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Regional disparity in continuously measured time-domain cerebrovascular reactivity indices: a scoping review of human literature

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Published 24 July 2023 © 2023 The Author(s). Published on behalf of Institute of Physics and Engineering in Medicine by IOP Publishing Ltd
, , Citation Amanjyot Singh Sainbhi et al 2023 Physiol. Meas. 44 07TR02 DOI 10.1088/1361-6579/acdfb6

0967-3334/44/7/07TR02

Abstract

Objective: Cerebral blood vessels maintaining relatively constant cerebral blood flow (CBF) over wide range of systemic arterial blood pressure (ABP) is referred to as cerebral autoregulation (CA). Impairments in CA expose the brain to pressure-passive flow states leading to hypoperfusion and hyperperfusion. Cerebrovascular reactivity (CVR) metrics refer to surrogate metrics of pressure-based CA that evaluate the relationship between slow vasogenic fluctuations in cerebral perfusion pressure/ABP and a surrogate for pulsatile CBF/cerebral blood volume. Approach: We performed a systematically conducted scoping review of all available human literature examining the association between continuous CVR between more than one brain region/channel using the same CVR index. Main Results: In all the included 22 articles, only handful of transcranial doppler (TCD) and near-infrared spectroscopy (NIRS) based metrics were calculated for only two brain regions/channels. These metrics found no difference between left and right sides in healthy volunteer, cardiac surgery, and intracranial hemorrhage patient studies. In contrast, significant differences were reported in endarterectomy, and subarachnoid hemorrhage studies, while varying results were found regarding regional disparity in stroke, traumatic brain injury, and multiple population studies. Significance: Further research is required to evaluate regional disparity using NIRS-based indices and to understand if NIRS-based indices provide better regional disparity information than TCD-based indices.

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Introduction

Cerebral autoregulation (CA) refers to the cerebral blood vessels' capacity to maintain a relatively constant cerebral blood flow (CBF) over a wide range of systemic arterial blood pressure (ABP) (Fog 1938, Lassen 1959). The mechanism behind maintaining constant CBF through constriction and dilation of cerebral blood vessels is often referred to as cerebrovascular reactivity (CVR) (Fog 1938, Lassen 1959). Although it should be noted that CVR is the broader term for CA, describing the physiologic process, therefore CVR and CA are not entirely interchangeable since CVR can occur outside the limits of autoregulation. Impairments in CA have been documented in various neuropathological states including stroke (Budohoski et al 2013, Xiong et al 2017, Budohoski and Czosnyka 2018, Czosnyka et al 2020) and traumatic brain injury (TBI) (Czosnyka et al 1997, Sorrentino et al 2012, Donnelly et al 2019, Åkerlund et al 2020, Bennis et al 2020, Zeiler et al 2020a, Depreitere et al 2021). CA can be visually represented by the Lassen autoregulatory curve, where CBF is plotted against cerebral perfusion pressure (CPP) or mean ABP (MAP), with this curve depicting relatively constant CBF between lower and upper limits of autoregulation (LLA and ULA) (Lassen 1974). When the brain is exposed to pressure-passive flow states, it can lead to hypoperfusion (i.e. ischemia) due to low CPP or MAP below the LLA or hyperperfusion (i.e. hyperemia) due to high CPP or MAP in excess of the ULA, and this can happen in a normal state but in neuropathological states, the region between the LLA and ULA is narrowed (Fog 1938, Lassen 1959, 1974). A significant driver of poor long-term outcomes in various neurological conditions has been attributed to exposure to impaired CA, as suggested in literature (Güiza et al 2015, 2017, Donnelly et al 2019, Åkerlund et al 2020, Zeiler et al 2020a, Donnelly et al 2021). Thus, it is becoming more apparent that monitoring CA continuously and accurately at the bedside is ideal for potential early detection, and future intervention, aimed at avoiding states of pressure passive flow.

Since continuous and accurate measures of CBF are not readily available to treating clinicians, the direct measurement of CA is not possible at bedside in humans. Although, we can indirectly measure CA at bedside with the use of surrogate metrics of CA, termed CVR metrics (Czosnyka et al 1997, Zeiler et al 2018b, 2020b). These continuous CVR metrics evaluate the relationship between slow vasogenic fluctuations in CPP/MAP and a surrogate for pulsatile CBF or cerebral blood volume (CBv (Panerai et al 2023)). The most readily studied, with widespread adoption by clinicians at bedside, are the CVR metrics based in the time-domain over the frequency-domain metrics. To obtain the raw physiological signals and derive the surrogate measures for pulsatile CBF/CBv, invasive, minimally-invasive, and non-invasive modalities can be used such as intracranial pressure (ICP) (Czosnyka et al 1997, Jaeger et al 2006, Zweifel et al 2008, Sorrentino et al 2012), transcranial doppler (TCD) (Czosnyka et al 1997), near-infrared spectroscopy (NIRS) (Zweifel et al 2010a, Zeiler et al 2017c, Chen et al 2020, Sainbhi et al 2022), thermal diffusion flowmetry (TDF) (Rosenthal et al 2011, Dias et al 2015, Highton et al 2015), laser doppler flowmetry (LDF) (Brady et al 2008, Zweifel et al 2010b, Lee et al 2011, 2012, Zeiler et al 2018a, 2018b), and brain tissue oxygen (PbtO2) (Jaeger et al 2006, Dengler et al 2013). For more information regarding non-invasive and minimally-invasive modalities, we refer the interested reader to a recently conducted narrative review from our group (Sainbhi et al 2022). CVR metrics are derived as moving Pearson correlation coefficients between slow-wave (i.e. 0.05–0.005 Hz) (Fraser et al 2013, Howells et al 2015) fluctuations in driving pressure for CBF, such as CPP or MAP, and a surrogate for pulsatile CBF/CBv (Lee et al 2009, Brady et al 2010, Zweifel et al 2010a, Zeiler et al 2017a, 2017c, Mathieu et al 2020, Gomez and Zeiler 2021, Zeiler 2021, Gomez et al 2021a). Currently, the pressure reactivity index (PRx, correlation between ICP and MAP) is the most established method of continuous bedside assessment of CVR, given routine use of invasive ICP monitoring in neurocritical care (Zweifel et al 2008, Czosnyka et al 2009, Copplestone and Welbourne 2018), with pre-clinical literature supporting both ICP and NIRS-based metrics in their ability to measure aspects of the LLA (Sainbhi et al 2021).

Despite increasing literature on the use of these continuous time-domain based CVR measures, there are some critical limitations regarding their use. First, CVR metrics derived from ICP, CPP, TDF, or PbtO2 currently rely on invasively placed monitors for acquisition of temporally resolved data related to a surrogate of pulsatile CBF (i.e. TDF, PbtO2) or CBv (ICP). This often limits their use to specialized centers, and to a single area of brain in the studies published to date (Czosnyka et al 1997, Steiner et al 2002, Jaeger et al 2006, Zweifel et al 2008, Rosenthal et al 2011, Sorrentino et al 2012, Dengler et al 2013, Dias et al 2015, Howells et al 2015, Lang et al 2015). Second, the non-invasive based indices, derived from TCD or NIRS monitoring, suffer from intra- and inter-operator reliability (i.e. TCD), or limited channel capacity (i.e. TCD: bilateral middle cerebral artery insonation (Zeiler and Smielewski 2018, Zeiler et al 2018c); NIRS: bifrontal optode placements (Gomez et al 2021a)). Thus, a common narrative between all of these continuous time-domain metrics is the limited spatial resolution in many of the human studies to date. This is despite early work on static and dynamic neuroimaging based techniques of CVR and CBF assessments demonstrating regional heterogeneity in physiologic responses in both states of health and disease (Wintermark et al 2001, Chieregato et al 2003, Aaslid et al 2007, Horsfield et al 2013, Tekes et al 2015, Zeiler et al 2017b, Saito et al 2018, Polinder-Bos et al 2020, Gomez et al 2022, Sainbhi et al 2022).

Thus, a comprehensive understanding of regional disparity in CVR measurements using continuous time-domain indices is required, so that existing knowledge gaps can be identified, and future research directed to address such short comings. The goal of this systematically conducted scoping review is to review human literature that assessed any documented association between continuous CVR between more than one brain region/channel using the same CVR index.

Materials and method

A systematically conducted scoping review of the available literature was conducted using the methodology outlined in the Cochrane Handbook for Systematic Reviews (Cochrane Handbook for Systematic Reviews of Interventions 2021). The data was reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) (Page et al 2021), and PRISMA Extension for Scoping Review (Tricco et al 2018). Appendix A of the Supplementary Materials provides the PRISMA checklist. The search strategy and methodology are similar to other scoping reviews published by our group (Hasen et al 2020, Froese et al 2020a, 2020b, 2021, Sainbhi et al 2021, Gomez et al 2021b, Batson et al 2022, Gomez et al 2022). The review questions and search strategy were decided upon by the supervisor (FAZ) and the primary author (ASS).

Search questions, population, and inclusion and exclusion criteria

The question posed for this scoping systematic review was: what human literature exists on regional disparities in continuous time-domain CVR between more than one brain region/channel? All studies, either prospective or retrospective, of any size were included.

The primary outcome was the association between measures of continuous time-domain CVR between more than one brain region or channel using the same CVR index. Continuous time-domain CVR measures were defined as those which are moving Pearson (linear) correlation coefficients between slow-wave fluctuations in a driving pressure for CBF (i.e. either MAP or CPP) and a surrogate for pulsatile CBF/CBv, as defined in the existing literature body (Zeiler et al 2018a, 2018b). The following cerebral monitoring techniques were considered eligible for the derivation of continuous CVR metrics: ICP, LDF CBF, NIRS, PbtO2, TCD or TDF CBF. Appendix B provides a table of the CVR metrics derived from these devices which were of interest in this review.

All studies whether prospective or retrospective, of all sizes, including any human studies that measured time-domain continuous metrics in more than one region or channel using and documented on the association between the regional/hemispheric data were eligible for inclusion in this review. Exclusion criteria were the following: non-English language, animal models, non-continuous CVR assessments, non-pressure based CVR measures (i.e. chemo-reactivity or CO2 reactivity testing), frequency-domain based continuously updating measures (i.e. transfer function (TF) and related metrics), and non-original works. The frequency-domain measures, such as autoregulatory index (ARI) (Tiecks et al 1995) or TF-ARI (Liu et al 2016), were part of the exclusion criteria because they are not easily computed continuously at the bedside (Zeiler et al 2017b, Gomez et al 2021c). While in TBI patients, ARI has been shown to correlate with time-domain based mean flow index (Mx) (Liu et al 2015), this study has been restricted to those based in the time-domain due to their ease of computation, making them a viable bedside metric. Time-domain based indices covered in this review have received much wider support for clinical adoption in continuous monitoring of patients with a variety of conditions (Czosnyka and Miller 2014, Hawryluk et al 2019, Depreitere et al 2021), and thus were the main focus for this particular scoping review.

Search strategy

MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, and Cochrane Library were searched from inception to the beginning of June 2022 using individualized search strategies for each database. The search strategies for all the databases can be seen in Appendix C of the Supplementary Materials. Finally, the reference lists of reviewed articles on regional disparities in continuous CVR were examined to ensure no references were left out.

Study selection

Using two reviewers (ASS and IM), a 2-step review of all articles returned by our search strategies was performed. First, the reviewers independently screened all titles and abstracts of the returned articles to decide whether they met the inclusion criteria. Second, the full text of the chosen articles was assessed to confirm whether they met the inclusion criteria, and that the primary outcome of regional disparities in continuous CVR was documented. Finally, any discrepancies between the two reviewers were resolved by a third party (FAZ).

Data collection

Data fields included the following: patient characteristics (such as biological sex, age, and relevant disease information), CVR indices measured, regions of brain assessed, primary/secondary outcomes, limitations, CVR values, CVR assessment characteristics, and conclusions regarding continuous indices.

Bias assessment

Given that the goal of this review was to provide a comprehensive scoping overview of the available literature, a formal bias assessment was not conducted.

Statistical analysis

A meta-analysis was not performed in this study because of the heterogeneity of study designs and data, and that the goal of the study was to perform a scoping overview of the available literature.

Results

Search results and study characteristics

The results of the search strategy across all databases and other sources are summarized in figure 1. There was a total of 11 478 articles identified from the databases searched. A total of 3031 articles were removed because of duplicated references, leaving 8447 articles to review. By applying the inclusion/exclusion criteria to the title and abstract of these articles, we identified 59 articles that fit these criteria. There were 5 articles added from references sections of articles identified from the first filter, which left 64 articles to review. On applying the inclusion/exclusion criteria to the full-text documents, only 22 were found eligible for inclusion in the systematic review. The articles excluded because they either did not report details around the association between measures of continuous CVR between more than one brain region or channel, were review articles, were non-human literature, or were non-relevant since they reported on non-pressure based CVR measures.

Figure 1.

Figure 1. PRISMA flow diagram.

Standard image High-resolution image

PRISMA, preferred reporting items for systematic reviews and meta-analysis

Appendix D gives a general overview of all 22 human studies with primary and secondary outcomes of the study and its limitations (Piechnik et al 1999, Czosnyka et al 2003, Lang et al 2003, Schmidt et al 2003a, 2003b, Soehle et al 2004, Yam et al 2005, Lavinio et al 2007, Joshi et al 2010, Reinhard et al 2003, 2004, 2005, 2008, 2010, Diedler et al 2011, Haubrich et al 2011, Budohoski et al 2015, Hori et al 2015, Bindra et al 2016, Adatia et al 2020, Meyer et al 2020, Zipfel et al 2020). Table 1 shows various CVR metrics assessed for each of the 8 disease categories: Healthy Volunteer (Piechnik et al 1999, Schmidt et al 2003b, Yam et al 2005, Reinhard et al 2008), Cardiac Surgery (Joshi et al 2010, Hori et al 2015), Endarterectomy (Reinhard et al 2003, 2004, Zipfel et al 2020), Intracerebral Hemorrhage (ICH) (Reinhard et al 2010), Subarachnoid Hemorrhage (SAH) (Soehle et al 2004, Budohoski et al 2015), Stroke (Reinhard et al 2005, Meyer et al 2020), TBI (Lang et al 2003, Schmidt et al 2003a, Lavinio et al 2007, Diedler et al 2011, Haubrich et al 2011), and Multiple Populations (Czosnyka et al 2003, Bindra et al 2016, Adatia et al 2020), respectively. Tables 2, 3, 4, 5, 6, 7, 8, and 9 describe eight categories of diseases. To measure surrogate for pulsatile CBF/CBv, 5 studies used NIRS (Diedler et al 2011, Hori et al 2015, Bindra et al 2016, Adatia et al 2020, Zipfel et al 2020), and 18 studies used TCD (Piechnik et al 1999, Czosnyka et al 2003, Lang et al 2003, Schmidt et al 2003a, 2003b, Soehle et al 2004, Yam et al 2005, Lavinio et al 2007, Joshi et al 2010, Reinhard et al 2003, 2004, 2005, 2008, 2010, Haubrich et al 2011, Budohoski et al 2015, Hori et al 2015, Meyer et al 2020) where one study used both (Hori et al 2015). All eligible studies reported on the association between measures of continuous CVR amongst more than one brain region or channel using the same CVR index. CVR indices measured in the studies included: 1 study measured cerebral flow velocity index with ABP (CFVx-a—correlation between ultrasound-tagged NIRS (UT-NIRS) data and MAP) (Hori et al 2015), 3 measured cerebral oximetry index with ABP (COx-a—correlation between rSO2 and ABP) (Bindra et al 2016, Adatia et al 2020, Zipfel et al 2020), 3 measured diastolic flow index with ABP (Dx-a—correlation between diastolic flow velocity (FVd) and ABP) (Reinhard et al 2003, 2004, 2008), 1 measured hemoglobin volume index with ABP (HVx-a—correlation between relative tissue hemoglobin concentration (rTHb) and ABP) (Zipfel et al 2020), 3 measured mean flow index (Mx—correlation between mean flow velocity (FVm) and CPP) (Czosnyka et al 2003, Schmidt et al 2003a, Lavinio et al 2007), 16 measured Mx with ABP (Mx-a—correlation between FVm and ABP) (Piechnik et al 1999, Czosnyka et al 2003, Lang et al 2003, Schmidt et al 2003b, Soehle et al 2004, Yam et al 2005, Lavinio et al 2007, Joshi et al 2010, Reinhard et al 2003, 2004, 2005, 2008, 2010, Haubrich et al 2011, Hori et al 2015, Meyer et al 2020), 4 measured systolic flow index with ABP (Sx-a—correlation between FVs and ABP) (Piechnik et al 1999, Reinhard et al 2003, Soehle et al 2004, Budohoski et al 2015), and 1 measured total hemoglobin index with ABP (THx-a—correlation between tissue hemoglobin index (THI) and ABP) (Diedler et al 2011). There were 4 studies with healthy volunteers (Piechnik et al 1999, Schmidt et al 2003b, Yam et al 2005, Reinhard et al 2008), two studies with Cardiac Surgery patients (Joshi et al 2010, Hori et al 2015), three studies with Endarterectomy patients (Reinhard et al 2003, 2004, Zipfel et al 2020), one study with Intracerebral Hemorrhage (ICH) patients (Reinhard et al 2010), two studies with Subarachnoid Hemorrhage (SAH) patients (Soehle et al 2004, Budohoski et al 2015), two studies with Stroke patients (Reinhard et al 2005, Meyer et al 2020), five studies with TBI patients (Lang et al 2003, Schmidt et al 2003a, Lavinio et al 2007, Diedler et al 2011, Haubrich et al 2011), three studies included had multiple populations (Czosnyka et al 2003, Bindra et al 2016, Adatia et al 2020), and two disease-based studies included healthy controls (Reinhard et al 2005, 2010).

Table 1. Disease categories with CVR metrics assessed.

Disease categoryNumber of included studiesCVR metrics assessed
Healthy volunteers (Piechnik et al 1999, Schmidt et al 2003b, Yam et al 2005, Reinhard et al 2008)4• Mx-a (Piechnik et al 1999, Schmidt et al 2003b, Yam et al 2005, Reinhard et al 2008)
  • Dx-a (Reinhard et al 2008)
  • Sx-a (Piechnik et al 1999)
Cardiac surgery (Joshi et al 2010, Hori et al 2015)2• Mx-a (Joshi et al 2010, Hori et al 2015)
  • CFVx-a (Hori et al 2015)
Endarterectomy (Reinhard et al 2003, 2004, Zipfel et al 2020)3• Dx-a (Reinhard et al 2003, 2004)
  • Mx-a (Reinhard et al 2003, 2004)
  • Sx-a (Reinhard et al 2003, 2004)
  • COx-a (Zipfel et al 2020)
  • HVx-a (Zipfel et al 2020)
Intracerebral hemorrhage (Reinhard et al 2010)1• Mx-a (Reinhard et al 2010)
Subarachnoid hemorrhage (Soehle et al 2004, Budohoski et al 2015)2• Mx-a (Soehle et al 2004)
  • Sx-a (Soehle et al 2004, Budohoski et al 2015)
Stroke (Reinhard et al 2005, Meyer et al 2020)2• Mx-a (Reinhard et al 2005, Meyer et al 2020)
TBI (Lang et al 2003, Schmidt et al 2003a, Lavinio et al 2007, Diedler et al 2011, Haubrich et al 2011)5• Mx (Schmidt et al 2003a, Lavinio et al 2007, Haubrich et al 2011)
  • Mx-a (Lang et al 2003, Lavinio et al 2007)
  • THx-a (Diedler et al 2011)
Multiple populations (Czosnyka et al 2003, Bindra et al 2016, Adatia et al 2020)3• COx-a (Bindra et al 2016, Adatia et al 2020)
  • Mx (Czosnyka et al 2003)
  • Mx-a (Czosnyka et al 2003)

ABP, arterial blood pressure; CFVx-a, cerebral flow velocity index with ABP; COx-a, cerebral oximetry index with ABP; Dx-a, diastolic flow index with ABP; HVx-a, hemoglobin volume index with ABP; Mx, mean flow index; Mx-a, Mx with ABP; Sx-a, systolic flow index with ABP; THx-a, total hemoglobin reactivity index with ABP.

Table 2. Regional disparity in continuous cerebrovascular reactivity: healthy volunteer studies only.

ReferencesPatient characteristicsCVR indices measuredCVR valuesCVR assessment characteristicsConclusions regarding regional disparity
Piechnik et al (1999)Healthy volunteers: 14 (11 male and 3 female; 20–44 years)• Mx-aHypocapnia:• Insonated MCA at a depth of 50 mm bilaterally• Increased Mx-a and Sx-a with vasodilation indicates strong passive association between slow waves in FV and ABP during weakened vascular reactivity
 Mean ABP:• Sx-aMx-a: −0.21  
 • Hypocapnia: 90.0 Sx-a: −0.35  
 • Normocapnia: 87.5 Normocapnia:• ABP was measured non-invasively via miniature cuff placed around middle finder of left hand • Leg cuffs were used to induce hypocapnia and hypercapnia• During hypercapnia, increased Mx-a (>0.4) and Sx-a (>0.2) were found in 86% and 79% of examinations, respectively
   • Mx-a: 0.21  
   • Sx-a: −0.07  
 • Hypercapnia: 99.1 Hypercapnia:• Mx-a and Sx-a were calculated among 36 consecutive samples of averaged ABP versus FVm and FVs, respectively• No differences between left and right for both Mx-a and Sx-a (p > 0.05)
   • Mx-a: 0.54  
   • Sx-a: 0.32  
Reinhard et al (2008)• Healthy volunteers: 56 (28 male and 28 female)• Dx-aPICA:• PICA and MCA monitored simultaneously with TCD• Dx-a and Mx-a did not differ between PICA and MCA
 • Mean age: 29 ± 10 years• Mx-a• Dx-a: −• ABP monitored continuously and non-invasively via finger plethysmography at heart level• No influence of age or sex on Dx-a or Mx-a were observed in either MCA or PICA
 • Systolic ABP: 108.0 ± 13.3 mmHg 0.03 ± 0.15• Mean Dx-a and Mx-a were calculated from 20 consecutive 3 s averages of CBFV versus diastolic and mean ABP values, respectively• No major difference between cerebellar and cerebral circulation was found based on these autoregulatory indices
 • Diastolic ABP: 59.0 ± 8.3 mmHg • Mx-a: 0.16 ± 0.14  
 • Heart rate: 62.0 ± 9.2 beats min−1  MCA:  
   • Dx-a: −0  
   03 ± 0.16  
   • Mx-a: 0.15 ± 0.17  
   Pearson correlation of PICA with MCA:  
   • Dx-a: r = 0.68, p < 0.001  
   • Mx-a: r = 0.71, p < 0.001  
Schmidt et al (2003b)• Healthy volunteers: 44 (33 male and 11 female)• Mx-aMx-a:• Insonated MCA bilaterally• Mx-a had high correlation coefficients between sides and low left–right difference
 • Mean age: 21 years (20–23 years) • Average value: 0.18 ± 0.19 average absolute left–right• ABP was measured non-invasively via miniature cuff placed around middle finder of left hand• 6 volunteers had Mx-a above threshold of 0.45:
   Difference: 0.07 ± 0.07• Mx-a was calculated over 40 consecutive 6 s epochs samples of mean ABP versus FVm• 4 with Mx-a above threshold on one side (0.552, 0.547, 0.527, and 0.513)
     • 2 with Mx-a above threshold on both sides (0.456 & 0.459 and 0.691 & 0.648)
Yam et al (2005)Young group:• Mx-aYoung group:• Bilateral MCAs identified to record CBFV using TCD• Nominal Mx-a difference of 0.1 was found between the groups (t = −1.24; p > 0.05)
 • Healthy volunteers: 16 • Mx-aleft: 0.24 ± 0.24• Continuous non-invasive ABP recording obtained on right radial artery using NIBP 
 • Mean age: 28 ± 5 years (23–42 years) • Mx-aright: 0.29 ± 0.23• Mx-a calculation used 10 000 data points sampled at 57.4 Hz 
 • Mean ABP: 80 ± 18 (50–102) • Mx-aL/R avg: 0.27 ± 0.23 (−0.08 to 0.75)  
 Old group Old group:  
 • Healthy volunteers: 16 • Mx-aleft: 0.39 ± 0.26  
 • Mean age: 54 ± 8 years (42–68 years) • Mx-aright: 0.34 ± 0.24  
 • Mean ABP: 82 ± 21 (47–104) • Mx-aL/R avg: 0.37 ± 0.24 (−0.09 to 0.75)  

ABP, arterial blood pressure; CBFV, cerebral blood flow velocity; CVR, cerebrovascular reactivity; Dx, diastolic flow index; Dx-a, Dx with ABP; FV, flow velocity; FVm, mean FV; FVs, systolic FV; Hz, hertz; MCA, middle cerebral artery; mmHg, millimeter of mercury; Mx, mean flow index; Mx-a, Mx with ABP; NIBP, non-invasive beat-to-beat blood pressure; PICA, posterior inferior cerebellar artery; Sx, systolic flow index; Sx-a, Sx with ABP; TCD, transcranial Doppler.

Table 3. Regional disparity in continuous cerebrovascular reactivity: cardiac surgery only.

  Joshi et al (2010)
 Hori et al (2015) Hypothermia group with Mx-a < 0.4 Hypothermia group with Mx-a > 0.4 Warm control group a
Inclusion criteriaPatients undergoing cardiac surgery with CPB that signed an informed consentPatients undergoing coronary artery bypass graft surgery and/or valvular surgery that required CPBPatients undergoing coronary artery bypass graft surgery and/or valvular surgery that required CPB
  • Age ≥45 years• Age ≥45 years
  • During CPB, there was period of active or passive cooling with arterial inflow temperature ≤34 °C (cooling phase) and rewarming phase to target temperature of 36 °C• Underwent CPB with constant warming of arterial inflow temperature ≥35 °C
Exclusion criteria
  • TCD monitoring not performed due to lack of transtemporal insonating window
  • During surgery, arterial inflow temperature varied between 34 °C and 35 °C
  • CPB with inconstant warming of arterial inflow
Cardiac surgery patients with CPB64 adults60 adults67 adults11 adults
Biological sex (male:female)38:2648:1153:1310:1
Age (mean ± SD, years)65 ± 8.866 ± 1164 ± 1067 ± 13
Prior cerebral vascular event (n, %)6 (%)5 (8%)6 (9%)2 (17%)
Prior transient ischemic attack (n, %)NR7 (12%)3 (4%)1 (8%)
Prior carotid endarterectomy (n, %)2 (3.1%)NRNRNR
Prior chronic obstructive pulmonary disease (n, %)11 (17.2%)6 (10%)6 (9%)2 (17%)
Prior myocardial infarction (n, %)(%)20 (34%)20 (29%)8 (67%)
Hypertension (n, %)43 (67.2%)44 (75%)45 (66%)9 (75%)
Diabetes (n, %)19 (29.7%)20 (34%)21 (31%)3 (25%)
Insulin treatment (n, %)NR18 (30%)17 (25%)3 (27%)
Congestive heart failure (n, %)12 (18.8%)11 (19%)9 (13%)3 (25%)
Peripheral vascular disease (n, %)6 (9.4%)10 (17%)5 (7%)1 (8%)
Left ventricular ejection fraction <30% (n, %)NR9 (15%)17 (25%)4 (33%)
Current smoker (n, %)11 (17.2%)9 (15%)7 (10%)1 (8%)
Previous smoker (n, %)34 (53.1%)NRNRNR
Duration of CPB (min)111 (75–148)116 ± 45121 ± 4785 ± 24
Duration of aortic cross-clamping (min)70 (54–90)73 ± 2876 ± 3334 ± 28
Mx-a left (mean ± SD)0.31 ± 0.170.25 ± 0.130.52 ± 0.140.434 ± 0.21 b
Mx-a right (mean ± SD)0.32 ± 0.170.26 ± 0.150.49 ± 0.160.40 ± 0.19 b
CFVx-a left (mean ± SD)0.33 ± 0.19NRNRNR
CFVx-a right (mean ± SD)0.35 ± 0.19NRNRNR
CVR assessment Characteristics• Insonated MCAs at a depth of between 35 and 52 mm bilaterally• Insonated MCAs at a depth of 35 and 52 mm bilaterally using TCD
 • Ultrasound-tagged NIRS signals were obtained via adhesive pads attached on the right and left sides of forehead• ABP was monitored invasively from radial artery
 • ABP was monitored invasively from radial artery• TCD and ABP data were sampled at 60 Hz
 • Continuous moving Pearson coefficient between MAP and TCD blood flow velocities (Mx-a) and between MAP and UT-NIRS signals (CFVx-a)• Mx-a was calculated between MAP versus TCD blood flow velocities
 • Mx-a and CFVx-a were calculated using consecutive, paired 10 s averaged values from 300 s duration, incorporating 30 data points for each index 
Conclusions regarding regional disparity• Statistically significant correlating and agreement between Mx-a and CFVx-a among the subjects (p < 0.001)• During cooling, Mx-a (left, 0.29 ± 0.18; right, 0.28 ± 0.18) was higher than baseline (left, 0.17 ± 0.21; right, 0.17 ± 0.20; p ≤ 0.0001)
 • Mx-a had similar values on both sides• During rewarming phase of CPB, Mx-a (left, 0.40 ± 0.19; right, 0.39 ± 0.19) increased as compared with baseline (p ≤ 0.0001) and cooling phase (p ≤ 0.0001) indicating impaired CBF autoregulation
 • CFVx-a had similar values on both sides• After CPB and before wound closure, Mx-a (left, 0.27 ± 0.20; right, 0.28 ± 0.21) was higher than baseline (left, p = 0.0004; right, p = 0.0003), no different than cooling phase of CPB (p = 0.8996) but lower than during rewarming phase (left, p ≤ 0.0001; right, p ≤ 0.0005)
  • There was no difference between left (p = 0.2948) and right sided (p = 0.2476) Mx-a between the first and second hour of CPB in the warm control group

a Warm control group had arterial inflow maintained at >35 °C. b Values reported for warm controls with impaired CBF autoregulation (Mx > 0.4).ABP, arterial blood pressure; CBF, cerebral blood flow; CFVx, cerebral flow velocity index; CFVx-a, CFVx with ABP; CPB, cardiopulmonary bypass; CVR, cerebrovascular reactivity; Hz, hertz; MAP, mean arterial blood pressure; MCA, middle cerebral artery; Mx, mean flow index; Mx-a, Mx with ABP; NIRS, near-infrared spectroscopy; NR, not reported; SD, standard deviation; TCD, transcranial doppler; UT-NIRS, ultrasound-tagged NIRS.

Table 4. Regional disparity in continuous cerebrovascular reactivity: endarterectomy studies only.

 Reinhard et al (2003)Reinhard et al (2004)Zipfel et al (2020)
 Degree of unilateral stenosisCEASPACNo shuntShunt
 A: 70%–79%B: 80%–89%C: 90%–99%D: 100%PrePostPrePostBaselineClampingPost-clampingBaselineClampingPost-clamping
Inclusion criteriaSevere unilateral stenosis ≥70% or occlusion of the ICASevere Unilateral stenosis ≥70% of the ICA undergoing CEA or SPACPatients who had CEA for severe carotid artery stenosis under local anaesthesia at the University of Tübingen between 2017 and 2019
 • Carotid stenosis or occlusion was defined as clinically symptomatic if transient ischemic attack or stroke (hemispheric or retinal ischemic symptoms) ipsilateral to the affected side had occurred during the last 2 years  
Exclusion criteriaInsufficient temporal bone windowInability to obtain stable Doppler signals due to:Asymptomatic and symptomatic patients with a stenosis grade of <70%
 • Relevant stenosis of the MCA• An absent temporal bone window or noncompliance of patients 
 • Current atrial fibrillation• Atrial fibrillation 
 • Ventricular extra beats per minute >4• Intolerance of 7% CO2 inhalation 
  • Unsuccessful carotid recanalization 
Severe carotid artery stenosis patients40 adults21 adults56 adults22 adults41 adults17 adults51 adults8 adults
 • Symptomatic stenosis or occlusion: 82 adults    
 • Asymptomatic stenosis or occlusion: 57 adults    
Biological sex (male:female)132:18 (150 patients studied from which 11 were excluded)NR42:17
Age (mean ± SD, years)67 ± 8 (150 patients studied from which 11 were excluded)NR73 ± 873 ± 5
Arterial hypertension (n, %)NRNRNRNRNRNRNRNR46 (90%)8 (100%)
Symptomatic stenosis (n, %)82 (59%)NRNRNRNR13 (25%)2 (25%)
Coronary artery disease (n, %)NRNRNRNRNRNRNRNR25 (49%)2 (25%)
Ipsilateral stenosis (mean ± SD, %)NRNRNRNRNRNRNRNR81 ± 185 ± 5
Contralateral stenosis (mean ± SD, %)NRNRNRNRNRNRNRNR57 ± 685 ± 15
COx-a ipsilateral (mean ± SD)NRNRNRNRNRNRNRNR0.18 ± 0.090.12 ± 0.130.12 ± 0.020.13 ± 0.100.32 ± 0.050.10 ± 0.05
COx-a contralateral (mean ± SD)NRNRNRNRNRNRNRNR0.16 ± 0.030.14 ± 0.020.12 ± 0.020.18 ± 0.050.23 ± 0.050.10 ± 0.05
Dx-a ipsilateral (mean ± SD)0.08 ± 0.160.15 ± 0.140.25 ± 0.190.26 ± 0.240.24 ± 0.22−0.02 ± 0.140.17 ± 0.220.03 ± 0.12NRNRNRNRNRNR
Dx-a contralateral (mean ± SD)0.01 ± 0.150.00 ± 0.150.01 ± 0.130.11 ± 0.220.00 ± 0.13−0.02 ± 0.120.04 ± 0.120.03 ± 0.09NRNRNRNRNRNR
HVx-a ipsilateral (mean ± SD)NRNRNRNRNRNRNRNR0.10 ± 0.040.07 ± 0.010.03 ± 0.020.08 ± 0.04−0.29 ± 0.100.03 ± 0.08
HVx-a contralateral (mean ± SD)NRNRNRNRNRNRNRNR0.04 ± 0.020.30 ± 0.200.03 ± 0.020.04 ± 0.030.15 ± 0.090.03 ± 0.02
Mx-a ipsilateral (mean ± SD)0.35 ± 0.180.45 ± 0.110.51 ± 0.180.51 ± 0.210.47 ± 0.210.24 ± 0.150.44 ± 0.210.26 ± 0.16NRNRNRNRNRNR
Mx-a contralateral (mean ± SD)0.27 ± 0.170.28 ± 0.110.30 ± 0.110.39 ± 0.170.26 ± 0.150.23 ± 0.160.26 ± 0.170.27 ± 0.12NRNRNRNRNRNR
Sx-a ipsilateral (mean ± SD)0.28 ± 0.180.34 ± 0.160.33 ± 0.190.32 ± 0.25NRNRNRNRNRNRNRNRNRNR
Sx-a contralateral (mean ± SD)0.21 ± 0.210.26 ± 0.130.22 ± 0.190.29 ± 0.21NRNRNRNRNRNRNRNRNRNR
CVR assessment characteristics• Insonated MCAs through temporal bone window with TCD using 2 MHz transducers bilaterally• Measurements performed with patients in supine position with 50° inclination of upper body• NIRS signals (rSO2 and rTHb) were directly measured via bilateral probes attached to the patient's frontal region
 • Continuous non-invasive ABP was recorded via servocontrolled finger plethysmograph with the patient's right hand positioned at heart level• CBFV measured by insonation of both MCAs through temporal bone window with TCD using 2 MHz transducers attached to a headband• MAP was taken invasively from arterial line
 • TCD and ABP data were sampled at 100 Hz• Continuous non-invasive ABP was recorded via servocontrolled finger plethysmograph with the patient's right hand positioned at heart level• COx-a and HVx-a were calculated over consecutive paired 10 second averaged values from 300 s epochs samples of MAP versus rSO2 and rTHb, respectively
 • Mean Dx-a, Mx-a, and Sx-a were calculated from 20 consecutive 3 s averages of CBFV versus diastolic, mean, and systolic ABP values, respectively• TCD and ABP data were sampled at 100 Hz 
  • Mean Dx-a, Mx-a, and Sx-a were calculated for 1 min periods of 10 min time series from 20 consecutive 3 s averages of CBFV versus diastolic, mean, and systolic ABP values, respectively 
  • Sx-a was not considered for analysis since it came out less reliably 
Conclusions regarding regional disparity• Dx-a (Groups A, B, C: p < 0.001; Group D: p < 0.01), Mx-a (Groups A, B, C: p < 0.001; Group D: p < 0.01), and HVx-a showed significant difference between ipsilateral side of stenosis versus contralateral side• Dx-a and Mx-a clearly showed poor autoregulation values before the procedure compared with contralateral sides• No shunt group showed a significant decrease in HVx-a and COx-a after clamping which indicates intact autoregulation
 • Correlation coefficient autoregulatory parameters did not significantly differ between symptomatic and asymptomatic stenosis• Patients with stenosis ≥90% had poorer ipsilateral values for Dx-a and Mx-a than patients with stenosis 75% to 89% (p < 0.05)• Baseline versus Clamping:
 • Clear side-to-side difference was found in unilateral stenosis ≥80% for Dx-a and Mx-a but not for Sx-a• Autoregulatory parameters noticeably improved reaching contralateral unaffected sides after recanalization of obstructed ICA• In no shunt group, there was a statistically significant decrease in COx-a ipsilaterally (p = 0.0214) while the contralateral values stayed stable
 • Dx-a and Mx-a showed the most pronounced difference between 70%–79%, and 80%–89% degree of stenosis groups while the 90%–99% and 100% degree of stenosis groups tended to have poorer values• Ipsilateral degree of autoregulatory improvement was highly significantly related to autoregulatory values before recanalization as shown by correlation coefficient analysis• In shunted group, there was statistically significant increase in ipsilateral COx-a (p = 0.048) prior to shunt insertion but not in the contralateral side.
 • Ipsilateral Dx-a and Mx-a proved to be more useful than Sx-a in terms of intergroup differences (groups A–C: p < 0.001; groups A–D: p < 0.01) • Pooled ipsilateral and contralateral data showed statistically significant increase in HVx-a in shunt patients (0.05 ± 0.01 versus 0.15 ± 0.02; p < 0.001) compared to no shunt patients (0.073 ± 0.020 versus 0.037 ± 0.014; p = 0.12)
   • Pooled ipsilateral and contralateral data showed statistically significant increase in COx-a in shunt patients (0.18 ± 0.05 versus 0.23 ± 0.01; p = 0.039) compared to no shunt patients (0.17 ± 0.04 versus 0.10 ± 0.01; p = 0.002)
   Baseline versus post-clamping:
   • In no shunt group, there was a statistically significant decrease in HVx-a ipsilaterally (p = 0.007) while the values remained stable contralaterally
   • COx-a showed no statistically significant difference in no shunt group
   • In shunted group, no significant differences were observed for COx-a or HVx-a ipsilaterally or contralaterally
   Clamping versus post-clamping:
   • Ipsilateral and contralateral COx-a and HVx-a remained stable in both no shunt and shunted groups
   CoW:
   • When comparing ipsilateral COx-a after clamping, statistically significant decrease of ipsilateral COx-a seen in group with intact CoW (0.18 ± 0.02 versus 0.14 ± 0.02; p = 0.013) as compared to contralateral COx-a or in patients with an impaired CoW
   • In patients without any anatomical effect, statistically significant decrease in COx-a during ipsilateral clamping (0.19 ± 0.03 versus 0.09 ± 0.02; p < 0.001) compared to contralateral COx-a (0.18 ± 0.01 versus 0.15 ± 0.03; p = 0.22) but no statistical significance difference in other values

ABP, arterial blood pressure; CBFV, cerebral blood flow velocity; CEA, carotid endarterectomy; CoW, Circle of Willis; COx, cerebral oxygenation index; COx-a, COx with ABP; CVR, cerebrovascular reactivity; Dx, diastolic flow index; Dx-a, Dx with ABP; HVx, hemoglobin volume index; HVx-a, HVx with ABP; ICA, internal carotid artery; MAP, mean arterial pressure; MCA, middle cerebral artery; MHz, megahertz; Mx, mean flow index; Mx-a, Mx with ABP; NIRS, near-infrared spectroscopy; NR, not reported; rSO2, regional oxygen saturation; rTHb, relative tissue hemoglobin concentration; SD, standard deviation; SPAC, stent-protected angioplasty of the carotid artery; Sx, systolic flow index; Sx-a, Sx with ABP.

Table 5. Regional disparity in continuous cerebrovascular reactivity: intracerebral hemorrhage (ich) studies only.

 Reinhard et al (2010)
 ICH Patients 
 Day 1Day 2Day 3Healthy Controls
Inclusion criteria• Patients admitted to neurocritical care units with spontaneous ICH confirmed on CT or MRI• Control persons had no history of cerebrovascular disease or any carotid artery obstruction on duplex ultrasound
Exclusion criteria• Internal carotid artery obstruction ≥70% on either side as shown in ultrasound or MR/CT angiography
 • Insufficient bilateral temporal bone window for insonation of MCA
 • Hemorrhage metastasis
 • Inability to tolerate TCD monitoring
ICH patients/healthy volunteers2655
Biological sex (male:female)21:544:11
Age (mean ± SD, years)65 ± 1164 ± 8
NIH stroke score on admission a (mean ± SD, patients)12 ± 7NA
GCS on admission a (mean; n; SE, patients)13 ± 2NA
 12.1 (n = 22; SE = 0.69)12.8 (n = 23; SE = 0.71)12.5 (n = 23; SE = 0.76)NA
Modified Rankin scale at 90 days (mean ± SD, patients)3.3 ± 1.9NA
Mortality at 90 day (n, %)2 (8%)NA
Deep location (n, %)21 (81%)NA
Lobar location (n, %)5 (19%)NA
ICH volume (mean ± SD, ml)26 ± 22NA
Intraventricular hemorrhage (n, %)14 (54%)NA
Hypertension (n, %)24 (92%)NR
Smoking (n, %)9 (35%)NR
Oral anticoagulation (n, %)5 (19%)NA
Mx-a ipsilateral (mean; n; SE)0.24 (n = 26; SE = 0.04)0.29 (n = 21; SE = 0.04)0.21 (n = 22; SE = 0.04)0.27 (SE = 0.02)
Mx-a contralateral (mean; n; SE)0.27 (n = 26; SE = 0.04)0.32 (n = 21; SE = 0.04)0.22 (n = 20; SE = 0.04) 
CVR assessment characteristics• CBFV assessed in both middle cerebral arteries with 2 MHz transducers by TCD
 • ABP continuously and non-invasively recorded via finger plethysmograph
 • Mx-a was formed from averaged 1 min correlation coefficients calculated from 20 consecutive 3 s averages of CBFV and ABP
 • Mx-a calculated from MCA sides ipsilateral and contralateral to the ICH
 • Three measurements of autoregulation were performed Day 1 (12–24 h after ictus), Day 3 (48–72 h) and Day 5 (96–120 h)
Conclusions regarding regional disparity• Mean values of Mx-a did not differ significantly across study points
 • Mean values of Mx-a did not differ when compared with healthy controls of ipsilateral and contralateral sides
 • On day 1, lower Mx-a related with higher age (both sides p = 0.013)
 • Between days 3 and 5, the modulus of Mx-a change was higher on affected sides (0.19 ± 0.16; p = 0.01) than of repeated measurements in controls (0.10 ± 0.11)
 • Between days 3 and 5, increasing ipsilateral Mx-a (worsening autoregulation) was related with: lower GCS on day 5 (p = 0.014)
 • Presence of ventricular hemorrhage (p = 0.0486)
 • On day 5, higher Mx-a (poorer autoregulation) was related with:
 • Lower GCS (ipsilateral: p < 0.001, contralateral: p = 0.006)
 • Presence of ventricular hemorrhage (ipsilateral: p = 0.011, contralateral: p = 0.018)
 • Lower nCPP (ipsilateral p = 0.024)
 • Higher ipsilateral Mx-a on day 5 was significant predictor for poor 90 day outcome (p = 0.013)
 • No significant differences in Mx-a values between measurements with or without intravenous vasodilating medication

a Assessed in non-intubated patients (n = 22).CBFV, cerebral blood flow velocity; CT, computed tomography; CVR, cerebrovascular reactivity; GCS, Glasgow Coma Scale; ICH, intracerebral hemorrhage; MCA, middle cerebral artery; MHz, megahertz; MR, magnetic resonance; MRI, magnetic resonance imaging; Mx, mean flow index; Mx-a, Mx with ABP; nCPP, non-invasive cerebral perfusion pressure; NIH, National Institutes of Health; NA, not applicable; NR, not reported; SD, standard deviation; SE, standard error; TCD, transcranial Doppler.

Table 6. Regional disparity in continuous cerebrovascular reactivity: SAH studies only.

 Budohoski et al (2015)Soehle et al (2004)
 Non-DCIDCIVasospasm
Inclusion criteria• Patients admitted to neurosurgery department between June 2010 and January 2012 with diagnosis of SAHPatients admitted with aneurysmal SAH
 • ≥18 years old 
 • Aneurysmal SAH confirmed with CT angiography or DSA 
 • Less than 5 d elapsed from ictus 
Exclusion criteria• Intracranial hemorrhage• No observed nonvasospastic period during the entire examination period
 • Acute hydrocephalus• Vasospasm occurred bilaterally
 • Seizures 
 • Metabolic derangements 
 • Infection with or without radiological signs of cerebral vasospasm 
SAH patients663215
Biological sex (male:female)47:1922:106:9
Age (mean ± SD, years)57 ± 1256 ± 1046 (range: 22–67)
WFNS grade (1:2:3:4:5, n)23:22:5:11:511:7:1:10:31:6:3:4:1
Modified Fisher grade (1:2:3:4, n)18:5:26:174:4:19:5NR
Vasospasm (n, %)24 (36%)28 (87.5%)15 (100%)
Mx-a ipsilateral (mean ± SD)NRNR0.44 ± 0.27
Mx-a contralateral (mean ± SD)NRNR0.34 ± 0.29
Sx-a ipsilateral (mean ± SD)• Overall: 0.03 ± 0.200.24 ± 0.23
 • Favorable*: 0.02 ± 0.20 
 • Unfavorable*: 0.06 ± 0.15 
 −0.01 ± 0.180.07 ± 0.21 
Sx-a contralateral (mean ± SD)• Overall: −0.04 ± 0.200.16 ± 0.25
 • Favorable*: −0.04 ± 0.20 
 • Unfavorable*: 0.01 ± 0.09 
 −0.07 ± 0.20−0.01 ± 0.20 
Sx-a interhemispheric difference• Overall: 0.16 ± 0.15NR
 • Favorable*: 0.16 ± 0.14 
 • Unfavorable*: 0.10 ± 0.11 
 0.14 ± 0.150.18 ± 0.16 
CVR assessment characteristics• Bilateral MCA FV via temporal window at depth of 45–60 mm with TCD• Bitemporal insonation of MCA at depth of 50 mm performed using TCD
 • ABP monitored either non-invasively or invasively from radial artery• ABP measured invasively from radial artery
 • Data recorded at 200 Hz frequency• Data sampled at frequency of 50 Hz
 • Sx-a was calculated using moving, linear correlation coefficient between 10 s averaged values of systolic FV and mean ABP from a 300 s window with a 10 s update frequency• Mx-a and Sx-a were calculated as mean average of Pearson's correlation coefficient calculated among 60 consecutive 5 s averaged values of ABP with mean and systolic FV, respectively
Conclusions regarding regional disparity• Worse autoregulation observed ipsilateral to ischemic hemisphere• On vasospasm side, both Mx-a (p = 0.006) and Sx-a (p = 0.044) were higher than on the contralateral side
 • Correlation between ipsilateral and contralateral Sx-a was lower in patents who developed DCI (p = 0.007)• Mx-a and Sx-a has a correlation (p < 0.001) on the side of vasospasm and on the contralateral side as well
 • DCI groups had overall worse autoregulation (p = 0.000 01 for Sx-a DCI versus non-DCI) accompanied by increased interhemispheric difference of autoregulation (p = 0.035), suggesting unilateral autoregulation failure 
 • Unilateral autoregulation failure became apparent on median day 2 post-ictus 
 • Unfavourable outcome patients had an overall worse autoregulation (p = 0.006 for Sx-a favourable versus unfavourable) accompanied by decreased interhemispheric difference of autoregulation (p = 0.027), suggesting bilateral autoregulation failure 
 • Bilateral autoregulation failure became apparent on median day 4 post-ictus 
 • Significant autoregulatory disturbances bilaterally, indicated by low interhemispheric difference of autoregulation, in 16 of 18 (89%) patients with unfavorable outcome 
 • Commonly, patients with DCI, having poor autoregulation on average, had high interhemispheric difference, suggesting unilateral disturbances 
 • Poor autoregulation with decreased interhemispheric difference was demonstrated by 17 out of 72 patients (24%) with favorable outcome and this was significantly less than in unfavorable outcome group (p = 0.0013) 

Table 7. Regional Disparity in continuous cerebrovascular reactivity: stroke studies only.

 Meyer et al (2020)Reinhard et al (2005)
 Successful recanalizationNo recanalizationStudy 1 (first 48 h)Study 2 (day 4–7 after ictus)Controls
Inclusion criteriaConsecutive patients with large vessel occlusive strokeAdmitted to stroke unit with acute cerebral ischemia:
 • Age ≥18 years• Signs of anterior circulation ischemia
 • Invasive blood pressure management• Absence of relevant obstructive carotid artery disease
 • Treatment in neurological intensive care unit (NICU)• Sufficient bilateral temporal bone window for insonation of the MCA
  Control groups:
  • No previous history of stroke
  • No previous history of significant (>30%) carotid obstruction on carotid ultrasound
Exclusion criteria• Posterior circulation strokes• Artifacts in Doppler and Finapres measurements
 • Pregnancy• Later MRI showed vertebrobasilar ischemia
 • Inability to insonate intracranial vessels• Refusal to attend second measurement
  • Transferal to remote hospital
Stroke patients/healthy volunteersTotal: 10Total: 10332925
 • Day 1: 10• Day 1: 10   
 • Day 2: 7• Day 2: 8   
 • Day 3: 6• Day 3: 7   
 • Day 4: 4• Day 4: 7   
Biological sex (male:female)4:64:623:1020:9NR
Age (mean ± SD, years)76.1 ± 9.278.2 ± 9.661 ± 1259 ± 1261 ± 13
Stroke side (left:right)5:54:6NRNRNA
Vessel Occlusion (ICA:M1:M2)3:5:22:7:1NRNRNA
Days in hospital20 (10–28)15 (2–46)NRNRNA
NIHSS19.8 ± 10.914.8 ± 5.44.5 ± 3.82.4 ± 2.7NA
Stroke volume (mean ± SD, cm3)81 ± 67197 ± 168NRNRNA
MAP (mean ± SD, mmHg)• Day 1: 81 ± 15• Day 1: 77 ± 1586 ± 1282 ± 14NR
 • Day 2: 83 ± 15• Day 2: 79 ± 12   
 • Day 3: 78 ± 17• Day 3: 76 ± 17   
 • Day 4: 81 ± 8• Day 4: 76 ± 19   
Heart rate (mean ± SD, min−1)• Day 1: 68 ± 18• Day 1: 67 ± 1468 ± 1368 ± 14NR
 • Day 2: 73 ± 22• Day 2: 67 ± 23   
 • Day 3: 77 ± 23• Day 3: 84 ± 29   
 • Day 4: 74 ± 22• Day 4: 81 ± 27   
Mx-a ipsilateral (mean ± SD)• Day 1: 0.58 ± 0.21• Day 1: NR0.19 ± 0.180.27 ± 0.160.20 ± 0.13
 • Day 2: 0.66 ± 0.17• Day 2: NR   
 • Day 3: 0.64 ± 0.21• Day 3: NR   
 • Day 4: 0.48 ± 0.36• Day 4: NR   
Mx-a contralateral (mean ± SD)• Day 1: 0.50 ± 0.20• Day 1: 0.45 ± 0.240.19 ± 0.180.25 ± 0.15 
 • Day 2: 0.48 ± 0.35• Day 2: 0.41 ± 0.33   
 • Day 3: 0.44 ± 0.34• Day 3: 0.34 ± 0.25   
 • Day 4: 0.18 ± 0.52• Day 4: 0.26 ± 0.28   
Mx-a interhemispheric differenceNRNR0.00 ± 0.110.02 ± 0.08±0.02 ± 0.06
CVR assessment characteristics• CBFV was measured in both MCAs via insonation through temporal window with 2 MHz TCD• CBFV was measured in both MCAs via insonation through temporal bone window with 2 MHz TCD
 • ABP was measured invasively via radial artery• Continuous ABP was measured non-invasively via servo-controlled finger plethysmograph with subject's right hand positioned at heart level
 • Mx-a was calculated using moving, linear correlation coefficient between 6 s averaged values of mean CBFV and MAP 3 min intervals• Mx-a was calculated as mean average of 1 min Pearson's correlation coefficients calculated among 20 consecutive 3 s averaged values of ABP with mean CBFV
Conclusions regarding regional disparity• CA impaired in both groups postinterventional• Not relevant side-to-side differences in Mx-a for both studies
 • Mx-a was slightly higher on stroke side than contralateral hemisphere in successful recanalization group but ipsilateral side could not be insonated in no recanalization group• Worsening CA later after stroke was indicated by Mx-a being slightly higher in study 2 than in study 1 (p < 0.05)
 • Contralateral Mx-a showed no significant differences between both groups (p = 0.59) 

ABP, arterial blood pressure; CA, cerebral autoregulation; CBFV, cerebral blood flow velocity; CVR, cerebrovascular reactivity; ICA, internal carotid artery; MAP, mean arterial pressure; MCA, middle cerebral artery; MHz, megahertz; mmHg, millimeter of mercury; MRI, magnetic resonance imaging; Mx, mean flow index; Mx-a, Mx with ABP; NA, not applicable; NICU, neurological intensive care unit; NIHSS, National Institutes of Health Stroke Scale; NR, not reported; SD, standard deviation; TCD, transcranial doppler.

Table 8. Regional disparity in continuous cerebrovascular reactivity: TBI studies only.

 Diedler et al (2011)Haubrich et al (2011)Lang et al (2003)Lavinio et al (2007)Schmidt et al (2003a)
Inclusion criteriaTBI patients admitted to Neurosciences Critical Care Unit between June 2008 and June 2009TBI patients with GCS <12:Head injuryHead injured adults admitted to Neuro Critical Care UnitHead injury patients admitted to Neuroscience Critical Care Unit between September 1995 and May 2002
 • Older than 16 years• Normocapnic baseline with CPP >70 mmHg• Intubated• Sedated 
 • Closed head injury• ETCO2 of > 35 mmHg (4.7kPa)• Ventilated• Ventilated 
 • Availability of ICP monitoring    
 • Informed assent    
Exclusion criteria• Artifact-free signal of ICP, THI, and ABP• Respiratory failureNRNR• Craniectomy (removal of the bone flap) patients
 • Minimum duration of 20 min• Being in early phase of TBI   
TBI patients37Total: 292510Total: 96
  • Establishing CPPOPT: 17  • Right lesion: 27
  • Maintaining CPPOPT: 12  • Left lesion: 33
     • Bilateral/diffuse lesion: 11
     • Lesion not located: 25
Biological sex (male:female, n)NRNR18:7NR84:12
Age (years)Median: 34, Range: 1–7839.0 ± 14.138 ± 13NRMedian: 31, Range: 16–76
GCS on admissionMedian: 7, Range: 2–15<127.1 ± 4NRMedian: 6, Range: 3–14
Outcome (Favorable [GOS 4–5]: Unfavorable [GOS 1–3], n)9:28NR15:10NR48:37 (available for only 85 patients)
Moderate Hypocapnia (kPa)NA4.25 ± 0.33NANANA
Mx left side (mean ± SD)NAEstablishing CPPOPT:NANR−0.013 ± 0.27
  • Baseline: 0.144 ± 0.295   
  • Moderate hypocapnia: −0.016 ± 0.17   
  Maintaining CPPOPT:   
  • Baseline: −0.257 ± 0.335   
  • Moderate hypocapnia: −0.201 ± 0.206   
Mx right side (mean ± SD)NAEstablishing CPPOPT:NANR−0.023 ± 0.27
  • Baseline: 0.168 ± 0.310   
  • Moderate hypocapnia: −0.004 ± 0.148   
  Maintaining CPPOPT:   
  • Baseline: 0.293 ± 0.267   
  • Moderate hypocapnia: −0.244 ± 0.170   
Mx left/right Difference (mean ± SD, absolute difference)NANANANR0.122 ± 0.16
Mx-a left side (mean ± SD)NANA• Immediate phase: 0.24 ± 0.35NRNA
   • Early phase: 0.21 ± 0.31  
   • Intermediate phase: 0.08 ± 0.35  
   • Late phase: 0.00 ± 0.34  
Mx-a right side (mean ± SD)NANA• Immediate phase: 0.26 ± 0.36NRNA
   • Early phase: 0.25 ± 0.35  
   • Intermediate phase: 0.23 ± 0.38  
   • Late phase: 0.09 ± 0.44  
Mx-a left/right difference (mean ± SD)NANRAverage difference:NRNA
   • Immediate phase: 0.15 ± 0.10  
   • Early phase: 0.24 ± 0.27  
   • Intermediate phase: 0.20 ± 0.36  
   • Late phase: 0.20 ± 0.13  
THx-a (right versus left, r)Range: r = 0.75 to r = −0.04 19 patients above median of r = 0.36 and 18 patients were below the medianNANANANA
CVR assessment characteristics• THI was measured bilaterally over frontal areas at a frequency of 2 Hz• FV assessed with TCD by insonating MCAs bilaterally at a depth of 51–53 mm• Bilateral MCA FVs were recorded using TCD• FVs in both MCAs were measured with TCD 2 MHz probes• TCD used to insonated left and right MCAs
 • ABP was measured invasively at heart level from radial or femoral artery with an intravascular line connected to a pressure transducer• ABP was measured invasively from radial artery• ABP was obtained invasively with radial artery fluid coupled system• ICP monitored with Codman parenchymal probes• ICP monitored with the aid of a micro transducer inserted intraparenchymally into the right frontal region
 • THx-a was calculated as moving correlation coefficient between 10 s averaged values of ABP and THI from a 300 s window• ICP was measured with intraparenchymal probe• For each hemisphere, Mx-a was calculated as moving correlation coefficient between ABP and CBFV from 65 000 simultaneously recorded data points sampled at 57.4 Hz• ABP monitored invasively through an arterial line positioned in the radial artery and connected to a pressure transducer• ABP monitored invasively from radial artery
  • Mx was calculated as moving correlation coefficient between consecutive 24 samples of 10 second averaged FV and CPP waveforms • nABP was monitored non-invasively with servo-controlled finger plethysmograph while the hand was kept steady at heart level• CPP calculated as difference between mean ABP and ICP
    • CPP was calculated as difference between ABP and ICP• Mx was calculated for both left and right sides as linear correlation coefficients among 36 consecutive samples of averaged CPP and time-averaged mean FV calculated for every 3 min epoch
    • Data was captured digitally at sampling rate of 50 Hz  
    • Mx was calculated as correlation coefficient between CPP mean and FV 
    • Mx-a was calculated as the correlation coefficient between nABP mean and FV mean 
Conclusions regarding regional disparity• When there is good agreement of THx-a on both sides then a comparison of PRx with THx-a was significant (p < 0.01)• During normocapnic baseline, patients with impaired Mx (left: 0.33 ± 0.149; right: 0.37 ± 0.24) significantly improved with moderate hypocapnia (left: 0.06 ± 0.27; right: −0.001 ± 0.17; p < 0.001) whereas patients with normal Mx baseline (left: −0.26 ± 0.24; right: −0.27 ± 0.23; p < 0.05) did not significantly change• Patients with hemispheric asymmetry did not have a worse outcome than patients without hemispheric asymmetry• Mx-a correlated positively with Mx (r = 0.755, p < 0.001)• Absolute left–right difference in Mx was not significantly correlated with ICP (r = −0.057), CPP (r = −0.112), or brain swelling (r = 0.01)
 • Level of agreement between THx-a indices of both sides ranged from high correlation (n = 19 patients, r = 0.75, p < 0.01) to no correlation (n = 18 patients, r = −0.04) while the median correlation was r = 0.36• Mx improved in patients where moderate hypocapnia was able to establish CPPOPT whereas Mx was maintained on both sides in patients that had CPPOPT established at normocapnia and maintained in moderate hypocapnia• In both hemispheres, CA is profoundly disturbed during immediate post-injury phase but gradually improves during the ICU course• CA asymmetry between Mx-a (calculated as Mx-aleft–Mx-aright) and Mx (calculated as Mxleft–Mxright) correlated positively (r = 0.857, p < 0.0001)• Absolute left–right difference in Mx correlated with left–right mean Mx (r = 0.24; p < 0.025), indicating that more autoregulation is impaired, the more asymmetrical it becomes
     • Significant correlation was seen between the left–right difference in Mx and the midline shift on CT scans (r = −0.42, p = 0.03) which indicates autoregulation is worse on side of brain swelling when there is a midline shift
     • Mx was higher ipsilateral to contusion than Mx on contralateral side (difference in Mx: 0.16 ± 0.2, p < 0.0035) suggesting autoregulation is worse on side of brain where lesion is present
     • Absolute left–right difference in Mx was higher in cases of unilateral contusion (0.14 ± 0.18) than in bilateral contusion (0.08 ± 0.1; p < 0.05) which suggests autoregulation is more asymmetrical in cases of unilateral lesion than in bilateral lesion cases
     • Left–right difference in Mx was significantly higher in patients who died (0.16 ± 0.04) than in those who survived (0.08 ± 0.05; p = 0.04)
     • Left and right mean Mx were significantly higher in patients who died (0.13 ± 0.05) than who survived (−0.03 ± 0.05; p = 0.002)
     • Patient outcome was independently correlated with asymmetry of autoregulation (p < 0.0015)
     • Left–right symmetry accompanies a preserved autoregulation while left–right asymmetry is associated with impaired autoregulation

ABP, arterial blood pressure; nABP, non-invasive ABP; CA, cerebral autoregulation; CBFV, cerebral blood flow velocity; CPP, cerebral perfusion pressure; CPPOPT, optimal CPP; CT, computed tomography; CVR, cerebrovascular reactivity; FV, flow velocity; ETCO2, end-tidal carbon dioxide; GCS, Glasgow Coma Scale; GOS, Glasgow Outcome Scale; Hz, hertz; ICP, intracranial pressure; ICU, intensive care unit; kPa, kilopascal; mmHg, millimeter of mercury; MCA, middle cerebral artery; Mx, mean flow index; Mx-a, Mx with ABP; NA, not applicable; NR, not reported; PRx, pressure reactivity index; SD, standard deviation; TBI, traumatic brain injury; THI, tissue hemoglobin index; THx, total hemoglobin reactivity index; THx-a, THx with ABP.

Table 9. Regional disparity in continuous cerebrovascular reactivity: multiple populations.

 Adatia et al (2020)Bindra et al (2016)Czosnyka et al (2003)
Inclusion criteriaPatients admitted to Neurocritical Care Unit between 2013 to 2017 who had multimodality monitoring of CA using NIRSPatients admitted to ICU between February and July 2014 as part of larger cohort investigating CA in patients admitted for cardiac arrest, sepsis, stroke, or TBI• Hemodynamic investigations using TCD part of routine clinical assessment for patients
 • Acutely comatose patients (GCS ≤8) with direct arterial pressure monitoring • Informed consent obtained in volunteers
Exclusion criteria• Patients with GCS ≤8 due to sedation or aphasia• Unable to get informed consent from next of kinNR
 • Unavailability of NIRS equipment  
 • Absence of daily CT scans throughout the monitoring period  
PatientsTotal: 104 adultsTotal: 19 adults• Healthy volunteer: 14 adults
 • With midline shift: 92 adults• Cardiac arrest: 1 adult• Head injury: 243 adults
 • Without midline shift: 12 adults• Sepsis: 8 adults• SAH: 15 adults
  • Stroke: 8 adults• Common carotid artery stenosis: 38 adults
  • TBI: 2 adults• Hydrocephalus: 35 adults
Biological Sex (male:female, n)• With midline shift: 49:43• Cardiac arrest: 1:0NR
 • Without midline shift: 6:6• Sepsis: 7:1 
  • Stroke: 5:3 
  • TBI: 1:1 
Age (years)• With midline shift: 59 ± 15• Total mean: 62.2 yearsNR
 • Without midline shift: 62 ± 16• Cardiac arrest: 51 years 
  • Sepsis: 67 years (33–87 years) 
  • Stroke: 58 years (28–70 years) 
  • TBI: 60 years (56–64 years) 
Diagnosis• ICH:NANR
 • With midline shift: 49  
 • Without midline shift: 3  
 • Aneurysmal subarachnoid hemorrhage:  
 • With midline shift: 19  
 • Without midline shift: 1  
 • TBI:  
 • With midline shift: 16  
 • Without midline shift: 3  
 • Status epilepticus:  
 • With midline shift: 0  
 • Without midline shift: 1  
 • Ischemic stroke:  
 • With midline shift: 12  
 • Without midline shift: 2  
 • Other (meningitis, hypoxic-ischemic encephalopathy):  
 • With midline shift: 0  
 • Without midline shift: 2  
Injury site (n)• Left:NANR
 • With midline shift: 28  
 • Without midline shift: 1  
 • Right:  
 • With midline shift: 24  
 • Without midline shift: 3  
 • Both:  
 • With midline shift: 8  
 • Without midline shift: 2  
 • Diffuse:  
 • With midline shift: 32  
 • Without midline shift: 6  
APACHE IIINR• Cardiac arrest: 104NR
  • Sepsis: 75 (47–141) 
  • Stroke: 77 (19–96) 
  • TBI: 49–81 
GCS6 ± 3• Cardiac arrest: 4NR
  • Sepsis: 9 (3–11) 
  • Stroke: 7 (3–11) 
  • TBI: 3–6 
COx-a ipsilateral (median)• With midline shift: 0.01 (IQR: 0.001–0.05)• Invasive average: 0.011 ± 0.13NA
 • Without midline shift: 0.05 (IQR: −0.01 to 0.15)• Non-invasive average: 0.006 ± 0.11 
COx-a contralateral (median)• With midline shift: 0.05 (IQR: −0.01 to 0.06) NA
 • Without midline shift: 0.06 (IQR: 0.005–0.14)  
Global COx-a (median)• With midline shift: 0.10 (IQR: 0.007–0.23)NANA
 • Without midline shift: 0.06 (IQR: −0.13 to 0.11)  
Mx/MX-aNANA• In healthy volunteers, Mx >0.4 in 86% of volunteers with high PaCO2
   • In head injury patients with bilateral TCD, Mx was significantly worse on contusion side and the side of the brain expansion in patients with midline shift
   • In SAH patients:
   • Baseline: 0.21 ± 0.24
   • Vasospasm: 0.46 ± 0.32
   • In carotid artery stenosis patients, side-to-side difference in Mx failed to correlate with degree of asymmetry
   • Severe disturbance in autoregulation in presence of bilateral-stenosis compared to unilateral-stenosis as indicated by Mx
   • In patients with hydrocephalus, Mx significantly correlated with resistance to CSF outflow (r = −0.41)
CVR assessment characteristics• Continuous rSO2 monitored with NIRS INVOS 5100• Continuous rSO2 monitored at a rate of 0.5 Hz using Foresight tissue oximeter using adhesive optodes placed on each side of patient's forehead below the hairlineMCA insonation:
 • ABP was measured invasively from radial or femoral artery catheters at 60 Hz where clinically required• ABP was measured invasively with radial intra-arterial catheter and transducer referenced to the level of the heart• In patients with head injury, MCA insonated daily either on the side of ICP bolt or bilaterally
 • COx-a was calculated as Pearson correlation coefficient over 10 second intervals between ABP and rSO2 in a 300 second window• ABP was monitored non-invasively using Finometer photoplethysmograph• In other patients and healthy volunteers, MCA was monitored during clinical test
 • Hourly COx-a values, taken from mean of all COx-a values obtained through the hour, were obtained separately for each hemisphere• Invasive and non-invasive COx-a were calculated as moving correlation coefficient between 30 consecutive samples of rSO2 with invasive and non-invasive ABP, respectively, averaged over 10 secondsICP monitoring:
 • Global COx-a was calculated as mean of the hourly COx-a values• Hemispheric asymmetry assessed as difference between right and left hemispheres of invasive and non-invasive COx-a values• In patients with head injury and SAH, ICP monitored continuously using micro-transducers inserted intraparenchymally into the frontal region
 • Absolute difference between • In hydrocephalus patients, ICP was monitored using external pressure transducer connected to manometer line
   ABP monitoring:
   • In patients with head injury and SAH, ABP was monitored invasively from radial or dorsalis pedis artery
   • In patients with hydrocephalus carotid artery stenosis and healthy volunteers, ABP was measured non-invasively using finger-cuff CPP was calculated by differencing ICP from ABP Mx/Mx-a was calculated as Pearson's correlation coefficient of 30–60 consecutive samples of mean FV with CPP/ABP
Conclusions regarding regional disparity• COx-a asymmetry worsens with each millimeter shift at pineal and septum• Interhemispheric difference of invasive COx-a correlated with interhemispheric difference of non-invasive COx-a (r = 0.81, p < 0.001)• In healthy volunteers, Mx/Mx-a significantly depended on PaCO2 since at high PaCO2, Mx > 0.4 in 86% of volunteers
 • For each 1 mm shift at pineal and septum, COx-a asymmetry increased by 0.002 ± 0.0005 (p = 0.001) and 0.002 ± 0.0002 (p < 0.001) in univariate analysis, and by 0.009 ± 0.004 (p < 0.001) and 0.005 ± 0.001 (p < 0.001) in multivariate analysis, respectively • In head injury patients with bilateral TCD, Mx/Mx-a was significantly worse on contusion side (p < 0.05) and the side of the brain expansion in patients with midline shift (p < 0.05)
 • COx-a asymmetry stayed within normal limits of autoregulation in patients without midline shift • Hemispheric differences of Mx/Mx-a were present in most of the patients who died in hospital (p < 0.05)
 • Beginning of monitoring, COx-a was greater on the injured side but by the end of monitoring, COx-a was greater on the contralateral side • In SAH patients, autoregulation was significantly worse during vasospasm (Mx/Mx-a = 0.46 ± 0.32) than at baseline (Mx/Mx-a = 0.21 ± 0.24; p = 0.021)
 • COx-a asymmetry did not show any associations with any outcomes (3, 6, and 12 months) • Autoregulation was significantly worse on vasospasm side compared to the contralateral side (p = 0.006)
 In multivariate analysis: • In carotid artery stenosis patients, worse pressure-autoregulation significantly correlated with impaired CO2 reactivity (p < 0.05)
 • Regardless of injury location, there was significant relationship between COx asymmetry with midline shift where beta coefficients are 0.013 ± 0.003 (p < 0.001) and 0.005 ± 0.002 (p = 0.004) at pineal, and 0.003 ± 0.001 (p = 0.04) and 0.007 ± 0.003 (p = 0.009) at septum for patients with unilateral injuries and bilateral injuries, respectively • Side-to-side difference in Mx/Mx-a failed to correlate with degree of asymmetry in contrast to data obtained in head injury patients
 • Significant relationship between COx asymmetry with midline shift in patients with frontal lesions (n = 23) where beta coefficients are 0.005 ± 0.002 (p = 0.002) at pineal and 0.004 ± 0.001 (p < 0.001) at septum • Severe disturbance in autoregulation in presence of bilateral-stenosis compared to unilateral-stenosis as indicated by Mx/Mx-a (p = 0.01)
 • Significant relationship between COx asymmetry with midline shift in patients without frontal lesions (n = 69) only at septum where beta coefficients are 0.001 ± 0.001 (p = 0.15) at pineal and 0.003 ± 0.0003 (p < 0.001) at septum • In patients with hydrocephalus, Mx/Mx-a significantly correlated with resistance to CSF outflow (r = −0.41; p < 0.03)
   • This indicates better autoregulation in patients with disturbed CSF circulation

ABP, arterial blood pressure; APACHE III, acute physiologic and chronic health evaluation 3 score; CA, cerebral autoregulation; COx, cerebral oximetry index; COx-a, COx with ABP; CPP, cerebral perfusion pressure; CT, computed tomography; CSF, cerebrospinal fluid; CVR, cerebrovascular reactivity; FV, flow velocity; GCS, Glasgow Coma Scale; Hz, hertz; ICH, intracranial hemorrhage; ICP, intracranial pressure; ICU, intensive care unit; IQR, interquartile range; MCA, middle cerebral artery; Mx, mean flow index; NA, not applicable; NIRS, near-infrared spectroscopy; NR, not reported; rSO2, regional cerebral oxygen saturation; SAH, subarachnoid hemorrhage; TBI, traumatic brain injury; TCD, transcranial Doppler.

Healthy volunteer studies

As seen in table 2, all of the healthy volunteer studies acquired cerebral blood flow velocity (CBFV) using TCD where most of them insonated the middle cerebral artery (MCA) bilaterally (Piechnik et al 1999, Schmidt et al 2003b, Yam et al 2005), while one monitored MCA and posterior inferior cerebellar artery (PICA) (Reinhard et al 2008). ABP was monitored non-invasively in all the studies and mean ABP (MAP) was used in the calculation of CVR indices (Piechnik et al 1999, Schmidt et al 2003b, Yam et al 2005, Reinhard et al 2008). All of the studies calculated Mx-a using mean CBFV versus MAP (Piechnik et al 1999, Schmidt et al 2003b, Yam et al 2005, Reinhard et al 2008), while one study also calculated Dx-a using mean CBFV and diastolic ABP (Reinhard et al 2008), and another study calculated Sx-a using mean CBFV and systolic ABP (Piechnik et al 1999). Most of the healthy volunteer studies reported that there were minimal to no difference between Mx-a from left and right sides (Piechnik et al 1999, Schmidt et al 2003b, Yam et al 2005) (p > 0.05 (Piechnik et al 1999), Yam et al 2005) along with one study reporting no difference between Sx from left and right sides (Piechnik et al 1999), and another study reporting no difference between Dx-a and Mx-a calculated via PICA and MCA (Reinhard et al 2008).

The study by Piechnik and colleagues found an increase in Mx-a (>0.4) and Sx-a (>0.2) due to hypercapnia compared to normocapnia in most patients (Piechnik et al 1999). Reinhard and colleagues did not find any influence of age or sex on Dx-a or Mx-a that were calculated by either PICA or MCA. They also stated no major difference was found between cerebellar or cerebral circulation based on the two autoregulatory indices, Dx-a and Mx-a (Reinhard et al 2008). Mx-a threshold between normal and abnormal autoregulation was set as 0.45 by Schmidt and colleagues after inferring from other studies that the threshold assessed with ABP is on average 0.15 greater than the threshold of 0.3 assessed with CPP and they found that 6 healthy volunteers in their study had Mx-a above the threshold either on one side in four volunteers or on both sides in two volunteers (Schmidt et al 2003b).

Cardiac surgery studies

There were only two studies with patients undergoing cardiac surgery that required cardiopulmonary bypass (CPB) using TCD to insonate the MCAs bilaterally as seen in table 3 (Joshi et al 2010, Hori et al 2015), while one study also used UT-NIRS to obtain signals from both sides of the forehead (Hori et al 2015). One of these studies calculated Mx-a and CFVx-a (Hori et al 2015), while the other study only measured Mx-a with a warm control group (arterial inflow temperature ≥35 °C) and two Hypothermia groups (arterial inflow temperature ≤34 °C), one with Mx-a <0.4 and other with Mx-a >0.4 (Joshi et al 2010). Both studies monitored ABP invasively from the radial artery and MAP was used in the calculation of CFVx-a and Mx-a with UT-NIRS signals and TCD flow velocities, respectively (Joshi et al 2010, Hori et al 2015). Hori and colleagues stated that CFVx-a had similar values on both left and right sides, and same was said for the Mx-a index when compared to both sides. Also, both CFVx-a and Mx-a correlated significantly with each other (p ≤ 0.001) (Hori et al 2015). No left versus right difference was found with Mx-a in the warm control group, while there was a very minor difference in Mx-a between both sides during cooling, rewarming, and after CPB phases in the study by Joshi and colleagues (Joshi et al 2010).

It was found that the cooling phase increased Mx-a on both sides (left, 0.29 ± 0.18; right, 0.28 ± 0.18) as compared with baseline (left, 0.17 ± 0.21; right, 0.17 ± 0.20; p ≤ 0.0001), while the rewarming phase increased Mx-a on both sides even higher (left, 0.40 ± 0.19; right, 0.39 ± 0.19) compared with baseline (p ≤ 0.0001) and cooling phase (p ≤ 0.0001) (Joshi et al 2010). Although before wound closure and after CPB, Mx-a on both sides decreased (left, 0.27 ± 0.20; right, 0.28 ± 0.21), being no different than the cooling phase (p = 0.8996), lower than rewarming phase (left, p ≤ 0.0001; right, p = 0.0005) but still higher than baseline (left, p = 0.0004; right, p = 0.0003) (Joshi et al 2010). Also, the warm control group showed no difference between left (p = 0.2948) and right sided (p = 0.2476) Mx-a between first and second hour of CPB (Joshi et al 2010).

Endarterectomy studies

There were three endarterectomy studies found during this review where two studies included patients with severe unilateral stenosis ≥70% of internal carotid artery (ICA) (Reinhard et al 2003, 2004), and included patients with severe carotid artery stenosis ≥70% (Zipfel et al 2020), as seen in table 4. Two studies insonated MCAs bilaterally using TCD to obtain CBFVs (Reinhard et al 2003, 2004), while the other obtained regional oxygen saturation (rSO2) and regional total hemoglobin (rTHb) from NIRS using bilateral probes attached to patient's frontal region (Zipfel et al 2020). ABP was recorded non-invasively in both studies by Reinhard and colleagues (Reinhard et al 2003, 2004) while the study by Zipfel and colleagues obtained ABP invasively from an arterial line (Zipfel et al 2020). The CVR indices Dx-a, Mx-a, and Sx-a were calculated in two of the studies by correlating CBFV versus diastolic, mean, and systolic ABP, respectively (Reinhard et al 2003, 2004), while the third study calculated COx-a and HVx-a by correlating MAP versus rSO2 and rTHb (Zipfel et al 2020). These studies showed that Dx-a (Groups A,B,C: p < 0.001 (Reinhard et al 2003); Group D: p < 0.01 (Reinhard et al 2003)), Mx-a (Groups A,B,C: p < 0.001 (Reinhard et al 2003); Group D: p < 0.01 (Reinhard et al 2003)), and HVx-a had significant difference between ipsilateral side of stenosis versus contralateral side (Reinhard et al 2003, 2004, Zipfel et al 2020) while Sx-a (Groups A,B: p < 0.01 (Reinhard et al 2003); Group C: p < 0.05 (Reinhard et al 2003)) either did not show a clear side-to-side difference (Reinhard et al 2003) or was considered less reliable (Reinhard et al 2004), along with COx-a not showing any statistically significant difference between both sides (Zipfel et al 2020).

The study by Reinhard group in 2003 reported that there was a clear side-to-side difference in unilateral stenosis ≥80% using the Dx-a and Mx-a TCD-based indices, but not for the Sx-a index (Reinhard et al 2003). In another study by Reinhard and colleagues in 2004, the Dx-a and Mx-a clearly showed poor autoregulation values on ipsilateral side compared to contralateral side (Reinhard et al 2004). Mx-a showed the most pronounced difference between 70%–79% and 80%–89% degree of stenosis groups and Dx-a had a similar trend (Reinhard et al 2003). In one study, patients with ≥90% degree of stenosis had poorer ipsilateral Dx-a and Mx-a values compared to patients with 75% to 89% degree of stenosis (p < 0.05) (Reinhard et al 2004), and this result was similar to another study by the same first author where the two 90%–99% and 100% groups tended to have poorer values of these two indices (Reinhard et al 2003). There was an autoregulatory improvement on the ipsilateral side after recanalization of obstructed ICA, where the autoregulatory values reached values similar to the contralateral unaffected sides (Reinhard et al 2004).

In the paper that used NIRS-based CVR indices, the no shunt group showed a significant decrease in COx-a and HVx-a after clamping, indicating intact autoregulation, while the shunted group did not, indicating impaired CVR. Compared to baseline, clamping showed significant decrease in ipsilateral COx-a (p = 0.0214) in no shunt group, while ipsilateral COx-a significantly increased prior to shunt insertion in shunted group (p = 0.048), and the pooled ipsilateral and contralateral data showed significant increases in COx-a (p = 0.039) and HVx-a (p < 0.001) in shunted patients (Zipfel et al 2020). Post-clamping compared to baseline showed significant decrease in ipsilateral HVx-a for the no shunt group (p = 0.007) (Zipfel et al 2020). Although post-clamping compared to clamping did not result in regional disparity as measured by COx-a and HVx-a, since they remained stable on both ipsilateral and contralateral sides in both the no shunt and shunt groups (Zipfel et al 2020). Also, when comparing ipsilateral COx-a after clamping, a significant decrease was seen in intact Circle of Willis (CoW) group (p = 0.013), and in patients without any anatomical effect, a significant decrease in ipsilateral COx-a was seen (p < 0.001).

Intracerebral hemorrhage (ICH) study

As seen in table 5, there was only one study with intracerebral hemorrhage (ICH) patients and healthy controls (Reinhard et al 2010). This study used TCD to acquire CBFV from both MCAs and recorded ABP non-invasively which were used to calculated the Mx-a index by correlating mean ABP with CBFV for both ipsilateral and contralateral sides to the ICH (Reinhard et al 2010). Reinhard and colleagues showed that the mean values of Mx-a did not differ across the study points and also did not differ on ipsilateral and contralateral sides when compared with healthy controls (Reinhard et al 2010). On day 5, higher Mx-a or poor autoregulation was related with lower GCS on both sides (ipsilateral: p < 0.001, contralateral: p = 0.006), presence of ventricular hemorrhage on both sides (ipsilateral: p = 0.011, contralateral: p = 0.018), and lower non-invasive CPP ipsilaterally (p = 0.024) (Reinhard et al 2010). Also, higher ipsilateral Mx-a on day 5 was a significant predictor for poor 90-day outcome (p = 0.013) (Reinhard et al 2010).

Subarachnoid hemorrhage (SAH) studies

For the subarachnoid hemorrhage (SAH) studies, there were only two found during this review that included patients with aneurysmal SAH, as seen in table 6 (Soehle et al 2004, Budohoski et al 2015). Both of these studies insonated MCAs bilaterally to acquire CBFV with TCD (Soehle et al 2004, Budohoski et al 2015), and ABP was acquired purely invasively from radial artery in one study (Soehle et al 2004), while the other study monitored the ABP either non-invasively or invasively from radial artery (Budohoski et al 2015). The CVR indices Mx-a (Soehle et al 2004), and Sx-a (Soehle et al 2004, Budohoski et al 2015) were calculated in these studies by correlating mean ABP with mean and systolic CBFV, respectively. Both of the studies observed worse autoregulation ipsilaterally than on the contralateral side (Soehle et al 2004, Budohoski et al 2015).

Soehle and colleagues found that both Mx-a (p = 0.006) and Sx-a (p = 0.044) were higher on vasospasm side than on contralateral side, and both of these indices correlated (p < 0.001) with each other on side of vasospasm, as well as the contralateral side (Soehle et al 2004). Budohoski and colleagues observed worse autoregulation via Sx-a on the ipsilateral side to delayed cerebral ischemia (DCI) and found that there was a lower correlation between ipsilateral and contralateral indices in patients who developed DCI (p = 0.007) (Budohoski et al 2015). Overall, the DCI group had worse autoregulation (p = 0.000 01 for Sx-a DCI versus non-DCI) accompanied with increased interhemispheric difference of autoregulation (p = 0.035), which suggests unilateral autoregulation failure. In the same study, it was found that patients with unfavorable outcome also had worse autoregulation (p = 0.006 for Sx-a favourable versus unfavourable) accompanied with decreased interhemispheric difference of autoregulation (p = 0.027), which suggests bilateral autoregulation failure (Budohoski et al 2015).

Stroke studies

There were also only two studies found with ischemic stroke patients where one group had patients with large vessel occlusive stroke (Meyer et al 2020), and the other study looked at patients admitted with acute cerebral ischemia, as seen in table 7 (Reinhard et al 2005). Both studies obtained CBFV bilaterally by insonating MCAs through temporal window with TCD (Reinhard et al 2005, Meyer et al 2020), but one study measured ABP invasively via radial artery (Meyer et al 2020) while the other study measured it non-invasively via finger plethysmograph (Reinhard et al 2005). The Mx-a CVR index was calculated in both studies by correlating CBFV versus MAP (Reinhard et al 2005, Meyer et al 2020). Meyer and colleagues observed that after interventional thrombectomy, CA was impaired in both successful recanalization and no recanalization groups on both ipsilateral and contralateral sides (except ipsilateral side could not be insonated in the no recanalization group) (Meyer et al 2020). While Reinhard and colleagues found no relevant side-to-side differences in Mx-a for their first 48 h study and Day 4–7 after ictus study (Reinhard et al 2005). Mx-a was slightly higher on stroke side than contralateral side, while contralateral Mx-a showed no significant difference between both groups (p = 0.59) in the study by Meyer and colleagues (Meyer et al 2020). In the study by Reinhard and colleagues, CA was observed to be worse later on after stroke, by Mx-a being slightly higher in Day 4–7 study than in the first 48 h study (p < 0.05) (Reinhard et al 2005).

Traumatic brain injury (TBI) studies

As given in table 8, five TBI studies were included in this review with varying GCS on admission (Lang et al 2003, Schmidt et al 2003a, Lavinio et al 2007, Diedler et al 2011, Haubrich et al 2011). Only one of these studies measured THI bilaterally over the frontal areas with NIRS (Diedler et al 2011) while the rest of the four studies insonated MCAs bilaterally via TCD to assess CBFV (Lang et al 2003, Schmidt et al 2003a, Lavinio et al 2007, Haubrich et al 2011). In all five TBI studies, ABP was measured invasively from either a radial or femoral artery (Lang et al 2003, Schmidt et al 2003a, Lavinio et al 2007, Diedler et al 2011, Haubrich et al 2011) while three studies measured ICP (Schmidt et al 2003a, Lavinio et al 2007, Haubrich et al 2011), and one study additionally measured ABP non-invasively (Lavinio et al 2007). Mx CVR index was calculated in three studies by correlating CBFV versus CPP (Schmidt et al 2003a, Lavinio et al 2007, Haubrich et al 2011), Mx-a index was calculated in two studies by correlating CBFV versus MAP (Lang et al 2003, Lavinio et al 2007), and only one study calculated THx-a index by correlating THI with MAP (Diedler et al 2011). Two studies reported similar Mx values between both left and right sides (Schmidt et al 2003a, Haubrich et al 2011) while the third study did not report any values for Mx (Lavinio et al 2007). Some patients had Mx-a asymmetry in one study but compared to patients without hemispheric asymmetry, they did not have a worse outcome (Lang et al 2003). With THx-a index, the level of agreement between both sides ranged from high (p < 0.01) to no correlation in patients for the one study calculating the index (Diedler et al 2011).

Although the level of agreement between both sides varied using THx-a index, there was a significant correlation between PRx and THx-a (p < 0.01) when there was good agreement of THx-a on both sides in the study by Diedler and colleagues (Diedler et al 2011). In the study by Lang and colleagues that used the Mx-a index, CA was disturbed in both hemispheres during immediate post-injury phase, but did gradually improve during the ICU course (Lang et al 2003). CA asymmetry between Mx-a and Mx, calculated by subtracting the right side index from the left side index for both indices, had a positive correlation (p < 0.0001) (Lavinio et al 2007). TBI patients in Haubrich and colleagues study that had impaired Mx on both left and right sides showed significant improvement with moderate hypocapnia for both sides (p < 0.001) while patients with normal Mx did not significantly change (p < 0.05) (Haubrich et al 2011). Schmidt and colleagues observed that absolute left–right difference in Mx correlated with left–right mean Mx (p < 0.025) which indicates that the more autoregulation is impaired, the more asymmetrical it becomes (Schmidt et al 2003a). Left–right difference in Mx correlated significantly with midline shift on computed tomography (CT) scans (p = 0.03) which shows autoregulation is worse on the side of brain swelling (Schmidt et al 2003a). They also observed that autoregulation is worse on the lesion side since Mx was higher ipsilaterally than contralaterally (p < 0.0035), and unilateral contusion cases had more asymmetrical autoregulation as compared to bilateral contusion cases (p < 0.05) (Schmidt et al 2003a). Also, it was observed that patients who died had significantly higher left–right difference Mx (p = 0.04), and left and right mean Mx than patients who survived (p = 0.002) (Schmidt et al 2003a). Asymmetry of autoregulation was correlated with patient outcome (p < 0.0015) and hence left–right symmetry seems to go with preserved autoregulation while left–right asymmetry is associated with impaired autoregulation.

Multiple population studies

Multiple population studies was the last group including a total of three studies whose inclusion criteria were acutely comatose patients with GCS ≤8 (Adatia et al 2020), patients admitted for cardiac arrest, sepsis, stroke, or TBI (Bindra et al 2016), and patients with head injury, SAH, carotid artery stenosis, or hydrocephalus (Czosnyka et al 2003), as described in table 9. Two of these studies monitored rSO2 bilaterally from the forehead with NIRS (Bindra et al 2016, Adatia et al 2020) while the third study insonated MCA's bilaterally with TCD (Czosnyka et al 2003). Invasive ABP was measured from radial or femoral artery in all three studies (Czosnyka et al 2003, Bindra et al 2016, Adatia et al 2020), but two studies also measured ABP non-invasively (Czosnyka et al 2003, Bindra et al 2016), and one study additionally monitored ICP (Czosnyka et al 2003). Then COx-a index was calculated in two studies by correlating rSO2 with MAP (Bindra et al 2016, Adatia et al 2020), and the third study calculated Mx/Mx-a by correlating CBFV with CPP and MAP, respectively (Czosnyka et al 2003).

Bindra and colleagues observed that the interhemispheric difference of COx-a calculated with invasive MAP correlated with interhemispheric difference of COx-a calculated with non-invasive MAP (p < 0.001) (Bindra et al 2016). While Adatia and colleagues observed that COx-a asymmetry worsened with each millimeter shift at the pineal gland (p = 0.001 and p < 0.001) and septum (p < 0.001 and p < 0.001) in univariate and multivariate analysis, respectively, while COx-a asymmetry stayed within normal limits in patients without midline shift, but COx-a asymmetry did not show any associations with 3, 6, or 12 month outcomes (Adatia et al 2020). Multivariate analysis showed mostly significant relationships between COx-a asymmetry with midline shift at pineal (p < 0.001, p = 0.004, p = 0.002, and p = 0.15), and septum (p = 0.04, p = 0.009, p < 0.001, and p < 0.001) for patients with unilateral injuries, bilateral injuries, frontal lesions, and without frontal lesions, respectively (Adatia et al 2020). Czosnyka and colleagues mentioned that the calculated Mx/Mx-a was significantly worse on contusion side (p < 0.05) or the side with midline shift (p < 0.05) in head injury patients, and most of the patients who died in hospital had hemispheric difference of Mx/Mx-a (p < 0.05). While in SAH patients, autoregulation was significantly worse on vasospasm side compared to contralateral side (p = 0.006) (Czosnyka et al 2003). In contrast to data obtained in head injury patients, the side-to-side difference in Mx/Mx-a failed to correlate with degree of asymmetry in carotid artery stenosis patients, while Mx/Mx-a indicated severe disturbance in autoregulation in presence of bilateral-stenosis compared to unilateral-stenosis (p = 0.01) (Czosnyka et al 2003). However, the results for healthy volunteers and hydrocephalus patients did not comment on the regional disparity of Mx/Mx-a (Czosnyka et al 2003).

Discussion

The included human studies reported on the regional disparity using either TCD-based CVR indices (Dx-a (Reinhard et al 2003, 2004, 2008), Mx (Czosnyka et al 2003, Schmidt et al 2003a, Lavinio et al 2007), Mx-a (Piechnik et al 1999, Czosnyka et al 2003, Lang et al 2003, Schmidt et al 2003b, Soehle et al 2004, Yam et al 2005, Lavinio et al 2007, Joshi et al 2010, Reinhard et al 2003, 2004, 2005, 2008, 2010, Haubrich et al 2011, Hori et al 2015, Meyer et al 2020), Sx-a (Budohoski et al 2015); Piechnik et al 1999, Reinhard et al 2003, Soehle et al 2004) or NIRS-based CVR indices (CFVx-a (Hori et al 2015), COx-a (Bindra et al 2016, Adatia et al 2020, Zipfel et al 2020), HVx-a (Zipfel et al 2020), THx-a (Diedler et al 2011)). The non-invasive nature of TCD and NIRS devices is a big advantage in generating CVR indices with multiple probes as compared to other invasive devices such as ICP, but the temporal resolution of TCD and NIRS needs to be improved to capture the pulse waveform data from the measurements. TCD suffers from intra- and inter-operator reliability, limiting the measurement time, and its spatial resolution is limited due to insonation of bilateral MCA (Zeiler and Smielewski 2018, Zeiler et al 2018c). Compared to TCD, NIRS measurement is not as limited, but the commercial NIRS used in clinical settings suffers from limited channel capacity (Gomez et al 2021a), limiting its spatial resolution. Currently there exists research NIRS systems offering increased spatial and temporal resolution by increasing the measurement frequency up to 250 Hz at multiple channels (Chen et al 2020, Gomez et al 2021d, Sainbhi et al 2022, Sainbhi et al 2023), but they are not FDA or Health Canada approved which limits their use to research settings. Previous literature has demonstrated regional heterogeneity in physiologic responses in healthy and diseased states using CVR and CBF assessments (Wintermark et al 2001, Chieregato et al 2003, Aaslid et al 2007, Horsfield et al 2013, Tekes et al 2015, Zeiler et al 2017b, Saito et al 2018, Polinder-Bos et al 2020, Gomez et al 2022, Sainbhi et al 2022), but there is an absence of assessments using NIRS-based CVR metrics, using either commercial of research multichannel NIRS systems, as exemplified by our scoping review. Through the comprehensive evaluation of the human studies on various disease states surrounding regional disparities in continuous CVR between more than one brain region/channel using the same CVR metric, some interesting findings deserve highlighting.

First, the available literature only included a handful of CVR metrics, so we can only comment on those select number of metrics that are based on TCD, and NIRS. This may be the case because it is easier to derive multichannel TCD- and NIRS-based indices by adding more channels due to their non-invasive nature compared to ICP-based indices where multiple invasive ICP probes cannot be inserted in different regions of the brain. The handful of studies evaluating TCD- and NIRS-based indices did comment on the regional disparity in various disease states with some studies also adding perturbations to look at the effect it has on the regional disparity. The study by Piechnik and colleagues observed an increase in Mx-a and Sx-a due to hypercapnia compared to normocapnia in most healthy volunteers (Piechnik et al 1999), while the study by Haubrich and colleagues showed that Mx significantly improved on both sides with moderate hypocapnia as compared to normocapnia (Haubrich et al 2011).

Second, there was minimal to no difference found between left and right sides for Dx-a (Reinhard et al 2008), Mx-a (Piechnik et al 1999, Schmidt et al 2003b, Yam et al 2005, Joshi et al 2010, Reinhard et al 2008, 2010, Hori et al 2015), Sx-a (Piechnik et al 1999), CFVx-a (Hori et al 2015), in all healthy volunteer, cardiac surgery, and ICH patient studies. This is anticipated for healthy volunteers and cardiac surgery patients, while ICH patients would be expected to have a difference, but it was not the case from the one study found on ICH patients. Most of these studies used TCD-based indices, Dx-a, Mx-a, and Sx-a, while only one of these studies used a NIRS-based CVR index, CFV-x. Although there were only two studies found for cardiac surgery, the study by Hori and colleagues was able to compare the CFVx-a and Mx-a between left and right sides and reported similar values (Hori et al 2015). Interestingly, Joshi and colleagues found that compared to baseline, cooling phase increased Mx-a on both sides, re-warming phase increased Mx-a even more on both sides, and after CPB, Mx-a on both sides came back down to cooling phase levels. While in warm control group, no difference was found in Mx-a between first and second hour of CPB for both sides (Joshi et al 2010). The single ICH study reported that mean values of Mx-a did not differ between the ipsilateral and contralateral sides as compared with healthy controls but mentioned that higher ipsilateral Mx-a on day 5 turned out to be a significant predictor for poor 90-day outcome (Reinhard et al 2010). This highlights the need for future work looking at regional disparity in healthy population and various disease states using NIRS-based indices.

Third, in all endarterectomy, and SAH studies, there was a significant difference reported between ipsilateral side of disease versus contralateral side with the following TCD-based and NIRS-based CVR indices: Dx-a (Reinhard et al 2003, 2004), Mx-a (Reinhard et al 2003, 2004, Soehle et al 2004, Budohoski et al 2015), Sx-a (Soehle et al 2004, Budohoski et al 2015), COx (Zipfel et al 2020), and HVx-a (Zipfel et al 2020). This is anticipated since endarterectomy and SAH patients are likely to have asymmetrical conditions. Although a TCD-based index, Sx-a, was reported to either not show a clear side-to-side difference (Reinhard et al 2003), or was considered less reliable (Reinhard et al 2004) in two endarterectomy studies, but this was contrary to two SAH studies that observed worse autoregulation on ipsilateral side to DCI (Budohoski et al 2015) and vasospasm (Soehle et al 2004) as compared to contralateral side with Mx-a and Sx-a. The NIRS-based indices, COx and HVx, showed statistically significant increases in shunted patients from the pooled ipsilateral and contralateral data. Compared to baseline, clamping showed significant decrease in ipsilateral COx-a for no shunt group while it showed an increase in shunted group, but when post-clamping, showed significant decrease in HVx for no shunt group when compared to baseline (Zipfel et al 2020). The Dx-a, Mx-a, and HVx-a indices in endarterectomy studies showed that the ipsilateral side had poor autoregulation values compared to the contralateral side (Reinhard et al 2003, 2004, Zipfel et al 2020), and patients with ≥90% degree of stenosis had poorer ipsilateral Dx-a and Mx-a values (Reinhard et al 2003, 2004).

Fourth, there were varying results regarding regional disparity in stroke, TBI, and multiple population studies where some reported no hemispheric asymmetry while others reported worse autoregulation ipsilaterally. One stroke study reported no side-to-side difference with Mx-a in patients admitted with acute cerebral ischemia, although autoregulation was observed to worsen later after stroke (Reinhard et al 2005). While the other stroke study reported that both successful recanalization and no recanalization groups had impaired autoregulation ipsilateral to large vessel occlusive stroke and on the contralateral side, but the ipsilateral side for no recanalization group could not be insonated (Meyer et al 2020). TBI studies reported varying regional disparities where Mx values between both sides were similar according to two studies (Schmidt et al 2003a, Haubrich et al 2011), patients with and without hemispheric asymmetry with Mx-a (Lang et al 2003), level of agreement between both sides ranged from high to no correlation using THx-a (Diedler et al 2011), a NIRS-based index, and one study reported a positive correlation of CA asymmetry between Mx-a and Mx, TCD-based, indices (Lavinio et al 2007). The TBI study that calculated THx-a stated a significant correlation between PRx and THx-a when there was a good agreement of THx-a on both sides (Diedler et al 2011). The TBI study by Schmidt and colleagues made interesting suggestions from their data such as autoregulation becomes more asymmetrical the more autoregulation is impaired, autoregulation is worse on the side of brain swelling and lesion side, and unilateral contusion cases had more asymmetrical autoregulation as compared to bilateral contusion cases (Schmidt et al 2003a). In the multiple population study by Czosnyka and colleagues, they found that Mx/Mx-a was significantly worse on the contusion side (side with midline shift) in head injury patients and on vasospasm side in SAH patients (Czosnyka et al 2003). In the same study the side-to-side difference in Mx/Mx-a failed to correlate with the degree of asymmetry in carotid artery stenosis patients, which was in contrast to data obtained in head injury patients (Czosnyka et al 2003). Looking at the NIRS-based index of COx-a, Bindra and colleagues stated the interhemispheric difference of COx-a correlated with each other, with the COx-a calculated with invasive and non-invasive MAP (Bindra et al 2016). While Adatia and colleagues observed that COx-a asymmetry worsened with each millimeter shift at pineal and septum, while COx-a asymmetry stayed within normal limits in patients without midline shift, and their multivariate analysis mostly showed significant relationships between COx-a asymmetry with midline shift at pineal and septum for patients with unilateral injuries, bilateral injuries, frontal lesions, and without frontal lesions (Adatia et al 2020).

Limitations

There are some significant limitations that deserve highlighting despite the interesting findings outlined in this scoping review. First, the literature uncovered was very heterogeneous in design which means that there was limited ability to cross-sectionally evaluate the relationship between studies based on various combinations of CVR indices used in each type of disease studies. Second, most studies used a small number of patients in their studies which is likely due to the fact that some patients either do not meet the inclusion criteria or if they do meet the criteria then sometimes the measured signals either do not get properly recorded or end up having too many artifacts. Such small numbers limit the definitiveness of the findings outlined and emphasizes further validation studies. Third, the number of studies per disease is as follows: four healthy volunteer studies, two cardiac surgery studies, three endarterectomy studies, one ICH study, two SAH studies, two stroke studies, five TBI studies, and three multiple population studies. So, comparing between the same disease state was difficult due to lack of studies found commenting on regional disparity of same CVR indices in more than one brain region/channel. Fourth, most of the studies were male dominated and this may not give the full information regarding regional disparity if we assume females hemispheric asymmetry according to disease is different than males. Fifth, all the studies only monitored two brain regions with mostly TCD-based along with some NIRS-based metrics. Most studies only insonated MCAs via transtemporal window with the TCD, while only one study insonated the PICA. No studies were found to insonate arteries such as ophthalmic, basilar, intracranial carotid through other acoustic windows such as transorbital, transforaminal, or submandibular windows (White and Venkatesh 2006, Purkayastha and Sorond 2012, Sainbhi et al 2022). Sixth, the temporal resolution was poor in the studies and most only commented on the mean CVR values for the recording session. TCDs have a practical limitation of less than one hour (Zeiler et al 2017b, Gomez et al 2021c, Sainbhi et al 2022) which explains the poor temporal resolution since most CVR indices measured in the studies were TCD-based. Seventh, the studies reduced the measured indices to grand averages over the short recording period or used limited consecutive points to calculate the CVR indices which restricts the ability to use any high resolution time-series techniques on the indices data. Although this simplifies the analysis, it is at the cost of losing the information encoded in the fluctuations of these indices over the recording period. Lastly, studies that evaluated CA using frequency-domain metrics such as ARI (Tiecks et al 1995), and TF-ARI (Liu et al 2016), were not part of the search strategy since these measures are either non-continuous, computationally complex, or not commonly used, although they may provide value in characterization of CA (Zeiler et al 2017b, Gomez et al 2021c).

Future directions

There are some important areas for future research moving forward. First, validation of above findings is required as some are based on single institution, single study findings, or limited patient numbers. Such work will require multi-institutional collaboration to combine patient data for studies with larger population. Second, as studies uncovered had very heterogeneous patient data, there is a need for more studies to use more homogenous patient datasets based on disease pattern, age, biological sex, and clinical demographics and covers the various disease states. Studying the regional disparity in population of healthy and various disease states is key to understanding how each disease state affects the regional disparity and which indices can better capture this hemispheric asymmetry. Third, spatial resolution needs to increase in order to monitor more brain regions. There is a reason why all the studies found calculated CVR indices based on TCD or NIRS, as these devices can provide a higher spatial resolution of continuous CVR monitoring compared to those derived invasively. The spatial resolution can be increased using multichannel functional NIRS that can measure both oxyhemoglobin and deoxyhemoglobin simultaneously at each channel while being able to remove scalp noise (Chen et al 2020, Gomez et al 2021d, Sainbhi et al 2022). Fourth, the temporal resolution of the data also needs to be increased to obtain pulse waveform data which is possible with NIRS and cumbersome with TCD, due to its practical limit. Obtaining high frequency data is valuable for concurrent derivation of waveform based cerebrovascular parameters that may be of interest in conjunction with CA. These parameters include pressure-flow dynamics, compliance/compensatory reserve, and autonomic function. Fifth, to obtain more comprehensive understanding of physiology, multiple continuous time-domain techniques such as CVR and other raw or derived metrics, should be simultaneously integrated. Sixth, to evaluate temporal changes in regional disparities in disease state as disease progresses, the data needs to be collected during both acute and subacute (long-term) phases and this requires entirely non-invasive, high spatial resolution systems such as NIRS. Seventh, to integrate regional CVR data with patient clinical conditions, patient-reported symptom surveys, and formalized neuropsychological testing toolkits need to be conducted for disease states. Eighth, for healthy control studies, several perturbations such as transient hyperemic response, orthostatic challenge, and neuropsychological tests along with vascular chemo-reactivity are needed, while collecting sufficient numbers of volunteers, to evaluate the impact of age and sex on healthy volunteer reference data. Lastly, evaluating network connectivity between regions is required, once high spatial and high temporal resolution systems are developed.

Conclusion

This literature demonstrates that regional disparity measured by TCD-based and NIRS-based CVR indices may differ according to the disease. In all healthy volunteer, cardiac surgery, and ICH patient studies, Dx-a, Mx-a, Sx-a, and CFVx-a indices showed that there was minimal difference between the measured left and right sides. While in all endarterectomy, and SAH studies, there was a significant difference reported between ipsilateral side of disease versus contralateral side using Dx-a, Mx-a, Sx-a, and HVx-a. Also, there were varying results reported regarding regional disparity in stroke, TBI, and multiple population studies. Some studies focused on small number of patients in a specific disease state, so the conclusions drawn from these studies should be taken with caution. There were not many studies evaluating regional disparity using NIRS-based indices, therefore additional research is required to further understand if NIRS-based indices are able to provide better regional disparity information than TCD-based indices.

Acknowledgments

This work was directly supported through the Manitoba Public Insurance (MPI) Professorship in Neuroscience and the Natural Sciences and Engineering Research Council of Canada (NSERC) (DGECR-2022-00260, RGPIN-2022-03621, ALLRP-576386-22, and ALLRP-578524-22).

Data availability statement

No new data were created or analysed in this study. Data will be available from 20 February 2023.

Funding

FAZ receives research support from NSERC, CIHR, the MPI Neuroscience Research Operating Fund, the Health Sciences Centre Foundation Winnipeg, the Canada Foundation for Innovation (CFI) (Project #: 38583), Research Manitoba (Grant #: 3906), the University of Manitoba VPRI Research Investment Fund (RIF), and the University of Manitoba MPI Professorship in Neuroscience.

AG is supported through the University of Manitoba Clinician Investigator Program and a Canadian Institutes of Health Research (CIHR) Fellowship (Grant #: 472286)

ASS is supported through the University of Manitoba Graduate Fellowship (UMGF)—Biomedical Engineering, NSERC (RGPIN-2022-03621) and the University of Manitoba Graduate Enhancement of Tri-Agency Stipend (GETS) program.

LF is supported through the University of Manitoba—Department of Surgery GFT Research Grant, the University of Manitoba—University Research Grant Program (URGP), the Biomedical Engineering (BME) Fellowship Grant at the University of Manitoba, and the Research Manitoba PhD Studentship.

KS is supported by the University of Manitoba MD/PhD program and the University of Manitoba Graduate Fellowship program.

NV is supported by NSERC (RGPIN-2022-03621).

Disclosures

There is no disclosure to make.

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Supplementary data PRISMA Checklist (0.1 MB DOCX)

Supplementary data CVR Metrics of Interest (0.1 MB DOCX)

Supplementary data Database Searches (0.1 MB DOCX)

Supplementary data General Overview of Characteristics of Included Studies (0.1 MB DOCX)