Physiol. Res. 68: 531-545, 2019 https://doi.org/10.33549/physiolres.934160 REVIEW Novel Approach to Evaluate Central Autonomic Regulation in Attention Deficit/Hyperactivity Disorder (ADHD) N. SEKANINOVA1,2, M. MESTANIK2,1, A. MESTANIKOVA1,2, A. HAMRAKOVA1,3, I. TONHAJZEROVA1,2 1Department of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic, 2Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic, 3Psychiatric Clinic, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, University Hospital Martin, Martin, Slovak Republic Received March 7, 2019 Accepted April 15, 2019 Epub Ahead of Print June 6, 2019 Summary Key words Attention deficit/hyperactivity disorder (ADHD) is one of the most ADHD • Neurobiology • Autonomic regulation • Pupillometry • commonly diagnosed developmental disorders in childhood Eye-tracking characterized by hyperactivity, impulsivity and inattention. ADHD manifests in the child’s development by deficits in cognitive, Corresponding author executive and perceptor-motor functions, emotional regulation I. Tonhajzerova, Department of Physiology and Biomedical and social adaptation. Although the exact cause has not yet been Center Martin, Jessenius Faculty of Medicine in Martin, Comenius known, the crucial role in the development of this disease plays University in Bratislava, Mala Hora 4C, 036 01 Martin, Slovak the interaction of genetic, neurobiological and epigenetic factors. Republic. E-mail: [email protected] According to current knowledge, ADHD is defined as a biological dysfunction of central nervous system with genetically or Introduction organically defined deficits in noradrenergic and dopaminergic neurotransmission associated with structural abnormalities, ADHD (Attention Deficit Hyperactivity especially in prefronto-striatal regions. In this context, Disorder according to American classification DSM-V) is a significant part of the difficulties could be due to a faulty a mental disease in the childhood with the highest control of fronto-striato-thalamo-cortical circuits important for prevalence, approximately 8-12 % worldwide, with attention, arousal and executive functions. Moreover, ADHD is a more frequent occurrence among boys compared to associated with abnormal autonomic regulation. Specifically, girls in a ratio of 3-5:1 (Biederman and Faraone 2005, reduced cardiac-linked parasympathetic activity associated with Skogli et al. 2013). ADHD is a common relative sympathetic dominance indexed by low heart rate neurodevelopmental disorder characterized by pervasive variability can represent a noninvasive marker for prefrontal and developmentally inappropriate levels of impulsivity, hypoactivity. However, the mechanisms underlying altered hyperactivity and inattention lasting at least 6 months autonomic regulation in ADHD are still unknown. In this aspect, with the beginning before the seventh year of age of the the evaluation of central autonomic regulation by noninvasive child and wide-ranging cognitive and behavioral methods, namely pupillometry and eye-tracking, may provide impairments, including deficits in working memory, novel information for better understanding of the neurobiological inhibitory control, and altered motivation (Sonuga-Barke pathomechanisms leading to ADHD. 2002). According to current knowledge, ADHD is PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online) 2019 Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic Fax +420 241 062 164, e-mail: [email protected], www.biomed.cas.cz/physiolres 532 Sekaninová et al. Vol. 68 defined as a biological dysfunction of central nervous volume, prefrontal cortex, basal ganglia (striatum), dorsal system (CNS) with genetically or organically defined anterior cingulate cortex, splenium of the corpus deficits in noradrenergic and dopaminergic callosum, and cerebellum, in particular the posterior neurotransmission. It is suggested that part of the inferior vermis (Emond et al. 2009). These widespread difficulties of ADHD is due to a faulty control of fronto- macrostructural changes suggest that many areas of the striato-talamo-cortical circuits important for the brain are associated with ADHD diagnosis in childhood. management of behavioral responses such as attention, In children and adolescents, ADHD symptoms such as arousal and executive functions (Barkley 1997). distractibility, impulsivity, hyperactivity and Moreover, according to Neurovisceral and Polyvagal forgetfulness were linked to decreased frontal and theory (Porges 1995, Thayer and Lane 2000, Porges temporal grey matter and also caudate and cerebellar 2007) these brain regions are part of volumes (Arnsten 2006). Excluding changes in volume, a complex autonomic network described by Benarroch studies of cortical development also showed a decrease in (1993) modulating the output to the sympathetic and cortical thickness (Batty et al. 2010) and a marked delay parasympathetic neurons. Thus, the abnormalities in in brain maturation where the grey matter peaks were autonomic regulatory mechanisms could reflect about 3 years later, most prominent in prefrontal regions pathomechanisms linked to ADHD. important in the control of cognitive processes, than in This article is aimed to summarize the latest healthy controls (Shaw et al. 2006, Shaw et al. 2007). In findings in the neurobiology of ADHD with focus on ADHD patients, DTI studies have revealed pupillometry and eye-tracking as novel methods suitable developmental changes in cortical white matter pathways for quantifying of central autonomic regulation/dys- in prefrontal regions and also in the pathways that regulation associated with ADHD. surround the basal ganglia and cerebellum reflecting decreased myelination of axons (D’Agati et al. 2010). Neurobiology of ADHD Growing evidence points to the fronto-striatal network involving lateral prefrontal cortex, dorsal anterior In the neurobiology of ADHD, several major cingulate cortex, the caudate nucleus and putamen as well research areas, namely neuroimaging, neurophysiology as fronto-parietal network as a likely contributor to the and neurochemistry, and genetics show that specific brain pathophysiology of ADHD (Bush et al. 2005). abnormalities are involved in the ADHD pathophysiology Neurobiological dysfunction of the circuits within the leading to changes in biochemical regulation in the brain prefrontal cortex, namely dorsal fronto-striatal, orbito- (Doggett 2004). fronto-striatal and fronto-cerebellar can lead to the symptoms of ADHD, such as impulsive and inattentive Neuroimaging studies behavior. Functionally, dorsal fronto-striatal circuitry is linked to cognitive control, whereas circuits between Relationships between brain morphology and striatum and orbitofrontal cortex are related to reward and ADHD can be identified by various neuroimaging motivation (Durston et al. 2011). Prefrontal cortex methods, mainly magnetic resonance imaging (MRI) and dysfunction results in reduced ability to exercise control its modalities. In MRI, the T1 imaging weighting is used (Casey et al. 2007). Dysfunction of ventral striatum can for the assessment of brain macrostructure, such as lead to deficits in motivation and reward processing, volume and structure of white and gray matter, and the whereas dysfunction in dorsal striatum can lead to diffusion tensor imaging (DTI) for the assessment of problems with ability to predict what events will occur brain microstructure, specifically to assess the integrity of (Scheres et al. 2007, Plichta et al. 2009). The fronto- the white matter pathways (Song et al. 2005). Initial brain cerebellar circuits are implicated in timing and building macrostructural studies revealed that children suffering temporal expectations and its dysfunction is related to from ADHD show smaller brain volumes in all regions problems of ability to predict when events will occur (Castellanos et al. 2002) however, some meta-analyses (Hoekzema et al. 2010). In addition, connections between report differences mainly in basal ganglia with total brain the prefrontal cortex and amygdala have been suggested or grey matter volume (Valera et al. 2007, Ellison-Wright to play a role in ADHD, in particular, fronto-amygdalar et al. 2008, Nakao et al. 2011). Specifically, ADHD circuits could be involved in assignment of emotional patients are characterized by reductions in total cerebral valence to events and also inputs from amygdala can 2019 Autonomic Regulation in ADHD 533 influence the recruitment of prefrontal control (Durston (Tomasi and Volkow 2012¸ Franzen et al. 2013). The et al. 2011). It is assumed that dysregulated functional SLF is a large bundle of white matter in each cerebral communications in these networks are the cause of the hemisphere that connects the parietal, temporal and behavioral dysfunction in ADHD diagnosis (Nagel et al. occipital lobes with ipsilateral frontal cortices. There are 2011). four subcomponents of the SLF (SLF I, SLF II, SLF III It is suggested that hyperactivity-impulsive and SLF IV also called arcuate fasciculus) with different symptoms are associated with changes in the striatum and functional contributions to behavior. SLF I connects the its connections (van Ewijk et al. 2012). The striatum medial and dorsal part of the frontal lobe with the includes the nucleus accumbens that forms a network cingulate and cingulum of the superior and medial