Anti-Yo Antibodies in Children With ADHD: First Results About Serum Cytokines

Abstract

Objective: We investigated whether ADHD children who are positive to Purkinje cell antibodies display pro-inflammatory activity associated with high cytokine serum levels. Method: Fifty-eight ADHD outpatients were compared with 36 healthy, age- and sex-matched children. Forty-five of the ADHD children were positive to anti-Yo antibodies, whereas 34 of the control children were negative. Interleukin 4 (IL-4), IL-6, IL-10, IL-17, tumor necrosis factor alpha (TNFα), and interferon gamma (IFNγ) cytokine serum levels were tested in ADHD children who were positive to anti-Yo antibodies and in the control children who were negative. Results: Anti-Yo antibodies were present to a greater extent in the ADHD group: 77.58% versus 22.42%. Significant differences emerged between the two groups in IL-6 and IL-10, with higher cytokine levels being detected in ADHD children than in controls. Conclusion: Immune processes in ADHD are likely to be associated with mediators of inflammation, such as cytokines. These results contribute to our understanding of action of neural antibodies and cytokines in ADHD.

Keywords

cytokines ADHD anti-Yo IL-6 IL-10

Introduction

ADHD is a neurobehavioral childhood disorder that is characterized by persistent and maladaptive symptoms of hyperactivity/impulsivity and inattention (Diagnostic and Statistical Manual of Mental Disorders, 5th ed. [DSM-5], American Psychiatric Association, 2013). Participants diagnosed with ADHD often display serious impairments in academic, social, and interpersonal functioning (Caci et al., 2014). ADHD is also associated with several comorbid psychiatric conditions such as mood disorders, disruptive behavior, and learning disabilities (Antshel et al., 2011). Despite considerable research efforts, the etiology and pathophysiology of ADHD remain unclear (Buske-Kirschbaum et al., 2013).

There is a growing belief that the immune system may be involved in the pathogenesis of various developmental, emotional, and learning disabilities, including ADHD (Steiner et al., 2012). In particular, the involvement of the autoimmune system in ADHD was hypothesized in a previous study by us in which the presence of the neuronal anti-Yo antibody was demonstrated in patients with this disorder (Passarelli et al., 2013). Toto et al. (2015) also found that antibasal ganglia antibody (ABGA) positivity was significantly higher in patients affected by ADHD than in controls and that serum antistreptolysin O (ASO) was also significantly more frequent in the ADHD group. Similar results were found by Giana et al. (2015) studying dopamine transporter (DAT) antibodies in a group of ADHD children. These findings lend support to the hypothesis that an inflammatory component is involved in the pathogenesis of ADHD. This hypothesis is hardly surprising if we bear in mind that numerous studies have reported changes in cytokine levels that are likely to be due to an inflammatory reaction in children affected by a range of neuropsychiatric diseases. A recent review (Buske-Kirschbaum et al., 2013) of psychoendocrine and neuroimmunological mechanisms of atopic eczema highlighted the possible comorbidity between this disease and ADHD. Cytokines elicited by inflammatory events may directly pass the blood-brain barrier or be carried via cytokine-specific transporters into the brain (Banks & Erickson, 2010). Moreover, peripheral cytokines may indirectly affect central nervous system (CNS) structures by activating vagal afferent fibers (Raison, Capuron, & Miller, 2006). When cytokines enter the brain, they exert a neuronal toxic effect, as has been demonstrated by Rosenkranz et al. (2005). By performing functional magnetic resonance imaging (fMRI) during an allergic episode, these authors detected altered neuronal activity in the anterior cingulate cortex (ACC) and in the prefrontal cortex (PFC). In this regard, the PFC is known to subserve executive cognitive functions such as planned behavior, decision making, motivation, and attention (Goto, Yang, & Otani, 2010).

Last, another possible effect upon brain activity has been reported by Anisman, Kokkinidis, and Merali (1996) and Zalcman et al. (1994), whose animal studies demonstrated that administration of interleukin 1 (IL-1), IL-2, IL-6, or interferon gamma (IFNγ) increased norepinephrine levels and reduced dopamine levels. Comparable changes in these neurotransmitters have been observed in ADHD patients (Arnsten, 2009).

In view of the growing body of evidence linking a generalized pro-inflammatory state and many psychiatric conditions, we hypothesize that an imbalance between pro- and anti-inflammatory cytokines, triggered by a neuroimmunological disorder, may play a role in the pathogenesis of some cases of ADHD. We focused on the cerebellum because a considerable number of articles have in recent years highlighted the role played by this region of the CNS in ADHD. A recent meta-analysis of 10 studies on the involvement of the cerebellum in ADHD (Stoodley, 2014) demonstrated that a common finding in these studies was significantly lower gray matter volume bilaterally in lobule IX. This is not an unexpected finding if we consider the modulating role played by the cerebellum. The aim of this study was thus to determine whether inflammation is possible in ADHD children and, if so, whether it is related to anticerebellum antibodies. Specifically, we assessed whether pro-inflammatory activity, as tested on the basis of IL-4, IL-6, IL-10, IL-17, tumor necrosis factor alpha (TNFα), and IFNγ cytokine levels, is present in ADHD children who were positive to antibodies of Purkinje cells from the cerebellum (Passarelli et al., 2013). This study was thus performed to verify whether the presence of anti-Purkinje cell antibodies (anti-Yo) is associated with inflammatory signs such as high pro-inflammatory cytokine serum levels.

Method

Participants

We studied 58 consecutive drug-naïve Caucasian ADHD outpatients, who were attending their first psychiatric examination (51 males and seven females; M_age = 113.66 months, SD = 27.62 months), diagnosed between January 1, 2014, and December 31, 2014, at the Clinic for Developmental Neurology and Psychiatry at the S. Pertini Hospital in Rome (Italy). The control participants, who comprised 36 healthy, age- and sex-matched Caucasian children (32 males and four females; M_age = 115.10 months, SD = 18.68 months), were randomly recruited, on the basis of a community survey, from two elementary and junior high schools from the same urban area in Rome (Italy). ANOVA for age was F = 1.10 (p = ns). The sex was matched by a Fisher’s exact test: The hypergeometric probability was .25 (ns).

Instruments

Clinical Assessment

Both the ADHD children and their parents separately received a semi-structured psychiatric interview: the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL 1.0; Kaufman, Birmaher, Brent, & Rao, 1997), which was administered by an experienced child psychiatrist. Moreover, the ADHD children and controls underwent an additional routine diagnostic assessment, including the ADHD Rating Scale (ADHD-RS; DuPaul, Power, Anastopoulos, & Reid, 1998) adapted for the Italian population (Marzocchi & Cornoldi, 2000), which was filled out by their parents and school teachers. This routine assessment was used to confirm the ADHD diagnosis, according to the DSM-5 criteria, in children with ADHD and to exclude the ADHD diagnosis in the control group. On the basis of the Wechsler Intelligence Scale for Children–Third Edition (WISC-III; Wechsler, 1991), all children with an intelligence quotient (IQ) < 70 were excluded. The two groups of children were matched for sex (p = ns at chi-square statistics) and age (p = ns at ANOVA test). All the children in both groups tested negative to common antibody tests for celiac disease and Hashimoto’s thyroiditis.

The medical history, neurological and physical examinations, and an electroencephalogram were used to exclude comorbid medical and neurological conditions. Any children with a history of atopic eczema or allergy were excluded. No infections or allergic diseases were detected during the blood examination. Written informed consent was obtained from the parents of all the participants enrolled in the study.

Immunohistochemistry and Western Blot

Antibodies to Yo (Purkinje cell cytoplasmic antibody type 1 [PCA-1]) were detected by indirect immunofluorescence assay (IFA). The method was performed on a commercially available substrate of primate cerebellum and gut (Euroimmun Italia). The presence of specific antibodies was determined by their reactions to cerebellar neurons (Purkinje, molecular, or granular cells). The patients’ sera were first diluted 1:10 in phosphate buffered saline (PBS)-Tween and then incubated with the substrate provided in the presence of fluorescein-labeled antihuman immunoglobulin G (IgG) conjugate to allow binding of the antibodies to the specific antigens of the substrate. A positive reaction showed granular staining of the Purkinje cell cytoplasm (anti-Yo antibody), whereas a negative reaction did not reveal any staining. Immunofluorescence was visualized by means of a fluorescence microscope (Leica, Leitz DMRB, Germany) at a magnification of at least 20 times.

Patients and control participants’ sera were assessed by means of the EUROLINE neuronal antigen kit (Euroimmun, Italia) for Western blot analysis. The kit consists of membrane chips with individual lines of purified, biochemically characterized antigens coated onto a separate membrane chip. The serum was diluted 1:100 in the sample buffer provided. The intensity of the bands was automatically evaluated using the computer program EUROLINE Scanner. All the analyses were performed in double blind experiments, that is, neither the participants enrolled in the study nor the researchers involved knew whether participants had been assigned to the control group or the experimental group. All the anti-Yo antibody serum determinations were performed blindly.

Cytokine Assay

The serum of the ADHD patients who tested positive to anti-Yo antibodies (N = 45) and the serum of 34 control children who were negative to anti-yo antibodies were subsequently subjected to the cytokine panel assay.

All the cytokines were analyzed by enzyme-linked immunosorbent assays (ELISAs) obtained from PharMingen (San Diego, California, United States) with the exception of IL-2, which was based on paired anticytokine antibodies and standards from Genzyme (Cambridge, Massachusetts). The ELISA tests were performed according to the manufacturer’s instructions (see standard procedure by PharMingen ELISA kit). All the tests were based on a common direct assay design. Detection was performed by means of biotinylated anticytokine antibodies, followed by the addition of streptavidin-conjugated horseradish peroxidase. Color reaction was developed by means of ABTS (2.2′ azinobis[3-ethylbenzthiazoline-6-sulfonate]), and analyte concentrations were calculated using SoftMax Pro software. All the cytokine serum determinations were performed blindly.

Statistical Analysis

Differences between the two groups (ADHD group and non-ADHD group) in gender and in anti-Yo antibodies were evaluated by means of Fisher’s exact test. One-way ANOVAs were used on age variable. ANOVAs were also performed to compare the serum cytokine concentrations of the ADHD and non-ADHD groups. The alpha level was set at .05 for all the analyses.

Results

The K-SADS PL 1.0 showed that the ADHD children were affected by the following comorbidities: Twenty-five had oppositional defiant disorder, one had generalized anxiety disorder, and one had enuresis. One of the children in the control group was also found to have enuresis.

Forty-five ADHD children were positive to anti-Yo antibodies (77.58%, four females; age = 112.80 ± 25 months, range = 72-210) and 13 negative (22.42%), whereas only two children of the control group were positive to anti-Yo antibodies (5.56%). The difference was significant at Fisher’s exact test—hypergeometric probability = .02. Forty-five ADHD patients and 34 children (four females; M_age = 115.10 ± 24.10 months, range = 72-204) of the control group were matched for cytokines. No differences were found between the two groups in gender (Fisher’s exact test: hypergeometric probability = .26; p = ns) and age (ANOVA: F = .23, p = ns).

Significant differences emerged between the two groups in IL-6 and IL-10 cytokine concentration levels, with ADHD children displaying higher levels than the non-ADHD group (see Table 1).

Table 1.

Differences Between ADHD and Control Children in Serum Cytokine Levels.

	ADHD group	Control group	Mann–Whitney U Test	p
	M rank	M rank	Mann–Whitney U Test	p
IL-2	30.50	30.50	442.00	ns
IL-4	30.50	30.50	442.00	ns
IL-6	34.06	25.85	321.00	.03
IL-10	33.34	26.79	345.50	.03
IL-17	30.37	30.67	437.50	ns
TNFα	30.50	30.50	442.00	ns
IFNγ	30.74	30.19	434.00	ns

Note. Significant IL-6 and IL-10 differences are shown in bold. IL = interleukin; IL-2, IL-4, IL-6, IL-10 IL-17 = cytokines; TNFα = tumor necrosis factor alpha; IFNγ = interferon gamma; ns = not significant.

Discussion

As we reported, a considerable proportion of ADHD children have a high level of antineural antibodies (ADHD group 77.58% vs. control group 22.42%; p = .02), a confirmation of the results of Passarelli et al. (2013). A high percentage of anti-Yo antibodies in psychiatric patients were detected in this study and in the study by Passarelli et al. Previous findings have reported that the detection of anti-Yo antibodies in the serum is generally associated with paraneoplastic syndromes, particularly in paraneoplastic cerebellar degeneration (PCD). This is a paraneoplastic syndrome associated with a wide range of tumors, including lung cancer, ovarian cancer, breast cancer, and Hodgkin’s lymphoma. Although the MRI may be negative, patients generally have typical cerebellar symptoms, such as dizziness, slurred speech, and ataxic gait, which are obviously not observed in ADHD children.

Moreover, the results of this study suggest that there is a possible association between immune processes and mediators of inflammation, such as cytokines, in ADHD. Indeed, we detected higher levels of IL-6 and IL-10 in an ADHD group positive to anti-Yo antibodies than in a control group. Our results thus suggest that a high antibody level might be correlated with the inflammatory cytokine level, which would thus point to the presence of inflammatory events.

As reported in other studies (Buske-Kirschbaum et al., 2013), the manifestation of chronic allergic inflammation in children, associated with increased inflammatory cytokine levels and exposure to stress in early life, have been found to interfere with the development of brain regions (e.g., the PFC, ACC, corpus callosum) and neurotransmitter systems (e.g., catecholaminergic and dopaminergic system) known to play a crucial role in executive functions, including attention, motivation motor, and cognitive control.

Altered maturation of these specific brain circuits may result in persistent neural or neuroendocrine changes, thereby increasing the risk of ADHD in a subset of the children affected by this syndrome. Thus, the previously reported increased level in serum IL-6 suggests that the endocrine system exerts an effect on brain receptors (Makhija & Karunakaran, 2013; Schiepers, Wichers, & Maes, 2005). There is also compelling evidence that inflammatory cytokines activate neuroimmune mechanisms that involve behaviorally and emotionally relevant brain circuits. In this regard, allergen exposure and/or an allergic reaction in animals have been found to stimulate limbic brain regions as well as avoidance behavior, increased anxiety, and reduced social behavior (Basso et al., 2003; Costa-Pinto, Basso, Britto, Malucelli, & Russo, 2005, 2007; Palermo-Neto & Guimaraes, 2000; Tonelli et al., 2009). In humans, altered neuronal activity of the ACC and the PFC during a chronic (allergic) episode has been demonstrated by means of fMRI (Rosenkranz et al., 2005). In conclusion, our results suggest the possible presence of this type of pathogenetic mechanism in part of the ADHD child population.

Another result is worthy of note. It is not only the IL-6 blood level that is higher in the ADHD group than in the control group but also the IL-10 level. In view of the well-known protective role of IL-10 (Iyer & Cheng, 2012), we may explain the lack of significant or serious damage in the MRI images of the cerebellum in ADHD participants (and at the neurological examination in our ADHD sample) by hypothesizing a protective role of IL-10 during inflammation. This is a hypothesis based exclusively on the results of Iyer and Cheng (2012), though we wish to point out that anti-Yo antibodies in paraneoplastic syndromes are frequently associated with cerebellar damage.

A crucial question is, “Why are IL-6 and IL-10 blood levels high, whereas those of other cytokines are not?” One answer may be that not every tissue expresses every cytokine. IL-6 and IL-10 are produced by several types of brain cells and are now known to be very important for the CNS. Their expression is affected in some of the most important brain diseases such as stroke, multiple sclerosis, Alzheimer’s disease, and meningitis and is associated with behavioral changes that occur during bacterial infections. Moreover, animal models strongly suggest that IL-6 and IL-10 may play a role in the neuropathology, and that it is therefore a clear target of strategic therapies (Erta, Quintana, & Hidalgo, 2012; Strle et al., 2001).

Taken together, our results confirm that anti-Yo antibodies, IL-6, IL-10, and ADHD are all correlated with immune processes and inflammation.

The limitations of our study include the fact that the results that emerge from the study do not demonstrate a causal relationship between anti-Yo antibodies, IL-6, and ADHD behavior. We merely report an association between these two phenomena. Moreover, although the role of cytokines as markers of inflammation is well known, in this article (as in numerous other articles on the association between cytokines and behavioral disorders), we were unable to demonstrate a specific link between the presence of auto-antibodies and cytokines. If these results are replicated on a larger sample of participants, other trials may be able to provide evidence of a causal relationship between these biological findings and ADHD. Another potential limitation is the fact that the number of participants included in this study does not guarantee a very high statistical power. Finally, the fact that we did not study the IL-1, IL-13, and IL-16 serum levels may be considered another limitation.

Conclusion

The results of our study shed light on the possible mechanism of action of neural antibodies and cytokines in a subset of ADHD children. This research may be developed further by comparing the anti-Yo antibodies and cytokine levels in ADHD children with those in a sample of psychiatric non-ADHD patients and in a control group. If the results of such a comparison were to confirm the findings of the present study, yet another interesting investigation would be a study on the symptomatology of ADHD children with and without high cytokine blood levels designed to detect any differences between the two groups. All these investigations would also make a significant contribution to diagnostic procedures. Last, a possible clinical and therapeutic use of such investigations might be the introduction of anti-IL-6 biological therapy as add-on treatment during classical pharmacological therapy in ADHD children.

Footnotes

Authors’ Note

“In memoriam” of one of the authors: Dr. Francesca Passarelli passed away prematurely in December 2014. She was actively involved in the organization and execution of this research.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Author Biographies

Renato Donfrancesco, MD, obtained the degree from Pisa University in 1977. He is a specialist in pediatrics and in child neuropsychiatry. He works at S. Pertini Hospital of Rome as senior consultant in the Child Neuropsychiatry Department.

Paola Nativio is a biologist and obtained the degree from “Sapienza” University of Rome on 2010. She works at Policlinico Umberto I of Rome, Department of Neurology and Psychiatry, as laboratory responsible for clinical research.

Angela Di Benedetto is a clinical, developmental and human relations psychologist, expert in psychodiagnostics and psychological evaluations. She is a cognitive-bahavioural psychotherapist in training.

Maria Pia Villa is professor of Pediatrics, Head of Department of Pediatrics and Sleep Center, University “Sapienza”, Faculty of Medicine, Sant’Andrea Hospital, Rome. She has carried out research about sleep-disordered breathing in children, pediatric pulmonology and allergy, pediatric neurology, continuously from 1976 to today, as evidenced by her international scientific production.

Elda Andriola is a psychologist and cognitive-behavior psychotherapist. She is professor of psychodiagnostics in infancy and childhood at LUMSA University, Department of Human Sciences, Rome.

Maria Grazia Melegari, MD, is a specialist in child neuropsychiatry. She works at “Scarpetta” outpatients Child and Adolescent Neuropsychiatry Service of ASL RM/A where she is also coordinator of the ADHD Center.

Enrica Cipriano, MD, obtained her degree from Sapienza University of Rome in 2012. She is training in Reumathology and Autoimmunity at Policlinico Umberto I - Sapienza University of Rome.

Michela Di Trani is a psychologist and psychotherapist. She has a PhD in dynamic, clinical, and developmental psychology and works in the Department of Dynamic and Clinical Psychology of Sapienza University of Rome.

References

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing.

Anisman

Kokkinidis

Merali

(1996). Interleukin-2 decreases accumbal dopamine efflux and responding for rewarding lateral hypothalamic stimulation. Brain Research, 731, 1-11.

Antshel

K. M.

Hargrave

T. M.

Simionescu

Kaul

Hendricks

Faraone

S. V.

(2011). Advances in understanding and treating ADHD. BMC Medicine, 10, 72-83.

Arnsten

A. F.

(2009). Toward a new understanding of attention deficit hyperactivity disorder pathophysiology: An important role for prefrontal cortex dysfunction. CNS Drugs, 23, 33-41.

Banks

W. A.

Erickson

M. A.

(2010). The blood-brain barrier and immune function and dysfunction. Neurobiological Disorders, 37, 26-32.

Basso

A. S.

Pinto

F. A.

Russo

Britto

L. R.

de Sá-Rocha

L. C.

Palermo Neto

(2003). Neural correlates of IgE-mediated food allergy. Journal of Neuroimmunology, 140, 69-77.

Buske-Kirschbaum

Schmitt

Plessow

Romanos

Weidinger

Roessner

(2013). Psychoendocrine and psychoneuroimmunological mechanisms in the comorbidity of atopic eczema and attention deficit/hyperactivity disorder. Psychoneuroendocrinology, 38, 12-23.

Caci

Doepfner

Asherson

Donfrancesco

Faraone

S. V.

Hervas

Fitzgerald

(2014). Daily life impairments associated with self-reported childhood/adolescent attention-deficit/hyperactivity disorder and experiences of diagnosis and treatment: Results from the European Lifetime Impairment Survey. European Psychiatry, 29, 316-323.

Costa-Pinto

F. A.

Basso

A. S.

Britto

L. R.

Malucelli

B. E.

Russo

(2005). Avoidance behavior and neural correlates of allergen exposure in a murine model of asthma. Brain, Behavior, and Immunity, 19, 52-60.

10.

Costa-Pinto

F. A.

Basso

A. S.

Russo

(2007). Role of mast cell degranulation in the neural correlates of the immediate allergic reaction in a murine model of asthma. Brain, Behavior and Immunity, 21, 783-790.

11.

DuPaul

G. J.

Power

T. J.

Anastopoulos

A. D.

Reid

(1998). ADHD Rating Scale-IV. New York, NY: Guilford.

12.

Erta

Quintana

Hidalgo

(2012). Interleukin-6, a major cytokine in the central nervous system. International Journal of Biological Science, 8, 1254-1266.

13.

Giana

Romano

Porfirio

M. C.

D’Ambrosio

Giovinazzo

Troianiello

. . . Adriani

(2015). Detection of auto-antibodies to DAT in the serum: Interactions with DAT genotype and psycho-stimulant therapy for ADHD. Journal of Neuroimmunology, 15, 212-222.

14.

Goto

Yang

C. R.

Otani

(2010). Functional and dysfunctional synaptic plasticity in prefrontal cortex: Roles in psychiatric disorders. Biological Psychiatry, 67, 199-207.

15.

Iyer

S. S.

Cheng

(2012). Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Critical Reviews in Immunology, 32, 23-63.

16.

Kaufman

Birmaher

Brent

Rao

(1997). Schedule for Affective Disorders and Schizophrenia for school-age children-present lifetime version (K-SADS-PL): Initial reliability and validity data. Journal of the American Academy of Child & Adolescent Psychiatry, 36, 980-988.

17.

Makhija

Karunakaran

(2013). The role of inflammatory cytokines on the aetiopathogenesis of depression. Australian & New Zealand Journal of Psychiatry, 47, 828-839.

18.

Marzocchi

G. M.

Cornoldi

(2000). Una scala di facile uso per la rilevazione dei comportamenti problematici dei bambini con deficit di attenzione e iperattività [An easy to use scale for the detection of dysfunctional behaviors in children with attention deficit hyperactivity disorder]. Psicologia Clinica dello Sviluppo [Developmental Clinical Psychology], 4, 43-64.

19.

Palermo-Neto

Guimaraes

R. K.

(2000). Pavlovian conditioning of lung anaphylactic response in rats. Life Science, 68, 611-623.

20.

Passarelli

Donfrancesco

Nativio

Pascale

Di Trani

Patti

A. M.

. . . Villa

M. P.

(2013). Anti-Purkinje cell antibody as a biological marker in attention deficit/hyperactivity disorder: A pilot study. Journal of Neuroimmunology, 15, 67-70.

21.

Raison

C. L.

Capuron

Miller

A. H.

(2006). Cytokines sing the blues: Inflammation and the pathogenesis of major depression. Trend Immunology, 27, 24-31.

22.

Rosenkranz

M. A.

Busse

W. W.

Johnstone

Swenson

C. A.

Crisafi

G. M.

Jackson

M. M.

. . . Davidson

R. J.

(2005). Neural circuitry underlying the interaction between emotion and asthma symptom exacerbation. Proceedings of the National Academy of Sciences, 102, 13319-13324.

23.

Schiepers

O. J. G.

Wichers

M. C.

Maes

(2005). Cytokines and major depression. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 29, 201-217.

24.

Steiner

Bogerts

Sarnyai

Walter

Gos

Bernstein

H. G.

Myint

A. M.

(2012). Bridging the gap between the immune and glutamate hypotheses of schizophrenia and major depression: Potential role of glial NMDA receptor modulators and impaired blood-brain barrier integrity. World Journal of Biological Psychiatry, 13, 482-492.

25.

Stoodley

C. J.

(2014). Distinct regions of the cerebellum show gray matter decreases in autism, ADHD, and developmental dyslexia. Frontiers in Systems Neuroscience, 20, 92.

26.

Strle

Zhou

J. H.

Shen

W. H.

Broussard

S. R.

Johnson

R. W.

Freund

G. G.

. . . Kelley

K. W.

(2001). Interleukin-10 in the brain. Critical Review Immunology, 21, 427-449.

27.

Tonelli

L. H.

Katz

Kovacsics

C. E.

Gould

T. D.

Joppy

Hoshino

. . . Postolache

T. T.

(2009). Allergic rhinitis induces anxiety-like behavior and altered social interaction in rodents. Brain, Behavior, and Immunity, 23, 784-793.

28.

Toto

Margari

Petruzzelli

M. G.

Tafuri

Margari

(2015). Antibasal ganglia antibodies and Antistreptolysin O in noncomorbid ADHD. Journal of Attention Disorders, 19, 965-970.

29.

Wechsler

(1991). WISC-III. NCS Pearson.

30.

Zalcman

Green-Johnson

J. M.

Murray

Nance

D. M.

Dyck

Anisman

Greenberg

A. H.

(1994). Cytokine-specific central monoamine alterations induced by interleukin-1,-2 and -6. Brain Research, 643, 40-49.