patients with drug-resistant MDD	Gedge et al. (57)
10 Hz, frontal cortex	NMD	One patient, 13 daily sessions	Increased dopaminergic activity after rTMS treatment, occurrence of psychotic symptoms should be considered a potential side effect of rTMS treatment	Zwanzger et al. (190)
10 Hz, DLPFC	MDD	29 patients, five sessions/week for 6 weeks	rTMS may promote neurogenesis or other effects that favor neuronal plasticity and may also be neuroprotective for patients with TRD	Furtado et al. (56)
20 Hz, left prefrontal cortex	RD	26 patients, 10 daily sessions	rTMS treatment brings about some improvement in refractory depression, especially for symptoms such as agitation, by influencing MHPG and BDNF	Yukimasa et al. (186)
1 Hz, M1	Stroke	24 patients, 10 daily sessions	Motor recovery of the severely affected hand after stroke appears to depend on excitability of the contralesional primary motor cortex	Theiling et al. (158)
5 Hz, M1	PD	12 patients, 15 sessions	5 Hz rTMS over M1 can improve bradykinesia in PD patients beyond the time of magnetic stimulation	Siebner et al. (148)
5 Hz, M1 + treadmill training	PD	20 patients, three sessions/week for 4 weeks	Combination of rTMS and treadmill training enhances the effect of treadmill training on modulation of corticomotor inhibition and improvement of walking performance in patients with PD	Yang et al. (180)
25 Hz, M1	PD	20 patients, six daily sessions	Improved motor performance in PD after repeated session of rTMS may be related to an elevation of serum dopamine concentration	Khedr et al. (86)
1 Hz or 20 Hz, M1	ALS and normal	Four patients and 10 healthy volunteers, eight daily sessions	rTMS might influence the BDNF production by interfering with neuronal activity	Angelucci et al. (6)
10 Hz, DLPFC	Normal	Seven healthy volunteers, one session	Extrastriatal DA modulation following acute rTMS of DLPFC with its effect limited to the specific areas of medial prefrontal cortex	Cho and Strafella (29)
5 Hz, SI & M1	Normal	10 patients, 25 sessions	rTMS can temporarily induce behaviorally relevant reorganization within a complex cortical network underlying human somatosensory experience	Pleger et al. (124)
10 Hz, M1 & OCC	Normal	Six healthy volunteers, series of 10 sessions	rTMS of the cerebral cortex causes dopamine release in the striatal projection of the stimulated area	Strafella et al. (155)
25 Hz, DLPFC	Normal	44 healthy volunteers, nine daily sessions	Serial high-frequency rTMS stimulations over the left DLPFC decrease serum BDNF levels in healthy male volunteers	Schaller et al. (139)

rTMS, repetitive transcranial magnetic stimulation; DLPFC, dorsolateral prefrontal cortex; SI, primary somatosensory cortex; M1, primary motor cortex; OCC, occipital cortex; ECT, electroconvulsive therapy; AD, Alzheimer's disease; NMD, nonpsychotic major depression; RD, refractory depression; MHPG, 3-methoxy-4-hydroxyphenylglycol; BDNF, brain-derived neurotrophic factor; PD, Parkinson's diseases; ALS, amyotrophic lateral sclerosis; MDD, major depressive disorder; TRD, treatment-resistant MDD.

Additionally, previous studies have suggested that long-term rTMS treatment induced in situ differentiation of SVZ-derived precursors into dopamine-producing neurons in a PD rat model with unilateral 6-OHDA-lesioned substantia nigra, and reduced amphetamine-induced rotations in behavioral experiments (11). Long-term rTMS treatment was also related to an increase in cell proliferation in the hippocampus. The treatment modulated the signaling pathway of ERK and increased BDNF protein expression in the hippocampus in mice with depression (52,166). However, the effect of rTMS on neurogenesis has not been well studied in stroke models.

Depending on its frequency and intensity, rTMS can temporarily enhance or inhibit excitability, and it can produce consistent and long-lasting effects on physiology within the cortex (124) and deep brain sites connected to the cortex (112). Previous studies showed that the neurogenic effects of rTMS can vary according to frequency and intensity (106,135). Investigations showed that cultured hippocampal neurons treated at a low frequency (1 Hz) had an increased number of processes and neurite length as well as altered ultrastructural parameters of the synapses, while high-intensity stimulation disrupted synaptic structure and was accompanied by a decreased survival rate and increased rate of apoptosis. However, the mechanisms of rTMS-mediated effects on neurogenesis in vivo still remain to be elucidated.

In clinical studies, rTMS has been used to treat neuropsychiatric diseases (17,53,190) and stroke (30,158). Several clinical trials have also revealed that rTMS offers therapeutic benefits on functional recovery after PD (7,148,176,180). rTMS treatment has been shown to improve motor function and cognition in patients with PD (187). Additionally, increased dopamine levels in serum and subcortical areas have been observed following rTMS in PD patients and experimental animals (23,29,86,155). Nevertheless, the underlying mechanism of rTMS still remains to be elucidated. Recently, several experiments have shown that rTMS has the ability to mediate neuroplasticity by enhancing the expressions of glutamate neurotransmitters and BDNF in rat brains (83,113,185). rTMS not only activated brain regions in terms of immediate early gene expression but also increased the expression of BDNF-TrkB signaling in rats and humans (41,66,73,170). Additionally, rTMS was found to modulate neurotrophic factors such as BDNF, cholecystokinin, and neuropeptide tyrosine, in healthy humans and patients with depression and ALS (6,186). A previous study suggested that rTMS may promote neurogenesis in the medial temporal lobe or have other effects that favor neuronal plasticity and may also be neuroprotective for patients with treatment-resistant major depressive disorders (56), whereas another study reported that serial high-frequency rTMS over the left dorsolateral prefrontal cortex decreased serum BDNF levels in healthy male volunteers (139).

Physical Exercise and Enriched Environment

Rearing animals in an enriched environment is a classic paradigm that has been used extensively in juvenile and adult rodents to study the effects of a complex combination of physical, cognitive, and social stimulation (98,132). An enriched environment can facilitate biochemical and morphological changes in the adult brain and promote functions in animals with brain injuries (98,175). Many studies have shown that environmental stimulation elicits various plastic responses in the adult brain, ranging from biochemical parameters to dendritic arborization, gliogenesis, and neurogenesis (32,71,98). Additionally, an enriched environment induces pronounced enhancement of neuronal elements such as neuronal cell body and nucleus size, dendritic branching, dendritic spine density, and the number of synapses (87,151,152,168).

Physical exercise and an enriched environment have a differential influence on neural stem/progenitor cells in the experimental studies (Table 7). Whereas physical exercise was found to increase the generation of early and late neural progenitors as well as increase gliogenesis, an enriched environment increased the neuronal differentiation of progenitor cells (87,92,154). The neurogenic effect of physical exercise manifests itself in the early stage of neuronal development through increased cell proliferation (92). On the other hand, the effect of an enriched environment on hippocampal cell genesis has been shown to include specific neurogenesis-promoting effects without having any influence on the generation of astrocytes (84,87). An environmental enrichment also has a survival-promoting effect on the progeny of neuronal precursor cells in the hippocampus. These neurons added to an increased granule cell number and hippocampal volume in an animal model (84). According to another study, the number of newborn cells in the dentate gyrus of the hippocampus was not altered 1 day after bromodeoxyuridine (BrdU) injections, whereas the number of surviving progenitors 1 month after BrdU injections was markedly increased in animals housed in an enriched environment. The increased number of progenitor progeny is most likely a result of increased survival of newborn progenitor progeny rather than an increase in the number of mitotic divisions among progenitor cells (115).

Table 7.

Endogenous Neurorestoration in Response to Physical Exercise and Enriched Environment in Experimental Studies

Factors	Model	Effects	References
Physical exercise	Normal	Increase neuronal development through increased cell proliferation	Kronenberg et al. (92)
	Normal	Increase the generation of early and late neural progenitors as well as increase gliogenesis	Steiner et al. (154)
	Stroke	Wheel-running exercise after cortical infarction attenuated the early poststroke activation of the SVZ germinal niche	Komitova et al. (90)
		Modulated the lesion-induced increase in cell proliferation in the SVZ, but did not affect activation of the dentate gyrus of the hippocampus early after cortical infarction
	Stroke	Treadmill exercise suppressed ischemia-induced increases in apoptosis and cell proliferation in the hippocampal dentate gyrus following transient global ischemia in gerbils	Lee et al. (97)
Enriched environment	Normal	Increased the neuronal differentiation of progenitor cells	Kronenberg et al. (92)
			Steiner et al. (154)
	Normal	Increased survival-promoting effect on the progeny of neuronal precursor cells in the hippocampus	Kempermann et al. (84)
		Increased number of surviving newly formed granule cells
		Increased total number of neurons in the dentate gyrus
	Normal	Increased survival of newborn progenitor progeny rather than an increase in the number of mitotic divisions among progenitor cells	Nilsson et al. (115)
	Stroke	Pronounced enhancement of the SVZ in the chronic poststroke phase	Komitova et al. (90)

SVZ, subventricular zone.

While the enriched housing and voluntary running exercise enhanced migration and survival of transplanted stem cells toward the injured region after stroke, postischemic exercise and an enriched environment differentially modulated SVZ cell genesis. An enriched environment increased the number of endogenous progenitor cells in the SVZ, suggesting that functional recovery can be augmented by environmental factors such as rehabilitation (69). On the other hand, wheel-running exercise after cortical infarction was found to attenuate the early poststroke activation of the SVZ germinal niche (87,90). In contrast to postischemic exercise, an enriched environment did not have attenuating effects on the SVZ activation, but increased proliferating NSCs and neuronal precursors (90). Additionally, treadmill exercise suppressed ischemia-induced apoptosis in the hippocampal dentate gyrus following transient global ischemia in gerbils, suggesting the possibility that treadmill exercise aids in recovery from stroke (87,97).

Adult hippocampal neurogenesis is a dynamic process that can be influenced by physiological and pathological factors. Postischemic-enriched housing did not significantly influence the total rate of mitotic cells or newborn neurons in the hippocampus. However, an enriched environment after cortical infarction enhanced hippocampal gliogenesis (87,88), increasing the ipsilateral generation of astrocytes normalizing the astrocyte-to-neuron ratio, which was significantly reduced in rats housed in standard cages (88). The findings of increased astrogliogenesis in the germinal niches in addition to increased generation of NG2⁺ glia and newborn surviving reactive astroglia in the postischemic neocortex suggest that some of the beneficial effects of an enriched environment on the postischemic brain might be mediated through a dynamic modulation of glial populations (89). Other studies reported no effects of physical exercise (20) or an enriched environment (20,87,89) on hippocampal progenitor cell proliferation after transient global ischemia in rats, although possible accelerated neuronal maturation was observed in enriched animals (20,87,89).

Physical exercise or an enriched environment as a rehabilitation therapy could play a role in therapies, either by itself alone or adjuvant to drug treatments or cell transplantation (63,143). As a mechanism for endogenous brain repair, rehabilitation exercise training induced neuronal differentiation in the dentate gyrus of the hippocampus (20,84,87). Particularly, enhanced maturation of newly formed cells was seen only with an enriched environment, raising the possibility that behavioral experience in a complex environment may be used as a rehabilitation strategy following ischemic insult (20). The lack of additional effects of physical exercise or an enriched environment on stroke-induced hippocampal neurogenesis suggests common pathways of regulation by lesion and by environmental interventions. Several studies have shown that, in a brain lesion, VEGF, IGF-1, or FGF-2 mediate the neurogenesis-promoting effects of an enriched environment and physical exercise (50,87,143,144,163). This possible mechanism was validated by inhibiting VEGF expression by RNA interference, which completely blocked the environmental induction of neurogenesis (22). The activation of BDNF and IGF-1 is related to neuroplasticity and can be measured both indirectly via serum in humans and directly from tissue in animals. The activation of these pathways improves trophic communication between neurons, thereby improving neuroplasticity. These molecular pathway activators culminate in neuroplasticity, as well as decrease apoptosis and oxidative stress (24,149).

Recent clinical trials have reported that patients with schizophrenia can benefit from resistance training; the program improved the mechanical efficiency of walking (67,149). Aerobic training also increases hippocampal volume in schizophrenia (119,149). However, no changes in BDNF or IGF-1 were observed in the study groups. In line with these results, recent studies have found no changes in BDNF or IGF-1 in patients with major depression exposed to a 3-month aerobic exercise intervention (91,149). Whereas other studies have also shown that resistance training does not increase serum concentrations of BDNF (59,156), it increases IGF-1 (25). On the other hand, aerobic training has been found to increase serum BDNF (13,61).

Although the biological mechanism of physical exercise is not clear, many clinical studies indeed show that exercise improves physical fitness in stroke patients (Table 8). For this reason, fitness training has been proposed as a beneficial approach for stroke patients. Some types of fitness trainings, particularly those involving walking, can improve exercise ability, walking, and balance after stroke (136). In stroke patients who have difficulties with walking, electromechanical-assisted gait training, using specialized machines to assist in walking, may improve recovery of independent walking in people after stroke (110). Another study investigating the effectiveness and safety of circuit class therapy on mobility in patients with stroke also reported the benefits of circuit classes in improving mobility (47). Additionally, treadmill training reportedly improved gait parameters in patients with PD (111). Thus, physiotherapy can be applied to maximize functional ability and minimize secondary complications through movement rehabilitation. While clinical trials have shown that physiotherapy has short-term benefits in PD, it is still unclear which approach is most effective (160). Meanwhile, the effects of exercise in ALS patients are not well understood. When weak muscles are worked beyond their maximal limits, they can be damaged (35). In addition, there is not enough information to draw reliable conclusions concerning the impact of fitness training on quality of life in stroke patients (136). Therefore, further research should address what frequency, duration, or period of exercise might be most effective at any stage or severity, if some tasks are better to practice than others (110), and underlying mechanisms such as induction of neurorestoration from endogenous neural stem cells.

Table 8.

Outcomes of Physical Exercise and Rehabilitation Therapy in Clinical Trials

Method	Model	Patients and Trial Number	Effects	References
Physical fitness training	Stroke	45 trials, involving 2,188 participants	Cardiorespiratory training reduces disability after stroke, and this may be mediated by improved mobility and balance. There is sufficient evidence to incorporate cardiorespiratory and mixed training, involving walking, within poststroke rehabilitation programs to improve the speed and tolerance of walking; improvement in balance may also occur	Saunders et al. (136)
Automated electromechanical and robotic-assisted gait training	Stroke	23 trials, involving 999 participants	People who receive electromechanical-assisted gait training in combination with physiotherapy after stroke are more likely to achieve independent walking than people who receive gait training without these devices. Specifically, people in the first 3 months after stroke and those who are not able to walk seem to benefit most from this type of intervention.	Mehrholz et al. (110)
Circuit class therapy	Stroke	Six trials, involving 292 participants	CCT is safe and effective in improving mobility for people after moderate stroke and may reduce inpatient length of stay	English and Hillier (47)
Treadmill training	PD	18 trials, involving 633 participants	Treadmill training did improve gait speed, and stride length, but walking distance and cadence did not improve. It seems that such devices could be beneficial and could be applied in routine rehabilitation	Mehrholz et al. (111)
Various physiotherapy interventions (general physiotherapy, exercise, treadmill training, cueing, dance, or martial arts)	PD	43 trials, involving 1,673 participants	A wide range of different physiotherapy techniques have been tested to treat PD. Considering the small number of participants, the wide variety of physiotherapy interventions and the outcomes assessed, there is insufficient evidence to support the use of one approach of physiotherapy intervention over another for the treatment of PD	Tomlinson et al. (160)
Exercise program	ALS	Two trials, involving 43 participants	Only two randomized studies of exercise in people with ALS. The trials compared an exercise program with usual care (stretching exercises). Combining the results from the two trials, exercise produced a greater average improvement in function (measured using an ALS-specific measurement scale) than usual care	Dal Bello-Haas and Florence (35)

ALS, amyotrophic lateral sclerosis; PD, Parkinson's disease; CCT, circuit class therapy.

Conclusion

That stem/progenitor cells are present in the adult brain and that the production of new neurons occurs in specific sites of the SVZ and hippocampus suggests the possibility of a treatment for neurological diseases. We reviewed neurorestoration from endogenous stem cells by exogenous factors including neurotrophic factors, hematopoietic growth factors, magnetic stimulation, and an enriched environment in both experimental studies and clinical trials. Taken together, these findings suggest the possibility that functional brain repair through induced neurorestoration from endogenous neural stem cells may soon be a clinical reality.

Footnotes

Acknowledgments

This study was supported by grants from the National Research Foundation (NRF-2014R1A2 A1A11052042, NRF-2015M3A9B4067068), the Ministry of Science and Technology, Republic of Korea. The authors declare no conflicts of interest.

References

Adams

H. P.

Jr. ; Davis

P. H.

; Leira

E. C.

; Chang

K. C.

; Bendixen

B. H.

; Clarke

W. R.

; Woolson

R. F.

; Hansen

M. D.

Baseline NIH Stroke Scale score strongly predicts outcome after stroke: A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology 53: 126–131; 1999.

Adusumilli

; Kattepogu

R. R.

; Krothapalli

S. R.

The clinical applications of Hematopoietic growth factor—GCSF. Asian J. Biomed. Pharmaceut. Sci. 2: 1–10; 2012.

Al-Jarrah

; Jamous

; Al Zailaey

; Bweir

S. O.

Endurance exercise training promotes angiogenesis in the brain of chronic/progressive mouse model of Parkinson's disease. NeuroRehabilitation 26: 369–373; 2010.

Alasheev

A. M.

; Belkin

A. A.

; Leiderman

I. N.

; Ivanov

R. A.

; Isakova

T. M.

Granulocyte-colony-stimulating factor for acute ischemic stroke: A randomized controlled trial (STEMTHER). Transl. Stroke Res. 2: 358–365; 2011.

Alvarez-Buylla

; Lim

D. A.

For the long run: Maintaining germinal niches in the adult brain. Neuron 41: 683–686; 2004.

Angelucci

; Oliviero

; Pilato

; Saturno

; Dileone

; Versace

; Musumeci

; Batocchi

A. P.

; Tonali

P. A.

; Di Lazzaro

Transcranial magnetic stimulation and BDNF plasma levels in amyotrophic lateral sclerosis. Neuroreport 15: 717–720; 2004.

Arias-Carrion

Basic mechanisms of rTMS: Implications in Parkinson's disease. Int. Arch. Med. 1: 2; 2008.

Arias-Carrion

; Drucker-Colin

[Neurogenesis as a therapeutic strategy to regenerate central nervous system]. Rev. Neurol. 45: 739–745; 2007.

Arias-Carrion

; Freundlieb

; Oertel

W. H.

; Hoglinger

G. U.

Adult neurogenesis and Parkinson's disease. CNS Neurol. Disord. Drug Targets 6: 326–335; 2007.

10.

Arias-Carrion

; Olivares-Bunuelos

; Drucker-Colin

[Neurogenesis in the adult brain]. Rev. Neurol. 44: 541–550; 2007.

11.

Arias-Carrion

; Verdugo-Diaz

; Feria-Velasco

; Millan-Aldaco

; Gutierrez

A. A.

; Hernandez-Cruz

; Drucker-Colin

Neurogenesis in the subventricular zone following transcranial magnetic field stimulation and nigrostriatal lesions. J. Neurosci. Res. 78: 16–28; 2004.

12.

Arvidsson

; Collin

; Kirik

; Kokaia

; Lindvall

Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat. Med. 8: 963–970; 2002.

13.

Babaei

; Azali Alamdari

; Soltani Tehrani

; Damirchi

Effect of six weeks of endurance exercise and following detraining on serum brain derived neurotrophic factor and memory performance in middle aged males with metabolic syndrome. J. Sports Med. Phys. Fitness 53: 437–443; 2013.

14.

Barker

A. T.

; Jalinous

; Freeston

I. L.

Non-invasive magnetic stimulation of human motor cortex. Lancet 1: 1106–1107; 1985.

15.

Beck

; Flachenecker

; Magnus

; Giess

; Reiners

; Toyka

K. V.

; Naumann

Autonomic dysfunction in ALS: A preliminary study on the effects of intrathecal BDNF. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 6: 100–103; 2005.

16.

Benraiss

; Chmielnicki

; Lerner

; Roh

; Goldman

S. A.

Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain. J. Neurosci. 21: 6718–6731; 2001.

17.

Bentwich

; Dobronevsky

; Aichenbaum

; Shorer

; Peretz

; Khaigrekht

; Marton

R. G.

; Rabey

J. M.

Beneficial effect of repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer's disease: A proof of concept study. J. Neural Transm. 118: 463–471; 2011.

18.

Bloch

; Bachoud-Levi

A. C.

; Deglon

; Lefaucheur

J. P.

; Winkel

; Palfi

; Nguyen

J. P.

; Bourdet

; Gaura

; Remy

; Brugieres

; Boisse

M. F.

; Baudic

; Cesaro

; Hantraye

; Aebischer

; Peschanski

Neuroprotective gene therapy for Huntington's disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: Results of a phase I study. Hum. Gene Ther. 15: 968–975; 2004.

19.

Brines

M. L.

; Ghezzi

; Keenan

; Agnello

; de Lanerolle

N. C.

; Cerami

; Itri

L. M.

; Cerami

Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc. Natl. Acad. Sci. USA 97: 10526–10531; 2000.

20.

Briones

T. L.

; Suh

; Hattar

; Wadowska

Dentate gyrus neurogenesis after cerebral ischemia and behavioral training. Biol. Res. Nurs. 6: 167–179; 2005.

21.

Cameron

H. A.

; Hazel

T. G.

; McKay

R. D.

Regulation of neurogenesis by growth factors and neurotransmitters. J. Neurobiol. 36: 287–306; 1998.

22.

Cao

; Jiao

; Zuzga

D. S.

; Liu

; Fong

D. M.

; Young

; During

M. J.

VEGF links hippocampal activity with neurogenesis, learning and memory. Nat. Genet. 36: 827–835; 2004.

23.

Carboni

; Spielewoy

; Vacca

; Nosten-Bertrand

; Giros

; Di Chiara

Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene. J. Neurosci. 21(Rc141): 141–144; 2001.

24.

Cassilhas

R. C.

; Lee

K. S.

; Fernandes

; Oliveira

M. G.

; Tufik

; Meeusen

; de Mello

M. T.

Spatial memory is improved by aerobic and resistance exercise through divergent molecular mechanisms. Neuroscience 202: 309–317; 2012.

25.

Cassilhas

R. C.

; Viana

V. A.

; Grassmann

; Santos

R. T.

; Santos

R. F.

; Tufik

; Mello

M. T.

The impact of resistance exercise on the cognitive function of the elderly. Med. Sci. Sports Exerc. 39: 1401–1407; 2007.

26.

Cavallaro

A. M.

; Lilleby

; Majolino

; Storb

; Appelbaum

F. R.

; Rowley

S. D.

; Bensinger

W. I.

Three to six year follow-up of normal donors who received recombinant human granulocyte colony-stimulating factor. Bone Marrow Transplant. 25: 85–89; 2000.

27.

Chakraborty

; White

S. M.

; Schaefer

T. S.

; Ball

E. D.

; Dyer

K. F.

; Tweardy

D. J.

Granulocyte colony-stimulating factor activation of Stat3 alpha and Stat3 beta in immature normal and leukemic human myeloid cells. Blood 88: 2442–2449; 1996.

28.

Cho

S. R.

; Benraiss

; Chmielnicki

; Samdani

; Economides

; Goldman

S. A.

Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease. J. Clin. Invest. 117: 2889–2902; 2007.

29.

Cho

S. S.

; Strafella

A. P.

rTMS of the left dorsolateral prefrontal cortex modulates dopamine release in the ipsilateral anterior cingulate cortex and orbitofrontal cortex. PLoS One 4: e6725; 2009.

30.

Corti

; Patten

; Triggs

Repetitive transcranial magnetic stimulation of motor cortex after stroke: A focused review. Am. J. Phys. Med. Rehabil. 91: 254–270; 2012.

31.

Cui

; Qu

; Xiao

; Zhao

; Jolkkonen

; Zhao

Stromal cell-derived factor-1 and its receptor CXCR4 in adult neurogenesis after cerebral ischemia. Restor. Neurol. Neurosci. 31: 239–251; 2013.

32.

Cummins

R. A.

; Walsh

R. N.

; Budtz-Olsen

O. E.

; Konstantinos

; Horsfall

C. R.

Environmentally-induced changes in the brains of elderly rats. Nature 243: 516–518; 1973.

33.

Curt

; Keck

M. E.

; Dietz

Functional outcome following spinal cord injury: Significance of motor-evoked potentials and ASIA scores. Arch. Phys. Med. Rehabil. 79: 81–86; 1998.

34.

Curtis

M. A.

; Kam

; Nannmark

; Anderson

M. F.

; Axell

M. Z.

; Wikkelso

; Holtas

; van Roon-Mom

W. M.

; Bjork-Eriksson

; Nordborg

; Frisen

; Dragunow

; Faull

R. L.

; Eriksson

P. S.

Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science 315: 1243–1249; 2007.

35.

Dal Bello-Haas

; Florence

J. M.

Therapeutic exercise for people with amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database Syst. Rev. 5: Cd005229; 2013.

36.

de Haan

; Engel

; Dontje

; Nijhof

; Loeffler

Mutual inhibition of murine erythropoiesis and granulopoiesis during combined erythropoietin, granulocyte colony-stimulating factor, and stem cell factor administration: In vivo interactions and dose-response surfaces. Blood 84: 4157–4163; 1994.

37.

Digicaylioglu

Erythropoietin in stroke: Quo vadis. Expert Opin. Biol. Ther 10: 937–949; 2010.

38.

Dirnagl

; Simon

R. P.

; Hallenbeck

J. M.

Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 26: 248–254; 2003.

39.

Doetsch

; Caille

; Lim

D. A.

; Garcia-Verdugo

J. M.

; Alvarez-Buylla

Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97: 703–716; 1999.

40.

Doetsch

; Hen

Young and excitable: The function of new neurons in the adult mammalian brain. Curr. Opin. Neurobiol. 15: 121–128; 2005.

41.

Doi

; Sato

; Fukuzako

; Takigawa

c-Fos expression in rat brain after repetitive transcranial magnetic stimulation. Neuroreport 12: 1307–1310; 2001.

42.

Dong

; Larner

A. C.

Activation of Akt kinase by granulocyte colony-stimulating factor (G-CSF): Evidence for the role of a tyrosine kinase activity distinct from the Janus kinases. Blood 95: 1656–1662; 2000.

43.

Ehrenreich

; Aust

; Krampe

; Jahn

; Jacob

; Herrmann

; Siren

A. L.

Erythropoietin: Novel approaches to neuroprotection in human brain disease. Metab. Brain Dis. 19: 195–206; 2004.

44.

Ehrenreich

; Hasselblatt

; Dembowski

; Cepek

; Lewczuk

; Stiefel

; Rustenbeck

H. H.

; Breiter

; Jacob

; Knerlich

; Bohn

; Poser

; Ruther

; Kochen

; Gefeller

; Gleiter

; Wessel

T. C.

; De Ryck

; Itri

; Prange

; Cerami

; Brines

; Siren

A. L.

Erythropoietin therapy for acute stroke is both safe and beneficial. Mol. Med. 8: 495–505; 2002.

45.

Ehrenreich

; Weissenborn

; Prange

; Schneider

; Weimar

; Wartenberg

; Schellinger

P. D.

; Bohn

; Becker

; Wegrzyn

; Jahnig

; Herrmann

; Knauth

; Bahr

; Heide

; Wagner

; Schwab

; Reichmann

; Schwendemann

; Dengler

; Kastrup

; Bartels

Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke 40: e647–656; 2009.

46.

England

T. J.

; Abaei

; Auer

D. P.

; Lowe

; Jones

D. R.

; Sare

; Walker

; Bath

P. M.

Granulocyte-colony stimulating factor for mobilizing bone marrow stem cells in subacute stroke: The stem cell trial of recovery enhancement after stroke 2 randomized controlled trial. Stroke 43: 405–411; 2012.

47.

English

; Hillier

S. L.

Circuit class therapy for improving mobility after stroke. Cochrane Database Syst. Rev. 7: Cd007513; 2010.

48.

Eriksdotter Jonhagen

; Nordberg

; Amberla

; Backman

; Ebendal

; Meyerson

; Olson

; Seiger; Shigeta

; Theodorsson

; Viitanen

; Winblad

; Wahlund

L. O.

Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 9: 246–257; 1998.

49.

Eriksson

P. S.

; Perfilieva

; Bjork-Eriksson

; Alborn

A. M.

; Nordborg

; Peterson

D. A.

; Gage

F. H.

Neurogenesis in the adult human hippocampus. Nat. Med. 4: 1313–1317; 1998.

50.

Fabel

; Fabel

; Tam

; Kaufer

; Baiker

; Simmons

; Kuo

C. J.

; Palmer

T. D.

VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur. J. Neurosci. 18: 2803–2812; 2003.

51.

Fan

Z. Z.

; Cai

H. B.

; Ge

Z. M.

; Wang

L. Q.

; Zhang

X. D.

; Li

; Zhai

X. B.

The efficacy and safety of granulocyte colony-stimulating factor for patients with stroke. J. Stroke Cerebrovasc. Dis. 24: 1701–1708; 2015.

52.

Feng

S. F.

; Shi

T. Y.

; Fan

; Wang

W. N.

; Chen

Y. C.

; Tan

Q. R.

Long-lasting effects of chronic rTMS to treat chronic rodent model of depression. Behav. Brain Res. 232: 245–251; 2012.

53.

Fitzgerald

P. B.

; Daskalakis

Z. J.

The effects of repetitive transcranial magnetic stimulation in the treatment of depression. Expert Rev. Med. Devices 8: 85–95; 2011.

54.

Floel

; Warnecke

; Duning

; Lating

; Uhlenbrock

; Schneider

; Vogt

; Laage

; Koch

; Knecht

; Schabitz

W. R.

Granulocyte-colony stimulating factor (G-CSF) in stroke patients with concomitant vascular disease—A randomized controlled trial. PLoS One 6: e19767; 2011.

55.

Fregni

; Pascual-Leone

Technology insight: Noninvasive brain stimulation in neurology-perspectives on the therapeutic potential of rTMS and tDCS. Nat. Clin. Pract. Neurol. 3: 383–393; 2007.

56.

Furtado

C. P.

; Hoy

K. E.

; Maller

J. J.

; Savage

; Daskalakis

Z. J.

; Fitzgerald

P. B.

An investigation of medial temporal lobe changes and cognition following antidepressant response: A prospective rTMS study. Brain Stimul. 6: 346–354; 2013.

57.

Gedge

; Beaudoin

; Lazowski

; du Toit

; Jokic

; Milev

Effects of electroconvulsive therapy and repetitive transcranial magnetic stimulation on serum brain-derived neurotrophic factor levels in patients with depression. Front. Psychiatry 3: 12; 2012.

58.

Gill

S. S.

; Patel

N. K.

; Hotton

G. R.

; O'Sullivan

; McCarter

; Bunnage

; Brooks

D. J.

; Svendsen

C. N.

; Heywood

Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat. Med. 9: 589–595; 2003.

59.

Goekint

; De Pauw

; Roelands

; Njemini

; Bautmans

; Mets

; Meeusen

Strength training does not influence serum brain-derived neurotrophic factor. Eur. J. Appl. Physiol. 110: 285–293; 2010.

60.

Goldman

S. A.

Disease targets and strategies for the therapeutic modulation of endogenous neural stem and progenitor cells. Clin. Pharmacol. Ther. 82: 453–460; 2007.

61.

Griffin

E. W.

; Mullally

; Foley

; Warmington

S. A.

; O'Mara

S. M.

; Kelly

A. M.

Aerobic exercise improves hippocampal function and increases BDNF in the serum of young adult males. Physiol. Behav. 104: 934–941; 2011.

62.

Gutierrez-Fernandez

; Fuentes

; Rodriguez-Frutos

; Ramos-Cejudo

; Vallejo-Cremades

M. T.

; Diez-Tejedor

Trophic factors and cell therapy to stimulate brain repair after ischaemic stroke. J. Cell. Mol. Med. 16: 2280–2290; 2012.

63.

Hagg

From neurotransmitters to neurotrophic factors to neurogenesis. Neuroscientist 15: 20–27; 2009.

64.

Hallett

Transcranial magnetic stimulation and the human brain. Nature 406: 147–150; 2000.

65.

Hasselblatt

; Jeibmann

; Riesmeier

; Maintz

; Schabitz

W. R.

Granulocyte-colony stimulating factor (G-CSF) and G-CSF receptor expression in human ischemic stroke. Acta Neuropathol. 113: 45–51; 2007.

66.

Hausmann

; Weis

; Marksteiner

; Hinterhuber

; Humpel

Chronic repetitive transcranial magnetic stimulation enhances c-fos in the parietal cortex and hippocampus. Brain Res. Mol. Brain Res. 76: 355–362; 2000.

67.

Heggelund

; Morken

; Helgerud

; Nilsberg

G. E.

; Hoff

Therapeutic effects of maximal strength training on walking efficiency in patients with schizophrenia—A pilot study. BMC Res. Notes 5: 344; 2012.

68.

Henriques

; Pitzer

; Schneider

Neurotrophic growth factors for the treatment of amyotrophic lateral sclerosis: Where do we stand? Front. Neurosci. 4: 32; 2010.

69.

Hicks

A. U.

; Hewlett

; Windle

; Chernenko

; Ploughman

; Jolkkonen

; Weiss

; Corbett

Enriched environment enhances transplanted subventricular zone stem cell migration and functional recovery after stroke. Neuroscience 146: 31–40; 2007.

70.

Hill

J. K.

; Gunion-Rinker

; Kulhanek

; Lessov

; Kim

; Clark

W. M.

; Dixon

M. P.

; Nishi

; Stenzel-Poore

M. P.

; Eckenstein

F. P.

Temporal modulation of cytokine expression following focal cerebral ischemia in mice. Brain Res. 820: 45–54; 1999.

71.

Holloway

R. L.

Jr. Dendritic branching: Some preliminary results of training and complexity in rat visual cortex. Brain Res. 2: 393–396; 1966.

72.

S. H.

; Yu

J. H.

; Park

E. S.

; Lee

J. E.

; Kim

H. O.

; Park

K. I.

; Kim

G. W.

; Park

C. I.

; Cho

S. R.

Induction of striatal neurogenesis enhances functional recovery in an adult animal model of neonatal hypoxic-ischemic brain injury. Neuroscience 169: 259–268; 2010.

73.

R. R.

; Schlaepfer

T. E.

; Aizenman

C. D.

; Epstein

C. M.

; Qiu

; Huang

J. C.

; Rupp

Repetitive transcranial magnetic stimulation activates specific regions in rat brain. Proc. Natl. Acad. Sci. USA 95: 15635–15640; 1998.

74.

Jin

; Mao

X. O.

; Sun

; Xie

; Greenberg

D. A.

Stem cell factor stimulates neurogenesis in vitro and in vivo. J. Clin. Invest. 110: 311–319; 2002.

75.

Jin

; Minami

; Lan

J. Q.

; Mao

X. O.

; Batteur

; Simon

R. P.

; Greenberg

D. A.

Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc. Natl. Acad. Sci. USA 98: 4710–4715; 2001.

76.

Jin

; Wang

; Xie

; Mao

X. O.

; Zhu

; Wang

; Shen

; Mao

; Banwait

; Greenberg

D. A.

Evidence for stroke-induced neurogenesis in the human brain. Proc. Natl. Acad. Sci. USA 103: 13198–13202; 2006.

77.

Jin

; Zhu

; Sun

; Mao

X. O.

; Xie

; Greenberg

D. A.

Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc. Natl. Acad. Sci. USA 99: 11946–11950; 2002.

78.

Johe

K. K.

; Hazel

T. G.

; Muller

; Dugich-Djordjevic

M. M.

; McKay

R. D.

Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev. 10: 3129–3140; 1996.

79.

Jung

K. H.

; Chu

; Lee

S. T.

; Kim

S. J.

; Sinn

D. I.

; Kim

S. U.

; Kim

; Roh

J. K.

Granulocyte colony-stimulating factor stimulates neurogenesis via vascular endothelial growth factor with STAT activation. Brain Res. 1073–1074: 190–201; 2006.

80.

Kam

; Curtis

M. A.

; McGlashan

S. R.

; Connor

; Nannmark

; Faull

R. L.

The cellular composition and morphological organization of the rostral migratory stream in the adult human brain. J. Chem. Neuroanat. 37: 196–205; 2009.

81.

Katayama

; Battista

; Kao

W. M.

; Hidalgo

; Peired

A. J.

; Thomas

S. A.

; Frenette

P. S.

Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124: 407–421; 2006.

82.

Keck

M. E.

; Pijnappels

; Schubert

; Colombo

; Curt

; Dietz

Stumbling reactions in man: Influence of corticospinal input. Electroencephalogr. Clin. Neurophysiol. 109: 215–223; 1998.

83.

Keck

M. E.

; Sillaber

; Ebner

; Welt

; Toschi

; Kaehler

S. T.

; Singewald

; Philippu

; Elbel

G. K.

; Wotjak

C. T.

; Holsboer

; Landgraf

; Engelmann

Acute transcranial magnetic stimulation of frontal brain regions selectively modulates the release of vasopressin, biogenic amines and amino acids in the rat brain. Eur. J. Neurosci. 12: 3713–3720; 2000.

84.

Kempermann

; Kuhn

H. G.

; Gage

F. H.

More hippocampal neurons in adult mice living in an enriched environment. Nature 386: 493–495; 1997.

85.

Kernie

S. G.

; Liebl

D. J.

; Parada

L. F.

BDNF regulates eating behavior and locomotor activity in mice. EMBO J. 19: 1290–1300; 2000.

86.

Khedr

E. M.

; Rothwell

J. C.

; Shawky

O. A.

; Ahmed

M. A.

; Foly

; Hamdy

Dopamine levels after repetitive transcranial magnetic stimulation of motor cortex in patients with Parkinson's disease: Preliminary results. Mov. Disord. 22: 1046–1050; 2007.

87.

Komitova

; Johansson

B. B.

; Eriksson

P. S.

On neural plasticity, new neurons and the postischemic milieu: An integrated view on experimental rehabilitation. Exp. Neurol. 199: 42–55; 2006.

88.

Komitova

; Perfilieva

; Mattsson

; Eriksson

P. S.

; Johansson

B. B.

Effects of cortical ischemia and postischemic environmental enrichment on hippocampal cell genesis and differentiation in the adult rat. J. Cereb. Blood Flow Metab. 22: 852–860; 2002.

89.

Komitova

; Perfilieva

; Mattsson

; Eriksson

P. S.

; Johansson

B. B.

Enriched environment after focal cortical ischemia enhances the generation of astroglia and NG2 positive polydendrocytes in adult rat neocortex. Exp. Neurol. 199: 113–121; 2006.

90.

Komitova

; Zhao

L. R.

; Gido

; Johansson

B. B.

; Eriksson

Postischemic exercise attenuates whereas enriched environment has certain enhancing effects on lesion-induced subventricular zone activation in the adult rat. Eur. J. Neurosci. 21: 2397–2405; 2005.

91.

Krogh

; Rostrup

; Thomsen

; Elfving

; Videbech

; Nordentoft

The effect of exercise on hippocampal volume and neurotrophines in patients with major depression—A randomized clinical trial. J. Affect. Disord. 165: 24–30; 2014.

92.

Kronenberg

; Reuter

; Steiner

; Brandt

M. D.

; Jessberger

; Yamaguchi

; Kempermann

Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli. J. Comp. Neurol. 467: 455–463; 2003.

93.

Kuhn

H. G.

; Winkler

; Kempermann

; Thal

L. J.

; Gage

F. H.

Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J. Neurosci. 17: 5820–5829; 1997.

94.

Lang

A. E.

; Gill

; Patel

N. K.

; Lozano

; Nutt

J. G.

; Penn

; Brooks

D. J.

; Hotton

; Moro

; Heywood

; Brodsky

M. A.

; Burchiel

; Kelly

; Dalvi

; Scott

; Stacy

; Turner

; Wooten

V. G.

; Elias

W. J.

; Laws

E. R.

; Dhawan

; Stoessl

A. J.

; Matcham

; Coffey

R. J.

; Traub

Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann. Neurol. 59: 459–466; 2006.

95.

Lapidot

; Petit

Current understanding of stem cell mobilization: The roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. Exp. Hematol. 30: 973–981; 2002.

96.

Lee

J. Y.

; Kim

S. H.

; Ko

A. R.

; Lee

J. S.

; Yu

J. H.

; Seo

J. H.

; Cho

B. P.

; Cho

S. R.

Therapeutic effects of repetitive transcranial magnetic stimulation in an animal model of Parkinson's disease. Brain Res. 1537: 290–302; 2013.

97.

Lee

M. H.

; Kim

S. S.

; Lee

T. H.

; Lim

B. V.

; Chang

H. K.

; Jang

M. H.

; Shin

M. C.

; Shin

M. S.

; Kim

C. J.

Treadmill exercise suppresses ischemia-induced increment in apoptosis and cell proliferation in hippocampal dentate gyrus of gerbils. Life Sci. 73: 2455–2465; 2003.

98.

Lee

M. Y.

; Yu

J. H.

; Kim

J. Y.

; Seo

J. H.

; Park

E. S.

; Kim

C. H.

; Kim

; Cho

S. R.

Alteration of synaptic activity-regulating genes underlying functional improvement by long-term exposure to an enriched environment in the adult brain. Neurorehabil. Neural Repair 27: 561–574; 2013.

99.

Leist

; Ghezzi

; Grasso

; Bianchi

; Villa

; Fratelli

; Savino

; Bianchi

; Nielsen

; Gerwien

; Kallunki

; Larsen

A. K.

; Helboe

; Christensen

; Pedersen

L. O.

; Nielsen

; Torup

; Sager

; Sfacteria

; Erbayraktar

; Gokmen

; Yilmaz

; Cerami-Hand

; Xie

Q. W.

; Coleman

; Cerami

; Brines

Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305: 239–242; 2004.

100.

; Wei

; Zhou

; Wang

; Zhao

; Zhang

SDF-1alpha induces angiogenesis after traumatic brain injury. Brain Res. 1444: 76–86; 2012.

101.

Licht

; Keshet

The vascular niche in adult neurogenesis. Mech. Dev. 138: 56–62; 2015.

102.

Lindholm

; Carroll

; Tzimagiogis

; Thoenen

Autocrine-paracrine regulation of hippocampal neuron survival by IGF-1 and the neurotrophins BDNF, NT-3 and NT-4. Eur. J. Neurosci. 8: 1452–1460; 1996.

103.

Liu

S. P.

; Lee

S. D.

; Lee

H. T.

; Liu

D. D.

; Wang

H. J.

; Liu

R. S.

; Lin

S. Z.

; Su

C. Y.

; Li

; Shyu

W. C.

Granulocyte colony-stimulating factor activating HIF-1alpha acts synergistically with erythropoietin to promote tissue plasticity. PLoS One 5: e10093; 2010.

104.

Liu

X. S.

; Chopp

; Zhang

R. L.

; Hozeska-Solgot

; Gregg

S. C.

; Buller

; Lu

; Zhang

Z. G.

Angiopoietin 2 mediates the differentiation and migration of neural progenitor cells in the subventricular zone after stroke. J. Biol. Chem. 284: 22680–22689; 2009.

105.

Liu

X. S.

; Zhang

Z. G.

; Zhang

R. L.

; Gregg

; Morris

D. C.

; Wang

; Chopp

Stroke induces gene profile changes associated with neurogenesis and angiogenesis in adult subventricular zone progenitor cells. J. Cereb. Blood Flow Metab. 27: 564–574; 2007.

106.

; Zhang

; Su

; Kang

; Geng

; Wang

; Luan

; Wang

; Cui

Magnetic stimulation modulates structural synaptic plasticity and regulates BDNF-TrkB signal pathway in cultured hippocampal neurons. Neurochem. Int. 62: 84–91; 2013.

107.

Y. P.

; Ma

M. M.

; Cheng

S. M.

; Ma

H. H.

; Yi

X. M.

; Xu

G. L.

; Liu

X. F.

Intranasal bFGF-induced progenitor cell proliferation and neuroprotection after transient focal cerebral ischemia. Neurosci. Lett. 437: 93–97; 2008.

108.

Mally

; Stone

T. W.

New advances in the rehabilitation of CNS diseases applying rTMS. Expert Rev. Neurother. 7: 165–177; 2007.

109.

McLay

R. N.

; Kimura

; Banks

W. A.

; Kastin

A. J.

Granulocyte-macrophage colony-stimulating factor crosses the blood–brain and blood–spinal cord barriers. Brain 120(Pt 11): 2083–2091; 1997.

110.

Mehrholz

; Elsner

; Werner

; Kugler

; Pohl

Electromechanical-assisted training for walking after stroke. Cochrane Database Syst. Rev. 7: Cd006185; 2013.

111.

Mehrholz

; Kugler

; Storch

; Pohl

; Hirsch

; Elsner

Treadmill training for patients with Parkinson's disease. Cochrane Database Syst. Rev. 9: Cd007830; 2015.

112.

Miniussi

; Rossini

P. M.

Transcranial magnetic stimulation in cognitive rehabilitation. Neuropsychol. Rehabil. 21: 579–601; 2011.

113.

Muller

M. B.

; Toschi

; Kresse

A. E.

; Post

; Keck

M. E.

Long-term repetitive transcranial magnetic stimulation increases the expression of brain-derived neurotrophic factor and cholecystokinin mRNA, but not neuropeptide tyrosine mRNA in specific areas of rat brain. Neuropsychopharmacology 23: 205–215; 2000.

114.

Nakatomi

; Kuriu

; Okabe

; Yamamoto

; Hatano

; Kawahara

; Tamura

; Kirino

; Nakafuku

Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110: 429–441; 2002.

115.

Nilsson

; Perfilieva

; Johansson

; Orwar

; Eriksson

P. S.

Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory. J. Neurobiol. 39: 569–578; 1999.

116.

Nutt

J. G.

; Burchiel

K. J.

; Comella

C. L.

; Jankovic

; Lang

A. E.

; Laws

E. R.

Jr. ; Lozano

A. M.

; Penn

R. D.

; Simpson

R. K.

Jr. ; Stacy

; Wooten

G. F.

Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 60: 69–73; 2003.

117.

Ochs

; Penn

R. D.

; York

; Giess

; Beck

; Tonn

; Haigh

; Malta

; Traub

; Sendtner

; Toyka

K. V.

A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 1: 201–206; 2000.

118.

Olson

; Backlund

E. O.

; Ebendal

; Freedman

; Hamberger

; Hansson

; Hoffer

; Lindblom

; Meyerson

; Stromberg

Intraputaminal infusion of nerve growth factor to support adrenal medullary autografts in Parkinson's disease. One-year follow-up of first clinical trial. Arch. Neurol. 48: 373–381; 1991.

119.

Pajonk

F. G.

; Wobrock

; Gruber

; Scherk

; Berner

; Kaizl

; Kierer

; Muller

; Oest

; Meyer

; Backens

; Schneider-Axmann

; Thornton

A. E.

; Honer

W. G.

; Falkai

Hippocampal plasticity in response to exercise in schizophrenia. Arch. Gen. Psychiatry 67: 133–143; 2010.

120.

Papayannopoulou

Current mechanistic scenarios in hematopoietic stem/progenitor cell mobilization. Blood 103: 1580–1585; 2004.

121.

Patel

N. K.

; Bunnage

; Plaha

; Svendsen

C. N.

; Heywood

; Gill

S. S.

Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: A two-year outcome study. Ann. Neurol. 57: 298–302; 2005.

122.

Pearl

R. G.

Erythropoietin and organ protection: Lessons from negative clinical trials. Crit. Care 18: 526; 2014.

123.

Pitzer

; Kruger

; Plaas

; Kirsch

; Dittgen

; Muller

; Laage

; Kastner

; Suess

; Spoelgen

; Henriques

; Ehrenreich

; Schabitz

W. R.

; Bach

; Schneider

Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis. Brain 131: 3335–3347; 2008.

124.

Pleger

; Blankenburg

; Bestmann

; Ruff

C. C.

; Wiech

; Stephan

K. E.

; Friston

K. J.

; Dolan

R. J.

Repetitive transcranial magnetic stimulation-induced changes in sensorimotor coupling parallel improvements of somatosensation in humans. J. Neurosci. 26: 1945–1952; 2006.

125.

Post

; Keck

M. E.

Transcranial magnetic stimulation as a therapeutic tool in psychiatry: What do we know about the neurobiological mechanisms? J. Psychiatr. Res. 35: 193–215; 2001.

126.

Prasad

; Kumar

; Sahu

J. K.

; Srivastava

M. V.

; Mohanty

; Bhatia

; Gaikwad

S. B.

; Srivastava

; Goyal

; Tripathi

; Bal

; Mishra

N. K.

Mobilization of stem cells using G-CSF for acute ischemic stroke: A randomized controlled, pilot study. Stroke Res. Treat. 2011: 283473; 2011.

127.

Ray

; Peterson

D. A.

; Schinstine

; Gage

F. H.

Proliferation, differentiation, and long-term culture of primary hippocampal neurons. Proc. Natl. Acad. Sci. USA 90: 3602–3606; 1993.

128.

Ridding

M. C.

; Rothwell

J. C.

Is there a future for therapeutic use of transcranial magnetic stimulation? Nat. Rev. Neurosci. 8: 559–567; 2007.

129.

Ringelstein

E. B.

; Thijs

; Norrving

; Chamorro

; Aichner

; Grond

; Saver

; Laage

; Schneider

; Rathgeb

; Vogt

; Charisse

; Fiebach

J. B.

; Schwab

; Schabitz

W. R.

; Kollmar

; Fisher

; Brozman

; Skoloudik

; Gruber

; Serena Leal

; Veltkamp

; Kohrmann

; Berrouschot

Granulocyte colony-stimulating factor in patients with acute ischemic stroke: Results of the AX200 for Ischemic Stroke trial. Stroke 44: 2681–2687; 2013.

130.

Riquelme

P. A.

; Drapeau

; Doetsch

Brain microecologies: Neural stem cell niches in the adult mammalian brain. Philos. Trans. R. Soc. Lond. B Biol. Sci. 363: 123–137; 2008.

131.

Roeder

; de Haan

; Engel

; Nijhof

; Dontje

; Loeffler

Interactions of erythropoietin, granulocyte colony-stimulating factor, stem cell factor, and interleukin-11 on murine hematopoiesis during simultaneous administration. Blood 91: 3222–3229; 1998.

132.

Rosenzweig

M. R.

; Bennett

E. L.

; Hebert

; Morimoto

Social grouping cannot account for cerebral effects of enriched environments. Brain Res. 153: 563–576; 1978.

133.

Rossini

P. M.

; Rossi

Clinical applications of motor evoked potentials. Electroencephalogr. Clin. Neurophysiol. 106: 180–194; 1998.

134.

Ruan

; Wang

; ZhuGe

; Jin

Coupling of neurogenesis and angiogenesis after ischemic stroke. Brain Res. 1623: 166–173; 2015.

135.

Saito

; Takayama

; Moriguchi

; Kotani

; Jimbo

Developmental effects of low frequency magnetic fields on P19-derived neuronal cells. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2009: 5942–5945; 2009.

136.

Saunders

D. H.

; Sanderson

; Brazzelli

; Greig

C. A.

; Mead

G. E.

Physical fitness training for stroke patients. Cochrane Database Syst. Rev. 10: Cd003316; 2013.

137.

Schabitz

W. R.

; Kollmar

; Schwaninger

; Juettler

; Bardutzky

; Scholzke

M. N.

; Sommer

; Schwab

Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia. Stroke 34: 745–751; 2003.

138.

Schabitz

W. R.

; Laage

; Vogt

; Koch

; Kollmar

; Schwab

; Schneider

; Hamann

G. F.

; Rosenkranz

; Veltkamp

; Fiebach

J. B.

; Hacke

; Grotta

J. C.

; Fisher

; Schneider

AXIS: A trial of intravenous granulocyte colony-stimulating factor in acute ischemic stroke. Stroke 41: 2545–2551; 2010.

139.

Schaller

; Sperling

; Richter-Schmidinger

; Muhle

; Heberlein

; Maihofner

; Kornhuber

; Lenz

Serial repetitive transcranial magnetic stimulation (rTMS) decreases BDNF serum levels in healthy male volunteers. J. Neural Transm. 121: 307–313; 2014.

140.

Schlager

G. W.

; Griesmaier

; Wegleiter

; Neubauer

; Urbanek

; Kiechl-Kohlendorfer

; Felderhoff-Mueser

; Keller

Systemic G-CSF treatment does not improve long-term outcomes after neonatal hypoxicischaemic brain injury. Exp. Neurol. 230: 67–74; 2011.

141.

Schneider

; Kruger

; Steigleder

; Weber

; Pitzer

; Laage

; Aronowski

; Maurer

M. H.

; Gassler

; Mier

; Hasselblatt

; Kollmar

; Schwab

; Sommer

; Bach

; Kuhn

H. G.

; Schabitz

W. R.

The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J. Clin. Invest. 115: 2083–2098; 2005.

142.

Sehara

; Hayashi

; Deguchi

; Zhang

; Tsuchiya

; Yamashita

; Lukic

; Nagai

; Kamiya

; Abe

Potentiation of neurogenesis and angiogenesis by G-CSF after focal cerebral ischemia in rats. Brain Res. 1151: 142–149; 2007.

143.

Seo

J. H.

; Kim

; Park

E. S.

; Lee

J. E.

; Kim

D. W.

; Kim

H. O.

; Im

S. H.

; Yu

J. H.

; Kim

J. Y.

; Lee

M. Y.

; Kim

C. H.

; Cho

S. R.

Environmental enrichment synergistically improves functional recovery by transplanted adipose stem cells in chronic hypoxic-ischemic brain injury. Cell Transplant. 22: 1553–1568; 2013.

144.

Seo

J. H.

; Yu

J. H.

; Suh

; Kim

M. S.

; Cho

S. R.

Fibroblast growth factor-2 induced by enriched environment enhances angiogenesis and motor function in chronic hypoxic-ischemic brain injury. PLoS One 8: e74405; 2013.

145.

Shang

; Deguchi

; Ohta

; Liu

; Zhang

; Tian

; Yamashita

; Ikeda

; Matsuura

; Funakoshi

; Nakamura

; Abe

Strong neurogenesis, angiogenesis, synaptogenesis, and antifibrosis of hepatocyte growth factor in rats brain after transient middle cerebral artery occlusion. J. Neurosci. Res. 89: 86–95; 2011.

146.

Shingo

; Sorokan

S. T.

; Shimazaki

; Weiss

Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J. Neurosci. 21: 9733–9743; 2001.

147.

Shyu

W. C.

; Lin

S. Z.

; Lee

C. C.

; Liu

D. D.

; Li

Granulocyte colony-stimulating factor for acute ischemic stroke: A randomized controlled trial. CMAJ 174: 927–933; 2006.

148.

Siebner

H. R.

; Mentschel

; Auer

; Conrad

Repetitive transcranial magnetic stimulation has a beneficial effect on bradykinesia in Parkinson's disease. Neuroreport 10: 589–594; 1999.

149.

Silva

B. A.

; Cassilhas

R. C.

; Attux

; Cordeiro

; Gadelha

A. L.

; Telles

B. A.

; Bressan

R. A.

; Ferreira

F. N.

; Rodstein

P. H.

; Daltio

C. S.

; Tufik

; Mello

M. T.

A 20-week program of resistance or concurrent exercise improves symptoms of schizophrenia: Results of a blind, randomized controlled trial. Rev. Bras. Psiquiatr. 37: 271–279; 2015.

150.

Siren

A. L.

; Fratelli

; Brines

; Goemans

; Casagrande

; Lewczuk

; Keenan

; Gleiter

; Pasquali

; Capobianco

; Mennini

; Heumann

; Cerami

; Ehrenreich

; Ghezzi

Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc. Natl. Acad. Sci. USA 98: 4044–4049; 2001.

151.

Sirevaag

A. M.

; Greenough

W. T.

Differential rearing effects on rat visual cortex synapses. II. Synaptic morphometry. Brain Res. 351: 215–226; 1985.

152.

Sirevaag

A. M.

; Greenough

W. T.

Differential rearing effects on rat visual cortex synapses. III. Neuronal and glial nuclei, boutons, dendrites, and capillaries. Brain Res. 424: 320–332; 1987.

153.

Sprigg

; Bath

P. M.

; Zhao

; Willmot

M. R.

; Gray

L. J.

; Walker

M. F.

; Dennis

M. S.

; Russell

Granulocyte-colony-stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: The Stem cell Trial of recovery EnhanceMent after Stroke (STEMS) pilot randomized, controlled trial (ISRCTN 16784092). Stroke 37: 2979–2983; 2006.

154.

Steiner

; Kronenberg

; Jessberger

; Brandt

M. D.

; Reuter

; Kempermann

Differential regulation of gliogenesis in the context of adult hippocampal neurogenesis in mice. Glia 46: 41–52; 2004.

155.

Strafella

A. P.

; Paus

; Fraraccio

; Dagher

Striatal dopamine release induced by repetitive transcranial magnetic stimulation of the human motor cortex. Brain 126: 2609–2615; 2003.

156.

Swift

D. L.

; Johannsen

N. M.

; Myers

V. H.

; Earnest

C. P.

; Smits

J. A.

; Blair

S. N.

; Church

T. S.

The effect of exercise training modality on serum brain derived neurotrophic factor levels in individuals with type 2 diabetes. PLoS One 7: e42785; 2012.

157.

Tao

; Black

I. B.

; DiCicco-Bloom

In vivo neurogenesis is inhibited by neutralizing antibodies to basic fibroblast growth factor. J. Neurobiol. 33: 289–296; 1997.

158.

Theilig

; Podubecka

; Bosl

; Wiederer

; Nowak

D. A.

Functional neuromuscular stimulation to improve severe hand dysfunction after stroke: Does inhibitory rTMS enhance therapeutic efficiency? Exp. Neurol. 230: 149–155; 2011.

159.

Thoenen

; Sendtner

Neurotrophins: From enthusiastic expectations through sobering experiences to rational therapeutic approaches. Nat. Neurosci. 5(Suppl): 1046–1050; 2002.

160.

Tomlinson

C. L.

; Herd

C. P.

; Clarke

C. E.

; Meek

; Patel

; Stowe

; Deane

K. H.

; Shah

; Sackley

C. M.

; Wheatley

; Ives

Physiotherapy for Parkinson's disease: A comparison of techniques. Cochrane Database Syst. Rev. 6: Cd002815; 2014.

161.

Tonchev

A. B.

; Yamashima

; Zhao

; Okano

H. J.

; Okano

Proliferation of neural and neuronal progenitors after global brain ischemia in young adult macaque monkeys. Mol. Cell. Neurosci. 23: 292–301; 2003.

162.

Toth

Z. E.

; Leker

R. R.

; Shahar

; Pastorino

; Szalayova

; Asemenew

; Key

; Parmelee

; Mayer

; Nemeth

; Bratincsak

; Mezey

The combination of granulocyte colony-stimulating factor and stem cell factor significantly increases the number of bone marrow-derived endothelial cells in brains of mice following cerebral ischemia. Blood 111: 5544–5552; 2008.

163.

Trejo

J. L.

; Carro

; Torres-Aleman

Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J. Neurosci. 21: 1628–1634; 2001.

164.

Tsai

T. H.

; Lu

C. H.

; Wallace

C. G.

; Chang

W. N.

; Chen

S. F.

; Huang

C. R.

; Tsai

N. W.

; Lan

M. Y.

; Sung

P. H.

; Liu

C. F.

; Yip

H. K.

Erythropoietin improves long-term neurological outcome in acute ischemic stroke patients: A randomized, prospective, placebo-controlled clinical trial. Crit. Care 19: 49; 2015.

165.

Tuszynski

M. H.

; Thal

; Pay

; Salmon

D. P.

; U

H. S.

; Bakay

; Patel

; Blesch

; Vahlsing

H. L.

; Ho

; Tong

; Potkin

S. G.

; Fallon

; Hansen

; Mufson

E. J.

; Kordower

J. H.

; Gall

; Conner

A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat. Med. 11: 551–555; 2005.

166.

Ueyama

; Ukai

; Ogawa

; Yamamoto

; Kawaguchi

; Ishii

; Shinosaki

Chronic repetitive transcranial magnetic stimulation increases hippocampal neurogenesis in rats. Psychiatry Clin. Neurosci. 65: 77–81; 2011.

167.

Ulich

T. R.

; del Castillo

; McNiece

I. K.

; Yi

E. S.

; Alzona

C. P.

; Yin

S. M.

; Zsebo

K. M.

Stem cell factor in combination with granulocyte colony-stimulating factor (CSF) or granulocyte-macrophage CSF synergistically increases granulopoiesis in vivo. Blood 78: 1954–1962; 1991.

168.

Walsh

R. N.

; Cummins

R. A.

Changes in hippocampal neuronal nuclei in response to environmental stimulation. Int. J. Neurosci. 9: 209–212; 1979.

169.

Walsh

; Cowey

Transcranial magnetic stimulation and cognitive neuroscience. Nat. Rev. Neurosci. 1: 73–79; 2000.

170.

Wang

H. Y.

; Crupi

; Liu

; Stucky

; Cruciata

; Di Rocco

; Friedman

; Quartarone

; Ghilardi

M. F.

Repetitive transcranial magnetic stimulation enhances BDNF-TrkB signaling in both brain and lymphocyte. J. Neurosci. 31: 11044–11054; 2011.

171.

Wang

; Zhang

; Wang

; Zhang

; Chopp

Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 35: 1732–1737; 2004.

172.

Wang

; Zhang

; Hafner

M. S.

; Wong

H. K.

; Jiao

; Chopp

Erythropoietin up-regulates SOCS2 in neuronal progenitor cells derived from SVZ of adult rat. Neuroreport 15: 1225–1229; 2004.

173.

Wang

; Cooke

M. J.

; Morshead

C. M.

; Shoichet

M. S.

Hydrogel delivery of erythropoietin to the brain for endogenous stem cell stimulation after stroke injury. Biomaterials 33: 2681–2692; 2012.

174.

Weissmiller

A. M.

; Wu

Current advances in using neurotrophic factors to treat neurodegenerative disorders. Transl. Neurodegener. 1: 14; 2012.

175.

Will

; Galani

; Kelche

; Rosenzweig

M. R.

Recovery from brain injury in animals: Relative efficacy of environmental enrichment, physical exercise or formal training (1990–2002). Prog. Neurobiol. 72: 167–182; 2004.

176.

A. D.

; Fregni

; Simon

D. K.

; Deblieck

; Pascual-Leone

Noninvasive brain stimulation for Parkinson's disease and dystonia. Neurotherapeutics 5: 345–361; 2008.

177.

Wunderlich

M. T.

; Ebert

A. D.

; Kratz

; Goertler

; Jost

; Herrmann

Early neurobehavioral outcome after stroke is related to release of neurobiochemical markers of brain damage. Stroke 30: 1190–1195; 1999.

178.

Yamashita

; Ninomiya

; Hernandez Acosta

; Garcia-Verdugo

J. M.

; Sunabori

; Sakaguchi

; Adachi

; Kojima

; Hirota

; Kawase

; Araki

; Abe

; Okano

; Sawamoto

Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. J. Neurosci. 26: 6627–6636; 2006.

179.

Yang

J. P.

; Liu

H. J.

; Liu

X. F.

VEGF promotes angiogenesis and functional recovery in stroke rats. J. Invest. Surg. 23: 149–155; 2010.

180.

Yang

Y. R.

; Tseng

C. Y.

; Chiou

S. Y.

; Liao

K. K.

; Cheng

S. J.

; Lai

K. L.

; Wang

R. Y.

Combination of rTMS and treadmill training modulates corticomotor inhibition and improves walking in Parkinson disease: A randomized trial. Neurorehabil. Neural Repair 27: 79–86; 2013.

181.

Yip

H. K.

; Chang

L. T.

; Chang

W. N.

; Lu

C. H.

; Liou

C. W.

; Lan

M. Y.

; Liu

J. S.

; Youssef

A. A.

; Chang

H. W.

Level and value of circulating endothelial progenitor cells in patients after acute ischemic stroke. Stroke 39: 69–74; 2008.

182.

Yip

H. K.

; Tsai

T. H.

; Lin

H. S.

; Chen

S. F.

; Sun

C. K.

; Leu

; Yuen

C. M.

; Tan

T. Y.

; Lan

M. Y.

; Liou

C. W.

; Lu

C. H.

; Chang

W. N.

Effect of erythropoietin on level of circulating endothelial progenitor cells and outcome in patients after acute ischemic stroke. Crit. Care 15: R40; 2011.

183.

J. H.

; Seo

J. H.

; Lee

J. E.

; Heo

J. H.

; Cho

S. R.

Time-dependent effect of combination therapy with erythropoietin and granulocyte colony-stimulating factor in a mouse model of hypoxic-ischemic brain injury. Neurosci. Bull. 30: 107–117; 2014.

184.

J. H. L.

; Jong

Eun

; Seo

Jung Hwa.

; Kim

J. Y.

; Cho

S.-R.

Induction of striatal regeneration delays motor deterioration in a mouse model of Huntington's disease. Tissue Eng. Regen. Med. 8: 164–172; 2011.

185.

Yue

; Xiao-lin

; Tao

The effects of chronic repetitive transcranial magnetic stimulation on glutamate and gamma-aminobutyric acid in rat brain. Brain Res. 1260: 94–99; 2009.

186.

Yukimasa

; Yoshimura

; Tamagawa

; Uozumi

; Shinkai

; Ueda

; Tsuji

; Nakamura

Highfrequency repetitive transcranial magnetic stimulation improves refractory depression by influencing catecholamine and brain-derived neurotrophic factors. Pharmacopsychiatry 39: 52–59; 2006.

187.

Zamir

; Gunraj

; Ni

; Mazzella

; Chen

Effects of theta burst stimulation on motor cortex excitability in Parkinson's disease. Clin. Neurophysiol. 123: 815–821; 2012.

188.

Zeng

; Ju

; Mao

Therapeutic potential of hepatocyte growth factor against cerebral ischemia (review). Exp. Ther. Med. 9: 283–288; 2015.

189.

Zhu

; Fan

; Frenzel

; Gasmi

; Bartus

R. T.

; Young

W. L.

; Yang

G. Y.

; Chen

Insulin growth factor-1 gene transfer enhances neurovascular remodeling and improves long-term stroke outcome in mice. Stroke 39: 1254–1261; 2008.

190.

Zwanzger

; Ella

; Keck

M. E.

; Rupprecht

; Padberg

Occurrence of delusions during repetitive transcranial magnetic stimulation (rTMS) in major depression. Biol. Psychiatry 51: 602–603; 2002.

Induction of Neurorestoration from Endogenous Stem Cells

Abstract

Keywords

Introduction

Neurotrophic Factors

Hematopoietic Growth Factors

Repetitive Transcranial Magnetic Stimulation

Physical Exercise and Enriched Environment

Conclusion

Footnotes

Acknowledgments

References