Apart from physical and cognitive training, there can be other interventions towards cognitive enhancement:
1. Noninvasive Brain Stimulation (NIBS)
NIBS is a set of technologies and techniques that are used to modulate excitability of the brain via transcranial stimulation. Transcranial magnetic stimulation (TMS) and transcranial current stimulation (TCS) are two mainly deployed modes of NIBS (1). It has been found that NIBS can induce neuroplastic effects via dopaminergic action. Moreover, the effects of NIBS are NMDA-R-dependent, indicating that the process has an effect on cognitive processes related to attention, spatial working memory, and verbal learning and memory (2).NIBS might, therefore, be more efficient when modulating brain regions relevant for compensatory activity in the aging individuals, at least for high-performing individuals.
2. Cognitive Enhancing Drugs (CED)
Neurotransmitters can be effectively targeted so as to enhance cognitive functioning. Mainly, the following different targets can be intervened:
a) Dopaminergic Cognitive Enhancing Drug
Methylphenidate (MPD) is a dopamine inhibiting and norepinephrine transporter that acts on the brain arousal system and the cerebral cortex increasing sympathomimetic activity of the CNS. MPD administration affects functional brain connectivity and activates the regions that are involved in memory and visual attention. MPD has been also reported to increase thalamic/striatal connectivity to the hypothalamus and amygdala which are the regions for critical memory and alertness (3).
Modafinil is another non-amphetamine compound that acts as a competitive binder to the dopamine receptor as well as inhibitor of noradrenaline uptake. Preclinical evidence has shown that modafinil improves cognition, mnemonic functions, spatial planning, attention, and performance accuracy (4). This drug also elevates extracellular serotonin, glutamate, histamine and orexin concentrations and decreases gamma-amino-butyric acid (GABA) levels. Modafinil has also been linked with hippocampal neurogenesis (5) and promotion of synapsis by positively influencing Brain Derived Neurotrophic Factor (BDNF) mRNA expression (6).
b) Glutamatergic Enhancing Drugs
Ampakines (AK) are positive allosteric modulators of a subtype of ionotropic glutamate
receptors, the AMPARs. AK-driven improvement has been reported in monkeys during complex cognitive tasks that was associated with functional connectivity in the frontal and temporal cortices (7). In preclinical studies involving aging individuals, AK was seen to counteract the age-related and amyloid-dependent impairment of Long Term Potentiation (LTP) and learning (8). Moreover, AK CX456 increases neurogenesis of stem cells and counteracts age-related diminishing of dendritic branches in the cortex and hippocampus of animal models (9).
In light of this evidence, we can use synergistic approaches combining both pharmacological and non-pharmacological techniques for ageing-related cognitive enhancement.
1. Nitsche, M.A. et al. (2006) Dopaminergic modulation of longlasting direct current-induced cortical excitability changes in the human motor cortex. Eur. J. Neurosci. 23, 1651–1657
2. Huang, Y.-Z. et al. (2007) The after-effect of human theta burst stimulation is NMD receptor dependent. Clin. Neurophysiol.118, 1028–1032
3. Farr, O.M. et al. (2014) The effects of methylphenidate on resting-state striatal, thalamic and global functional connectivity in healthy adults. Int. J. Neuropsychopharmacol. 17, 1177–1191
4. Battleday, R.M. and Brem, A.-K. (2015) Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: a systematic review. Eur. Neuropsychopharmacol. 25,1865–1881
5. Nagata, T. et al. Association between DNA methylation of the BDNF promoter region and clinical presentation in Alzheimer’s disease. Dement. Geriatr. Cogn. Dis. Extra 5, 64–73
6. Dell’Osso, B. et al. (2014) Wake-promoting pharmacotherapy for psychiatric disorders. Curr. Psychiatry Rep. 16, 524
7. Porrino, L.J. et al. (2005) Facilitation of task performance and removal of the effects of sleep deprivation by an ampakine (CX717) in nonhuman primates. PLoS Biol. 3, e299
8. Jurado, S. (2018) AMPA receptor trafficking in natural and pathological aging. Front. Mol. Neurosci. 10, 446
9. Dickstein, D.L. et al. (2013) Dendritic spine changes associated with normal aging. Neuroscience 251, 21–32
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