Relationship between Handedness and the Geometry of the Branches of the Aortic Arch Anica Jansen van Vuuren Department of Psychology University of Cape Town Supervisor: Professor Mark Solms Word Count: Abstract: 295 Main Body: 10000 1     Abstract Handedness is the most obvious behavioural asymmetry in humans. Asymmetrical regional cerebral blood volume changes, particularly in the left premotor and parietal regions, occur contra- lateral to hand dominance during mental and motor activity. While a potential link between hemispheric and anatomical lateralisation has been investigated, research into the influence of asymmetrical vascular geometry is severely lacking. This study explores the relationship between handedness and the geometry of the arterial branches of the aortic arch, analysing potential asymmetries between the left common carotid (LC) and the combined right common carotid and brachiocephalic trunk (RC-BT complex) of left-handed and right-handed individuals. Selected geometric parameters of the vessels were measured, including minimum, mean, and maximum diameters, length, angle deviation, mean artery angle, and calculated resistance to blood flow. A revised version of the Edinburgh Handedness Inventory classified a sample of 71 participants, aged 21 to 96, into relevant handedness categories (left-handed = 8; right-handed = 62). An in-depth analysis of computed tomography angiography scans with RadiAnt DICOM Viewer (64-bit) imaging software was conducted. The findings confirm that right-handed individuals had dominant LC arteries (21.57% increased flow) that are presumably responsible for the higher metabolic demand of the left hemisphere of the brain (5.7%) in such individuals. Conversely, left-handed individuals had dominant RC-BT complex arteries (61.57% increased flow) that are responsible for a higher metabolic demand of the right hemisphere (16.21%). This difference was particularly evident in the geometric parameters of minimum and maximum arterial diameters, and calculated resistance to blood flow. Measurements of right-handers’ alternate arterial branching patterns showed a significant increase in overall blood flow resistance in both vessels, with a particular increase in RC-BT complex resistance. Therefore, despite the branching abnormality, a handedness- related bias was still evident. The findings concur with existing hemodynamic studies of the carotid arteries. 2     Keywords: handedness, cerebral lateralisation, language, aortic arch, common carotid artery, arterial geometry. 3     Introduction Handedness is the most obvious behavioural asymmetry in humans (Cagnie, Petrovic, Voet, Barbaix, & Cambie, 2006). Given its relation to hemispheric asymmetry of cognitive functions, principally language, the phenomenon of lateral manual preference has been of interest to neuropsychologists for years (Reiss & Reiss, 1999). However, the neurobiological basis for hand preference, and therefore for neurocognitive asymmetry, is still not understood (Amunts, Jancke, Mohlberg, Steinmetz, & Zilles, 2000). Nevertheless, it has become clear that handedness interacts with a number of variables, including aspects of hemispheric lateralization, sex, age, family history, writing posture, and the type of lateralized task (Hannay, 1988). Various studies have investigated genetic, neurobiological, and socio-cultural aspects of handedness. This study investigates the hypothesis that handedness is strongly associated with asymmetrical cerebral blood flow caused by the asymmetrical vascular anatomy of the human body, particularly asymmetries in the arterial geometry of branches of the aortic arch. Background Handedness is not a straightforward a topic. A distinction needs to be made between hand preference and hand proficiency, while the evaluation of hand preference is also contentious. Some researchers focus solely on hand preference during writing tasks, while others evaluate it over a number of activities, placing handedness on a continuum ranging from extreme right-handed (RH) at one end of the scale, extreme left-handed (LH) at the other, and ambidextrousness in between (Zillmer, Spiers & Culbertson, 2008). Researchers who define handedness through the assessment of efficient task completion emphasise proficiency as the determining factor of hand dominance (Zillmer et al., 2008). Although a positive correlation has been demonstrated repeatedly between these two perspectives, some studies reveal dissociation, suggesting that asymmetrical preference and proficiency are distinct entities (see Triggs, Calvanio, Levine, Heaton, & Heilman, 2000 for review). 4     Between 6 and 16% of the world’s population is LH, and 2 to 3% are ambidextrous, showing no clear hand preference or proficiency. However, studies frequently group ambidextrous participants with LH ones, causing the two-way comparison between RH and non-RH to be more common in research than between RH and LH (Thilers, MacDonald, & Herlitz, 2007). Left-handedness is more common in males (13%) than in females (11%) (Thilers et al., 2007; Vuoksimaa, Koskenvuo, Rose, & Kaprio, 2009). A meta-analysis of 43 studies suggests that LH males are up to 25% more common than LH females (Sommer, Aleman, Somers, Boks, & Kahn, 2008). These sex differences are greater in non-Western samples than in Western ones, suggesting that cultural (or possibly racial) factors are moderators of handedness (Sommer et al., 2008). Failure to understand the biological origins of handedness has resulted in the historical stigmatisation of LH individuals. This norm deviation has been perceived historically as an indication of mental deficiency, sickliness, undesirability, incompetence, and clumsiness (Porac & Martin, 2007). As a result, the tradition of “converting” left-dominant individuals is a social practice common in many cultures (Provins, 1997). Forced conversion from a young age is associated with memory disorders, concentration deficits, dyslexia problems, spatial disorientation, and disorders of fine motor skills (Sattler, 2004). Investigating the biological substrates of handedness is imperative in moving towards alleviating social stigmatisation and subsequent problematic “conversion” practices (Siebner et al., 2002). Mechanisms of Handedness Decussation of the sensory and motor tracts from the brain to the spinal cord results in the right cerebral hemisphere showing greater involvement in the sensory motor control and representation of the left side of the body, whereas the left hemisphere is more associated with the right side (Zillmer et al., 2008). Although the relationships between different aspects of hemispheric lateralisation are still speculative, the strong association between handedness, language, and motor 5     functioning has led researchers to use handedness as an indirect indicator of hemispheric specialization (Dadda, Cantalupo, & Hopkins, 2006). Despite uncertainty surrounding the origins of handedness, neuropsychological studies of asymmetric clinical phenomena such as aphasia have shown that in addition to their contralateral control of sensory motor functioning, the two cerebral hemispheres of the brain mediate different cognition functions (Herve, Crivello, Perchey, Mazoyer, & Tzourio-Mazoye, 2006). In RH individuals, the left hemisphere mediates language and praxic functions, whereas the right hemisphere is more involved in visuospatial and attentional functions (Josse & Tzourio-Mazoyer, 2004). Left-handers are less laterally differentiated than RH individuals, as evidenced by their relative bilaterality of language functioning, and by the presentation of transient aphasia following left hemisphere lesions (Knecht et al., 2000). The LH population is heterogeneous with respect to the direction of lateralization, with approximately 60% reflecting RH lateralisation, whereas roughly 40% have a reverse pattern (Roberts, 1969). Most handedness studies correlate anatomical asymmetries of the brain with handedness, such as the size of the frontal and occipital lobes, and the upper lift of the right sylvian fissure (Josse, Segheir, Kherif, & Price, 2008). However, none of these studies successfully identified a biological substrate of these anatomical asymmetries (Herve et al., 2006). Importantly, however, direction of causality cannot be inferred from these correlation studies (Beaton, 1997). Few studies have focused on other (non-cerebral) anatomical asymmetries directly related to handedness. Older suppositions dating from the 19th and the beginning of the 20th century proposed that a number of possible variables played a role in determining handedness, including arm length, asymmetries in the blood supply to the extremities, and bone-weight (Amunts et al., 2000). 6     Handedness and Asymmetrical Blood Flow The hypothesis that hemispheric lateralisation is related to asymmetrical cerebral blood flow and therefore to asymmetries in the vascular system, is not new (Cagnie et al., 2006). Blood flow to the brain is closely associated with metabolic requirements of the tissue for glucose and oxygen (Siesjo, 1978). However, large increases in flow are necessary to produce small increases in oxygen metabolic rates. Buxton and Frank (1997) approximate this required flow increase to be 19% for a 5% enhancement in localised cerebral oxygen metabolism. Identifying these regional variations in blood flow forms the basis for mapping localised brain activation patterns, such as positron emission tomography and functional magnetic resonance imaging (Buxton, Wong, & Frank, 1998). Regional cerebral blood volume changes during mental and motor activity (Rijsberg & Ingvar, 1968). Studies have shown that activation of the contralateral primary motor cortex and dorsal premotor cortex is 20 times stronger than the activation of the ipsilateral cortex during complex distal hand movements (Haaland, Elsinger, Mayer, Durgerian, & Rao, 2004; Kim et al., 1993; Vivani, Perani, Grassi, Bettinardi, & Fazio, 1998). Right-handers with brain damage show greater ipsilateral motor impairment following left hemisphere damage versus right hemisphere damage (Haaland & Harrington, 1996). Handedness therefore reflects functional hemispheric asymmetry during motor control. The nature and extent of this asymmetry and its relation to hemispheric dominance have long been debated (Kim et al., 1993; Vivani et al., 1998). An extreme hypothesis argues that movement is initially generated in the dominant hemisphere and is subsequently replicated in the non-dominant one (Geschwind, 1975). This hypothesis is supported by studies of identical rhythmic movements, which illustrate that during the performance of motor tasks, the dominant hand leads the non-dominant one by approximately 25 ms, irrespective of movement speed (Stucchi & Vivani, 1993). Arteriographic studies conclude that the mechanical properties of large arteries play an important role in regulation of cerebral blood flow (Magun, 1973; Nichols & O’Rourke, 1998). 7     Each artery resists blood flow based on its geometric features, forming an important pressure gradient across the arteries between the aorta and the large arteries of the brain (Kanzow & Dieckhoff, 1969). Luminal diameter serves as the most influential geometric property related to blood flow resistance (Ku, 1997; Lusis, 2000; Mitchell, 2003; 2004). However, side branches and mild curvatures as low as 15º are sufficient to impede blood flow (Banerjee, Cho & Back, 1992; Manbachi, Hoi, Wasserman, Lakatta, & Steiman, 2011; Staalsen et al., 1995). This alteration in flow is a result of swirling, flow separation, and secondary flow (Doorly & Sherwin, 2009; Ku, 1997). Investigating the geometry of the larger arteries that feed the brain is important for the identification of asymmetrical cerebral blood flow and blood flow resistance. Recent studies investigating this relationship are based on the assumption that RH individuals have dominant left vertebral arteries, and vice-versa for LH individuals (Zaina et al., 2003). The vertebral arteries were focused upon because they lead directly to the brain, and because variations in the normal anatomy of the extracranial vertebral arteries are relatively common (Cagnie et al., 2006). Significant variations in diameter, flow velocities, and flow volume have been recorded between the two vertebral arteries, as the left vertebral artery typically has more dominant blood flow than the right (Jeng & Yip, 2004). However, a correlation analysis between the diameter of the vessels and hand dominance failed to produce significant results (Cagnie et al., 2006). This could be due to the small sample size ⎯ only 50 participants were included (29 RH, 21 LH). Vertebral arteries are not the most appropriate place to look for the sources of asymmetrical cerebral blood flow. These two arteries, which stem from the left and right subclavian arteries, feed the basilar artery, which in turn splits into the right and left posterior cerebral arteries (Figure 1). Therefore, geometric asymmetries in the vertebral arteries are irrelevant for investigating asymmetrical cerebral blood delivery because they merge into a single source of posterior cerebral blood flow. Contrastingly, the right and left internal carotid arteries feed the most asymmetrical region of the brain directly and independently (Figure 1). Therefore, branching and geometrical 8     asymmetries in these arteries should be key to exploring asymmetrical cerebral blood flow (Mitchell, 2004). Figure 1. Scheme of distribution of the conventional arterial branching pattern Disparities in flow rates between the right and left internal carotid arteries have been reported in relation to handedness. Bogren, Buonocore and Gu (1994) established normal carotid artery flow rates in five LH and five RH individuals, with the RH having higher flow rates in the left internal carotid artery than in the right, and the LH having higher flow rates in the right internal carotid artery (p = .007). However, the internal carotid arteries branch from larger vessels that originate at, or are close to, the aortic arch. Therefore, cerebral blood flow should also be directly influenced by the geometry of these core vessels. However, no significant differences in left and right common carotid artery flow rates were found by Bogren et al. (1994), possibly due to their small sample size. Aging results in significant changes in the structure and function of the cardiovascular system, including increased arterial wall thickening, which has been shown to occur asymmetrically 9     (Oxenham & Sharpe, 2003). Onbas et al. (2007) confirm that handedness is a significant factor influencing intima-media thickness of the common carotid arteries, as hemodynamic stress and intimal damage is larger in the LC in RH compared to LH individuals. This provides indirect evidence of physiological asymmetry of functions, as intima-media wall thickening is highly associated with shear stress (Shaaban & Duerinckx, 2000). Further vascular asymmetries are found in the conventional aortic arch branching pattern. Even though in most mammals the two common carotid arteries branch symmetrically from the brachiocephalic trunk (BT), a human branching asymmetry is evident. The RC shares a common trunk with the right subclavian artery (RS), stemming from the BT, whereas the LC and left subclavian artery (LS) stem directly from the aortic arch (Alsaif & Ramadan, 2010) (Figure 1 and 2). Arteries feeding the right hemisphere branch four times before reaching the hemisphere, whereas arteries feeding the left hemisphere branch three times. This asymmetry predicts decreased blood flow efficiency in the arterial path feeding the right hemisphere, as additional branching results in blood flow disturbance, decreased vessel diameter, and increased vessel angle deviation (Tortora & Derrickson, 2006). Furthermore, handedness is symmetrical in most mammals with symmetric aortic branching, whereas humans display a large RH bias (Carmon, Harishanu, Lowinger, & Lavy, 1972). Figure 2. Common variations of aortic arch branching patterns.