- Email: [email protected]
Asymmetrical Brain Plasticity: Physiology and Pathology
Journal Pre-proofs Review Asymmetrical brain plasticity: physiology and pathology M. Esteves, E. Ganz, N. Sousa, H. Leite-Almeida PII: DOI: Reference:
S0306-4522(20)30042-7 https://doi.org/10.1016/j.neuroscience.2020.01.022 NSC 19481
To appear in:
Neuroscience
Received Date: Revised Date: Accepted Date:
27 June 2019 11 January 2020 14 January 2020
Please cite this article as: M. Esteves, E. Ganz, N. Sousa, H. Leite-Almeida, Asymmetrical brain plasticity: physiology and pathology, Neuroscience (2020), doi: https://doi.org/10.1016/j.neuroscience.2020.01.022
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 IBRO. Published by Elsevier Ltd. All rights reserved.
Title: Asymmetrical brain plasticity: physiology and pathology
Esteves Ma,b,c, Ganz Ea,b,c, Sousa Na,b,c and Leite-Almeida Ha,b,c
aLife
and Health Sciences Research Institute (ICVS), School of Medicine, University of
Minho, Campus de Gualtar, Braga 4710-057, Portugal; bICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal; cClinical Academic Center – Braga, Braga, Portugal
Corresponding author: Hugo Leite-Almeida; Life and Health Sciences Research Institute (ICVS); Universidade do Minho; Campus de Gualtar; 4710-057 Braga; Portugal; Telephone:+351253604931; Email: [email protected]
Key words: cognitive function, laterality, recovery, aging, training, maladaptation
Abstract The brain is inherently asymmetrical. How that attribute, manifest both structurally ( volumetric, cytological, molecular) as well as functionally, relates to cognitive function, is not fully understood. Since the early descriptions of Paul Broca and Marc Dax it has been known that the processing of language in the brain is fundamentally asymmetrical. Contemporary imaging studies have corroborated early observations, and have also revealed significant functional links to multiple other systems, such as those sub serving memory or emotion. Recent studies have demonstrated that laterality is both plastic and adaptive. Learning and training have shown to effect regional changes in asymmetry, such as that observed in the volume of the planum temporale associated with musical practice. Increasing task complexity has been demonstrated to induce recruitment of contralateral regions, suggesting that laterality is a manifestation of functional reserve. Indeed, in terms of cognitive function, successful aging is often associated with a reduction of asymmetrical activity. The goal of this review is to survey and critically appraise the current literature addressing brain laterality, both morphological and functional, with particular emphasis on the asymmetrical plasticity associated with environmental factors and training. The plastic recruitment of contralateral areas associated with aging and unilateral lesions will be discussed in the context of the loss of asymmetry as a compensatory mechanism, and specific instances of maladaptive plasticity will be explored.
Introduction Gross examination of the brain reveals it to be asymmetrical, with the right frontal and the left occipital lobes extending across the midline, as if the entire structure is twisted in counterclockwise manner, a phenomenon often called the Yakovlevian torque (LeMay, 1976;Toga and Thompson, 2003). Asymmetries in the central nervous system are present at virtually all levels of structure and function, including regional volumes (Esteves et al., 2017;Esteves et al., 2019a;Goldberg et al., 2013;Good et al., 2001;Raz et al., 2004;Takao et al., 2011a;Watkins et al., 2001), cortical thickness (Chiarello et al., 2016;Kong et al., 2018;Luders et al., 2006;Plessen et al., 2014;Zhou et al., 2013), connectivity (Buchel et al., 2004;Ocklenburg et al., 2013;Takao et al., 2011a;Takao et al., 2011b;Thiebaut de Schotten et al., 2011) as well as cellular and molecular organization (Chance, 2014). Broadly defined, brain asymmetry refers to structural or functional differences between homotopic areas in the left and right hemispheres. Arguably, the most well-described example of an asymmetrically organized function is that of language, which in more than 80% of individuals is processed predominantly in the left hemisphere (Hugdahl and Westerhausen, 2016). This hemispheric specialization appears to be functionally relevant, having been demonstrated to be advantageous in the execution of verbal tasks regardless of the direction of asymmetry (i.e. both left and right biases are associated with better function) (Hirnstein et al., 2013;Mellet et al., 2014). Processing asymmetry has been observed in a broad range of functional processes and attributes including: episodic memory (left dominant for encoding and right for retrieval) (Habib et al., 2003), pseudoneglect (right) (Zago et al., 2017), emotional valence (left: positive/approach, right: for negative/avoidance) (Berkman and Lieberman, 2010;Brunoni et al., 2016;Schutter, 2009), impulsivity (right) (Gordon, 2015), risk-taking (left) (Telpaz and Yechiam, 2014), and face processing (right) (Yovel et al., 2008;Zhen et al., 2015). Asymmetry of lateralized functional specialization has been hypothesized to confer evolutionary advantage via a number of candidate mechanisms, including: duplication avoidance in order to maximize brain tissue usage (Denenberg, 1981;Vallortigara et al., 2011), reduction of computation time by avoiding trans-callosal transmission (Ringo et al., 1994), or by increasing the capacity for performing multiple simultaneous tasks through partitioning (Vallortigara et al., 2011). It is important to know however, that no function is 100 % lateralized, and instead are characterized by greater involvement of one hemisphere, but also involving participation of the other. Possible explanations of this fact include the potential requirement that the function be integrated with processes occurring in the contralateral hemisphere, that complete lateralization would increase the vulnerability to lesion-induced deficits (Saur et al.,
2006;Thulborn et al., 1999) or that the ability to plastically improve function in response to lesion or training would be impaired (Ellis et al., 2013;Hull and Vaid, 2007;Ohnishi et al., 2001). In this review, we will summarize the literature regarding asymmetric plasticity, both that which occurs physiologically, such as with training, as well as what manifest as a response to a destructive lesion or evolving pathological process. Emphasis will be placed on the understanding of its role in reconciling functional demand with available neural substrate.
Environment and training Early life environment, including that in utero, play a crucial role in the development of brain asymmetry. Amongst the most relevant factors are light, posture, and certain hormones (Duboc et al., 2015;Gunturkun and Ocklenburg, 2017). One striking example is the effect of asymmetrical light exposure upon the development of the chick visual system. During the course of maturation within the egg, the right eye is exposed to light and the left is occluded. The asymmetry results in visual pathway projections which differ dramatically one from another, and subsequently manifest as functional specialization for each eye: left for predator and right for food discrimination (Concha et al., 2012). On the other hand, stimuli which are not inherently lateralized may lead to functional and structural manifestations. Cognitive stimulation in the form of handling during neonatal development, or environmental enrichment, has been shown to increase right (but not left) hippocampus short and long-term potentiation (LTP) (Tang et al., 2008), as well as to increase the volumetric asymmetry in the same direction (Verstynen et al., 2001). At cognitive and behavioral levels, handling results in left paw preference (Tang and Verstynen, 2002) – see also (Cunha et al., 2017) regarding paw preference at population level in the rat – and is associated with social memory (Tang and Reeb, 2004;Tang et al., 2003) in association with the dynamics of right-turning in a novel environment (Tang and Reeb, 2004;Tang et al., 2003), as well as with corticosterone levels (Tang et al., 2003). Neonatal environment manipulation demonstrated to be linked to a lateralized response to stress. If dopamine (DA) receptors are blocked in the left, but not right, infralimbic cortex, environmentally enriched animals manifest an abnormally low increase in adrenocorticotropic hormone (ACTH) plasma levels and faster corticosterone reduction in response to acute stress. In animals not subject to neonatal enrichment, DA metabolism in the prefrontal cortex (PFC) is asymmetric, with activity seen to be greater on the left (Sullivan and Dufresne, 2006). A continuous stressor (repeated restrain) results in the inversion of this asymmetry (Sullivan and Dufresne, 2006), while also leading to a reduction in volume of the left, but not right, cingulate
cortex (Cerqueira et al., 2005), suggesting a more complex, bilateral relationship between the lateralized PFC and stress. Much less information is available regarding the environmental influence upon laterality in early human development. In contrast to the described influence of neonatal environment upon lateralization in the rat, human fetal thumb-sucking preference appears to be a strong predictor of later handedness (Hepper et al., 2005), suggesting that this particular phenotype may be independent of environmental influence. On the other hand, in children and adults, the training of asymmetrically-processed functions has been associated with asymmetric plasticity. Musicians with perfect pitch, for example, show increased leftward asymmetry of the planum temporale (i.e. left volume > right) (Keenan et al., 2001;Schlaug et al., 1995), attributed primarily to reduced volume in the right hemisphere (Keenan et al., 2001). It is not clear whether the asymmetry is due to early music training-induced plasticity, or is a consequence of in utero development (Keenan et al., 2001). Music processing has been shown to induce both left supramarginal gyrus (Ellis et al., 2013) and planum temporale (Ohnishi et al., 2001) activation. The observed asymmetry is a function of the cumulative number of hours of musical practice and age of musical training initiation, respectively, and may thus be a consequence of regional plastic changes. Similarly, the learning of a second language also has been associated with lateralized plasticity. A large meta-analysis has demonstrated that early bilinguals (those who learned both languages before 6 years of age) demonstrate a profile of bilateral activation for both languages, while in those who acquire the second language later, left hemisphere involvement is greater, accompanied by lower second language proficiency (Hull and Vaid, 2007). The finding would appear to suggest that there is greater plasticity at a younger age, leading to early recruitment of the right hemisphere, which in turn, results in higher performance at increased cognitive load. In the case of spatial memory, London taxi drivers who had acquired intensive navigation information and experience were found to have an increased volume of right posterior hippocampal gray matter (Maguire et al., 2000;Maguire et al., 2006). In summary, accumulating evidence across multiple species (Table 1) suggests (i) that lateralized stimuli during development induce hemispheric specialization of function; that early-life environment influences (ii) brain structure and function, (iii) behavior, and (iv) HPA axis modulation by higher cortical structures. Training has been found to asymmetrically modulate both (v) structure and function , presumably to facilitate performance of the specific, learned tasks. The mechanisms underlying environment and training-induced lateralized plasticity remain elusive. Studies of synaptic plasticity in the mouse hippocampus have delineated lateralization phenomena which may play a role. It has been demonstrated that hippocampal
LTP induces CA3-CA1 synapse strengthening only from inputs originated in the left, but not the right, CA3 (Kohl et al., 2011;Shipton et al., 2014). The finding has been associated with the differential expression of GluN2B at CA1 synapses targeted by projections arriving from the left and right CA3 (Kohl et al., 2011), as well as with the ability to perform a spatial long-term memory task (Shipton et al., 2014). The observations suggest that pre-existing asymmetries in receptors or associated pathways may be linked to laterality and manifest sensitivity to stimuli. It is of significance that while these observations were manifest in C57BL/6 mice, they could not be reproduced in Lister-Hooded rats, thus suggesting that the responsible mechanisms may be species and/or strain specific (Martin et al., 2019).
Aging Age-related decline of such functions as processing speed and encoding of episodic memories is well-recognized (Hedden and Gabrieli, 2004). It has been observed, however, that such decline is highly variable from subject to subject, a finding which has been attributed to individual variation in the (in)ability to recruit additional regions to compensate for loss of function. Cabeza and colleagues reported that older subjects who recruit the PFC bilaterally during the performance of a verbal memory task, manifest performance levels similar to younger subjects, in whom activation is lateralized (Cabeza, 2002;Cabeza et al., 2002). Those older subjects manifesting lateralized recruitment, on the other hand, show decreased performance. The findings suggest that age-related contralateral activation has an adaptive role, and gave rise to the Hemispheric Asymmetry Reduction in Older Adults (HAROLD) model (Cabeza, 2002;Cabeza et al., 2002). However, when a whole-brain analysis is performed, the observed bilateral activation seem to be relatively unspecific. Older subjects recruit additional regions in both hemispheres in order to achieve higher performance, to the formulation of an alternative explanation, known as the Compensation Related Utilization of Neural Circuits Hypothesis (CRUNCH) (Reuter-Lorenz and Cappell, 2008). Regardless of model specifics, it seems clear that the ability to plastically adapt, and to bring about the recruitment of additional regions, including those in the contralateral hemisphere, plays a significant role in the maintenance of functions that are normally found to be lateralized in younger subjects. Additional evidence relating to asymmetry in the elderly comes from manipulation studies. In one such experiment, disruption of the ipsilateral motor cortex using cathodal transcranial direct current stimulation (ctDCS) slowed learning of a complex unimanual motor task in aged, but not young subjects (Zimerman et al., 2014). When the aged cohort was further stratified, the
disruption was more prominent in the eldest participants (Zimerman et al., 2014). In a naming test, repetitive magnetic transcranial stimulation (rTMS) was used to investigate the asymmetrical recruitment of the left dorso-lateral prefrontal cortex. Greater differences between left and right involvement of this structure was correlated with superior performance. Poorly performing elders were mainly affected by left stimulation, while high performers presented a reduced leftward bias (Manenti et al., 2013b). Nevertheless, other work also suggests that these two models may not be applicable to all regions or functions, or that additional factors not currently incorporated into the models may need to be taken into account. A recent study determined that regions found to be asymmetrically (left>right) activated during recall in young subjects, showed the same pattern in older participants, even though the magnitude of the asymmetry was less due to decreased left, rather than increased right, activation. Additionally, the authors found no association between lateralized recruitment and task performance, or of longitudinal memory loss over a period of eight years (Roe et al., 2019). In a study from our lab, we observed that older subjects performing a working memory task showed mainly symmetrical activation, while higher accuracy was seen to be associated with increased (leftward) functional asymmetry of the superior parietal lobule (Esteves et al., 2018). Similarly, training aged subjects to perform a dual task was demonstrated to improve performance, and was accompanied by an increase in (leftward) asymmetry in ventral PFC activation (Erickson et al., 2007). In a series of manipulation studies, rTMS interferent modulation of the left dorsolateral PFC affected encoding of episodic memory in aged low performers, but no differences were found in aged high performers when this was applied to either hemisphere (Manenti et al., 2011). The same group has demonstrated that stimulation of the left or right dorsolateral PFC or parietal cortex using transcranial direct current stimulation (tDCS) improved episodic memory retrieval in young adults, whereas in older subjects, the effect was found only with left-sided stimulation (Manenti et al., 2013a). The relative roles of the structure and function in age-related plasticity remain unclear. The middle frontal gyrus, for example, has been observed to lose greater volume on the right than left hemisphere with advancing age. The functional consequences of asymmetrical volume loss and the associations between such volume, such as those associated with regional activation and memory retrieval performance, are demonstrably different for young and old adults (Rajah et al., 2011). In young adults, greater right middle frontal gyrus volume is associated with greater bilateral activity in the dorsolateral PFC and inferior parietal cortex, while in older adults, a larger right middle frontal gyrus is accompanied by decreased activity in the parahippocampal cortex and anterior cingulate. From the functional standpoint, in young adults higher activity in the left
dorsolateral PFC and right inferior parietal cortex is positively correlated with performance, while in older subjects enhanced performance is associated with decreased parahippocampal and anterior cingulate activation (Rajah et al., 2011). The functional models previously cited suggest that, with aging, decreased asymmetry reflects compensatory plasticity and is associated with better cognitive performance. In contrast, we have previously reported that when assessing volume asymmetry in aged subjects, a greater degree of asymmetry was always associated with improved neuropsychological score. The correlation was seen to be valid for a variety of cognitive tasks and attributes including learning and memory (superior frontal gyrus and lateral ventricle), cognitive flexibility (thalamus), vocabulary (posterior cingulate) and depressive mood (insula) (Esteves et al., 2017). Additionally, when longitudinally assessing subcortical plasticity in the same cohort 18 months later, we determined that alterations in cognitive flexibility and more general cognitive performance are correlated with changes in the magnitude of caudate and thalamus structural asymmetry (Esteves et al., 2019a). In conclusion, the role of asymmetrical plasticity in the maintenance of cognitive function during aging remains elusive. Comparisons between young and old, as well as between good and poor aged performers suggest a significant role of the non-dominant hemisphere (see Table 1 for details). Substantial evidence exists supporting the position that the association is more complex than either the HAROLD and CRUNCH models suggest. Additional longitudinal studies, a better understanding of the structure-function relationships, and the assessment of cognitive tasks beyond those of learning and memory, will be of the utmost importance for a more comprehensive understanding of this process.
Lesion-induced plasticity The recovery of function following stroke-induced aphasia in adults has been associated with a left-to-right shift in the activation of language-related regions, particularly when the lesion (of the left hemisphere) is extensive (Crosson et al., 2007) and/or in the early recovery process (Saur et al., 2006). In a similar fashion, activation of the sensorimotor cortex of the non-lesioned hemisphere plays an important role in motor recovery following insult (Cao et al., 1998;Chollet et al., 1991). In rodent models, this phenomenon has been associated with plastic changes, including: increased turnover of mushroom spines (Takatsuru et al., 2009), increased dendritic complexity and length (Biernaskie et al., 2004;Biernaskie and Corbett, 2001), and alterations in the somatosensory receptive fields, accompanied by an increased number of neurons receiving stimulation from multiple limbs (Obi et al., 2018). Human pediatric literature documents the
observation that strokes occurring during school age have, in general, a better prognosis than those occurring in more immature brains, such as those in the perinatal period, which are generally associated with life-long disabilities (Lansing et al., 2004;Pavlovic et al., 2006). It has been suggested that the phenomenon may reflect a delicate balance between greater plasticity at younger ages and the requirement that the younger children must learn for the first time (rather than relearn) the diverse motor and cognitive skills (Dunbar and Kirton, 2018). Structural and functional immaturity at the time of lesion occurrence may also explain why functions are affected differently. Language, for instance, which is highly lateralized in the adult brain (see Introduction), seems to be equally affected by left or right perinatal stroke (Lansing et al., 2004) but often recovers to normal levels (Dunbar and Kirton, 2018;Francois et al., 2019;Pavlovic et al., 2006). Such recovery has been associated with regions in the right hemisphere newly assuming language function, as reflected in observed changes in white matter tracts and connectivity (Francois et al., 2019), as well as with bilateral activation of temporal regions (Raja Beharelle et al., 2010), consistent with both ipsi- and contralateral plasticity. Motor impairment is the leading cause of disability after perinatal stroke and is characterized by very limited recovery (Dunbar and Kirton, 2018;Kirton, 2017). In this situation, contralesional plasticity appears to be mostly maladaptive. Projections from the non-lesioned hemisphere to the paretic limb are associated with poorer motor performance after both perinatal and childhood stroke (Kirton, 2017). In contrast, cognitive, intellectual and behavioral functions, including general cognition (IQ), attention, processing speed or memory, all of which are not clearly lateralized in the adult brain, demonstrate varying degrees of recovery after stroke at young ages (Dunbar and Kirton, 2018;Lansing et al., 2004;Pavlovic et al., 2006). The data on stroke (see Table 2) are suggestive of, and consistent with, identified attributes of asymmetrical plasticity, namely: (i) there is not a linear association between age and lateralized plasticity-related recovery; (ii) in the adult brain, the non-lesioned hemisphere has a transient role in the recovery of lateralized function, consistent with the proposal that completely lateralized specialization increases susceptibility to lesion-induced deficits; (iii) even in an immature brain, highly lateralized functions such as language and motor function, can have completely disparate recovery levels, and (iv) functions that are not typically highly lateralized, show reduced recovery after unilateral lesion. In those instances where compensation from the non-lesioned hemisphere is hindered, it is possible that the failure is a consequence of features intrinsic to the involved circuits, such as the number of intra- and interhemispheric connections, and/or a left/right asymmetry of receptors, dendritic spines, or molecular machinery. Additional
clinical observations, as well as experimental models, offer opportunities to further delineate the mechanisms and processes involved.
Maladaptive plasticity and asymmetry stability Plasticity in the nervous system may be maladaptive (Table 2). For example, noxious input as consequence of injury and/or inflammation, may induce structural and functional changes which lead to the persistence of pain long after the resolution of primary event (Apkarian et al., 2009;Chapman and Vierck, 2017;Kuner and Flor, 2016). The chronic pain thus established is often associated with cognitive deficits and mood disorders – see for instance (Leite-Almeida et al., 2015;Moriarty et al., 2011;Yalcin et al., 2014) –, specific features and consequences of which vary according to the site (left or right) of pain location. Clinical assessments have shown that pain originating in the left is more likely to be associated with anxiety (Gagliese et al., 1995;Schiff and Gagliese, 1994). Rodent studies have replicated this finding and also demonstrated that a chronic neuropathic lesion on the right leads to impairments of working memory, attentional set-shifting and impulsivity (Leite-Almeida et al., 2012). The findings suggest that the lateralized input induces central plasticity asymmetrically. Consistent with this hypothesis is the demonstration that in a rodent model, unilateral neuropathic lesions have been shown to alter resting-state networks in an asymmetrical manner (Baliki et al., 2014). Additionally, orbitofrontal cortex activation during attentional set-shifting has been demonstrated to be shifted to the left in animals with right-sided lesion, resulting in impairment of the ability to perform this task (Leite-Almeida et al., 2014). On the other hand, split-brain individuals (those whose corpora callosa were severed in order to control intractable epilepsy) show negligible duplication of lateralized functions (Gazzaniga, 2005). Instead, the brains of these persons appear to have adopted strategies, such as behavioral cueing, which enable inter-hemispheric collaboration (Volz and Gazzaniga, 2017). Thus, while it is the case that, even in adulthood, external asymmetrical stimuli are able to induce lateralized plasticity, in those individuals who underwent callosotomy, the adaptation seems to be more a behavioral modification rather than one modulated by central plasticity. Observations such as these tend to suggest that asymmetrical plasticity originate not only from communication between hemispheres but also, and possibly primarily, from the periphery (e.g. in the form of pain, light exposure, movement, etc.). Conclusions based upon the functional imaging of callosotomized individuals are, however, largely speculative given the very limited sample size.
Conclusions In conclusion, there is substantial evidence that asymmetry, both structural and functional, is essential for the optimal execution of a wide range of cognitive and emotional processes (Esteves et al., 2019b). Asymmetry improves efficiency while simultaneously conserving functional reserve which might prove essential for recovery from injury in disease. Functional specialization (e.g. through training), as well as rehabilitation, rely on CNS plastic capacity at both intra- and inter-hemispheric levels. Multiple factors influence plastic capacity, an important one of which is the age at which the lesion, stimulus or training occurs. In order to more clearly define the role of asymmetric plasticity, longitudinal studies which emphasize the time parameter of cognitive change (aging: cognitive decline, childhood; cognitive development, training: physiological or rehabilitative) will be essential. Better understanding of the basic mechanisms underlying these processes offers the prospect of facilitating the development of optimal strategies for both rehabilitation and training to task.
Acknowledgments This work was supported by the project NORTE‐01‐0145‐FEDER‐000013 through the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER), and funded by the European Commission (FP7) “SwitchBox ‐ Maintaining health in old age through homeostasis” (Contract HEALTH‐F2‐2010‐259772), and co‐financed by the Portuguese North Regional Operational Program (ON.2 – O Novo Norte), under the National Strategic Reference Framework (QREN), through FEDER, and by the Fundação Calouste Gulbenkian (Portugal) (Contract grant number: P‐139977; project “TEMPO ‐ Better mental health during ageing based on temporal prediction of individual brain ageing trajectories”) and by “PANINI ‐ Physical Activity and Nutrition INfluences In ageing” (European Commission (Horizon 2020), Contract GA 675003). ME was supported by the Fundação para a Ciência e a Tecnologia (FCT) grant SFRH/BD/52291/2013 and Institute for Scientific Information on Coffee (ISCI) grant UMINHO/BPD/45/2018, project ISIC_2017_NS
References
Apkarian AV, Baliki MN, Geha PY (2009), Towards a theory of chronic pain. Prog Neurobiol 87:81-97. Baliki MN, Chang PC, Baria AT, Centeno MV, Apkarian AV (2014), Resting-sate functional reorganization of the rat limbic system following neuropathic injury. Scientific reports 4:6186. Berkman ET, Lieberman MD (2010), Approaching the bad and avoiding the good: lateral prefrontal cortical asymmetry distinguishes between action and valence. Journal of cognitive neuroscience 22:1970-1979. Biernaskie J, Chernenko G, Corbett D (2004), Efficacy of Rehabilitative Experience Declines with Time after Focal Ischemic Brain Injury. The Journal of Neuroscience 24:1245. Biernaskie J, Corbett D (2001), Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth after focal ischemic injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 21:5272-5280.
Brunoni AR, Moffa AH, Fregni F, Palm U, Padberg F, Blumberger DM, Daskalakis ZJ, Bennabi D, et al. (2016), Transcranial direct current stimulation for acute major depressive episodes: meta-analysis of individual patient data. The British journal of psychiatry : the journal of mental science 208:522-531. Buchel C, Raedler T, Sommer M, Sach M, Weiller C, Koch MA (2004), White matter asymmetry in the human brain: a diffusion tensor MRI study. Cerebral cortex (New York, NY : 1991) 14:945-951. Cabeza R (2002), Hemispheric asymmetry reduction in older adults: the HAROLD model. Psychology and aging 17:85-100. Cabeza R, Anderson ND, Locantore JK, McIntosh AR (2002), Aging Gracefully: Compensatory Brain Activity in High-Performing Older Adults. NeuroImage 17:1394-1402. Cao Y, D’Olhaberriague L, Vikingstad EM, Levine SR, Welch KMA (1998), Pilot Study of Functional MRI to Assess Cerebral Activation of Motor Function After Poststroke Hemiparesis. Stroke 29:112-122. Cerqueira JJ, Catania C, Sotiropoulos I, Schubert M, Kalisch R, Almeida OF, Auer DP, Sousa N (2005), Corticosteroid status influences the volume of the rat cingulate cortex - a magnetic resonance imaging study. Journal of psychiatric research 39:451-460. Chance SA (2014), The cortical microstructural basis of lateralized cognition: a review. Frontiers in psychology 5:820. Chapman CR, Vierck CJ (2017), The Transition of Acute Postoperative Pain to Chronic Pain: An Integrative Overview of Research on Mechanisms. J Pain 18:359 e351-359 e338. Chiarello C, Vazquez D, Felton A, McDowell A (2016), Structural asymmetry of the human cerebral cortex: Regional and between-subject variability of surface area, cortical thickness, and local gyrification. Neuropsychologia. Chollet F, Dipiero V, Wise RJS, Brooks DJ, Dolan RJ, Frackowiak RSJ (1991), The functional anatomy of motor recovery after stroke in humans: A study with positron emission tomography. Annals of neurology 29:63-71.
Concha ML, Bianco IH, Wilson SW (2012), Encoding asymmetry within neural circuits. Nat Rev Neurosci 13:832-843. Crosson B, McGregor K, Gopinath KS, Conway TW, Benjamin M, Chang Y-L, Moore AB, Raymer AM, et al. (2007), Functional MRI of language in aphasia: a review of the literature and the methodological challenges. Neuropsychology review 17:157-177. Cunha AM, Esteves M, das Neves SP, Borges S, Guimaraes MR, Sousa N, Almeida A, LeiteAlmeida H (2017), Pawedness Trait Test (PaTRaT)-A New Paradigm to Evaluate Paw Preference and Dexterity in Rats. Frontiers in behavioral neuroscience 11:192. Denenberg VH (1981), Hemispheric laterality in animals and the effects of early experience. Behavioral and Brain Sciences 4:1-21. Duboc V, Dufourcq P, Blader P, Roussigne M (2015), Asymmetry of the Brain: Development and Implications. Annual review of genetics 49:647-672. Dunbar M, Kirton A (2018), Perinatal stroke: mechanisms, management, and outcomes of early cerebrovascular brain injury. The Lancet Child & adolescent health 2:666-676. Ellis RJ, Bruijn B, Norton AC, Winner E, Schlaug G (2013), Training-mediated leftward asymmetries during music processing: a cross-sectional and longitudinal fMRI analysis. NeuroImage 75:97-107. Erickson KI, Colcombe SJ, Wadhwa R, Bherer L, Peterson MS, Scalf PE, Kim JS, Alvarado M, et al. (2007), Training-induced plasticity in older adults: effects of training on hemispheric asymmetry. Neurobiology of aging 28:272-283. Esteves M, Magalhaes R, Marques P, Castanho TC, Portugal-Nunes C, Soares JM, Almeida A, Santos NC, et al. (2018), Functional Hemispheric (A)symmetries in the Aged Brain-Relevance for Working Memory. Frontiers in aging neuroscience 10:58. Esteves M, Marques P, Magalhaes R, Castanho TC, Soares JM, Almeida A, Santos NC, Sousa N, et al. (2017), Structural laterality is associated with cognitive and mood outcomes: An assessment of 105 healthy aged volunteers. NeuroImage 153:86-96.
Esteves M, Moreira PS, Marques P, Castanho TC, Magalhaes R, Amorim L, Portugal-Nunes C, Soares JM, et al. (2019a), Asymmetrical subcortical plasticity entails cognitive progression in older individuals. Aging Cell 18:e12857. Esteves M, Sousa N, Leite-Almeida H (2019b), Righteousness (and lefteousness) of the old brain. Aging (Albany NY) 11:4779-4780. Francois C, Ripolles P, Ferreri L, Muchart J, Sierpowska J, Fons C, Sole J, Rebollo M, et al. (2019), Right Structural and Functional Reorganization in Four-Year-Old Children with Perinatal Arterial Ischemic Stroke Predict Language Production. eNeuro 6. Gagliese L, Schiff BB, Taylor A (1995), Differential consequences of left- and right-sided chronic pain. The Clinical journal of pain 11:201-207. Gazzaniga MS (2005), Forty-five years of split-brain research and still going strong. Nat Rev Neurosci 6:653-659. Goldberg E, Roediger D, Kucukboyaci NE, Carlson C, Devinsky O, Kuzniecky R, Halgren E, Thesen T (2013), Hemispheric asymmetries of cortical volume in the human brain. Cortex; a journal devoted to the study of the nervous system and behavior 49:200-210. Good CD, Johnsrude I, Ashburner J, Henson RN, Friston KJ, Frackowiak RS (2001), Cerebral asymmetry and the effects of sex and handedness on brain structure: a voxel-based morphometric analysis of 465 normal adult human brains. NeuroImage 14:685-700. Gordon HW (2015), Laterality of Brain Activation for Risk Factors of Addiction. Current drug abuse reviews. Gunturkun O, Ocklenburg S (2017), Ontogenesis of Lateralization. Neuron 94:249-263. Habib R, Nyberg L, Tulving E (2003), Hemispheric asymmetries of memory: the HERA model revisited. Trends in cognitive sciences 7:241-245. Hedden T, Gabrieli JD (2004), Insights into the ageing mind: a view from cognitive neuroscience. Nat Rev Neurosci 5:87-96.
Hirnstein M, Hugdahl K, Hausmann M (2013), How brain asymmetry relates to performance – a large-scale dichotic listening study. Frontiers in psychology 4:997. Hugdahl K, Westerhausen R (2016), Speech processing asymmetry revealed by dichotic listening and functional brain imaging. Neuropsychologia 93:466-481. Hull R, Vaid J (2007), Bilingual language lateralization: a meta-analytic tale of two hemispheres. Neuropsychologia 45:1987-2008. Keenan JP, Thangaraj V, Halpern AR, Schlaug G (2001), Absolute pitch and planum temporale. NeuroImage 14:1402-1408. Kirton A (2017), Advancing non-invasive neuromodulation clinical trials in children: Lessons from perinatal stroke. European Journal of Paediatric Neurology 21:75-103. Kohl MM, Shipton OA, Deacon RM, Rawlins JN, Deisseroth K, Paulsen O (2011), Hemispherespecific optogenetic stimulation reveals left-right asymmetry of hippocampal plasticity. Nature neuroscience 14:1413-1415. Kong XZ, Mathias SR, Guadalupe T, Glahn DC, Franke B, Crivello F, Tzourio-Mazoyer N, Fisher SE, et al. (2018), Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium. Proceedings of the National Academy of Sciences of the United States of America 115:E5154-e5163. Kuner R, Flor H (2016), Structural plasticity and reorganisation in chronic pain. Nat Rev Neurosci 18:20-30. Lansing AE, Max JE, Delis DC, Fox PT, Lancaster J, Manes FF, Schatz A (2004), Verbal learning and memory after childhood stroke. Journal of the International Neuropsychological Society : JINS 10:742-752. Leite-Almeida H, Cerqueira JJ, Wei H, Ribeiro-Costa N, Anjos-Martins H, Sousa N, Pertovaara A, Almeida A (2012), Differential effects of left/right neuropathy on rats' anxiety and cognitive behavior. Pain 153:2218-2225.
Leite-Almeida H, Guimaraes MR, Cerqueira JJ, Ribeiro-Costa N, Anjos-Martins H, Sousa N, Almeida A (2014), Asymmetric c-fos expression in the ventral orbital cortex is associated with impaired reversal learning in a right-sided neuropathy. Molecular pain 10:41. Leite-Almeida H, Pinto-Ribeiro F, Almeida A (2015) Animal Models for the Study of Comorbid Pain and Psychiatric Disorders. In: Modern trends in pharmacopsychiatry, vol. 30, pp. 1-21. LeMay M (1976), Morphological cerebral asymmetries of modern man, fossil man, and nonhuman primate. Annals of the New York Academy of Sciences 280:349-366. Luders E, Narr KL, Thompson PM, Rex DE, Jancke L, Toga AW (2006), Hemispheric asymmetries in cortical thickness. Cerebral cortex (New York, NY : 1991) 16:1232-1238. Maguire EA, Gadian DG, Johnsrude IS, Good CD, Ashburner J, Frackowiak RS, Frith CD (2000), Navigation-related structural change in the hippocampi of taxi drivers. Proceedings of the National Academy of Sciences of the United States of America 97:4398-4403. Maguire EA, Woollett K, Spiers HJ (2006), London taxi drivers and bus drivers: a structural MRI and neuropsychological analysis. Hippocampus 16:1091-1101. Manenti R, Brambilla M, Petesi M, Ferrari C, Cotelli M (2013a), Enhancing verbal episodic memory in older and young subjects after non-invasive brain stimulation. Frontiers in aging neuroscience 5:49. Manenti R, Brambilla M, Petesi M, Miniussi C, Cotelli M (2013b), Compensatory networks to counteract the effects of ageing on language. Behavioural brain research 249:22-27. Manenti R, Cotelli M, Miniussi C (2011), Successful physiological aging and episodic memory: a brain stimulation study. Behavioural brain research 216:153-158. Martin SJ, Shires KL, da Silva BM (2019), Hippocampal Lateralization and Synaptic Plasticity in the Intact Rat: No Left–Right Asymmetry in Electrically Induced CA3-CA1 Long-Term Potentiation. Neuroscience 397:147-158.
Mellet E, Zago L, Jobard G, Crivello F, Petit L, Joliot M, Mazoyer B, Tzourio-Mazoyer N (2014), Weak language lateralization affects both verbal and spatial skills: an fMRI study in 297 subjects. Neuropsychologia 65:56-62. Moriarty O, McGuire BE, Finn DP (2011), The effect of pain on cognitive function: a review of clinical and preclinical research. Prog Neurobiol 93:385-404. Obi K, Amano I, Takatsuru Y (2018), Role of dopamine on functional recovery in the contralateral hemisphere after focal stroke in the somatosensory cortex. Brain research 1678:146-152. Ocklenburg S, Hugdahl K, Westerhausen R (2013), Structural white matter asymmetries in relation to functional asymmetries during speech perception and production. NeuroImage 83:1088-1097. Ohnishi T, Matsuda H, Asada T, Aruga M, Hirakata M, Nishikawa M, Katoh A, Imabayashi E (2001), Functional Anatomy of Musical Perception in Musicians. Cerebral Cortex 11:754–760. Pavlovic J, Kaufmann F, Boltshauser E, Capone Mori A, Gubser Mercati D, Haenggeli CA, Keller E, Lutschg J, et al. (2006), Neuropsychological problems after paediatric stroke: two year follow-up of Swiss children. Neuropediatrics 37:13-19. Plessen KJ, Hugdahl K, Bansal R, Hao X, Peterson BS (2014), Sex, age, and cognitive correlates of asymmetries in thickness of the cortical mantle across the life span. The Journal of neuroscience : the official journal of the Society for Neuroscience 34:6294-6302. Raja Beharelle A, Dick AS, Josse G, Solodkin A, Huttenlocher PR, Levine SC, Small SL (2010), Left hemisphere regions are critical for language in the face of early left focal brain injury. Brain : a journal of neurology 133:1707-1716. Rajah MN, Languay R, Grady CL (2011), Age-related changes in right middle frontal gyrus volume correlate with altered episodic retrieval activity. The Journal of neuroscience : the official journal of the Society for Neuroscience 31:17941-17954.
Raz N, Gunning-Dixon F, Head D, Rodrigue KM, Williamson A, Acker JD (2004), Aging, sexual dimorphism, and hemispheric asymmetry of the cerebral cortex: replicability of regional differences in volume. Neurobiology of aging 25:377-396. Reuter-Lorenz PA, Cappell KA (2008), Neurocognitive Aging and the Compensation Hypothesis. Current Directions in Psychological Science 17:177-182. Ringo JL, Doty RW, Demeter S, Simard PY (1994), Time is of the essence: a conjecture that hemispheric specialization arises from interhemispheric conduction delay. Cerebral cortex (New York, NY : 1991) 4:331-343. Roe JM, Vidal-Pineiro D, Sneve MH, Kompus K, Greve DN, Walhovd KB, Fjell AM, Westerhausen R (2019), Age-Related Differences in Functional Asymmetry During Memory Retrieval Revisited: No Evidence for Contralateral Overactivation or Compensation. Cerebral cortex (New York, NY : 1991). Saur D, Lange R, Baumgaertner A, Schraknepper V, Willmes K, Rijntjes M, Weiller C (2006), Dynamics of language reorganization after stroke. Brain : a journal of neurology 129:13711384. Schiff BB, Gagliese L (1994), The consequences of experimentally induced and chronic unilateral pain: reflections of hemispheric lateralization of emotion. Cortex; a journal devoted to the study of the nervous system and behavior 30:255-267. Schlaug G, Jancke L, Huang Y, Steinmetz H (1995), In vivo evidence of structural brain asymmetry in musicians. Science 267:699-701. Schutter DJ (2009), Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: a meta-analysis. Psychological medicine 39:65-75. Shipton OA, El-Gaby M, Apergis-Schoute J, Deisseroth K, Bannerman DM, Paulsen O, Kohl MM (2014), Left-right dissociation of hippocampal memory processes in mice. Proceedings of the National Academy of Sciences of the United States of America 111:15238-15243.
Sullivan RM, Dufresne MM (2006), Mesocortical dopamine and HPA axis regulation: role of laterality and early environment. Brain research 1076:49-59. Takao H, Abe O, Yamasue H, Aoki S, Sasaki H, Kasai K, Yoshioka N, Ohtomo K (2011a), Gray and white matter asymmetries in healthy individuals aged 21-29 years: a voxel-based morphometry and diffusion tensor imaging study. Human brain mapping 32:1762-1773. Takao H, Hayashi N, Ohtomo K (2011b), White matter asymmetry in healthy individuals: a diffusion tensor imaging study using tract-based spatial statistics. Neuroscience 193:291-299. Takatsuru Y, Fukumoto D, Yoshitomo M, Nemoto T, Tsukada H, Nabekura J (2009), Neuronal circuit remodeling in the contralateral cortical hemisphere during functional recovery from cerebral infarction. The Journal of neuroscience : the official journal of the Society for Neuroscience 29:10081-10086. Tang AC, Reeb BC (2004), Neonatal novelty exposure, dynamics of brain asymmetry, and social recognition memory. Developmental psychobiology 44:84-93. Tang AC, Reeb BC, Romeo RD, McEwen BS (2003), Modification of Social Memory, Hypothalamic-Pituitary-Adrenal Axis, and Brain Asymmetry by Neonatal Novelty Exposure. The Journal of Neuroscience 23:8254-8260. Tang AC, Verstynen T (2002), Early life environment modulates 'handedness' in rats. Behavioural brain research 131:1-7. Tang AC, Zou B, Reeb BC, Connor JA (2008), An epigenetic induction of a right-shift in hippocampal asymmetry: selectivity for short- and long-term potentiation but not post-tetanic potentiation. Hippocampus 18:5-10. Telpaz A, Yechiam E (2014), Contrasting losses and gains increases the predictability of behavior by frontal EEG asymmetry. Frontiers in behavioral neuroscience 8:149. Thiebaut de Schotten M, Ffytche DH, Bizzi A, Dell'Acqua F, Allin M, Walshe M, Murray R, Williams SC, et al. (2011), Atlasing location, asymmetry and inter-subject variability of white matter tracts in the human brain with MR diffusion tractography. NeuroImage 54:49-59.
Thulborn KR, Carpenter PA, Just MA (1999), Plasticity of language-related brain function during recovery from stroke. Stroke 30:749-754. Toga AW, Thompson PM (2003), Mapping brain asymmetry. Nat Rev Neurosci 4:37-48. Vallortigara G, Chiandetti C, Sovrano VA (2011), Brain asymmetry (animal). Wiley Interdisciplinary Reviews: Cognitive Science 2:146-157. Verstynen T, Tierney R, Urbanski T, Tang A (2001), Neonatal novelty exposure modulates hippocampal volumetric asymmetry in the rat. Neuroreport 12:3019-3022. Volz LJ, Gazzaniga MS (2017), Interaction in isolation: 50 years of insights from split-brain research. Brain : a journal of neurology 140:2051-2060. Watkins KE, Paus T, Lerch JP, Zijdenbos A, Collins DL, Neelin P, Taylor J, Worsley KJ, et al. (2001), Structural asymmetries in the human brain: a voxel-based statistical analysis of 142 MRI scans. Cerebral cortex (New York, NY : 1991) 11:868-877. Yalcin I, Barthas F, Barrot M (2014), Emotional consequences of neuropathic pain: Insight from preclinical studies. Neurosci Biobehav Rev 47C:154-164. Yovel G, Tambini A, Brandman T (2008), The asymmetry of the fusiform face area is a stable individual characteristic that underlies the left-visual-field superiority for faces. Neuropsychologia 46:3061-3068. Zago L, Petit L, Jobard G, Hay J, Mazoyer B, Tzourio-Mazoyer N, Karnath HO, Mellet E (2017), Pseudoneglect in line bisection judgement is associated with a modulation of right hemispheric spatial attention dominance in right-handers. Neuropsychologia 94:75-83. Zhen Z, Yang Z, Huang L, Kong XZ, Wang X, Dang X, Huang Y, Song Y, et al. (2015), Quantifying interindividual variability and asymmetry of face-selective regions: a probabilistic functional atlas. NeuroImage 113:13-25. Zhou D, Lebel C, Evans A, Beaulieu C (2013), Cortical thickness asymmetry from childhood to older adulthood. NeuroImage 83:66-74.
Zimerman M, Heise KF, Gerloff C, Cohen LG, Hummel FC (2014), Disrupting the ipsilateral motor cortex interferes with training of a complex motor task in older adults. Cerebral cortex (New York, NY : 1991) 24:1030-1036.
Species
Stimulus
Age
Assessment conditions
Age
Behavioral outcomes
Physiological outcomes
References
Chicken
unilateral light stimulation of the eye
In ovo
NA
young (chick)
Specialization of the left and right eyes for predator and food discrimination
Asymmetrical connections of the visual pathways
Concha et al., 2012
NA
young adult
Increased probability of lefthandedness, improved social memory, changed left/right turning dynamics in a novel environment
acute stress/unilateral infralimbic cortex dopamine antagonism
young adult
NA
repeated stress
young adult
NA
handling/environmental enrichment
Neonatal
Rat
chronic hypercortisolism
young adult
NA
adult
NA
perfect pitch
child
NA
young adult
NA
child
melodic and rhythmic discrimination task
child and adult
NA
child
classical music hearing
adult
NA
second language learning
child (<6 years old)
dichotic listening, visual hemifield or dual task
nondefined (metaanalysis)
NA
driving a taxi
adult
NA
adult
NA
old
dual task performance
old
Training improved performance in the task in both young and old groups
old
Association between improved memory performance in older subjects and bilateral
musical training
Human
dual task training
aging
NA
source memory task
Reduced basal corticosterone levels. Increased short- and long-term potentiation of the right hippocampus, decreased leftward volumetric hippocampal asymmetry Reduced increase in ACTH levels and faster corticosterone reduction in handled animals after left manipulation Inversion of prefrontal cortex' asymmetrical dopamine metabolism (right>left in handled animals) Reduced volume of the left cingulate cortex Reduced right planum temporale volume and increased leftward volumetric asymmetry in musicians with perfect pitch in comparison with nonmusicians and musicians without perfect pitch Increased left (but not right) supramarginal gyrus activation in association with hours of musical training Negative correlation between left planum temporale activation and age of training initiation. No associations with duration of musical training. For both languages, bilateral activation in early (<6 years old) and left dominance in later bilinguals. Left hemisphere activation is higher when second language proficiency is lower Positive correlation between right posterior hippocampal volume and time spent as a taxi driver Aged subjects show increased left and decreased right ventral PFC activation during post-training task performance. These changes make the pattern of activation more similar to the adult group of subjects. Activation of right prefrontal cortex in young and lowperforming older subjects. Bilateral activation in high-
Tang and Verstynen, 2002; Tang and Reeb, 2004; Tang et al, 2003; Tang et al., 2008; Verstynen et al., 2001
Sullivan and Dufresne, 2006
Sullivan and Dufresne, 2006 Cerqueira et al., 2005
Keenan et al., 2001; Schlaug et al., 1995
Ellis et al., 2013
Ohnishi et al., 2001
Hull and Vaid, 2007
Maguire et al.,2000; Maguire et al.,2006
Erickson et al., 2007
Cabeza et al., 2002
prefrontal cortex activation (see central outcomes)
NA
complex motor skill learning/ctDCS interference with the ipsilateral motor cortex
old
NA
action naming task/unilateral dorsolateral PFC rTMS
old
NA
encoding and retrieval/unilateral dorsolateral PFC rTMS
old
NA
memory retrieval
old
NA
memory task
old
NA
encoding and retrieval/ unilateral parietal cortex or dorsolateral PFC tDCS
old
NA
memory retrieval
NA
general cognition and cognitive flexibility
old
old
Decreased learning in aged subjects, in comparison with young. Within the aged group, higher disruption in older subjects Improved verbal reaction time and accuracy associated with reduced leftward asymmetry Decreased encoding in low performers when interfering with the left dorsolateral PFC. No effects in high performers or retrieval.
Old subjects have worse task (retrieval) than younger participants
Association between asymmetrical activation and performance (see central outcomes) Improved retrieval in young adults associated with left or right PFC or parietal stimulation. In older subjects, improvements only with left stimulation Age-related alterations in the associations between structure, activation and cognitive performance (see text)
Longitudinal cognitive changes associated with variations in structural asymmetry (see central outcomes)
performing older subjects
NA
Zimerman et al., 2014
NA
Manenti et al., 2013
NA
Manenti et al., 2011
Parietal and frontal regions show left>right activation during recall, independently of age (young vs old). This asymmetry is lower in aged subjects, mostly due to reduced left activation. No associations with task performance or longitudinal (8 years) memory loss Bilateral activation in the majority of regions. Higher left activation of the superior parietal lobule associated with higher accuracy.
NA
Larger volume loss on right than left middle frontal gyrus with age. Age-related alterations in the associations between structure, activation and cognitive performance (see text) Longitudinal cognitive changes associated with variations in volumetric asymmetry. Increased leftward asymmetry of the thalamus associated with improved cognitive flexibility. Increased leftward asymmetry of the caudate associated with decreased cognitive flexibility and improved general cognition.
Roe et al., 2019
Esteves et al., 2018
Manenti et al., 2013
Rajah et al., 2011
Esteves et al., 2019
Table 1 – Main conclusions of all research papers regarding the role of asymmetrical plasticity in physiological conditions. ACTH = adrenocorticotropic hormone; ctDCS = cathodal transcranial direct current stimulation; NA = non-applicable; PFC = prefrontal cortex; rTMS = repetitive magnetic transcranial stimulation.
Species
Stimulus
Age
Assessment conditions
Age
Behavioral outcomes
NA
stimulation of the contralateral limb
young adult
Decreased sensation in the affected limb that recovers after 1-2 weeks. Antagonism of AMPA/kainate receptors shows that this recovery is associated with contralesional involvement.
NA
adult
NA
dopamine antagonism in the contralesional somatosensory cortex
adult
Dopamine antagonism delays nociceptive recovery without changing the strokeinduced changes in the receptive fields
NA
Obi et al., 2018
young adult
NA
Early rehabilitation improves motor function, dendritic length and complexity in the contralesional motor cortex. Dendritic length is negatively correlated with the amount of remaining tissue on the lesioned hemisphere
Biernaskie and Corbett, 2001; Biernaskie et al., 2004
young adult
Pain on the left hindlimb is associated with increased anxiety-like behavior. Pain on the right hindlimb is associated with cognitive deficits: decreased working memory, reversal learning, and increased impulsive-like behavior
NA
LeiteAlmeida et al., 2012
attentional setshifting task
young adult
Animals with right chronic neuropathic pain require more trials to learn the reversal part of the task (i.e. reversing relevant and irrelevant clues)
NA
NA
NA
young adult
stroke of the somatosensory cortex
adult
middle cerebral artery occlusion
Rat
unilateral chronic neuropathic pain
left neuropathic pain
young adult
young adult
young adult
Basal activity of the contralesional somatosensory cortex increases after stroke. Returns to normal values after 4 weeks. Increase in the turnover of mushroom spines in contralesional somatosensory cortex' pyramidal neurons. Returns to normal after 2 weeks Overactivation of the contralesional somatosensory cortex upon stimulation of the injured limb. Four weeks after the stroke, when there is functional recovery, activity is similar to the one found upon stimulation of the non-injured limb Contralesional sensorimotor cortex increases number of neurons that receive inputs from multiple limbs. This number increases with postlesional time. Increased dopamine levels in the contralesional sensorimotor cortex one (but not two) weeks after lesion
References
young adult
NA
Mouse
Physiological outcomes
physical rehabilitation
anxiety-like, working memory, reference memory, attentional setshifting and impulsive-like behavior
Set-shifting task induces left>right ventral orbital PFC activation in animals with right hindpaw chronic pain, but right>left activation in sham and left pain animals Twenty-eight days after injury, increased right (contralateral) intrahemispheric connectivity and decreased interhemispheric connectivity, when compared to sham. No differences in the left hemisphere
Takatsuru et al., 2009
Takatsuru et al., 2009
Obi et al., 2018
LeiteAlmeida et al., 2014
Baliki et al., 2014
pre and perinatal
verbal fluency
child and young adult
Symmetrical/asymmetrical recruitment associated with language ability (see central outcomes)
perinatal
language assessment
child (4 years old)
Language abilities mostly within the normal range
left stroke
Human
neonatal and child
development and intelligence tests
child
child
verbal learning
child
stroke
Stroke associated with reduced processing speed, perceptual organization, visuo-spatial skills and auditory short-term memory. In terms of IQ, stroke in midchildhood and left lesions have a better prognosis Recall and recognition deficits in stroke patients when compared with controls. These are greater in earlier age of onset (<12 months old). No differences when comparing left and right strokes
aphasic stroke
adult
aphasia tests
adult
Early recovery associated with contralateral (right) activation in languagerelated areas (see central outcomes)
hemiplegic/hemiparetic stroke
adult
hand movement
adult
Recovery associated with contralesional activation (see central outcomes)
unilateral chronic pain
adult
psychiatric disorder assessment
adult
Higher hypochondriasis and hysteria scores in patients with left pain, in comparison with patients with right pain
Anterior languagerelated regions show a rightward pattern of activation, while posterior regions are bilaterally recruited. Language functioning is associated with leftward and symmetrical activation of anterior and posterior regions, respectively Passive language listening associated with right activation of language-related regions. Rightward asymmetry of the arcuate fasciculus in stroke patients, which is positively correlated with better language production. Rightward asymmetry of superior temporalinferior frontal gyri connectivity also associated with improved language production
Raja Beharelle et al., 2010
François et al., 2019
NA
Pavlovic et al., 2006
NA
Lansing et al., 2004
In the subacute phase, higher activation in the contralesional (right) Broca's and supplementary motor regions associate with better aphasia recovery. In the chronic phase, this shift is no longer beneficial Movement of the recovered hand associated with ipsilateral (contralesional) activation of the sensorimotor cortex and contralateral activation of the cerebellum NA
Saur et al., 2006
Chollet et al. 1991; Cao et al., 1998
Gagliese et al., 1995
Table 2 – Main conclusions of all research papers regarding the role of asymmetrical plasticity in pathological conditions. NA = non-applicable; PFC = prefrontal cortex.
Highlights:
Functional asymmetries are necessary for cognitive and emotional function; Lateralized structural and functional adaptation can be observed throughout life; In physiological conditions, lateralized plasticity is necessary for CNS specialized functions;
In pathological conditions, such plasticity can be adaptive or maladaptive, depending on the stimulus and age of onset; Mechanisms underlying left/right differences in plasticity remain elusive.
S0306-4522(20)30042-7 https://doi.org/10.1016/j.neuroscience.2020.01.022 NSC 19481
To appear in:
Neuroscience
Received Date: Revised Date: Accepted Date:
27 June 2019 11 January 2020 14 January 2020
Please cite this article as: M. Esteves, E. Ganz, N. Sousa, H. Leite-Almeida, Asymmetrical brain plasticity: physiology and pathology, Neuroscience (2020), doi: https://doi.org/10.1016/j.neuroscience.2020.01.022
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 IBRO. Published by Elsevier Ltd. All rights reserved.
Title: Asymmetrical brain plasticity: physiology and pathology
Esteves Ma,b,c, Ganz Ea,b,c, Sousa Na,b,c and Leite-Almeida Ha,b,c
aLife
and Health Sciences Research Institute (ICVS), School of Medicine, University of
Minho, Campus de Gualtar, Braga 4710-057, Portugal; bICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal; cClinical Academic Center – Braga, Braga, Portugal
Corresponding author: Hugo Leite-Almeida; Life and Health Sciences Research Institute (ICVS); Universidade do Minho; Campus de Gualtar; 4710-057 Braga; Portugal; Telephone:+351253604931; Email: [email protected]
Key words: cognitive function, laterality, recovery, aging, training, maladaptation
Abstract The brain is inherently asymmetrical. How that attribute, manifest both structurally ( volumetric, cytological, molecular) as well as functionally, relates to cognitive function, is not fully understood. Since the early descriptions of Paul Broca and Marc Dax it has been known that the processing of language in the brain is fundamentally asymmetrical. Contemporary imaging studies have corroborated early observations, and have also revealed significant functional links to multiple other systems, such as those sub serving memory or emotion. Recent studies have demonstrated that laterality is both plastic and adaptive. Learning and training have shown to effect regional changes in asymmetry, such as that observed in the volume of the planum temporale associated with musical practice. Increasing task complexity has been demonstrated to induce recruitment of contralateral regions, suggesting that laterality is a manifestation of functional reserve. Indeed, in terms of cognitive function, successful aging is often associated with a reduction of asymmetrical activity. The goal of this review is to survey and critically appraise the current literature addressing brain laterality, both morphological and functional, with particular emphasis on the asymmetrical plasticity associated with environmental factors and training. The plastic recruitment of contralateral areas associated with aging and unilateral lesions will be discussed in the context of the loss of asymmetry as a compensatory mechanism, and specific instances of maladaptive plasticity will be explored.
Introduction Gross examination of the brain reveals it to be asymmetrical, with the right frontal and the left occipital lobes extending across the midline, as if the entire structure is twisted in counterclockwise manner, a phenomenon often called the Yakovlevian torque (LeMay, 1976;Toga and Thompson, 2003). Asymmetries in the central nervous system are present at virtually all levels of structure and function, including regional volumes (Esteves et al., 2017;Esteves et al., 2019a;Goldberg et al., 2013;Good et al., 2001;Raz et al., 2004;Takao et al., 2011a;Watkins et al., 2001), cortical thickness (Chiarello et al., 2016;Kong et al., 2018;Luders et al., 2006;Plessen et al., 2014;Zhou et al., 2013), connectivity (Buchel et al., 2004;Ocklenburg et al., 2013;Takao et al., 2011a;Takao et al., 2011b;Thiebaut de Schotten et al., 2011) as well as cellular and molecular organization (Chance, 2014). Broadly defined, brain asymmetry refers to structural or functional differences between homotopic areas in the left and right hemispheres. Arguably, the most well-described example of an asymmetrically organized function is that of language, which in more than 80% of individuals is processed predominantly in the left hemisphere (Hugdahl and Westerhausen, 2016). This hemispheric specialization appears to be functionally relevant, having been demonstrated to be advantageous in the execution of verbal tasks regardless of the direction of asymmetry (i.e. both left and right biases are associated with better function) (Hirnstein et al., 2013;Mellet et al., 2014). Processing asymmetry has been observed in a broad range of functional processes and attributes including: episodic memory (left dominant for encoding and right for retrieval) (Habib et al., 2003), pseudoneglect (right) (Zago et al., 2017), emotional valence (left: positive/approach, right: for negative/avoidance) (Berkman and Lieberman, 2010;Brunoni et al., 2016;Schutter, 2009), impulsivity (right) (Gordon, 2015), risk-taking (left) (Telpaz and Yechiam, 2014), and face processing (right) (Yovel et al., 2008;Zhen et al., 2015). Asymmetry of lateralized functional specialization has been hypothesized to confer evolutionary advantage via a number of candidate mechanisms, including: duplication avoidance in order to maximize brain tissue usage (Denenberg, 1981;Vallortigara et al., 2011), reduction of computation time by avoiding trans-callosal transmission (Ringo et al., 1994), or by increasing the capacity for performing multiple simultaneous tasks through partitioning (Vallortigara et al., 2011). It is important to know however, that no function is 100 % lateralized, and instead are characterized by greater involvement of one hemisphere, but also involving participation of the other. Possible explanations of this fact include the potential requirement that the function be integrated with processes occurring in the contralateral hemisphere, that complete lateralization would increase the vulnerability to lesion-induced deficits (Saur et al.,
2006;Thulborn et al., 1999) or that the ability to plastically improve function in response to lesion or training would be impaired (Ellis et al., 2013;Hull and Vaid, 2007;Ohnishi et al., 2001). In this review, we will summarize the literature regarding asymmetric plasticity, both that which occurs physiologically, such as with training, as well as what manifest as a response to a destructive lesion or evolving pathological process. Emphasis will be placed on the understanding of its role in reconciling functional demand with available neural substrate.
Environment and training Early life environment, including that in utero, play a crucial role in the development of brain asymmetry. Amongst the most relevant factors are light, posture, and certain hormones (Duboc et al., 2015;Gunturkun and Ocklenburg, 2017). One striking example is the effect of asymmetrical light exposure upon the development of the chick visual system. During the course of maturation within the egg, the right eye is exposed to light and the left is occluded. The asymmetry results in visual pathway projections which differ dramatically one from another, and subsequently manifest as functional specialization for each eye: left for predator and right for food discrimination (Concha et al., 2012). On the other hand, stimuli which are not inherently lateralized may lead to functional and structural manifestations. Cognitive stimulation in the form of handling during neonatal development, or environmental enrichment, has been shown to increase right (but not left) hippocampus short and long-term potentiation (LTP) (Tang et al., 2008), as well as to increase the volumetric asymmetry in the same direction (Verstynen et al., 2001). At cognitive and behavioral levels, handling results in left paw preference (Tang and Verstynen, 2002) – see also (Cunha et al., 2017) regarding paw preference at population level in the rat – and is associated with social memory (Tang and Reeb, 2004;Tang et al., 2003) in association with the dynamics of right-turning in a novel environment (Tang and Reeb, 2004;Tang et al., 2003), as well as with corticosterone levels (Tang et al., 2003). Neonatal environment manipulation demonstrated to be linked to a lateralized response to stress. If dopamine (DA) receptors are blocked in the left, but not right, infralimbic cortex, environmentally enriched animals manifest an abnormally low increase in adrenocorticotropic hormone (ACTH) plasma levels and faster corticosterone reduction in response to acute stress. In animals not subject to neonatal enrichment, DA metabolism in the prefrontal cortex (PFC) is asymmetric, with activity seen to be greater on the left (Sullivan and Dufresne, 2006). A continuous stressor (repeated restrain) results in the inversion of this asymmetry (Sullivan and Dufresne, 2006), while also leading to a reduction in volume of the left, but not right, cingulate
cortex (Cerqueira et al., 2005), suggesting a more complex, bilateral relationship between the lateralized PFC and stress. Much less information is available regarding the environmental influence upon laterality in early human development. In contrast to the described influence of neonatal environment upon lateralization in the rat, human fetal thumb-sucking preference appears to be a strong predictor of later handedness (Hepper et al., 2005), suggesting that this particular phenotype may be independent of environmental influence. On the other hand, in children and adults, the training of asymmetrically-processed functions has been associated with asymmetric plasticity. Musicians with perfect pitch, for example, show increased leftward asymmetry of the planum temporale (i.e. left volume > right) (Keenan et al., 2001;Schlaug et al., 1995), attributed primarily to reduced volume in the right hemisphere (Keenan et al., 2001). It is not clear whether the asymmetry is due to early music training-induced plasticity, or is a consequence of in utero development (Keenan et al., 2001). Music processing has been shown to induce both left supramarginal gyrus (Ellis et al., 2013) and planum temporale (Ohnishi et al., 2001) activation. The observed asymmetry is a function of the cumulative number of hours of musical practice and age of musical training initiation, respectively, and may thus be a consequence of regional plastic changes. Similarly, the learning of a second language also has been associated with lateralized plasticity. A large meta-analysis has demonstrated that early bilinguals (those who learned both languages before 6 years of age) demonstrate a profile of bilateral activation for both languages, while in those who acquire the second language later, left hemisphere involvement is greater, accompanied by lower second language proficiency (Hull and Vaid, 2007). The finding would appear to suggest that there is greater plasticity at a younger age, leading to early recruitment of the right hemisphere, which in turn, results in higher performance at increased cognitive load. In the case of spatial memory, London taxi drivers who had acquired intensive navigation information and experience were found to have an increased volume of right posterior hippocampal gray matter (Maguire et al., 2000;Maguire et al., 2006). In summary, accumulating evidence across multiple species (Table 1) suggests (i) that lateralized stimuli during development induce hemispheric specialization of function; that early-life environment influences (ii) brain structure and function, (iii) behavior, and (iv) HPA axis modulation by higher cortical structures. Training has been found to asymmetrically modulate both (v) structure and function , presumably to facilitate performance of the specific, learned tasks. The mechanisms underlying environment and training-induced lateralized plasticity remain elusive. Studies of synaptic plasticity in the mouse hippocampus have delineated lateralization phenomena which may play a role. It has been demonstrated that hippocampal
LTP induces CA3-CA1 synapse strengthening only from inputs originated in the left, but not the right, CA3 (Kohl et al., 2011;Shipton et al., 2014). The finding has been associated with the differential expression of GluN2B at CA1 synapses targeted by projections arriving from the left and right CA3 (Kohl et al., 2011), as well as with the ability to perform a spatial long-term memory task (Shipton et al., 2014). The observations suggest that pre-existing asymmetries in receptors or associated pathways may be linked to laterality and manifest sensitivity to stimuli. It is of significance that while these observations were manifest in C57BL/6 mice, they could not be reproduced in Lister-Hooded rats, thus suggesting that the responsible mechanisms may be species and/or strain specific (Martin et al., 2019).
Aging Age-related decline of such functions as processing speed and encoding of episodic memories is well-recognized (Hedden and Gabrieli, 2004). It has been observed, however, that such decline is highly variable from subject to subject, a finding which has been attributed to individual variation in the (in)ability to recruit additional regions to compensate for loss of function. Cabeza and colleagues reported that older subjects who recruit the PFC bilaterally during the performance of a verbal memory task, manifest performance levels similar to younger subjects, in whom activation is lateralized (Cabeza, 2002;Cabeza et al., 2002). Those older subjects manifesting lateralized recruitment, on the other hand, show decreased performance. The findings suggest that age-related contralateral activation has an adaptive role, and gave rise to the Hemispheric Asymmetry Reduction in Older Adults (HAROLD) model (Cabeza, 2002;Cabeza et al., 2002). However, when a whole-brain analysis is performed, the observed bilateral activation seem to be relatively unspecific. Older subjects recruit additional regions in both hemispheres in order to achieve higher performance, to the formulation of an alternative explanation, known as the Compensation Related Utilization of Neural Circuits Hypothesis (CRUNCH) (Reuter-Lorenz and Cappell, 2008). Regardless of model specifics, it seems clear that the ability to plastically adapt, and to bring about the recruitment of additional regions, including those in the contralateral hemisphere, plays a significant role in the maintenance of functions that are normally found to be lateralized in younger subjects. Additional evidence relating to asymmetry in the elderly comes from manipulation studies. In one such experiment, disruption of the ipsilateral motor cortex using cathodal transcranial direct current stimulation (ctDCS) slowed learning of a complex unimanual motor task in aged, but not young subjects (Zimerman et al., 2014). When the aged cohort was further stratified, the
disruption was more prominent in the eldest participants (Zimerman et al., 2014). In a naming test, repetitive magnetic transcranial stimulation (rTMS) was used to investigate the asymmetrical recruitment of the left dorso-lateral prefrontal cortex. Greater differences between left and right involvement of this structure was correlated with superior performance. Poorly performing elders were mainly affected by left stimulation, while high performers presented a reduced leftward bias (Manenti et al., 2013b). Nevertheless, other work also suggests that these two models may not be applicable to all regions or functions, or that additional factors not currently incorporated into the models may need to be taken into account. A recent study determined that regions found to be asymmetrically (left>right) activated during recall in young subjects, showed the same pattern in older participants, even though the magnitude of the asymmetry was less due to decreased left, rather than increased right, activation. Additionally, the authors found no association between lateralized recruitment and task performance, or of longitudinal memory loss over a period of eight years (Roe et al., 2019). In a study from our lab, we observed that older subjects performing a working memory task showed mainly symmetrical activation, while higher accuracy was seen to be associated with increased (leftward) functional asymmetry of the superior parietal lobule (Esteves et al., 2018). Similarly, training aged subjects to perform a dual task was demonstrated to improve performance, and was accompanied by an increase in (leftward) asymmetry in ventral PFC activation (Erickson et al., 2007). In a series of manipulation studies, rTMS interferent modulation of the left dorsolateral PFC affected encoding of episodic memory in aged low performers, but no differences were found in aged high performers when this was applied to either hemisphere (Manenti et al., 2011). The same group has demonstrated that stimulation of the left or right dorsolateral PFC or parietal cortex using transcranial direct current stimulation (tDCS) improved episodic memory retrieval in young adults, whereas in older subjects, the effect was found only with left-sided stimulation (Manenti et al., 2013a). The relative roles of the structure and function in age-related plasticity remain unclear. The middle frontal gyrus, for example, has been observed to lose greater volume on the right than left hemisphere with advancing age. The functional consequences of asymmetrical volume loss and the associations between such volume, such as those associated with regional activation and memory retrieval performance, are demonstrably different for young and old adults (Rajah et al., 2011). In young adults, greater right middle frontal gyrus volume is associated with greater bilateral activity in the dorsolateral PFC and inferior parietal cortex, while in older adults, a larger right middle frontal gyrus is accompanied by decreased activity in the parahippocampal cortex and anterior cingulate. From the functional standpoint, in young adults higher activity in the left
dorsolateral PFC and right inferior parietal cortex is positively correlated with performance, while in older subjects enhanced performance is associated with decreased parahippocampal and anterior cingulate activation (Rajah et al., 2011). The functional models previously cited suggest that, with aging, decreased asymmetry reflects compensatory plasticity and is associated with better cognitive performance. In contrast, we have previously reported that when assessing volume asymmetry in aged subjects, a greater degree of asymmetry was always associated with improved neuropsychological score. The correlation was seen to be valid for a variety of cognitive tasks and attributes including learning and memory (superior frontal gyrus and lateral ventricle), cognitive flexibility (thalamus), vocabulary (posterior cingulate) and depressive mood (insula) (Esteves et al., 2017). Additionally, when longitudinally assessing subcortical plasticity in the same cohort 18 months later, we determined that alterations in cognitive flexibility and more general cognitive performance are correlated with changes in the magnitude of caudate and thalamus structural asymmetry (Esteves et al., 2019a). In conclusion, the role of asymmetrical plasticity in the maintenance of cognitive function during aging remains elusive. Comparisons between young and old, as well as between good and poor aged performers suggest a significant role of the non-dominant hemisphere (see Table 1 for details). Substantial evidence exists supporting the position that the association is more complex than either the HAROLD and CRUNCH models suggest. Additional longitudinal studies, a better understanding of the structure-function relationships, and the assessment of cognitive tasks beyond those of learning and memory, will be of the utmost importance for a more comprehensive understanding of this process.
Lesion-induced plasticity The recovery of function following stroke-induced aphasia in adults has been associated with a left-to-right shift in the activation of language-related regions, particularly when the lesion (of the left hemisphere) is extensive (Crosson et al., 2007) and/or in the early recovery process (Saur et al., 2006). In a similar fashion, activation of the sensorimotor cortex of the non-lesioned hemisphere plays an important role in motor recovery following insult (Cao et al., 1998;Chollet et al., 1991). In rodent models, this phenomenon has been associated with plastic changes, including: increased turnover of mushroom spines (Takatsuru et al., 2009), increased dendritic complexity and length (Biernaskie et al., 2004;Biernaskie and Corbett, 2001), and alterations in the somatosensory receptive fields, accompanied by an increased number of neurons receiving stimulation from multiple limbs (Obi et al., 2018). Human pediatric literature documents the
observation that strokes occurring during school age have, in general, a better prognosis than those occurring in more immature brains, such as those in the perinatal period, which are generally associated with life-long disabilities (Lansing et al., 2004;Pavlovic et al., 2006). It has been suggested that the phenomenon may reflect a delicate balance between greater plasticity at younger ages and the requirement that the younger children must learn for the first time (rather than relearn) the diverse motor and cognitive skills (Dunbar and Kirton, 2018). Structural and functional immaturity at the time of lesion occurrence may also explain why functions are affected differently. Language, for instance, which is highly lateralized in the adult brain (see Introduction), seems to be equally affected by left or right perinatal stroke (Lansing et al., 2004) but often recovers to normal levels (Dunbar and Kirton, 2018;Francois et al., 2019;Pavlovic et al., 2006). Such recovery has been associated with regions in the right hemisphere newly assuming language function, as reflected in observed changes in white matter tracts and connectivity (Francois et al., 2019), as well as with bilateral activation of temporal regions (Raja Beharelle et al., 2010), consistent with both ipsi- and contralateral plasticity. Motor impairment is the leading cause of disability after perinatal stroke and is characterized by very limited recovery (Dunbar and Kirton, 2018;Kirton, 2017). In this situation, contralesional plasticity appears to be mostly maladaptive. Projections from the non-lesioned hemisphere to the paretic limb are associated with poorer motor performance after both perinatal and childhood stroke (Kirton, 2017). In contrast, cognitive, intellectual and behavioral functions, including general cognition (IQ), attention, processing speed or memory, all of which are not clearly lateralized in the adult brain, demonstrate varying degrees of recovery after stroke at young ages (Dunbar and Kirton, 2018;Lansing et al., 2004;Pavlovic et al., 2006). The data on stroke (see Table 2) are suggestive of, and consistent with, identified attributes of asymmetrical plasticity, namely: (i) there is not a linear association between age and lateralized plasticity-related recovery; (ii) in the adult brain, the non-lesioned hemisphere has a transient role in the recovery of lateralized function, consistent with the proposal that completely lateralized specialization increases susceptibility to lesion-induced deficits; (iii) even in an immature brain, highly lateralized functions such as language and motor function, can have completely disparate recovery levels, and (iv) functions that are not typically highly lateralized, show reduced recovery after unilateral lesion. In those instances where compensation from the non-lesioned hemisphere is hindered, it is possible that the failure is a consequence of features intrinsic to the involved circuits, such as the number of intra- and interhemispheric connections, and/or a left/right asymmetry of receptors, dendritic spines, or molecular machinery. Additional
clinical observations, as well as experimental models, offer opportunities to further delineate the mechanisms and processes involved.
Maladaptive plasticity and asymmetry stability Plasticity in the nervous system may be maladaptive (Table 2). For example, noxious input as consequence of injury and/or inflammation, may induce structural and functional changes which lead to the persistence of pain long after the resolution of primary event (Apkarian et al., 2009;Chapman and Vierck, 2017;Kuner and Flor, 2016). The chronic pain thus established is often associated with cognitive deficits and mood disorders – see for instance (Leite-Almeida et al., 2015;Moriarty et al., 2011;Yalcin et al., 2014) –, specific features and consequences of which vary according to the site (left or right) of pain location. Clinical assessments have shown that pain originating in the left is more likely to be associated with anxiety (Gagliese et al., 1995;Schiff and Gagliese, 1994). Rodent studies have replicated this finding and also demonstrated that a chronic neuropathic lesion on the right leads to impairments of working memory, attentional set-shifting and impulsivity (Leite-Almeida et al., 2012). The findings suggest that the lateralized input induces central plasticity asymmetrically. Consistent with this hypothesis is the demonstration that in a rodent model, unilateral neuropathic lesions have been shown to alter resting-state networks in an asymmetrical manner (Baliki et al., 2014). Additionally, orbitofrontal cortex activation during attentional set-shifting has been demonstrated to be shifted to the left in animals with right-sided lesion, resulting in impairment of the ability to perform this task (Leite-Almeida et al., 2014). On the other hand, split-brain individuals (those whose corpora callosa were severed in order to control intractable epilepsy) show negligible duplication of lateralized functions (Gazzaniga, 2005). Instead, the brains of these persons appear to have adopted strategies, such as behavioral cueing, which enable inter-hemispheric collaboration (Volz and Gazzaniga, 2017). Thus, while it is the case that, even in adulthood, external asymmetrical stimuli are able to induce lateralized plasticity, in those individuals who underwent callosotomy, the adaptation seems to be more a behavioral modification rather than one modulated by central plasticity. Observations such as these tend to suggest that asymmetrical plasticity originate not only from communication between hemispheres but also, and possibly primarily, from the periphery (e.g. in the form of pain, light exposure, movement, etc.). Conclusions based upon the functional imaging of callosotomized individuals are, however, largely speculative given the very limited sample size.
Conclusions In conclusion, there is substantial evidence that asymmetry, both structural and functional, is essential for the optimal execution of a wide range of cognitive and emotional processes (Esteves et al., 2019b). Asymmetry improves efficiency while simultaneously conserving functional reserve which might prove essential for recovery from injury in disease. Functional specialization (e.g. through training), as well as rehabilitation, rely on CNS plastic capacity at both intra- and inter-hemispheric levels. Multiple factors influence plastic capacity, an important one of which is the age at which the lesion, stimulus or training occurs. In order to more clearly define the role of asymmetric plasticity, longitudinal studies which emphasize the time parameter of cognitive change (aging: cognitive decline, childhood; cognitive development, training: physiological or rehabilitative) will be essential. Better understanding of the basic mechanisms underlying these processes offers the prospect of facilitating the development of optimal strategies for both rehabilitation and training to task.
Acknowledgments This work was supported by the project NORTE‐01‐0145‐FEDER‐000013 through the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER), and funded by the European Commission (FP7) “SwitchBox ‐ Maintaining health in old age through homeostasis” (Contract HEALTH‐F2‐2010‐259772), and co‐financed by the Portuguese North Regional Operational Program (ON.2 – O Novo Norte), under the National Strategic Reference Framework (QREN), through FEDER, and by the Fundação Calouste Gulbenkian (Portugal) (Contract grant number: P‐139977; project “TEMPO ‐ Better mental health during ageing based on temporal prediction of individual brain ageing trajectories”) and by “PANINI ‐ Physical Activity and Nutrition INfluences In ageing” (European Commission (Horizon 2020), Contract GA 675003). ME was supported by the Fundação para a Ciência e a Tecnologia (FCT) grant SFRH/BD/52291/2013 and Institute for Scientific Information on Coffee (ISCI) grant UMINHO/BPD/45/2018, project ISIC_2017_NS
References
Apkarian AV, Baliki MN, Geha PY (2009), Towards a theory of chronic pain. Prog Neurobiol 87:81-97. Baliki MN, Chang PC, Baria AT, Centeno MV, Apkarian AV (2014), Resting-sate functional reorganization of the rat limbic system following neuropathic injury. Scientific reports 4:6186. Berkman ET, Lieberman MD (2010), Approaching the bad and avoiding the good: lateral prefrontal cortical asymmetry distinguishes between action and valence. Journal of cognitive neuroscience 22:1970-1979. Biernaskie J, Chernenko G, Corbett D (2004), Efficacy of Rehabilitative Experience Declines with Time after Focal Ischemic Brain Injury. The Journal of Neuroscience 24:1245. Biernaskie J, Corbett D (2001), Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth after focal ischemic injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 21:5272-5280.
Brunoni AR, Moffa AH, Fregni F, Palm U, Padberg F, Blumberger DM, Daskalakis ZJ, Bennabi D, et al. (2016), Transcranial direct current stimulation for acute major depressive episodes: meta-analysis of individual patient data. The British journal of psychiatry : the journal of mental science 208:522-531. Buchel C, Raedler T, Sommer M, Sach M, Weiller C, Koch MA (2004), White matter asymmetry in the human brain: a diffusion tensor MRI study. Cerebral cortex (New York, NY : 1991) 14:945-951. Cabeza R (2002), Hemispheric asymmetry reduction in older adults: the HAROLD model. Psychology and aging 17:85-100. Cabeza R, Anderson ND, Locantore JK, McIntosh AR (2002), Aging Gracefully: Compensatory Brain Activity in High-Performing Older Adults. NeuroImage 17:1394-1402. Cao Y, D’Olhaberriague L, Vikingstad EM, Levine SR, Welch KMA (1998), Pilot Study of Functional MRI to Assess Cerebral Activation of Motor Function After Poststroke Hemiparesis. Stroke 29:112-122. Cerqueira JJ, Catania C, Sotiropoulos I, Schubert M, Kalisch R, Almeida OF, Auer DP, Sousa N (2005), Corticosteroid status influences the volume of the rat cingulate cortex - a magnetic resonance imaging study. Journal of psychiatric research 39:451-460. Chance SA (2014), The cortical microstructural basis of lateralized cognition: a review. Frontiers in psychology 5:820. Chapman CR, Vierck CJ (2017), The Transition of Acute Postoperative Pain to Chronic Pain: An Integrative Overview of Research on Mechanisms. J Pain 18:359 e351-359 e338. Chiarello C, Vazquez D, Felton A, McDowell A (2016), Structural asymmetry of the human cerebral cortex: Regional and between-subject variability of surface area, cortical thickness, and local gyrification. Neuropsychologia. Chollet F, Dipiero V, Wise RJS, Brooks DJ, Dolan RJ, Frackowiak RSJ (1991), The functional anatomy of motor recovery after stroke in humans: A study with positron emission tomography. Annals of neurology 29:63-71.
Concha ML, Bianco IH, Wilson SW (2012), Encoding asymmetry within neural circuits. Nat Rev Neurosci 13:832-843. Crosson B, McGregor K, Gopinath KS, Conway TW, Benjamin M, Chang Y-L, Moore AB, Raymer AM, et al. (2007), Functional MRI of language in aphasia: a review of the literature and the methodological challenges. Neuropsychology review 17:157-177. Cunha AM, Esteves M, das Neves SP, Borges S, Guimaraes MR, Sousa N, Almeida A, LeiteAlmeida H (2017), Pawedness Trait Test (PaTRaT)-A New Paradigm to Evaluate Paw Preference and Dexterity in Rats. Frontiers in behavioral neuroscience 11:192. Denenberg VH (1981), Hemispheric laterality in animals and the effects of early experience. Behavioral and Brain Sciences 4:1-21. Duboc V, Dufourcq P, Blader P, Roussigne M (2015), Asymmetry of the Brain: Development and Implications. Annual review of genetics 49:647-672. Dunbar M, Kirton A (2018), Perinatal stroke: mechanisms, management, and outcomes of early cerebrovascular brain injury. The Lancet Child & adolescent health 2:666-676. Ellis RJ, Bruijn B, Norton AC, Winner E, Schlaug G (2013), Training-mediated leftward asymmetries during music processing: a cross-sectional and longitudinal fMRI analysis. NeuroImage 75:97-107. Erickson KI, Colcombe SJ, Wadhwa R, Bherer L, Peterson MS, Scalf PE, Kim JS, Alvarado M, et al. (2007), Training-induced plasticity in older adults: effects of training on hemispheric asymmetry. Neurobiology of aging 28:272-283. Esteves M, Magalhaes R, Marques P, Castanho TC, Portugal-Nunes C, Soares JM, Almeida A, Santos NC, et al. (2018), Functional Hemispheric (A)symmetries in the Aged Brain-Relevance for Working Memory. Frontiers in aging neuroscience 10:58. Esteves M, Marques P, Magalhaes R, Castanho TC, Soares JM, Almeida A, Santos NC, Sousa N, et al. (2017), Structural laterality is associated with cognitive and mood outcomes: An assessment of 105 healthy aged volunteers. NeuroImage 153:86-96.
Esteves M, Moreira PS, Marques P, Castanho TC, Magalhaes R, Amorim L, Portugal-Nunes C, Soares JM, et al. (2019a), Asymmetrical subcortical plasticity entails cognitive progression in older individuals. Aging Cell 18:e12857. Esteves M, Sousa N, Leite-Almeida H (2019b), Righteousness (and lefteousness) of the old brain. Aging (Albany NY) 11:4779-4780. Francois C, Ripolles P, Ferreri L, Muchart J, Sierpowska J, Fons C, Sole J, Rebollo M, et al. (2019), Right Structural and Functional Reorganization in Four-Year-Old Children with Perinatal Arterial Ischemic Stroke Predict Language Production. eNeuro 6. Gagliese L, Schiff BB, Taylor A (1995), Differential consequences of left- and right-sided chronic pain. The Clinical journal of pain 11:201-207. Gazzaniga MS (2005), Forty-five years of split-brain research and still going strong. Nat Rev Neurosci 6:653-659. Goldberg E, Roediger D, Kucukboyaci NE, Carlson C, Devinsky O, Kuzniecky R, Halgren E, Thesen T (2013), Hemispheric asymmetries of cortical volume in the human brain. Cortex; a journal devoted to the study of the nervous system and behavior 49:200-210. Good CD, Johnsrude I, Ashburner J, Henson RN, Friston KJ, Frackowiak RS (2001), Cerebral asymmetry and the effects of sex and handedness on brain structure: a voxel-based morphometric analysis of 465 normal adult human brains. NeuroImage 14:685-700. Gordon HW (2015), Laterality of Brain Activation for Risk Factors of Addiction. Current drug abuse reviews. Gunturkun O, Ocklenburg S (2017), Ontogenesis of Lateralization. Neuron 94:249-263. Habib R, Nyberg L, Tulving E (2003), Hemispheric asymmetries of memory: the HERA model revisited. Trends in cognitive sciences 7:241-245. Hedden T, Gabrieli JD (2004), Insights into the ageing mind: a view from cognitive neuroscience. Nat Rev Neurosci 5:87-96.
Hirnstein M, Hugdahl K, Hausmann M (2013), How brain asymmetry relates to performance – a large-scale dichotic listening study. Frontiers in psychology 4:997. Hugdahl K, Westerhausen R (2016), Speech processing asymmetry revealed by dichotic listening and functional brain imaging. Neuropsychologia 93:466-481. Hull R, Vaid J (2007), Bilingual language lateralization: a meta-analytic tale of two hemispheres. Neuropsychologia 45:1987-2008. Keenan JP, Thangaraj V, Halpern AR, Schlaug G (2001), Absolute pitch and planum temporale. NeuroImage 14:1402-1408. Kirton A (2017), Advancing non-invasive neuromodulation clinical trials in children: Lessons from perinatal stroke. European Journal of Paediatric Neurology 21:75-103. Kohl MM, Shipton OA, Deacon RM, Rawlins JN, Deisseroth K, Paulsen O (2011), Hemispherespecific optogenetic stimulation reveals left-right asymmetry of hippocampal plasticity. Nature neuroscience 14:1413-1415. Kong XZ, Mathias SR, Guadalupe T, Glahn DC, Franke B, Crivello F, Tzourio-Mazoyer N, Fisher SE, et al. (2018), Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium. Proceedings of the National Academy of Sciences of the United States of America 115:E5154-e5163. Kuner R, Flor H (2016), Structural plasticity and reorganisation in chronic pain. Nat Rev Neurosci 18:20-30. Lansing AE, Max JE, Delis DC, Fox PT, Lancaster J, Manes FF, Schatz A (2004), Verbal learning and memory after childhood stroke. Journal of the International Neuropsychological Society : JINS 10:742-752. Leite-Almeida H, Cerqueira JJ, Wei H, Ribeiro-Costa N, Anjos-Martins H, Sousa N, Pertovaara A, Almeida A (2012), Differential effects of left/right neuropathy on rats' anxiety and cognitive behavior. Pain 153:2218-2225.
Leite-Almeida H, Guimaraes MR, Cerqueira JJ, Ribeiro-Costa N, Anjos-Martins H, Sousa N, Almeida A (2014), Asymmetric c-fos expression in the ventral orbital cortex is associated with impaired reversal learning in a right-sided neuropathy. Molecular pain 10:41. Leite-Almeida H, Pinto-Ribeiro F, Almeida A (2015) Animal Models for the Study of Comorbid Pain and Psychiatric Disorders. In: Modern trends in pharmacopsychiatry, vol. 30, pp. 1-21. LeMay M (1976), Morphological cerebral asymmetries of modern man, fossil man, and nonhuman primate. Annals of the New York Academy of Sciences 280:349-366. Luders E, Narr KL, Thompson PM, Rex DE, Jancke L, Toga AW (2006), Hemispheric asymmetries in cortical thickness. Cerebral cortex (New York, NY : 1991) 16:1232-1238. Maguire EA, Gadian DG, Johnsrude IS, Good CD, Ashburner J, Frackowiak RS, Frith CD (2000), Navigation-related structural change in the hippocampi of taxi drivers. Proceedings of the National Academy of Sciences of the United States of America 97:4398-4403. Maguire EA, Woollett K, Spiers HJ (2006), London taxi drivers and bus drivers: a structural MRI and neuropsychological analysis. Hippocampus 16:1091-1101. Manenti R, Brambilla M, Petesi M, Ferrari C, Cotelli M (2013a), Enhancing verbal episodic memory in older and young subjects after non-invasive brain stimulation. Frontiers in aging neuroscience 5:49. Manenti R, Brambilla M, Petesi M, Miniussi C, Cotelli M (2013b), Compensatory networks to counteract the effects of ageing on language. Behavioural brain research 249:22-27. Manenti R, Cotelli M, Miniussi C (2011), Successful physiological aging and episodic memory: a brain stimulation study. Behavioural brain research 216:153-158. Martin SJ, Shires KL, da Silva BM (2019), Hippocampal Lateralization and Synaptic Plasticity in the Intact Rat: No Left–Right Asymmetry in Electrically Induced CA3-CA1 Long-Term Potentiation. Neuroscience 397:147-158.
Mellet E, Zago L, Jobard G, Crivello F, Petit L, Joliot M, Mazoyer B, Tzourio-Mazoyer N (2014), Weak language lateralization affects both verbal and spatial skills: an fMRI study in 297 subjects. Neuropsychologia 65:56-62. Moriarty O, McGuire BE, Finn DP (2011), The effect of pain on cognitive function: a review of clinical and preclinical research. Prog Neurobiol 93:385-404. Obi K, Amano I, Takatsuru Y (2018), Role of dopamine on functional recovery in the contralateral hemisphere after focal stroke in the somatosensory cortex. Brain research 1678:146-152. Ocklenburg S, Hugdahl K, Westerhausen R (2013), Structural white matter asymmetries in relation to functional asymmetries during speech perception and production. NeuroImage 83:1088-1097. Ohnishi T, Matsuda H, Asada T, Aruga M, Hirakata M, Nishikawa M, Katoh A, Imabayashi E (2001), Functional Anatomy of Musical Perception in Musicians. Cerebral Cortex 11:754–760. Pavlovic J, Kaufmann F, Boltshauser E, Capone Mori A, Gubser Mercati D, Haenggeli CA, Keller E, Lutschg J, et al. (2006), Neuropsychological problems after paediatric stroke: two year follow-up of Swiss children. Neuropediatrics 37:13-19. Plessen KJ, Hugdahl K, Bansal R, Hao X, Peterson BS (2014), Sex, age, and cognitive correlates of asymmetries in thickness of the cortical mantle across the life span. The Journal of neuroscience : the official journal of the Society for Neuroscience 34:6294-6302. Raja Beharelle A, Dick AS, Josse G, Solodkin A, Huttenlocher PR, Levine SC, Small SL (2010), Left hemisphere regions are critical for language in the face of early left focal brain injury. Brain : a journal of neurology 133:1707-1716. Rajah MN, Languay R, Grady CL (2011), Age-related changes in right middle frontal gyrus volume correlate with altered episodic retrieval activity. The Journal of neuroscience : the official journal of the Society for Neuroscience 31:17941-17954.
Raz N, Gunning-Dixon F, Head D, Rodrigue KM, Williamson A, Acker JD (2004), Aging, sexual dimorphism, and hemispheric asymmetry of the cerebral cortex: replicability of regional differences in volume. Neurobiology of aging 25:377-396. Reuter-Lorenz PA, Cappell KA (2008), Neurocognitive Aging and the Compensation Hypothesis. Current Directions in Psychological Science 17:177-182. Ringo JL, Doty RW, Demeter S, Simard PY (1994), Time is of the essence: a conjecture that hemispheric specialization arises from interhemispheric conduction delay. Cerebral cortex (New York, NY : 1991) 4:331-343. Roe JM, Vidal-Pineiro D, Sneve MH, Kompus K, Greve DN, Walhovd KB, Fjell AM, Westerhausen R (2019), Age-Related Differences in Functional Asymmetry During Memory Retrieval Revisited: No Evidence for Contralateral Overactivation or Compensation. Cerebral cortex (New York, NY : 1991). Saur D, Lange R, Baumgaertner A, Schraknepper V, Willmes K, Rijntjes M, Weiller C (2006), Dynamics of language reorganization after stroke. Brain : a journal of neurology 129:13711384. Schiff BB, Gagliese L (1994), The consequences of experimentally induced and chronic unilateral pain: reflections of hemispheric lateralization of emotion. Cortex; a journal devoted to the study of the nervous system and behavior 30:255-267. Schlaug G, Jancke L, Huang Y, Steinmetz H (1995), In vivo evidence of structural brain asymmetry in musicians. Science 267:699-701. Schutter DJ (2009), Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: a meta-analysis. Psychological medicine 39:65-75. Shipton OA, El-Gaby M, Apergis-Schoute J, Deisseroth K, Bannerman DM, Paulsen O, Kohl MM (2014), Left-right dissociation of hippocampal memory processes in mice. Proceedings of the National Academy of Sciences of the United States of America 111:15238-15243.
Sullivan RM, Dufresne MM (2006), Mesocortical dopamine and HPA axis regulation: role of laterality and early environment. Brain research 1076:49-59. Takao H, Abe O, Yamasue H, Aoki S, Sasaki H, Kasai K, Yoshioka N, Ohtomo K (2011a), Gray and white matter asymmetries in healthy individuals aged 21-29 years: a voxel-based morphometry and diffusion tensor imaging study. Human brain mapping 32:1762-1773. Takao H, Hayashi N, Ohtomo K (2011b), White matter asymmetry in healthy individuals: a diffusion tensor imaging study using tract-based spatial statistics. Neuroscience 193:291-299. Takatsuru Y, Fukumoto D, Yoshitomo M, Nemoto T, Tsukada H, Nabekura J (2009), Neuronal circuit remodeling in the contralateral cortical hemisphere during functional recovery from cerebral infarction. The Journal of neuroscience : the official journal of the Society for Neuroscience 29:10081-10086. Tang AC, Reeb BC (2004), Neonatal novelty exposure, dynamics of brain asymmetry, and social recognition memory. Developmental psychobiology 44:84-93. Tang AC, Reeb BC, Romeo RD, McEwen BS (2003), Modification of Social Memory, Hypothalamic-Pituitary-Adrenal Axis, and Brain Asymmetry by Neonatal Novelty Exposure. The Journal of Neuroscience 23:8254-8260. Tang AC, Verstynen T (2002), Early life environment modulates 'handedness' in rats. Behavioural brain research 131:1-7. Tang AC, Zou B, Reeb BC, Connor JA (2008), An epigenetic induction of a right-shift in hippocampal asymmetry: selectivity for short- and long-term potentiation but not post-tetanic potentiation. Hippocampus 18:5-10. Telpaz A, Yechiam E (2014), Contrasting losses and gains increases the predictability of behavior by frontal EEG asymmetry. Frontiers in behavioral neuroscience 8:149. Thiebaut de Schotten M, Ffytche DH, Bizzi A, Dell'Acqua F, Allin M, Walshe M, Murray R, Williams SC, et al. (2011), Atlasing location, asymmetry and inter-subject variability of white matter tracts in the human brain with MR diffusion tractography. NeuroImage 54:49-59.
Thulborn KR, Carpenter PA, Just MA (1999), Plasticity of language-related brain function during recovery from stroke. Stroke 30:749-754. Toga AW, Thompson PM (2003), Mapping brain asymmetry. Nat Rev Neurosci 4:37-48. Vallortigara G, Chiandetti C, Sovrano VA (2011), Brain asymmetry (animal). Wiley Interdisciplinary Reviews: Cognitive Science 2:146-157. Verstynen T, Tierney R, Urbanski T, Tang A (2001), Neonatal novelty exposure modulates hippocampal volumetric asymmetry in the rat. Neuroreport 12:3019-3022. Volz LJ, Gazzaniga MS (2017), Interaction in isolation: 50 years of insights from split-brain research. Brain : a journal of neurology 140:2051-2060. Watkins KE, Paus T, Lerch JP, Zijdenbos A, Collins DL, Neelin P, Taylor J, Worsley KJ, et al. (2001), Structural asymmetries in the human brain: a voxel-based statistical analysis of 142 MRI scans. Cerebral cortex (New York, NY : 1991) 11:868-877. Yalcin I, Barthas F, Barrot M (2014), Emotional consequences of neuropathic pain: Insight from preclinical studies. Neurosci Biobehav Rev 47C:154-164. Yovel G, Tambini A, Brandman T (2008), The asymmetry of the fusiform face area is a stable individual characteristic that underlies the left-visual-field superiority for faces. Neuropsychologia 46:3061-3068. Zago L, Petit L, Jobard G, Hay J, Mazoyer B, Tzourio-Mazoyer N, Karnath HO, Mellet E (2017), Pseudoneglect in line bisection judgement is associated with a modulation of right hemispheric spatial attention dominance in right-handers. Neuropsychologia 94:75-83. Zhen Z, Yang Z, Huang L, Kong XZ, Wang X, Dang X, Huang Y, Song Y, et al. (2015), Quantifying interindividual variability and asymmetry of face-selective regions: a probabilistic functional atlas. NeuroImage 113:13-25. Zhou D, Lebel C, Evans A, Beaulieu C (2013), Cortical thickness asymmetry from childhood to older adulthood. NeuroImage 83:66-74.
Zimerman M, Heise KF, Gerloff C, Cohen LG, Hummel FC (2014), Disrupting the ipsilateral motor cortex interferes with training of a complex motor task in older adults. Cerebral cortex (New York, NY : 1991) 24:1030-1036.
Species
Stimulus
Age
Assessment conditions
Age
Behavioral outcomes
Physiological outcomes
References
Chicken
unilateral light stimulation of the eye
In ovo
NA
young (chick)
Specialization of the left and right eyes for predator and food discrimination
Asymmetrical connections of the visual pathways
Concha et al., 2012
NA
young adult
Increased probability of lefthandedness, improved social memory, changed left/right turning dynamics in a novel environment
acute stress/unilateral infralimbic cortex dopamine antagonism
young adult
NA
repeated stress
young adult
NA
handling/environmental enrichment
Neonatal
Rat
chronic hypercortisolism
young adult
NA
adult
NA
perfect pitch
child
NA
young adult
NA
child
melodic and rhythmic discrimination task
child and adult
NA
child
classical music hearing
adult
NA
second language learning
child (<6 years old)
dichotic listening, visual hemifield or dual task
nondefined (metaanalysis)
NA
driving a taxi
adult
NA
adult
NA
old
dual task performance
old
Training improved performance in the task in both young and old groups
old
Association between improved memory performance in older subjects and bilateral
musical training
Human
dual task training
aging
NA
source memory task
Reduced basal corticosterone levels. Increased short- and long-term potentiation of the right hippocampus, decreased leftward volumetric hippocampal asymmetry Reduced increase in ACTH levels and faster corticosterone reduction in handled animals after left manipulation Inversion of prefrontal cortex' asymmetrical dopamine metabolism (right>left in handled animals) Reduced volume of the left cingulate cortex Reduced right planum temporale volume and increased leftward volumetric asymmetry in musicians with perfect pitch in comparison with nonmusicians and musicians without perfect pitch Increased left (but not right) supramarginal gyrus activation in association with hours of musical training Negative correlation between left planum temporale activation and age of training initiation. No associations with duration of musical training. For both languages, bilateral activation in early (<6 years old) and left dominance in later bilinguals. Left hemisphere activation is higher when second language proficiency is lower Positive correlation between right posterior hippocampal volume and time spent as a taxi driver Aged subjects show increased left and decreased right ventral PFC activation during post-training task performance. These changes make the pattern of activation more similar to the adult group of subjects. Activation of right prefrontal cortex in young and lowperforming older subjects. Bilateral activation in high-
Tang and Verstynen, 2002; Tang and Reeb, 2004; Tang et al, 2003; Tang et al., 2008; Verstynen et al., 2001
Sullivan and Dufresne, 2006
Sullivan and Dufresne, 2006 Cerqueira et al., 2005
Keenan et al., 2001; Schlaug et al., 1995
Ellis et al., 2013
Ohnishi et al., 2001
Hull and Vaid, 2007
Maguire et al.,2000; Maguire et al.,2006
Erickson et al., 2007
Cabeza et al., 2002
prefrontal cortex activation (see central outcomes)
NA
complex motor skill learning/ctDCS interference with the ipsilateral motor cortex
old
NA
action naming task/unilateral dorsolateral PFC rTMS
old
NA
encoding and retrieval/unilateral dorsolateral PFC rTMS
old
NA
memory retrieval
old
NA
memory task
old
NA
encoding and retrieval/ unilateral parietal cortex or dorsolateral PFC tDCS
old
NA
memory retrieval
NA
general cognition and cognitive flexibility
old
old
Decreased learning in aged subjects, in comparison with young. Within the aged group, higher disruption in older subjects Improved verbal reaction time and accuracy associated with reduced leftward asymmetry Decreased encoding in low performers when interfering with the left dorsolateral PFC. No effects in high performers or retrieval.
Old subjects have worse task (retrieval) than younger participants
Association between asymmetrical activation and performance (see central outcomes) Improved retrieval in young adults associated with left or right PFC or parietal stimulation. In older subjects, improvements only with left stimulation Age-related alterations in the associations between structure, activation and cognitive performance (see text)
Longitudinal cognitive changes associated with variations in structural asymmetry (see central outcomes)
performing older subjects
NA
Zimerman et al., 2014
NA
Manenti et al., 2013
NA
Manenti et al., 2011
Parietal and frontal regions show left>right activation during recall, independently of age (young vs old). This asymmetry is lower in aged subjects, mostly due to reduced left activation. No associations with task performance or longitudinal (8 years) memory loss Bilateral activation in the majority of regions. Higher left activation of the superior parietal lobule associated with higher accuracy.
NA
Larger volume loss on right than left middle frontal gyrus with age. Age-related alterations in the associations between structure, activation and cognitive performance (see text) Longitudinal cognitive changes associated with variations in volumetric asymmetry. Increased leftward asymmetry of the thalamus associated with improved cognitive flexibility. Increased leftward asymmetry of the caudate associated with decreased cognitive flexibility and improved general cognition.
Roe et al., 2019
Esteves et al., 2018
Manenti et al., 2013
Rajah et al., 2011
Esteves et al., 2019
Table 1 – Main conclusions of all research papers regarding the role of asymmetrical plasticity in physiological conditions. ACTH = adrenocorticotropic hormone; ctDCS = cathodal transcranial direct current stimulation; NA = non-applicable; PFC = prefrontal cortex; rTMS = repetitive magnetic transcranial stimulation.
Species
Stimulus
Age
Assessment conditions
Age
Behavioral outcomes
NA
stimulation of the contralateral limb
young adult
Decreased sensation in the affected limb that recovers after 1-2 weeks. Antagonism of AMPA/kainate receptors shows that this recovery is associated with contralesional involvement.
NA
adult
NA
dopamine antagonism in the contralesional somatosensory cortex
adult
Dopamine antagonism delays nociceptive recovery without changing the strokeinduced changes in the receptive fields
NA
Obi et al., 2018
young adult
NA
Early rehabilitation improves motor function, dendritic length and complexity in the contralesional motor cortex. Dendritic length is negatively correlated with the amount of remaining tissue on the lesioned hemisphere
Biernaskie and Corbett, 2001; Biernaskie et al., 2004
young adult
Pain on the left hindlimb is associated with increased anxiety-like behavior. Pain on the right hindlimb is associated with cognitive deficits: decreased working memory, reversal learning, and increased impulsive-like behavior
NA
LeiteAlmeida et al., 2012
attentional setshifting task
young adult
Animals with right chronic neuropathic pain require more trials to learn the reversal part of the task (i.e. reversing relevant and irrelevant clues)
NA
NA
NA
young adult
stroke of the somatosensory cortex
adult
middle cerebral artery occlusion
Rat
unilateral chronic neuropathic pain
left neuropathic pain
young adult
young adult
young adult
Basal activity of the contralesional somatosensory cortex increases after stroke. Returns to normal values after 4 weeks. Increase in the turnover of mushroom spines in contralesional somatosensory cortex' pyramidal neurons. Returns to normal after 2 weeks Overactivation of the contralesional somatosensory cortex upon stimulation of the injured limb. Four weeks after the stroke, when there is functional recovery, activity is similar to the one found upon stimulation of the non-injured limb Contralesional sensorimotor cortex increases number of neurons that receive inputs from multiple limbs. This number increases with postlesional time. Increased dopamine levels in the contralesional sensorimotor cortex one (but not two) weeks after lesion
References
young adult
NA
Mouse
Physiological outcomes
physical rehabilitation
anxiety-like, working memory, reference memory, attentional setshifting and impulsive-like behavior
Set-shifting task induces left>right ventral orbital PFC activation in animals with right hindpaw chronic pain, but right>left activation in sham and left pain animals Twenty-eight days after injury, increased right (contralateral) intrahemispheric connectivity and decreased interhemispheric connectivity, when compared to sham. No differences in the left hemisphere
Takatsuru et al., 2009
Takatsuru et al., 2009
Obi et al., 2018
LeiteAlmeida et al., 2014
Baliki et al., 2014
pre and perinatal
verbal fluency
child and young adult
Symmetrical/asymmetrical recruitment associated with language ability (see central outcomes)
perinatal
language assessment
child (4 years old)
Language abilities mostly within the normal range
left stroke
Human
neonatal and child
development and intelligence tests
child
child
verbal learning
child
stroke
Stroke associated with reduced processing speed, perceptual organization, visuo-spatial skills and auditory short-term memory. In terms of IQ, stroke in midchildhood and left lesions have a better prognosis Recall and recognition deficits in stroke patients when compared with controls. These are greater in earlier age of onset (<12 months old). No differences when comparing left and right strokes
aphasic stroke
adult
aphasia tests
adult
Early recovery associated with contralateral (right) activation in languagerelated areas (see central outcomes)
hemiplegic/hemiparetic stroke
adult
hand movement
adult
Recovery associated with contralesional activation (see central outcomes)
unilateral chronic pain
adult
psychiatric disorder assessment
adult
Higher hypochondriasis and hysteria scores in patients with left pain, in comparison with patients with right pain
Anterior languagerelated regions show a rightward pattern of activation, while posterior regions are bilaterally recruited. Language functioning is associated with leftward and symmetrical activation of anterior and posterior regions, respectively Passive language listening associated with right activation of language-related regions. Rightward asymmetry of the arcuate fasciculus in stroke patients, which is positively correlated with better language production. Rightward asymmetry of superior temporalinferior frontal gyri connectivity also associated with improved language production
Raja Beharelle et al., 2010
François et al., 2019
NA
Pavlovic et al., 2006
NA
Lansing et al., 2004
In the subacute phase, higher activation in the contralesional (right) Broca's and supplementary motor regions associate with better aphasia recovery. In the chronic phase, this shift is no longer beneficial Movement of the recovered hand associated with ipsilateral (contralesional) activation of the sensorimotor cortex and contralateral activation of the cerebellum NA
Saur et al., 2006
Chollet et al. 1991; Cao et al., 1998
Gagliese et al., 1995
Table 2 – Main conclusions of all research papers regarding the role of asymmetrical plasticity in pathological conditions. NA = non-applicable; PFC = prefrontal cortex.
Highlights:
Functional asymmetries are necessary for cognitive and emotional function; Lateralized structural and functional adaptation can be observed throughout life; In physiological conditions, lateralized plasticity is necessary for CNS specialized functions;
In pathological conditions, such plasticity can be adaptive or maladaptive, depending on the stimulus and age of onset; Mechanisms underlying left/right differences in plasticity remain elusive.