Cent. Eur. J. Med. • 7(1) • 2012 • 1-8 DOI: 10.2478/s11536-011-0121-2

Central European Journal of Medicine

Brain asymmetry, immunity,

Review article Zlatislav Stoyanov*, Lyoubka Decheva, Irina Pashalieva, Piareta Nikolova Department of Physiology and Pathophysiology Medical University “Prof. Paraskev Stoyanov” 55 Marin Drinov Str., 9002 Varna, Bulgaria

Received 17 December 2010; Accepted 3 October 2011 Abstract: The principle of symmetry-asymmetry is widely presented in the structural and functional organization of the nonliving and living nature. One of the most complex manifestations of this principle is the left-right asymmetry of the . The present review summarizes previous and contemporary literary data regarding the role of in neuroimmunomodulation. Some handedness-related peculiarities are outlined additionally. Brain asymmetry is considered to be imprinted in the formation and regulation of the individual’s responses and relationships at an immunological level with the external and internal environment. The assumptions that the hemispheres modulate immune response in an asymmetric manner have been confirmed in experiments on animals. Some authors assume that the right hemisphere plays an indirect role in neuroimmunomodulation, controlling and suppressing the left hemispheric inductive signals. Keywords: Brain asymmetry • Hemispheric control • Immunity • Handedness.

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1. Introduction 2. Hemispheric lateralization in neuroimmunomodulation The principle of symmetry-asymmetry is widely pre- sented in the structural and functional organization of The fact that structural and functional asymmetry is a the nonliving and living nature. One of the most complex fundamental trait of the brain generated expectations manifestations of this principle is the left–right asym- that brain asymmetry is implicated in the neural control metry of the human brain [1]. The term “brain asym- of immune functions. In 1975 Semenov and Chuprikov metry” summarizes the anatomical, neurochemical, postulated that brain asymmetry is imprinted in the for- physiological and behavioral differences between the mation and regulation of the individual’s reactivity and two halves of the brain [2,3]. The psychophysiology of relationships at an immunological level with the external sensory functions and perception, cognitive processes, and internal environment [11]. attention, learning and memory, and emotions are com- The assumptions that the hemispheres modulate mon objects of interests to the investigators of cerebral immune response in an asymmetric manner have been lateralization [1,4]. Since the end of the 20th century, confirmed in experiments on animals. In one of the first the asymmetries in autonomic-physiologic functions studies Bardos et al. [12] found out that NK-cell (natural have been included in the realm of scientists, and in killers) activity was significantly impaired following left particular the neural control of cardiac activity, endo- cortical lesions, whereas right cortical lesions exerted crine functions and immunity [5,6]. The present review no observable influence on NK-cell activity, as com- summarizes previous and contemporary literary data pared with normal control animals. Renoux et al. [13] regarding the role of brain asymmetry in neuroimmu- observed weight reduction in lymphoid organs (spleen nomodulation. Some handedness-related peculiarities and thymus), and a decreased number of splenic T-cells are additionally outlined because it is well known that (Thy-1+) also in left cortical lesioned mice. The study left-handers show some specificity in the patterns of of lymphocyte proliferation in response to mitogen cerebral lateralization [7-10]. stimulation provided evidence that left cortical ablation

* E-mail: [email protected] 1 Brain asymmetry, immunity, handedness

significantly suppresses the response of splenic lym- stimulate the HPA axis to increase the plasma levels of phocytes to T-cell specific mitogens such as phytohe- corticosterone, and (b) the cortical regulation of cortisol magglutinin and concanavalin [5]. An opinion exists secretion is under the primary control of the right hemi- that left hemispheric influences enhance the reactivity sphere [5,15]. Our previous investigations (although on of different T-cell dependent immune mechanisms and, different physiological functions) also provided evidence in general, immune functions under physiological con- that hypothalamic-pituitary-glandular axes operate in ditions, whereas right hemispheric influences have a a dependent relationship with individual differences in predominantly immunosuppressive effect [14,15]. Some brain asymmetry [23,24]. authors assumed that the right hemisphere plays an Hori et al. [25] focused their attention on the roles indirect role in neuroimmunomodulation, controlling and and mechanisms of neural communication between the suppressing the left hemispheric inductive signals [16]. brain and the immune system, and summarized: (a) pri- The data from studies in humans parallel those mary and secondary lymphoid organs are sympatheti- involving observations in animals. Kang et al. [17] found cally innervated; (b) different types of immunocompetent significantly higher levels of NK-cell activity in subjects cells possess alpha- and beta-adrenergic receptors; with pronounced left frontal electroencephalographic (c) the exposure of lymphocytes and macrophages to (EEG) activation, as compared to subjects with right adrenergic agonists in vitro modulates their functions; frontal activation. According to Davidson [18], individu- (d) a surgical or chemical sympathectomy alters the als with predominant right frontal activation are immu- immune responses in rodents; (e) the altered activities nosupressed. Gruzelier et al. [19] reported a significant of the splenic sympathetic nerves is causally related to positive correlation between higher left-sided activation the alteration in immunological responses (for instance (lower EEG amplitude) and CD8+ T-lymphocytes count, NK cytotoxicity). Regarding the roles and mechanisms and, conversely, relatively higher right-sided activation of the parasympathetic control of lymphoid organs, associated with lower CD8+ count. Meador et al. [20] some data suggest that the thymic vagal efferent nerve compared postoperative to preoperative T-lymphocyte may be involved in the central modulation of immunity indices in epileptic patients who had undergone neu- [25]. In the context of functional brain asymmetry and its rosurgical treatment. The researchers found that the links with immunity, it is a noteworthy fact that the right absolute lymphocyte count, total T-cells (CD3+), helper hemisphere predominantly modulates the sympathetic T-cells (CD3+4+), cytotoxic/suppressor cells (CD3+8+), nervous system, and the left hemisphere predominantly and total suppressor cells (CD8+) were reduced follow- modulates parasympathetic activity (according to exper- ing surgical interventions on the language-dominant imental data and clinical observations) [26-30]. Abramov hemisphere, however, they increased after non-domi- et al. [31], discussing their own results on differences nant hemisphere resections. In the study of Clow and in the functional properties of thymocytes from left and colleagues, the influence of lateralized transcranial right thymus lobes, also considered the differences in magnetic stimulation on secretory immunoglobulin A the sympathetic and parasympathetic innervation of the (sIgA) concentrations in the saliva was examined [19]. contralateral lobes of the thymus, and stressed the dif- The main finding, according to the authors, was an ferentiated hemispheric control of the two branches of increase in sIgA following left-sided cortical stimulation. the autonomic nervous system. The molecular basis of brain–immune interac- tions remains insufficiently understood, but in sev- 3. Brain–immune system eral publications the role of cytokines has been outlined interactions [15,22,32,33]. Cytokines, besides regulating immune responses, function as mediators of an afferent path- What are the channels through which the brain and the way to the brain, and probably are a part of a neuro- immune system communicate? The exact mechanisms endocrine-immune signalling system [32]. An important of this interaction are not fully understood. Betancur et al. role in asymmetrical brain immunomodulation has been [21] searched for, an engagement of the hypothalamic- ascribed to brain IL-1β and interleukin-6 (IL-6). Both pituitary-adrenal (HPA) axis in the relationships between interleukins can regulate the neuro-endocrine-immune brain asymmetry and immune response. Later on Shen network by invoking autonomic, neuro-endocrine, and et al. [22] argued that cytokines (such as interleukins) behavioural action [32,33]. The publications of Fu et regulate immune responses, possibly through activation al. [15] and Shen et al. [22] presented intriguing data of the HPA axis, and HPA axis activities are related to about an asymmetrical distribution of IL-1β and IL-6 in brain lateralization. There are two supporting facts in this the mouse brain: the basal levels of IL-1β and IL-6 are context: (a) it is known that interleukin-1β (IL-1β) can higher in the right cortex than in the left. The authors

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proposed that the rightward asymmetry in IL-1β and IL-6 Geschwind and Behan [37] revealed that the incidence is probably related to the differences between the right of diseases associated with disorders in the immune and left cerebral immunomodulatory functions (in mice system is two and a half times higher in left-handers particularly) [15]. than in right-handers. The specific diseases are ulcer- ative colitis, Crohn’s disease, coeliacia, Hashimoto’s thyroiditis, thyrotoxicosis, diabetes, migraine, myasthe- 4. Handedness-related differences nia gravis, and rheumatoid arthritis. According to the researchers cited, one of the possible explanations for Is there a reason to think that handedness-related dif- the observed association between immune disorders ferences exist in immune functions and pathology? The and left-handedness is the existence of separate genes data from animal studies, using paw preference as an on the same chromosome, with incomplete penetrance, analogy of human handedness and as an index of brain for left-handedness and immune disease. Norman lateralization, suggest that the answer is “yes”. Neveu Geschwind, however, has been more inclined to explain et al. [34] studied the association between lymphocyte the association by the mechanisms suggested in the responsiveness and paw preference in mice and found testosterone hypothesis of lateralization, known as the a higher level of phytohemagglutinin- and concanavalin- Geschwind, Behan and Galaburda (GBG) hypothesis induced proliferation in left-pawed animals. Abramov [37,38]. This hypothesis states that the high intrauterine et al. [31] reported that the concanavalin(A)-stimulated levels of testosterone impede the growth of certain proliferation of thymocytes from the left and right lobes regions of the left hemisphere, which leads to right of thymus was significantly different, and the direction of hemisphere language dominance and an increase of differences depended on the hemispheric dominance in left-handedness. Simultaneously, the higher levels of motor control. In mice with right-dominant hemispheres testosterone suppress development of the thymus. The (left paw preference) thymocytes from the left lobe of elimination of T-lymphocytes reacting to self-antigens is thymus demonstrated a higher level of concanavalin- probably impaired, which in turn determine autoimmune stimulated proliferation than those from the right lobe. reactions later in life. Corresponding data from animal In mice with left hemispheric dominance the associa- studies has appeared: several articles have documented tion was found to be the opposite. Quaranta et al. [35] that testosterone administration leads to destruction of reported evidence that brain asymmetry modulates the bursa of Fabricius in chicken embryos [39]. immune responses in dogs too, and described a more The GBG hypothesis has many critics and oppo- complex picture of associations between preferred nents because of the controversial results obtained in paw and blood immune parameters. The researchers the subsequent attempts by many researchers to prove observed that, in comparison to right-pawed and ambi- the high prenatal testosterone theory [40,41], and espe- dextrous dogs, in left-pawed dogs: (a) the percentage of cially because of the report of Grimshaw et al. [42] that granulocytes (in leukocyte formula) is lower; (b) the per- children exposed in utero to higher levels of testosterone centage of lymphocytes is higher; (c) the total number of were more likely to be right-handed. Recently, however, lymphocyte cells is higher; (d) the number of γ-globulins some studies (including our own investigation) using the is lower. The above mentioned findings of Fu et al. [15] finger length ratio (second to fourth digit) as a biomarker and Shen et al. [22] about asymmetric hemispheric for the prenatal levels of testosterone have shown indi- distribution of brain IL-6 and IL-1β had “handedness”- rect evidence for a relationship between higher prenatal related peculiarities. For instance, IL-1β levels in the left testosterone and left-handedness [43-47]. were higher for ambidextrous mice than Against this background, understandably, both for right-pawed animals, and IL-6 levels in the left cortex types of data can be found in the literature, supporting were higher for left-pawed mice than for right-pawed. as well as contradicting the idea that left-handers are IL-1 and IL-6 are considered to play an immunosuppres- characterized by specificity in immune reactivity and are sive role in the central nervous system [36]. Thus, it can predisposed to autoimmune reactions. Peculiarities of be speculated that the immune-enhancing effects of the the immune system in left-handers were indicated for left hemisphere (see above) should be weakened in left- instance by data of Chengappa and colleagues [48,49]. pawed (non-right-pawed) mice, and left-pawed animals They found in left-handers higher levels of autoantibod- should be at a higher risk of immune disorders [15]. ies to thyroglobulin and thyroid microsomal antigen, The speculation made about health risks in left- and an association between non-right-sided functional pawed animals corresponds with data coming from asymmetries and lower interleukin-2 production (IL-2 is clinical studies suggesting handedness-related differ- an important autocrine growth factor and T-lymphocytes ences in immunity among humans. The investigations of activator). In the study of Lengen et al. [50] the correlation

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between “anomalous cerebral dominance” (including diabetic patients. McМanus and Wysocki [60], in agree- left-handedness) and deviations in immunity has been ment with an earlier study of Betancur et al. [61], did not analyzed by checking the markers of cell-mediated establish an association between left-handedness and immunity. The authors found that, in comparison with allergies. Furthermore, the authors established a lower right-handers, left-handers demonstrate a significant re- rate of arthritis and ulcer disease in left-handers. duction in inflammatory cell types: CD3+ T-cells, CD4+ The discussion on immunity regularly provokes a dis- Т-cells (Т-helpers), HLA-Dr (antigen-presenting cells), cussion on the risks of cancer. The most discussed, but and CD16/CD57+-cells (natural killers). still unsolved question, is whether left-handed women Searleman and Fugagli [51], similarly to Geschwind are predisposed to breast cancer [62-66]. In some and Behan, reported a higher incidence of left-handed- publications a higher frequency of left-handedness has ness among patients with Crohn’s disease and ulcerative been reported in breast cancer patients. Ramadhani et colitis. The association between left-handedness and al. [66] estimated that the risk of breast cancer is 39% increased risk of inflammatory bowel diseases (Crohn’s higher in left-handed women. The authors hypotheti- disease and ulcerative colitis) has been confirmed in cally explained the association between handedness probably the largest study of the problem (a sample of and breast cancer by influences of intrauterine sex hor- 17,197 subjects living in Great Britain), carried out by monal environment (effects of testosterone, Morris et al. [52]. and progesterone). It is well known that such influences Krommydas et al. [53] found that the percentage can be assumed as etiological factors for breast cancer of left-handers is 14.8% in asthmatic children, against as well as for left-handedness [66]. However, contrary 8.9% in non-asthmatics. In patients with allergic rhinitis, to data suggesting increased breast cancer risk in left- the authors reported figures similar to those observed handers, Stellman et al. [65], studying post-menopausal in asthmatics. According to the data presented by Preti women, found a decreased risk of breast cancer in et al. [54], among children with asthma, the percentage left-handed women. This finding is intriguing because of of individuals with mixed handedness is higher than the observed prevalence of left-handed subjects among the percentage of left-handers. A significant associa- the women who used replacement therapy tion between non-right-handedness and drug allergies, (therapy which increases risks of breast cancer). The and non-right-handedness and skin allergies has been results of Stellman et al. [65] are in agreement with the established in the study of Bryden et al. [55]. data reported in an earlier publication of Olsson and Gardener et al. [56] estimate a 62% increased risk Ingvar [63]. of (immune-mediated inflammatory disease damaging myelin sheaths) among women who were naturally left-handed as compared to those who 5. Brain asymmetry and immunity: were naturally right-handed. Coren [57] found that the mind–body relation left-handers are twice as likely to suffer diabetes type 1 (disease with immune-mediated damage of the endo- It is well known that stressful life events and chronic crine tissue of pancreas). The point of view of Preti and stress adversely affect the immune system and im- colleagues [54] is slightly different: they argued that dia- mune responses [19,67,68]. Negative emotionality and betes type 1 is associated with a mixed type of manual depression have been associated with decreased im- dominance rather than with left-handedness. Uslu et munity and an increased risk of autoimmune disease, al. [58] observed a lower rate of helminth infections in as well as cancer initiation or progression [17,67,69]. left-handers and considered the finding as suggestive One of the four main theories concerning the cortical of a different immune machinery in left-handed people. lateralization of emotional processing, the “Valence The results coming from another stream of stud- Model”, postulates that the right hemisphere is special- ies however are incongruent with the data presented ized with regard to negative emotion and that the left above. Searleman and Fugagli [51] did not find a signifi- hemisphere is specialized with regard to positive emo- cant relationship between left-handedness and diabetes tion (for review see Ref. [70]). Evidence exists that the type 1, despite their findings that in males with type 1 left frontal region is activated during the experience and diabetes the likelihood of being left-handed is slightly expression of positive emotions, and the right frontal re- higher than in males with type 2 diabetes. Clavero et gion is activated during the experience and expression al. [59] reported similar findings: the researchers did not of negative emotions [18,71]. A question arises whether confirm the association between left-handedness and a relationship exists between both asymmetries hosted autoimmune diabetes type 1, despite the trend observed in the frontal regions – the asymmetry of emotional pro- for lower rates of strong right-handers among type 1 cessing and the asymmetry of brain immunomodulation.

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Several studies searched for an answer to this question. left-pawed mice showed a decreased variation in Davidson and colleagues [72] elaborated the earlier corticosterone, less than right-pawed mice. It is known reported research of the team [17] in which the scien- that stressors activate the HPA axis and adrenal corti- tists examined also whether self-reported emotional costeroid secretion. The function of this response is a state (depression and anxiety) and stress level were suppressive modulation of immune functions, aimed at related to the patterns of frontal asymmetry and immune maintaining a normal, healthy state. According to the responses. The data in the recent study confirmed the authors, the results demonstrate that left-pawed mice authors’ suggestions that subjects with increased rela- have lower HPA axis reactivity, and therefore, may tive right-sided prefrontal activation would show larger display lower anti-inflammatory effects during stress. decreases in NK function in response to the stress. These lower effects may be insufficient to allow the Furthermore Davidson et al. [72] found that the subjects mice to adapt, and this could be one of the reasons why with greater right-sided activation show less of a rise in the left-pawed mice have a higher incidence of immune NK function in response to a positive emotional chal- mediated disorders (for reference, see Ref. [33]). lenge. Similar results were reported by Rosenkranz et al. In the same stressful condition, left-pawed and right- [67] who investigated the relations between central and pawed mice displayed a heterogeneous direction and peripheral physiological measures that reflect individual intensity of changes for IL-1 and IL-6, not only in the differences in both dispositional affect and affective re- cortex, but also in the hippocampus, the hypothalamus activity and immune function (measured in vivo by using and limbic structures involved in emotion. The results of an influenza vaccine challenge). The researchers found Su and colleagues indicated that higher IL-1 and IL-6 that subjects characterized by a more negative affective concentrations in the cortex, higher IL-6 concentration style (subjects with greater relative right-prefrontal EEG in the hippocampus and hypothalamus, and significant activation) demonstrated weaker antibody response to alterations of interleukin concentrations after acute influenza vaccination. stress tended to be most noticeable in left-pawed mice. Frontal EEG asymmetry is considered a trait-like Having in mind some adverse effects of the elevated characteristic associated with peculiarities of the indi- levels of cytokines (IL-1β, IL-6, TNF-α) on integrative viduals’ temperament, emotional reactivity and disposi- brain functions, Su et al. [33] concluded that their find- tion to depression [18,73]. Many researchers share the ings suggest why left-pawed mice may be susceptible point of view that left-handers differ, to some degree, to suffer from some mood, behaviour or neuroimmune from right-handers regarding the emotionality and affec- disorders resulting from these cytokines. tive style [74-76]: findings exist that left-handedness is related to proneness to psychological distress, depres- sion, anxiety, domination of the behavioral inhibition 6. Conclusion system (predominantly linked to the right hemisphere relating to inhibition of behavior and negative affect). Our The data presented in this review, despite some of them studies revealed higher psychophysiological reactivity being inconsistent, suggest that functional brain later- to mental stress in left-handers, as compared to right- alization is spread over the neural control of immune handers [77,78]. Against this background, taking into functions. Moreover, individual differences in brain account that individual differences in the affective style asymmetry, such as handedness-related ones, may and reactivity can influence the immune function [72], additionally shape the brain-immune interactions. Fur- surprisingly few research attempts have been made to ther study and a clear understanding of the established examine the possible relationship between autoimmune relationship would be helpful in determining the causes vulnerability and emotionality and psychophysiological and mechanisms of some immune and autoimmune reactivity in left-handers. In a recent publication Su et disorders, and neoplasms. Based on this, by taking into al. [33] reported that plasma corticosterone responses account individual differences in brain asymmetry, more in mice under predator stress (analogous to psycho- adequate prophylactic and therapeutic strategies can logical stress in humans) are “handedness”-dependent: be devised.

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