What is Neuroplasticity? – A Simplified Guide

ADULT NEUROGENESIS IN HEALTH AND DISEASE

A fundamental mechanism of neuroplasticity in the adult brain is neurogenesis, which describes the birth of new neurons in two regions of the brain: the hippocampus and the olfactory bulb. [Zhao et al. 2008]

Neurons are continuously generated from a proliferating population of neural stem cells (NSCs) that then become incorporated into the existing neuronal circuitry.

• In the dentate gyrus of the hippocampus, the generation of adult-born neurons is critical for hippocampal-dependent memory acquisition, memory formation, and memory maintenance. These adult-born neurons play a functional role in pattern separation and thus prevent any possible memory interference. [Clelland et al. 2009]
• Neurogenesis occurs in the subventricular zone of the lateral ventricles, after which the new neurons migrate anteriorly to the olfactory bulb. Adult olfactory bulb neurogenesis is essential for detecting external chemical cues and for olfactory memory. [Lledo et al. 2008]

The process of neurogenesis is regulated by the environment and an individual’s experiences and physiological status. Injury and disease can also induce migration of neural stem cells to the site of injury, where they may be appropriately incorporated into established circuits.

The majority of psychiatric and neurological disorders have been associated with changes in neuroplasticity, including reductions in neurogenesis and deficits in long-term potentiation. Furthermore, aberrant neurogenesis can also promote the destabilisation of neuronal circuits and contribute to cognitive impairment. [Mu and Gage 2011]; [Cho et al. 2015]

Dementia: 

• Ageing progressively compromises hippocampal-dependent neurogenesis and has been shown to play a role in some of the cognitive deficits associated with Alzheimer’s disease. [Moreno-Jimenez et al. 2019]

Epilepsy:

• As a result of seizure activity, there are notable increases in hippocampal neurogenesis. Although most of these new cells die, many survive and migrate to the wrong location where they differentiate incorrectly. These neurons are suggested to play a role in the persistence of epileptic pathology. [Jessberger and Parent 2015]

Ischemic stroke:

• Although the impact of ischaemic stroke is size and location-dependent, more than one-third of stroke patients will develop cognitive impairment. [Pendlebury and Rothwell 2015]; [Brainin et al. 2015]
• After a severe stroke, it is hypothesised that the powerful neurogenic burst observed in the hippocampus modifies newborn granule cells and increases the forgetting of old memories. [Epp et al. 2016]

Schizophrenia

• Recently published data suggest that in some cases of schizophrenia, there may be underlying defects in neurogenesis during adolescence, which is a critical period for both adult neurogenesis and the development of a first psychotic episode. [Iannitelli et al. 2017]
• Read more about synaptic pruning in schizophrenia, where microglia play an important role in neuroplasticity and pruning. 
• Microglial activation can affect neurogenesis and neuroplasticity through reductions of BDNF.

Depression:

• The neurogenesis hypothesis of depression states that stress-induced cortisol elevations play an indirect yet detrimental role in hippocampal neurogenesis.
• Furthermore, it is already established that several antidepressants are known to positively influence neurogenesis by increasing neural precursor cell proliferation. [Boldrini et al. 2009]
• Inflammation is involved in specific subsets of depression which is known to reduce neuroplasticity by reducing neurotrophic factors such as BDNF. [Rege, 2021]
• Read more on inflammation in depression

Neuroinflammation:

• Inflammation plays a vital role in determining the balance between neurogenesis and neurodegeneration.
• Microglial cells are critical modulators of neurogenesis. [Shohayeb et al. 2018]
• In the normal state, the balance is tipped in favour of neurogenesis.
• However, when microglia are activated due to stress, infection, injury, etc., pro-inflammatory cytokines are released, enhancing gliogenesis at the expense of neurogenesis.
• Microglia reach an immunomodulatory state in the next stage, releasing anti-inflammatory cytokines, moving the balance towards neurogenesis.

Traumatic Brain Injury:

Stages of neuroplasticity: [Su et al., 2016]

1. Immediate changes: Cell death occurs along with a decrease in cortical inhibitory pathways for 1 to 2 days which recruits or unmasks new and secondary neuronal networks.
2. A shift of cortical pathway activity from inhibitory to excitatory.
3. Neuronal proliferation and synaptogenesis. Both neuronal and nonneuronal cells (i.e., endothelial progenitors, glial cells, and inflammatory cells) are recruited to replace the damaged cells, facilitate gliotic scar tissue, and revascularise.
4.  Weeks after injury: New synaptic markers and axonal sprouting are upregulated, allowing for remodelling and cortical changes for recovery.
5. Long-lasting morphologic changes occur in the hippocampus after TBI, including the growth of cell soma and recruitment of neurons to the hippocampus.
6. Neuropsychiatry of Traumatic Brain Injury (TBI) – Pathogenesis, Comorbidity and Treatment

Identifying appropriate environmental and behavioural signals that promote neurogenesis in different regions of the adult brain could potentially assist in developing neurotherapeutics that enhance the brain’s innate plastic capacity to adapt after neuronal injury or disease. [Voss et al. 2017]

INTERVENTIONS TO ENHANCE NEUROPLASTICITY

Cognitive neurotherapeutics is a novel treatment approach that may treat or prevent a variety of neurological and psychiatric disorders.

Clinical therapies can promote neuroplastic changes across multiple clinical phenotypes by improving cerebral perfusion, synaptic plasticity, brain volume and connectivity, neurogenesis, and regulation of trophic factors.

Cognitive training :

• These exercises train attention, working memory, problem-solving, and executive functioning to recruit neuroplasticity regulators. [Vinogradov et al. 2012]
• However, cognitive training exercises will need to be sufficiently nuanced to recruit specific regulators in the right cognitive domain to become a targeted approach.
• There is no clear evidence that Brain Training Programs as commercially available products are efficacious as advertised, and studies show methodological issues. [Rossignoli-Palomeque et al., 2018]

Neuropharmaceuticals: [Su et al., 2016]

Agents for Neuroprotection:

• Administration of compounds that protect neural tissue from cytotoxic and excitotoxic effects of the injury cascade, e.g. Free radical scavengers
• Agents reducing excitotoxicity: e.g. progesterone metabolite, allopregnanolone, also act as a potent agonist of the GABAA receptor to reduce excitotoxic cell death.

Agents for Neurogenesis :

• Endogenous neurotrophic growth factors: e.g. nerve growth factor (NGF), BDNF, glia-derived nerve factor (GDNF) and insulin-like growth factor 1 (IGF-1), have integral roles in stimulating NSC proliferation, differentiation and central nervous system development.
• S100B appears to be a stimulator for neurogenesis after TBI.
• Nitric oxide enhances neurogenesis and angiogenesis through the mediation of guanylyl cyclase and the formation of guanylate cyclase.
• Direct infusion, viral vector delivery, cell grafts, and short peptide mimetics have been investigated; however, procedure invasiveness and/or BBB impermeability are significant safety and efficacy issues, respectively. [Shohayeb et al. 2018]

Stem cells.

• Mesenchymal stem cells (MSCs) / Neural stem cells (NSCs) and the Transplantation of embryonic stem cells (ESCs) have been studied.
• Animal studies have shown promising results in using stem cells to ameliorate the sequelae of TBI. Exogenous stem cell transplantation into the injured brain can counteract direct neuronal loss to secondary inflammatory sequelae and even provide trophic factors for a nurturing microenvironment. [Su et al., 2016]

Medications:

• Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine
• Serotonin and noradrenergic reuptake inhibitors (SNRIs) like duloxetine
• Cholinergic agonists such as donepezil
• Glutaminergic partial antagonists like amantadine. [Puderbaugh & Emmady, 2021.]
• Amantadine has been shown to improve recovery in patients in a minimally conscious or vegetative state after a severe TBI. Amantadine has also been shown to increase left prefrontal cortex activation in association with improved cognitive functioning in patients with chronic TBI.
• In animal studies of TBI, researchers have used amphetamine, other catecholamine and cholinergic agonists, plus NMDA receptor agonists to stimulate brain activity and improve recovery rate, but research shows administering these agents without behavioural stimulation may not be enough. [Stein et al., 2003]
• Only antioxidants, cyclosporin A (Phase II only), Erythropoietin and Progesterone, have been studied in human phase II and III trials and are showing some promise. [Su et al., 2016]

Psychedelics:

• Psychedelics promote neuroplasticity through an increase in BDNF.
• Most psychedelics activate the 5HT2A receptor, which activates multiple signalling cascades leading to calcium and glutamate release that stimulates synaptic plasticity. Increased glutamate in the cortex can further stimulate synaptic plasticity via AMPA receptors on pyramidal neurons, increasing BDNF and further glutamate release in the cortex. [De Vos et al., 2021]

Studies show that a single administration of a psychedelic produces rapid changes in plasticity mechanisms on a molecular, neuronal, synaptic, and dendritic level. The expression of plasticity-related genes and proteins, including Brain-Derived Neurotrophic Factor (BDNF), is changed after a single administration of psychedelics, resulting in changed neuroplasticity. The latter included more dendritic complexity, which outlasted the acute effects of the psychedelic. Repeated administration of a psychedelic directly stimulated neurogenesis and increased BDNF mRNA levels up to a month after treatment. 

• DMT has an affinity for both the 5 HT2A receptors and for the Sigma 1 receptor (S1R), which is highly expressed in the hippocampus and is a stimulator of synaptic plasticity.
• LSD also stimulates S1R indirectly via activation of the neurosteroid dehydroepiandrosterone (DHEA), which stimulates synaptic plasticity and neurogenesis.

Erythropoietin (EPO):

Both EPO and EPOr are widely present in the brain. Expression of EPO receptor is significantly increased in neurons, glia, and endothelial cells after TBI.

EPO appears to promote neuroprotection through binding to EpoR and activating JAK-2/NF-kB and PI3K signalling pathways. [Galgano et al., 2017]

Neurosteroids:

• Neurosteroids such as progesterone and allopregnanolone promote neuronal and behavioural recovery in TBI because of their actions at multiple levels that lead to the reduction of free radicals, inflammatory cytokines, and apoptosis in the area of the brain injury
• They enhance the inhibitory tone in the brain, which provides neuroprotection by counteracting the pathways upregulated by TBI. [Stein et al., 2003]

DHEAS (Dehydroepiandrosterone Sulfate)

• DHEAS can increase the excitatory tone of the brain through GABA-A antagonism. Such changes may be beneficial during the chronic phase of the injury instead of the acute phase. [Stein et al., 2003]
• DHEAS also increases NMDA sensitivity, releasing noradrenaline in the hippocampus and cerebral cortex.
• It is also a cholinergic agonist, and the recovery of cholinergic activity has been linked with improved cognitive and motor performance.
• As DHEA levels increase with physical exertion, it may be possible that rehabilitation techniques will raise DHEA levels, which will stimulate neural growth and recovery of function.

Neurosteroids in Psychiatry – Pharmacology | Mechanisms of Action | Clinical Application

Minocycline:

• Minocycline increases the proliferation capacity of neural stem cells (NSC). [Indharty et al., 2020]
• Minocycline restored neurogenesis in the hippocampus and reduced activated microglia contributing to its anti-inflammatory effects. [Ekdahl et al., 2003]
• Read more on Minocycline in Depression

Physical exercise :

• Physical exercise is known to induce neurogenesis as well as have the ability to enhance CNS metabolism and catecholamine neurotransmission. [van Praag 2008]
• Furthermore, exercises that are cognitively demanding activate higher-order cognitive processes that benefit executive functioning processes. [Pesce 2012]
• PE increases neuroplasticity via neurotrophic factors (BDNF, GDNF, and NGF) and receptor (TrkB and P75NTR) production providing improvements in neuroplasticity and cognitive function (learning and memory) in human and animal models. [de Sousa Fernandes et al., 2020]
• Read more on the Antidepressant benefits of exercise. 

Forced use and recovery: [Stein et al., 2003]

• In brain injury, researchers have demonstrated convincingly that if patients are forced to use the impaired limb, dramatic and sustained recovery can be observed.
• Thus, there may be critical periods in which this type of rehabilitative method should be avoided.
• Forced use or environmental stimulation early after an injury can worsen the extent of brain damage and, in some cases, increase the severity of behavioural deficits.

Enriched environments :

• Environments that encourage sensory, motor, cognitive and social behaviours are suggested to promote recovery from brain injuries. [Alwis and Rajan 2014]
• However, most studies have used animal models as this strategy would be difficult to control for in human clinical trials. [Shaffer, 2016]
• Foreign language training and music exposure in the early years were associated with a reduced risk of mild cognitive impairment (MCI) in the Rush Memory and Aging Project [Wilson et al., 2014].
• Learning music is associated with neuroplastic changes and an improvement in a range of cognitive functions. [Shaffer, 2016]

Diet:

Hara Hachi bu:

• Research suggests that Hara hachi bu, or “eat until you are 80% full,” has been an important factor in longevity. [Willcox et al., 2014]
• Reducing calories by 30% is associated with an average of 20% improvement in verbal memory after 3 months.
• Some of these cognitive and general health benefits of calorie restriction in humans are thought to be related to reducing inflammation and oxidative damage, improved insulin signalling in the brain, neurotrophic factor signalling, improving synaptic resilience to damage and modifying the number, architecture, and performance of synapses. [Witte et al.,2009], [Mattson et al.,2018]

Polyphenol:

• The polyphenol resveratrol also increases longevity while preserving memory and hippocampal microstructure. [Witte et al., 2014]
• This polyphenol occurs naturally in grapes, purple grape juice and some berries such as blueberries and cranberries.

Cocoa flavonoids:

• They stimulate angiogenesis, neurogenesis and changes in neuron morphology, mainly in regions involved in learning and memory. [Nehlig, 2013]
• They are neuroprotective and can enhance mood and cognitive function.[Latif, 2013]

Curcumin: 

• Curcumin is a neuroprotective polyphenol with anti-inflammatory, antioxidant and neurogenetic properties. [Ramaholimihaso et al., 2020]

Omega -3 Fatty acids: 

• Humans cannot create Omega 3 fatty acids and rely on exogenous sources.
• Omega 3 PUFA has been shown to increase the levels of several signalling factors involved in synaptic plasticity, thus leading to the increase of dendritic spines and synapses and the enhancement of hippocampal neurogenesis even at old age. They also have anti-inflammatory properties, which contribute to neuroprotection. [Cutuli, 2017]

Love, meditation and reduced stress:

• Meditation, social network and affection have all been shown to have neuroprotective properties and may enhance neuroplastic changes. [Shaffer, 2016]

Sleep:

• Chronic sleep deprivation is associated with increased inflammation and decreased BDNF and can lead to cognitive deficits and metabolic dysfunction.
• A primary function of sleep appears to be the activation of the glymphatic system to promote the efficient elimination of neurotoxic waste products produced during wakefulness. The glymphatic system also facilitates the brain-wide distribution of several compounds, including glucose, lipids, amino acids, growth factors, and neuromodulators. [Jessen et al., 2015]
• Sleep restores synaptic plasticity, with beneficial effects on learning processes, while sleep deprivation induces alteration in LTP/LTD mechanisms, increases cortical excitability, and negatively impacts learning. [Gorgoni et al., 2013]

SUMMARY

In this article, we provide an overview of neuroplasticity and narrow down the definition of neuroplasticity from a scientific perspective.

Neuroplasticity can best be defined as changes in the brain in response to intrinsic or extrinsic stimuli. These changes may be functional or maladaptive.

Neuroplastic changes occur in several neurological and psychiatric disorders. However, the best-studied is traumatic brain injury.

There is increasing interest in modulating these neuroplastic pathways as treatment options in neuropsychiatry.

Finally, if cognitive neurotherapeutics are to be used to harness the neuroplastic potential of the human brain, then age, sex, genetics, and individual pathology will need to be considered before implementation.

A range of pharmacological and non-pharmacological strategies show benefits in neurogenesis and neuroprotection.

Strategies such as sleep hygiene, diet, exercise are low-cost ways of ‘enhancing neuroplasticity’.

As research continues, we may be able to utilise these treatments further to help guide the brain back to health.