Regional Neurovascular Coupling and Cognitive Performance in Those with Low Blood Pressure Secondary to High-Level Spinal Cord Injury: Improved by Alpha-1 Agonist Midodrine Hydrochloride

Abstract

Individuals with high-level spinal cord injury (SCI) experience low blood pressure (BP) and cognitive impairments. Such dysfunction may be mediated in part by impaired neurovascular coupling (NVC) (i.e., cerebral blood flow responses to neurologic demand). Ten individuals with SCI 4T6 spinal segment, and 10 age-and sex-matched controls were assessed for beat-by-beat BP, as well as middle and posterior cerebral artery blood flow velocity (MCAv, PCAv) in response to a NVC test. Tests were repeated in SCI after 10 mg midodrine (alpha 1 -agonist). Verbal fluency was measured before and after midodrine in SCI, and in the control group as an index of cognitive function. At rest, mean BP was lower in SCI (70 ± 10 versus 92 ± 14 mm Hg; Po0.05); however, PCAv conductance was higher (0.56 ± 0.13 versus 0.39 ± 0.15 cm/second/mm Hg; Po0.05). Controls exhibited a 20% increase in PCAv during cognition; however, the response in SCI was completely absent (Po0.01). When BP was increased with midodrine, NVC was improved 70% in SCI, which was reflected by a 13% improved cognitive function (Po0.05). Improvements in BP were related to improved cognitive function in those with SCI (r 2 ¼ 0.52; Po0.05). Impaired NVC, secondary to low BP, may partially mediate reduced cognitive function in individuals with high-level SCI. INTRODUCTIONSpinal cord injury (SCI) is a devastating condition often resulting in disturbed motor, sensory, and autonomic function. As a result of disrupted descending autonomic spinal pathways after SCI, sympathetic vasomotor tone is impaired, often resulting in arterial hypotension. 1 Those with injury at or above T 6 spinal segment, because of a myriad of potential mechanisms (including decentralization of sympathetically mediated vasomotor tone in the splanchnic region and legs) have more profound autonomic disturbances including resting hypotension and orthostatic hypotension as compared with those with lower level SCI. 2 An abundance of evidence, from both animal and human studies, demonstrated that there is an association between low blood pressure (BP) and a variety of cognitive impairments. 3,4 There is well-established evidence that individuals with SCI have a high rate of traumatic brain injury that can result in a significant number of cognitive dysfunctions. 5 However, the high prevalence of cognitive dysfunction (i.e., between 10% and 60%) in SCI 6,7 is likely to be at least partially due to widespread hypotension. 8 This notion is further highlighted by a significant positive relationship between systolic BP (SBP) and cognitive function in the SCI population. 9

Neurovascular coupling in humans: Physiology, methodological advances and clinical implications

“…For example, chronic hypotension depresses cognitive activity and resting CBF, which is directly mediated by neurovascular coupling. 72,80 Conversely, cognitive activity can be improved with pharmacological treatment of hypotension, through improvements in neurovascular coupling; 52,81 82 In order to increase the clinical utility of neurovascular coupling as an end-point treatment target, there is a need for an automated and standardized protocol for analysis, which produces interpretable metrics.…”

“…Both the P1 and P2 segments have been utilized with similar results, however a consistent segment should be maintained throughout a given study. 52,55,73,92,93 Lastly, often only the posterior window is suitable for insonating intracranial vessels in the elderly, due to skull thickening with advancing age. 94 Some studies have reported that 10À15% of individuals will have inadequate windows for insonating intracranial cerebral vessels; 95 as such, it may be advantageous to utilize other techniques such as NIRS (see next section) in addition to TCD for studies in the elderly or those with related cerebrovascular pathology.…”

“…for further analysis. 52 The amount of data analysis required for the latter two approaches is significant, with a variety of processing steps required to coalesce contours into interpretable metrics.…”

Inter-day reliability of blood pressure and cerebral blood flow velocities in persons with spinal cord injury and intact controls

“…22,49 Our data support the notion that not only is MFV reduced in persons with SCI compared to AB controls, but SFV and DFV are also significantly lower. These findings indicate persistent cerebral hypoperfusion throughout the entire cardiac cycle in hypotensive individuals with chronic SCI, which may contribute to the increased incidence of cerebrovascular disease 50 and ischemic stroke, 18 as well as cognitive deficits, 23,51,52 and impairment in health related QOL. 10 …”

“…17 Further, an increased incidence of hemorrhagic and ischemic stroke was noted in the Taiwanese SCI population (n=2806) compared to propensity-score matched controls (n = 28,060), which the authors speculate may relate to fluctuations in BP. 18 Transcranial Doppler ultrasound (TCD) technology has been used to non-invasively assess CBF velocity (CBFv) at the middle cerebral artery (MCA) [19][20][21][22][23][24] and the posterior cerebral arteries 23,24 in the SCI population. From TCD recordings of the MCA, reduced resting CBFv has been documented in persons with SCI 22,25 and altered static and dynamic autoregulation compared to controls is reported.…”