NEURAL REGENERATION RESEARCH www.nrronline.org Perspective The power of “touch” and early rat pups from postnatal days (PND) 1 to PND12, also improved visual acuity enriched stimulation: neuroplasticity development at PND25. Most importantly, these authors reported that blood levels effects in rodents and preterm of IGF-1 and insulin growth factor binding protein 3 were increased in massaged infants infants, and an increased number of IGF-1-positive neurons was found in the visual and auditory cortex of massaged rat pups. Moreover, circulating cortisol Alberto Fernández-Teruel* levels were reduced in massaged infants and corticosterone levels were reduced Early postnatal stimulation, e.g., neonatal Teruel et al., 2002; Weaver et al., 2007). in the stimulated rat pups. Remarkably, handling (NH) in its most frequent form, Following the idea that tactile stimulation the antagonism of IGF-1 activity reversed and environmental enrichment (EE, the (i.e., “touch”), such as that provided the effects of massage in rat pups, as well exposure of juvenile animals, usually by the mother rats, was a crucial factor as the positive developmental effects of during several weeks, to environments in the long-lasting beneficial effects of EE (administered between PND18 and involving rich and variable sensory these early sensory-enriched treatments, PND25) on visual acuity in rats (see Ciucci stimulation) produce profound and long- Schanberg and Field (1987) tried to model et al., 2007; cited by Guzzetta et al., 2009). lasting behavioral and neurobiological the licking-grooming behavior of the These findings suggest a causal role of effects. Both treatments reduce anxiety mother by stroking the rat pups with a soft IGF-1 function in mediating the brain and stress sensitivity, and improve wet paintbrush. This kind of stimulation, maturational effects of tactile (massage) neurodevelopment and learning/memory and EE stimulation (Guzzetta et al., 2009). administered during the first neonatal i n u n co n d i t i o n e d a n d co n d i t i o n e d These studies by Guzzetta and co-workers weeks reversed the negative effects of tasks in laboratory rodents. In addition, constituted the first clear evidence of maternal separation stress on growth and both manipulations lead to long lasting positive brain maturational effects of growth hormone secretion. Likewise, the ‘‘protective’’ effects against age-related neonatal massage therapy in human neonatal stimulation reversed maternal hippocampal neurodegeneration, cognitive infants. These are important findings, separation stress effects on ornithine deficits and associated stress-related since it is known that chronic excessive decarboxylase activity (the first enzyme neuroendocrine processes (e.g., Meaney cortisol inhibits growth hormone secretion in the synthesis of polyamines, which et al., 1988; Fernández-Teruel et al., 1997, and weight gain, and the latter hormone are involved in the regulation of protein 2002). The present commentary is focused normally stimulates IGF-1 synthesis. synthesis), on hypothalamus-pituitary- on summarizing relevant evidence on the Thus, this suggests that by decreasing adrenal axis function (Schanberg and enduring positive effects of early enriched cortisol and increasing IGF-1, massage Field, 1987), as well as on brain-derived sensory (NH- or EE-like) stimulation therapy in preterm human neonates (and neurotrophic factor and synaptophysin on neurobehavioral development and NH treatment in rats) seems to facilitate expression (for further references see neuroplasticity (including the promotion weight gain and, according to Guzzetta et Guzzetta et al., 2009). Along these lines, of neural regeneration or the prevention al. findings, accelerates brain maturation Field and co-workers applied a similar of neurodegeneration) in rodents, and (Schanberg and Field 1987; Field et al., stimulation treatment (called “massage”) to discuss the possible clinical relevance 2008; Guzzetta et al., 2009). to preterm human infants (Schanberg and and translatability of similar treatment Field 1987; Field et al., 2008), and found approaches to humans. Postnatal tactile and enriched sensory that such a massage therapy led to faster weight gain, increased vagal tone, lower stimulation and recovery from brain The power of “touch”: from NH treatment damage: Altogether, massage therapy cortisol levels and decreased stress-related in rodents to massage therapy of preterm in preterm human infants, and enriched behavior. Massaged infants showed better human infants: At least part of the long sensory stimulation (NH, EE) in rodents, neurodevelopmental scores and earlier lasting neurodevelopmental effects of appear to display potent and long-term discharge from the hospital. Importantly, exposure to NH or to early (prenatal and positive effects on development, brain in addition to a greater weight gain, the infantile) EE in rats have been attributed development and neuroplasticity. Do such preterm neonates receiving massage to the presence of enhanced “positive” neuroplasticity effects extend to positive therapy exhibited increased levels of maternal behavior (e.g. increases of neuroregeneration effects in brain-injured serum insulin and insulin-like growth licking/grooming of pups; Weaver et al., subjects? As said above, both NH and EE factor-1 (IGF-1; Field et al., 2008). 2007; see Guzzetta et al., 2009). NH, EE treatments are capable of preventing the and high levels of positive maternal care The specific mechanisms underlying age-related neuronal degeneration in the lead to enduring beneficial effects on the effects of massage therapy on brain hippocampus (Figure 1), and this goes behavior, cognition, and hypothalamus- development and plasticity in human along with NH and EE complete prevention pituitary-adrenal axis function. Moreover, infants are still an open issue. The study of age-related spatial learning/memory these environmentally-enriched conditions by Guzzetta et al. (2009) was outstanding deficits (Meaney et al., 1988; Fernández- influence hippocampal glucocorticoid in this respect. They found that, in rat Teruel et al., 1997; Figure 1). It has receptors, hippocampal synaptogenesis pups and preterm infants, massage been proposed that a likely mechanism and function, and neuroplasticity through therapy improved the maturation of mediating NH and EE prevention of (for example) their effects on nerve growth visual evoked potentials, visual acuity and age-related hippocampus-dependent factor-inducible protein A-, brain-derived electroencephalographic activity across all impairments might involve the attenuation neurotrophic factor- and glutamate brain regions (i.e., across all the electrodes; of the ‘‘glucocorticoid-glutamate-calcium’’ receptor-mediated processes (Fernández- Guzzetta et al., 2009). EE treatment of neurotoxic cascade (Fernández-Teruel et 1248 ｜NEURAL REGENERATION RESEARCH｜Vol 17｜No. 6｜June 2022 Perspective NEURAL REGENERATION RESEARCH www.nrronline.org and prevents the increase of amyloid Y A precursor protein and the decrease of growth associated protein 43 in hippocampus and cerebral cortex (growth associated protein 43 is a protein related to neuronal regenerative processes, axon terminal growth and experience- NH EE dependent neuroplasticity; Durán-Carabali et al., 2020). In a related vein, it is also noteworthy that EE of adolescent male rats (administered from PND35 to PND57– 66) rescues the impairments of adult neuroplasticity (LTP) and hippocampal Figure 1 ｜ NH and EE treatments display lifelong protective effects against neurodegeneration in the rat hippocampus. neurogenesis induced by pre-pubertal Representative microphotographs (original magnification, 290×) of neurons from CA1 hippocampal stress (administered between PND25–27; field in male rats from the outbred RLA/Verh (Roman low-avoidance) rat line (findings were the same Rule et al., 2020). Such an EE treatment for their RHA/Verh–Roman high-avoidance-counterparts; Meaney et al., 1988; Fernández-Teruel et al., a l s o re ve rs e s a mygd a l a f u n c t i o n a l 1997; for similar results with NH treatment). Y: Young, untreated, 5-month-old rats; A: Aged, untreated, 24-month-old rats; NH: aged (24 months old) rats, treated with neonatal handling; EE: aged (24 months alterations and hippocampus-dependent old) rats, treated with environmental enrichment from 6 weeks of age until 7 months of age. Brains cognitive impairments produced by early were embedded in paraffin and cut into 6-μm coronal sections, collected in parallel series, and stained life stress (Rule et al., 2020). Of note, none with hematoxylin-eosin for the demonstration of hippocampal cytoarchitecture and atrophic neurons of the aforementioned EE studies used (Fernández-Teruel et al., 1997). The red-blue arrowheads show neurons with normal morphological isolated animals as controls (i.e., in all features, in contrast with atrophic neurons–indicated by the blue arrow- displaying a dystrophic morphology with discernible retraction of the cell body and increased eccentricity. Note that Y rats have cases they used animals housed in groups normal neurons, whereas A rats show neuronal atrophy (i.e. neurodegeneration), which is prevented of > 2 per cage), which improves the by NH and EE treatments (as well as by combining both treatments; not shown; Fernández-Teruel et al., possible translatability of their findings to 1997). The semi-quantitative evaluation of neuronal atrophy in several sections (from medial to caudal humans. hippocampus), per rat and experimental group, from CA1, CA2, CA4, fascia dentata and the hylus, can be seen in Fernández-Teruel et al. (1997, Table IV). In short, we used a scoring scale of “–” (no atrophy, Given the increased vulnerability of 0 points) and “+, ++, +++, ++++” (1–4 points of neuronal atrophy, for each section and rat of a given male subjects to perinatal brain insults experimental group). Results: According to this scoring method, and pooling the results from both RLA/ Verh and RHA/Verh rats, the 3 treated (NH, EE and NH + EE) groups and the 5 hippocampal regions, the (Muntsant et al., 2019), and that most mean neuronal atrophy scores were: Y rats, 0.5; A rats, 3.2; “treated and aged” (NH, EE or NH + EE) studies have used only one sex for analysis groups, 0.7 (P < 0.05 between the “treated and aged” group and the A group; see Table IV by Fernández- in this field (an exception is Muntsant Teruel et al., 1997). These anti-neurodegeneration effects were paralleled by complete prevention of the et al., 2019), it is necessary to design age-related hippocampus-dependent spatial learning/memory deficits in NH-, EE- and NH + EE-treated protocols including sexual dimorphism rats (Fernández-Teruel et al., 1997; figure partially adapted from Fernández-Teruel et al., 1997). as an objective of study. Moreover, more precise and unbiased (stereological) al., 2002). But, are these early sensory- effects were statistically similar between methods of neuropathological analysis are enriched treatments able to reverse or both sexes, which could be because the desirable for future studies. attenuate neuronal damage produced authors did not use unbiased stereological by brain insults? Brain injury induced quantification procedures (Muntsant et Conclusions and perspectives: Enriched by perinatal hypoxia-ischemia (HI) is an al., 2019). sensory stimulation, applied during early brain insult that is directly related the neonatal (and even prenatal), pre- The findings by Muntsant et al. (2019) to perinatal morbidity and various neuro- pubertal or adolescent periods, most are generally in line with the study by commonly in the form of massage therapy, developmental deficits, and preterm Rodrigues et al. (2004), who showed that NH or EE (involving soft tactile and infants are at increased risk of HI injury. postnatal tactile (NH-like) stimulation multisensory stimulation), has a dramatic Male human infants are more vulnerable of male rats enduringly prevented the and long lasting impact on development, than females to brain insult. In one study, HI deleterious effects on hippocampal neurodevelopment and neuroplasticity. male and female mice were submitted and dentate gyrus volume in adulthood Depending upon the particular treatments to HI (PND7) and NH treatment (PND1- (Rodrigues et al., 2004). HI-induced and whether they are applied to human 21). Sensorimotor, behavioral, cognitive neurodegeneration is attributed to infants or rodents, such effects are (among and brain neuropathological measures excessive glutamate function and calcium others): (i) increased growth hormone, were taken at PND70–90 (Muntsant et influx (leading to excitotoxicity). In this IGF-1 and weight gain; (ii) improved al., 2019). Male mice appeared to be regard, we have found suggestive evidence cortical maturation/neuroplasticity; more vulnerable to HI-induced long-term that NH treatment enduringly protects (iii) reduced stress-related behaviors memory impairment, and NH attenuated against N-methyl-D-aspartate-induced and hypothalamus-pituitary-adrenal- such a deficit more clearly in males than seizures in rats (Fernández-Teruel et al., axis activity; (iv) increased levels of in females (Muntsant et al., 2019). NH treatment significantly attenuated HI- 2002). neurotrophic factors; (v) increased brain induced neuropathology in several brain Remarkably, prenatal and early postnatal neuroregeneration following brain insults regions (hippocampus, thalamus, caudate/ EE in male rats has also been found to (e.g., HI); (vi) increased hippocampal putamen, neocortex, corpus callosum) enduringly attenuate the HI-induced neurogenesis and cognitive function; and in males, whereas the effect of NH was deleterious neurodevelopmental and (vii) decreased age-related hippocampal also significant but of lower magnitude in cognitive effects. The treatment also neurodegeneration and cognitive females (corpus callosum and neocortex). attenuates the hippocampal molecular impairments. A recent neurobiological However, the neuropathological HI and cellular damage produced by HI, m o d e l p ro p o s e s t h a t e a r l y ta c t i l e NEURAL REGENERATION RESEARCH｜Vol 17｜No. 6｜June 2022｜1249 NEURAL REGENERATION RESEARCH www.nrronline.org Perspective and multisensory stimulation (NH or neuroplasticity observed in rodents are Fernández-Teruel A, Giménez-Llort L, Escorihuela EE) enhance glutamate N-methyl-D- generalizable to humans. This will require RM, Gil L, Aguilar R, Steimer T, Tobeña A aspartate receptor-mediated synaptic more comprehensive and longitudinal (2002) Early-life handling stimulation and environmental enrichment: Are some of their a c t i v i t y / p l a st i c i t y ( e . g . , l o n g te r m clinical studies, which also include more effects mediated by similar neural mechanisms? synaptic potentiation), which modulates direct measures of brain function as well Pharmacol Biochem Behav 73:233-245. dopaminergic, opioid and serotoninergic as neuroendocrine parameters, along Field T, Diego M, Hernandez-Reif M, Dieter JNI, pathways in limbic areas and other regions the lines (for example) of the study by Kumar AM, Schanberg S, Kuhn C (2008) Insulin (e.g., prefrontal cortex) within the neural Guzzetta et al. (2009). and insulin-like growth factor-1 increased in reward systems. The resulting enduring preterm neonates following massage therapy. J st r u c t u ra l c h a n ge s a re s u p p o r te d / The author gratefully acknowledges Dev Behav Pediatr 29:463-466 maintained by neurotrophic factors (e.g. support from grants PSI2017-82257-P, Finlayson F, Olsen J, Dusing SC, Guzzetta brain-derived neurotrophic factor), whose PID2020-114697GB-I00, and 2017SGR- A, Eeles A, Spittle A (2020) Supporting function may in turn be facilitated by the 1586 (to AFT). Play, Exploration, and Early Development Intervention (SPEEDI) for preterm infants: a above activated serotoninergic circuits (Fu feasibility randomised controlled trial in an and Depue 2019). Alberto Fernández-Teruel* Department of Psychiatry and Forensic Medicine Australian context. Early Hum Dev doi: 10.1016/ Whatever the specific neuro-molecular & Institute of Neurosciences, School of Medicine, j.earlhumdev.2020.105172. mechanisms, given the enormous and Autonomous University of Barcelona, Bellaterra, Fu Y, Depue RA (2019) A novel neurobehavioral long-term neuroplasticity potential Barcelona, Spain framework of the effects of positive early (particularly according to animal studies) *Correspondence to: Alberto Fernández-Teruel, postnatal experience on incentive and PhD, Albert.fernandez.teruel@uab.cat. consummatory reward sensitivity. Neurosci of massage/tactile stimulation (NH) https://orcid.org/0000-0001-5993-7058 Biobehav Rev 107:615-640. and EE, this allows proposing that Guzzetta A, Baldini S, Bancale A, Baroncelli L, these interventions may have a future (Alberto Fernández-Teruel) Date of submission: March 15, 2021 Ciucci F, Ghirri P, Putignano E, Sale A, Viegi A, important value in clinical conditions. Berardi N, Boldrini A, Cioni G, Maffei L (2009) Date of decision: April 21, 2021 Massage therapy is increasingly being Date of acceptance: June 19, 2021 Massage accelerates brain development and applied in infant neonatal care units with Date of web publication: November 12, 2021 the maturation of visual function. J Neurosci positive results (Guzzetta et al., 2009; 29:6042- 6051. Niemi, 2017). Most interestingly, some https://doi.org/10.4103/1673-5374.327336 Meaney MJ, Aitken DH, Berkel C, Bhatnagar S, forms of EE interventions are also being How to cite this article: Fernández-Teruel A Sapolsky R (1988) Effects of neonatal handling evaluated in clinical controlled trials. (2022) The power of “touch” and early enriched on age-related impairments associated with the stimulation: neuroplasticity effects in rodents and hippocampus. Science 239:766-768. It is worth mentioning, in that regard, preterm infants. Neural Regen Res 17(6):1248-1250. Muntsant A, Shrivastava K, Recasens M, Giménez- the pilot randomized controlled trials Llort L (2019) Severe perinatal hypoxic-ischemic carried out by Finlayson, Dusing and Copyright license agreement: The Copyright License Agreement has been signed by the author brain injury induces long-term sensorimotor colleagues (Finlayson et al., 2020). In both deficits, anxiety-like behaviors and cognitive before publication. randomized controlled trials (Australia, and Plagiarism check: Checked twice by iThenticate. impairment in a sex-, age- and task-selective Virginia, USA) the authors have evaluated Peer review: Externally peer reviewed. manner in C57BL/6 mice but can be modulated the effects of an EE-like program, named Open access statement: This is an open access by neonatal handling. Front Behav Neurosci SPEEDI (“Supporting play, exploration, journal, and articles are distributed under the 13:7. and early development intervention”), terms of the Creative Commons Attribution- Niemi AN (2017) Review of randomized controlled which involves multisensory stimulation NonCommercial-ShareAlike 4.0 License, which trials of massage in preterm infants. Children allows others to remix, tweak, and build upon the 4:21. of preterm infants (5 days/week) starting work non-commercially, as long as appropriate Rodrigues AL, Arteni NS, Abel C, Zylbersztejn D, in the neonatal care unit and continuing Chazan R, Viola G, Xavier L, Achaval M, Netto at home, for a total of approximately credit is given and the new creations are licensed under the identical terms. CA (2004) Tactile stimulation and maternal 15 weeks (Finlayson et al., 2020, and separation prevent hippocampal damage in rats Open peer reviewer: Luz Elena Durán‐Carabali, references therein). The findings of these Universidade Federal do Rio Grande do Sul, Brazil. submitted to neonatal hypoxia-ischemia. Brain randomized controlled trials are very Additional file: Open peer review report 1. Res 1002:94-99. promising, showing the superiority of the Rule L, Yang J, Watkin H, Hall J, Brydges NM (2020) SPEEDI vs. “usual care group” in some Environmental enrichment rescues survival and measures of problem-solving behavior, References function of adult-born neurons following early and motor, receptive and expressive Durán-Carabali LE, Kawa Odorcyk F, Greggio S, life stress. Mol Psychiatry doi: 10.1038/s41380- Teribele Venturin G, Farias Sanches E, Garcia 020-0718-4. communication scores at approximately SG, Soares-Carvalho A, Avila-Pedroso T, de Schanberg SM, Field TM (1987) Sensory 1-month follow-up (Finlayson et al., 2020, Sá Couto-Pereira N, Costa da Costa J, Dalmaz deprivation stress and supplemental stimulation and references therein). This shows C, Rigon-Zimmer E, Netto CA.(2020) Pre- in the rat pup and preterm human neonate. how EE-like protocols, “conceptually” and early postnatal enriched environmental Child Development 58:1431-1447. similar to those used in rodent research, experiences prevent neonatal hypoxia-ischemia Weaver IC, D’Alessio AC, Brown SE, Hellstrom may be used in human infants, and late neurodegeneration via metabolic and IC, Dymov S, Sharma S, Szyf M, Meaney MJ indirectly suggests that the SPEEDI neuroplastic mechanisms. J Neurochem doi: (2007) The transcription factor nerve growth stimulation program might optimize 10.1111/jnc.15221. factor-inducible protein A mediates epigenetic neurodevelopmental processes, thus Fernández-Teruel A, Escorihuela RM, Castellano programming: altering epigenetic marks by providing the basis for conducting larger B, González B, Tobeñaa A (1997) Neonatal immediate-early genes. J Neurosci 27:1756- handling and environmental enrichment effects 1768. clinical trials (Finlayson et al., 2020, and on emotionality, novelty/reward seeking, references therein). and age-related cognitive and hippocampal P-Reviewer: Duran-Carabali LE; C-Editors: Zhao M, There is still a long way to go to establish impairments: focus on the Roman rat lines. Liu WJ, Qiu Y; T-Editor: Jia Y whether the long lasting effects of NH and Behav Genet 27:513-525. EE on neurobehavioral development and 1250 ｜NEURAL REGENERATION RESEARCH｜Vol 17｜No. 6｜June 2022