Effects of dominant and non-dominant passive arm manoeuvres on the neurovascular coupling response

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1 Effects of dominant and non-dominant passive arm manoeuvres on the neurovascular coupling response Osian Llwyd 1,2, Ronney B. Panerai 1,2 and Thompson G. Robinson 1,2 1 Department of Cardiovascular Sciences, Cerebral Haemodynamics in Ageing and Stroke Medicine Research Group, University of Leicester, Leicester, LE2 7LX, UK. 2 NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK. Osian Llwyd, corresponding author at: Department of Cardiovascular Sciences, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, LE2 7LX, UK; T: +44 (0) ; address: o.llwyd@leicester.ac.uk Acknowledgments We would like to thank Nazia P. Saeed for her work in applying for ethical approval. TGR is an National Institute for Health Research Senior Investigator. This study was supported by the UK Engineering and Physical Sciences Research Council (EPSRC), grant No. EP/K041207/1. The data created during this research are openly available at the Leicester Research Archive, University of Leicester, Leicester, U.K. Compliance with ethical standards Conflict of Interest The authors have no conflicts of interest to declare. 1

2 Abstract Purpose - Models designed to study neurovascular coupling () describe a possible cerebral hemisphere dominance dependent on task completed and preference in handedness. We investigated whether passive arm manoeuvre performed with dominant (Dom-Arm) or non-dominant arm (ND- Arm) stimulated haemodynamic differences in either contralateral (Cont-H) or ipsilateral (Ipsil-H) cerebral hemisphere. Methods - Healthy individuals lying in supine position, had measurements of beat-to-beat blood pressure (BP, mmhg), electrocardiogram (HR, bpm), end-tidal CO 2 (etco 2, mmhg) and bilateral insonation of the middle cerebral arteries (MCA, cm.s -1 ). Arm movement was performed for 60 s with passive flexion and extension of the elbow (1 Hz), before manoeuvre was repeated on other arm. Data were normalised and effect of treatment was analysed for differences between manoeuvres and within each time period. Results - Seventeen (8 males) healthy volunteers, aged 56 ± 7 years, were studied. Dom-Arm and ND-Arm manoeuvres stimulated a comparable temporal response in peripheral and cerebral haemodynamic parameters between Cont-H and Ipsil-H. Conclusions - Both manoeuvres can be used to evoke similar bilateral MCA responses in assessing. This finding should lead to more efficient protocols when using passive arm movement for studies in healthy subjects. Key words Neurovascular Coupling; Passive Arm; Dominant Hand; Cerebral Blood Flow; Cerebral Hemisphere; Transcranial Doppler Ultrasound. Abbreviations ANOVA Analysis of variance CBF Cerebral Blood Flow CBFV CBF velocity Cont-H Contralateral Hemisphere CrCP Critical Closing Pressure Dom-Arm Dominant Arm etco 2 end-tidal CO 2 Ipsil-H Ipsilateral Hemisphere MCA Middle Cerebral Arteries MCBFV Mean Cerebral Blood Flow Velocity ND-Arm Non-Dominant Arm Neurovascular coupling RAP Resistance Area Product 2

3 Introduction Neurovascular coupling () describes the association between neuronal activity and the localised response in cerebral blood flow (CBF) that is needed to suffice metabolic demand. To study in humans, brain activity within specific regions can be stimulated with a range of tasks that are visual (Yamaguchi et al. 2014), motor (Hirth et al. 1997), or cognitive (Williams et al. 2017) in nature. These paradigms will promote a transient hyperaemic response that can be measured with functional neuroimaging techniques such as positron emission tomography (PET) (Colebatch et al. 1991), functional magnetic resonance imaging (fmri) (Rao et al. 1993) or near infrared spectroscopic imaging (Hirth et al. 1997). The portability and temporal resolution of transcranial Doppler ultrasonography (TCD) makes it an ideal method to assess cerebral haemodynamics in response to specific tasks and neural activities in both healthy (Salinet et al. 2012) and diseased individuals (Phillips et al. 2016; Salinet et al. 2013). We have previously used a passive sensorimotor paradigm with TCD to demonstrate impairment after ischaemic stroke. A comparison between the use of the dominant arm (Dom-Arm) in healthy individuals and the affected arm in stroke patients showed a weakened response in cerebral haemodynamics by the patients (Salinet et al. 2013). One limitation to this study (Salinet et al. 2013) was that only Dom-Arm was used to study healthy controls, whereas depending on the handedness of the patient and the side affected by hemiparesis, both Dom-Arm or the non-dominant arm (ND-Arm) were used to stimulate in the stroke population. The dominant and non-dominant hand have evolved different roles to manipulate objects (Hammond 2002). Models designed to study in humans describe a possible cerebral hemisphere dominance that is dependent on the task completed and the preference in handedness (Sitzer et al. 1994; Haaland & Harrington 1996; Hirth et al. 1997; Alahmadi et al. 2015). For example, studies have demonstrated the dominance of the contralateral motor cortex to a single motor movement with an augmented or larger haemodynamic response in regions located in the contralateral hemisphere (to the manoeuvre) than the ipsilateral hemisphere (Sitzer et al. 1994; Hirth et al. 1997; Moody et al. 2005). Though ipsilateral motor projections are thought to play a minor role in simple motor tasks, it is likely that they contribute to more complex tasks (Haaland & Harrington 1996). However, few studies have used TCD to investigate whether a task performed by each arm can evoke different functional hyperaemic responses within the contralateral or ipsilateral hemisphere (Hirth et al. 1997; Cuadrado et al. 1999). Thus, our aim was to determine in healthy individuals whether haemodynamic differences exist in the contralateral (Cont-H) or ipsilateral (Ipsil-H) hemispheres to a passive sensorimotor paradigm when it is performed with the Dom-Arm or ND-Arm. Based on our previous findings (Salinet et al. 2013) demonstrating a bilateral increase of CBF in stroke and control groups that performed a passive motor paradigm, we hypothesised that no differences would exist in cerebral haemodynamic responses during manoeuvres with either the Dom-Arm or ND-Arm. Methods A total of 24 older healthy participants were recruited from departmental staff and their friends or relatives. The protocol was approved by North East - Newcastle & North Tyneside 1 Research Ethics Committee (Ref: 14/NE/1003) and all participants gave written and informed consent before assessments. The study was conducted in a dedicated cardiovascular research laboratory at Leicester Royal Infirmary (Leicester, U.K.) that had a controlled temperature (20-24 o C) and was free from distraction. 3

4 Each individual abstained from caffeine, alcohol and nicotine for at least 4 hours before the assessment. After lying in a supine position for a minimum of 15 minutes the procedure was randomised to begin with either the left or right arm. On the opposite hand, measurements of beat-tobeat blood pressure (BP, mmhg) were conducted with a Finometer (FMS, Arnhem, Netherlands). TCD (Viasys Companion III; Viasys Healthcare, San Diego, CA, USA) was used for bilateral insonation of the middle cerebral arteries (MCA; CBF velocity (CBFV), cm.s -1 ). Two transducers (2 MHz) attached to a headframe (Compumedics, DWL, Germany) were positioned on the temporal bone at an angle and depth (40-60 mm) that yielded the maximum reflected signal. Both probes were matched by position, angle, strength of signal and blood flow velocity. Capnography (Capnocheck Plus, Kent, UK) and nasal cannulae recorded end-tidal CO 2 (etco 2, mmhg), and three-lead electrocardiogram recorded heart rate (HR). The paradigm was performed as described previously (Salinet et al. 2012; Salinet et al. 2013). The procedure included a 90 s baseline recording, where the investigator held the hand of the participant 60 s prior to the manoeuvre, in order to make the participant feel at ease and to limit any sudden sensory stimulation occurring during the paradigm. A metronome (MA-30, KORG) linked with a digital output was used to pace and mark the 60 s paradigm where the arm of the individual was passively flexed and then extended (at 90 o ) to each signal. A further 60 s of recovery was recorded before the manoeuvre was repeated on the other arm following a change in placement of the Finometer to the opposite hand. The manoeuvre was performed once on each arm, with a brief demonstration to the manoeuvre before each recording, to ensure there was a level of compliance by the participant to allow a relaxed and passive movement of each arm. Data were simultaneously recorded onto a data acquisition system (PHYSIDAS, Department of Medical Physics, University Hospitals of Leicester) for subsequent off-line analysis using a sampling rate of 500 samples s -1. BP was calibrated at the start of each recording and all signals were visually inspected to identify artefacts and noise, with narrow spikes (<100 ms) removed by linear interpolation. CBF velocity (CBFV) channels were subjected to a median filter and all signals were low-pass filtered with a cut-off frequency of 20 Hz. The R R interval was automatically marked from the ECG and continuous HR (bpm) was plotted against time. Occasional missed marks were remarked at the time points at which they occurred. Mean arterial BP (MABP), mean CBFV (MCBFV) values and other parameters were calculated for each cardiac cycle throughout the whole recording, which includes 1-minute baseline, 1-minute passive arm manoeuvre and 1-minute recovery (see Fig. 1 for one individual example). The end of each expiratory phase was detected in the etco 2 signal, linearly interpolated, and resampled with each cardiac cycle. Beat-to-beat data were spline interpolated and resampled at 5 samples/s to produce signals with a uniform time-base. The instantaneous relationship between BP and MCBFV was used to estimate critical closing pressure (CrCP) and resistance area product (RAP) for each cardiac cycle using the first harmonic method (Panerai 2003). RAP, as the slope of the pressure-velocity instantaneous relationship, was calculated as RAP= P1/V1 where P1 and V1 are the first harmonics of BP and CBFV waveform for each cardiac cycle waveform. Using this value, CrCP can then be calculated as CrCP= MABP-RAP*MCBFV, where MABP and MCBFV are the mean values of BP and CBFV for the same cardiac cycle. The mark at the start of the arm manoeuvre was used as a point of synchronism to obtain population mean and SD curves for each separate contribution for Cont-H and Ipsil-H. Two individuals were left-handed (determined by the preference in writing and throwing) and the data recordings gathered from the cerebral hemispheres for these individuals were transposed and assigned so that their dominant and non-dominant hemispheres matched the right-handed individuals. 4

5 e tc O 2 (m m H g ) C r C P (m m H g ) C r C P (m m H g ) H R (b p m ) R A P (m m H g.c m.s -1 ) R A P (m m H g.c m.s -1 ) M A B P (m m H g ) M C B F V (c m.s -1 ) M C B F V (c m.s -1 ) Statistical Analysis The recordings were separated into three regions of interests based on time: (1) Baseline (-60 to 0 s); (2) response (0 to 70 s); (3) Recovery (70 to 120 s). Data were normalised to 30 s of baseline prior to arm manoeuvre. The whole-time period for each region was used to calculate the mean values and area under curve (normalised mean values multiplied by length of time in s, AUC). Each time period was first analysed separately for differences between hemispheres during Dom-Arm and ND-Arm, by comparing the mean values or AUC, using a repeated measures ANOVA for cerebral haemodynamics (CBFV, RAP, CrCP) measured in each cerebral hemisphere, or a paired student t-test for the peripheral cardiovascular parameters (MABP, HR) and etco 2. To measure differences between time-periods within each hemisphere and for interaction between two variables (time and hemispheres), a two-way repeated measures ANOVA was used, with a post hoc analysis (Tukey s) used where appropriate, and a value of p<0.05 was defined as level of statistical significance. The time-base mean values and SD, comprising the 60 s duration for the response period and 60 s duration for recovery period were searched for the largest magnitude of change in cerebral haemodynamics immediately following the start and end of each manoeuvre. These summary data (mean, SD, number) were then compared using one-way ANOVA. (a) (d) 6 0 (e) (b) 8 0 (f) 1.6 (g) (c) 4 0 (h) 6 0 (i) Fig. 1 - Time course of beat-to-beat averages for a 54-year-old right handed male, in mean arterial blood pressure (MABP; a), heart rate (HR; b), end-tidal CO 2 (etco 2; c), cerebral blood flow velocity (CBFV; d & e), resistance area product (RAP; f & g) and critical closing pressure (CrCP; h & i) during a manoeuvre with the dominant arm, where black bar indicates duration. (d, f, h) Response in cerebral hemisphere corresponding to Contralateral Hemisphere. (e, g, i) Response in cerebral hemisphere corresponding to Ipsilateral Hemisphere 5

6 Results Of the 24 participants recruited, three individuals were excluded for not having an acoustic window, one for having poor beat-to-beat BP measurements, and one with an unforeseen history of heart disease. Two further individuals were excluded during subsequent analysis due to poor quality recordings. Therefore, data are presented for 17 individuals (8 male), with a mean ± standard deviation (SD) age of 56 ± 7 years. Absolute values of baseline data are summarised in table 1. Prior to manoeuvres with ND-Arm or Dom-Arm, all parameters were comparable except for RAP (p = 0.033). Tukey s multiple comparison test showed no further significant differences between groups in RAP. Each arm manoeuvre initiated a similar temporal response in MABP, HR and etco 2 (Fig. 2) as there was no difference in any parameter between time periods with either arm manoeuvre, for either normalised mean values or AUC (Table 2 and 3 respectively, in appendices). A small rise in MABP (Fig. 2a) at the end of the manoeuvre was followed by a decrease during recovery period (Table 2). These later changes coincided with a significant rise to HR (1.9% and 2.3%; Fig. 2b) during recovery period (compared to baseline) that was matched by both ND-Arm and Dom-Arm respectively. There was no difference in etco 2 (Fig. 2c) between time periods. Table 1 Baseline values for cerebral and peripheral haemodynamic parameters. ND-Arm Dom-Arm Cont-H Ipsil-H Ipsil-H Cont-H p value Cerebral MCBFV (cm.s -1 ) 51.1 ± ± ± ± RAP (mmhg.cm.s -1 ) 0.99 ± ± ± ± CrCP (mmhg) 39.0 ± ± ± ± Peripheral MABP (mmhg) 88 ± ± HR (bpm) 64 ± 9 63 ±.26 etco 2 (mmhg) 39.5 ± ± Data presented as mean ± standard deviation. p value, repeated measures one-way ANOVA (Cerebral) or paired t-test (Peripheral). ND-Arm, non-dominant arm; Dom-Arm, dominant arm; Cont-H, contralateral hemisphere; Ipsil-H, ipsilateral hemisphere; MCBFV, mean cerebral blood flow velocity; RAP, resistance area product; CrCP, critical closing pressure; MABP, mean arterial blood pressure; HR, heart rate; etco 2, end-tidal CO 2. Both arm manoeuvres initiated a similar temporal haemodynamic response in CBFV, RAP and CrCP (Fig. 3) as no difference was found within each time period when these parameters were compared between arm manoeuvres and cerebral hemispheres, for either normalised mean values (Table 2), AUC (Table 3) or maximum magnitude of changes (Table 4, in appendices). When changes in mean values were compared between time periods (Table 2), both arm manoeuvres instigated significant changes to mean CBFV in both cerebral hemispheres during the period (4.9% to 7.4%) compared to baseline and then again during the recovery period (-1.3% to -2.5%) when compared to (Fig. 3a & b). The two-way ANOVA for MCBFV showed a significant interaction between time and hemispheres (p = 0.022). The changes in RAP following the start of arm manoeuvres were shorter (lasting 20 s, Fig. 3c & d) and no difference was found in mean values between baseline and period (-1.4% to -2.5%). 6

7 e tc O 2 ( % ) H R ( % ) M A B P (% ) During the recovery period when compared to, significant changes were observed in Cont-H during both arm manoeuvres (2.3% and 0.3%). The reduction in CrCP (-1.6% to -4.1%) following the start of the arm manoeuvres was similar to RAP, but lasted for the duration of the paradigm (Fig. 3e & f). Only the Ipsil-H with the ND-Arm was not deemed different to baseline. All cerebral hemispheres demonstrated a greater CrCP during the recovery period that was significant to the period (1.4% to 3.2%). (a) (b) (c) Fig. 2 - Time course of population normalised averages in mean arterial blood pressure (MABP; a), heart rate (HR; b) and end-tidal CO 2 (etco 2; c) during manoeuvres with the Dominant (black line with square symbol) and Non-Dominant arms (grey line), where black bar indicates duration. Bars represent the largest ± SD at the point of occurrence 7

8 C r C P ( % ) C r C P ( % ) R A P (% ) R A P (% ) M C B F V (% ) M C B F V (% ) (a) (b) (c) (d) 8 0 (e) 8 0 (f) Fig. 3 Time course of population normalised averages in cerebral blood flow velocity (CBFV; a & b), resistance area product (RAP; c & d) and critical closing pressure (CrCP; e & f) during manoeuvres with the dominant (Dom-Arm, black line with square symbol) and non-dominant (ND- Arm, grey line) arms, where black bar indicates duration. (a, c, e) Response in cerebral hemispheres corresponding to Dom-Arm/Contralateral Hemisphere and ND-Arm/Ipsilateral Hemisphere. (b, d, f) Response in cerebral hemispheres corresponding to Dom-Arm/Ipsilateral Hemisphere and ND- Arm/Contralateral Hemisphere. Bars represent the largest ± SD at the point of occurrence Discussion This study demonstrated that passive arm manoeuvres with either Dom-Arm or ND-Arm can evoke similar cerebral haemodynamic responses within the MCA as measured by TCD in either contralateral or ipsilateral cerebral hemispheres. The changes in peripheral cardiovascular parameters that occurred later during the paradigm were also matched when using either arm. Studies have previously reported bilateral cortical control of distal hand movements when tasks require increased cognitive requirements due to a complex movement (Colebatch et al. 1991; Rao et al. 1993; Stoeckel & Binkofski 2010) or have consecutive and repeated tasks (Colebatch et al. 1991; Solodkin et al. 2001). Performing hand grips with the Dom-Arm or ND-Arm can evoke similar bilateral functional hyperaemic response (Ward & Frackowiak 2003). However, neuroimaging techniques with large spatial resolution that can compare multiple regional changes (i.e. PET and fmri) have further 8

9 highlighted the lateralization of additional cerebral regions when using dominant or non-dominant arm (Ward & Frackowiak 2003; Alahmadi et al. 2015). A study by Sitzer et al. (1994)(Sitzer et al. 1994) showed that PET and TCD had good agreement in assessing changes in somatosensory stimulation, but also demonstrated lateralization of CBFV to the left cerebral hemisphere after sequential finger movements in the right hand. There is growing evidence that ipsilateral motor projections play a minor role in simple motor tasks and contribute more during complex tasks (Stoeckel & Binkofski 2010). However, it has also been reported that an unnatural non-dominant hand movement may additionally require activation of the ipsilateral motor area (Kawashima et al. 1993). With contradictory evidence, dependent on tasks and methods of measurements, our aim was to establish whether differences exist when using TCD to measure the response to a passive sensorimotor paradigm. This study demonstrated that there were no haemodynamic differences in either MCA, when the Dom-Arm or ND-Arm was used repeatedly for 1 minute. This confirms the findings by others (Colebatch et al. 1991; Solodkin et al. 2001), that simple consecutive motor tasks can stimulate regions of cortical motor control within both cerebral hemispheres. Our previous studies in healthy individuals (Moody et al. 2005; Williams et al. 2017) highlighted that, although there was a bilateral rise in CBFV during tasks that require cognitive function, such as left-handed puzzle paradigm, there was also contralateral cerebral hemisphere dominance in CBFV. An ipsilateral rise in CBF that was similar to the contralateral CBF rise within this study suggests that such a passive arm manoeuvre may trigger comparable neuronal activity in the motor cortex and surrounding regions of both hemispheres. It is unknown whether the bilateral haemodynamic response within this study is hence due to the simplicity of the motor task and the lack of cognitive input required by the participant that would avoid hemispheric lateralization of neuronal activity, the repetitive nature of the paradigm, or a combination of the two. We also described previously, differences between two successive baseline recordings in RAP when the Finapres was placed on the opposite hand (Moody et al. 2005). This was replicated in this study, and although a higher RAP value was detected when the Finometer was recording on the non-dominant hand, it was within ranges representative of healthy individuals (Patel et al. 2016) and the following response was comparable between hemispheres and arm manoeuvres. When the data were compared between time periods, there was more variability identified between data-sets; with Dom-Arm producing more consistent data between time periods and cerebral hemispheres. Limitations As the study was conducted in a population aged 50 years and over, these responses may only be applicable to this age range, though others have reported regional cortical differences according to age in response to motor tasks (Ward & Frackowiak 2003; Guzzetta et al. 2007). The low spatial resolution of TCD allows one region of the MCA to be measured during the response. This limits the methods we used to conjointly monitor and detect changes that have been reported in the literature that occur in other regions. However, the MCA provides the majority of blood flow to cortical regions required for sensorimotor movement and the response detected in this study, with two overshoots in CBF separated by a prolonged plateau, demonstrates the sensitivity of these measurements to such a paradigm. The lack of cardiovascular interference at the start of the manoeuvre also suggest that changes in CBF were a response to. The Finometer is an essential non-invasive method for providing continuous beat-to-beat measurements in arterial BP that allows further analysis in cerebral haemodynamics and 9

10 autoregulation. To maintain constant arterial diameter within the finger being measured a small amount of pressure is applied with each heart-beat. If this triggered a sensory evoked response in the contralateral hemisphere it would have been minor as there has been no indication of a response in previous studies or in the baseline recordings. As aforementioned, only RAP had differences during baseline when Finometer was applied to non-dominant hand, which warrants further investigation. Conclusion This study demonstrates that a passive sensorimotor paradigm with either Dom-Arm or ND-Arm can be used to stimulate an equivalent response in both MCAs. This has implications in studies that cannot repeat the paradigm on both arms or need to use either arm due to any other constraints, such as in stroke patients. In addition, these results support a simplified protocol utilising either the Dom- Arm or ND-Arm in healthy volunteer studies. Appendices Table 2 Changes in normalised values for cerebral and peripheral haemodynamic parameters following each arm manoeuvre. ND-Arm Dom-Arm Parameter Region Cont-H Ipsil-H Ipsil-H Cont-H p value Inter. Cerebral MCBFV (%) 6.5 ± 3.9* -2.5 ± 4.4* # 4.9 ± 3.7* -1.5 ± 4.5 # 5.9 ± 5.7* -1.4 ± 4.8* # 7.4 ± 6.0* -1.3 ± 4.1* # RAP (%) -2.1 ± ± ± ± ± 4.6* # 0.4 ± ± ± 6.9 # 0.50 CrCP (%) -3.5 ± 5.0* 2.3 ± 6.3 # -1.6 ± ± 5.5* # -4.1 ± 7.3* 1.4 ± 7.2 # -3.4 ± 8.3* 2.7 ± 6.7 # Peripheral MABP (%) 0.8 ± ± ± 0.4 ± HR (%) 1.2 ± ± ± 2.8* 2.3 ± 3.2* 0.73 etco 2 (%) -1.2 ± ± ± ± Data presented as mean ± standard deviation for % changes from baseline., neurovascular coupling response;, recovery from response; ND-Arm, non-dominant arm; Dom-Arm, dominant arm; Cont-H, contralateral hemisphere; Ipsil-H, ipsilateral hemisphere; Inter., Interaction; MCBFV, mean cerebral blood flow velocity; RAP, resistance area product; CrCP, critical closing pressure; MABP, mean arterial blood pressure; HR, heart rate; etco 2, end-tidal CO 2; p value, repeated measures one-way ANOVA (Cerebral) or paired t-test (Peripheral); ANOVA Interaction, Time x Hemisphere effect by two-way repeated measures ANOVA followed by post hoc test by Tukey s multiple comparison: *, p<0.05 vs. Baseline; #, p < 0.05 vs

11 Table 3 Changes in AUC (with respect to changes from baseline) for cerebral and peripheral haemodynamic parameters following each arm manoeuvre. ND-Arm Dom-Arm Parameter Region Cont-H Ipsil-H Ipsil-H Cont-H p value Cerebral MCBFV (%.s) Bas. -12 ± ± ± ± ± ± ± ± RAP (%.s) CrCP (%.s) Peripheral MABP (%.s) HR (%.s) etco 2 (%.s) Bas. Bas. Bas. Bas. Bas ± ± ± ± ± -244 ± 113 ± -13 ± 55 ± 28 ± 5 ± 88 ± 96 ± -34 ± -84 ± -37 ± ± -40 ± -149 ± 18 ± 29 ± -113 ± 159 ± ± -45 ± -95 ± 23 ± 23 ± -290 ± 69 ± -10 ± 81 ± 19 ± -1 ± 95 ± 115 ± -18 ± -38 ± -49 ± ± -40 ± -175 ± 13 ± 31 ± -239 ± 134 ± Data presented as mean ± standard deviation. Bas., baseline before manoeuvre;, neurovascular coupling response;, recovery from manoeuvre; ND-Arm, non-dominant arm; Dom-Arm, dominant arm; Cont-H, contralateral hemisphere; Ipsil-H, ipsilateral hemisphere; MCBFV, mean cerebral blood flow velocity; RAP, resistance area product; CrCP, critical closing pressure; MABP, mean arterial blood pressure; HR, heart rate; etco 2, end-tidal CO 2; p value, paired t-test (Peripheral) or RM one-way ANOVA (Cerebral) followed by Tukey s multiple comparison. Table 4 Largest magnitude of change for normalised values of cerebral haemodynamic parameters following the start and end of each arm manoeuvre. ND-Arm Dom-Arm Parameter Region Cont-H Ipsil-H Ipsil-H Cont-H p value MCBFV (%) Start End 12.6 ± ± ± ± ± ± ± ± RAP (%) Start End -7.1 ± ± ± ± ± ± ± ± CrCP (%) Start End -5.4 ± ± ± ± ± ± ± ± Data presented as mean ± standard deviation; ND-Arm, non-dominant arm; Dom-Arm, dominant arm; Cont-H, contralateral hemisphere; Ipsil-H, ipsilateral hemisphere; MCBFV, mean cerebral blood flow velocity; RAP, resistance area product; CrCP, critical closing pressure; MABP, mean arterial blood pressure; HR, heart rate; etco 2, end-tidal CO 2. p value, one-way ANOVA. 11

12 References Alahmadi, A.A.S. et al., Differential involvement of cortical and cerebellar areas using dominant and nondominant hands: An FMRI study. Human Brain Mapping, 36: Colebatch, J.G. et al., Regional cerebral blood flow during voluntary arm and hand movements in human subjects. Journal of Neurophysiology, 65: Cuadrado, M.L. et al., Bihemispheric contribution to motor recovery after stroke: A longitudinal study with transcranial doppler ultrasonography. Cerebrovascular Diseases, 9: Guzzetta, A. et al., Brain representation of active and passive hand movements in children. Pediatric Research, 61: Haaland, K.Y. & Harrington, D.L., Hemispheric asymmetry of movement. Current Opinion in Neurobiology, 6: Hammond, G., Correlates of human handedness in primary motor cortex: A review and hypothesis. Neuroscience and Biobehavioral Reviews, 26: Hirth, C. et al., Simultaneous assessment of cerebral oxygenation and hemodynamics during a motor task. A combined near infrared and transcranial Doppler sonography study. Advances in Experimental Medicine and Biology, 411: Kawashima, R. et al., Regional cerebral blood flow changes of cortical motor areas and prefrontal areas in humans related to ipsilateral and contralateral hand movement. Brain Research, 623: Moody, M. et al., Cerebral and systemic hemodynamic changes during cognitive and motor activation paradigms. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 288: R Panerai, R.B., The critical closing pressure of the cerebral circulation. Medical Engineering & Physics, 25: Patel, N. et al., The Leicester cerebral haemodynamics database: normative values and the influence of age and sex. Physiological Measurement, 37: Phillips, A.A. et al., Neurovascular coupling in humans: Physiology, methodological advances and clinical implications. Journal of Cerebral Blood Flow & Metabolism, 36: Rao, S.M. et al., Functional magnetic resonance imaging of complex human movements. Neurology, 43: Salinet, A.S.M., Robinson, T.G. & Panerai, R.B., Cerebral blood flow response to neural activation after acute ischemic stroke: A failure of myogenic regulation? Journal of Neurology, 260: Salinet, A.S.M., Robinson, T.G. & Panerai, R.B., Reproducibility of cerebral and peripheral haemodynamic responses to active, passive and motor imagery paradigms in older healthy volunteers: A ftcd study. Journal of Neuroscience Methods, 206: Sitzer, M., Knorr, U. & Seitz, R.J., Cerebral hemodynamics during sensorimotor activation in humans. Journal of Applied Physiology, 77: Solodkin, A. et al., Lateralization of motor circuits and handedness during finger movements. European Journal of Neurology, 8: Stoeckel, M.C. & Binkofski, F., The role of ipsilateral primary motor cortex in movement control and recovery from brain damage. Experimental Neurology, 221:

13 Ward, N.S. & Frackowiak, R.S.J., Age-related changes in the neural correlates of motor performance. Brain, 126: Williams, C.A.L. et al., Transcranial Doppler ultrasonography in the assessment of neurovascular coupling responses to cognitive examination in healthy controls: A feasibility study. Journal of Neuroscience Methods, 284: Yamaguchi, Y. et al., Effects of vasodilatation and pressor response on neurovascular coupling during dynamic exercise. European Journal of Applied Physiology, 115: