We define cerebral vascular reactivity (CVR) as the ratio of the change in blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) signal (S) to an increase in blood partial pressure of CO2 (PCO2): % Δ S/Δ PCO2 mm Hg. Our aim was to further characterize CVR into dynamic and static components and then study 46 healthy subjects collated into a reference atlas and 20 patients with unilateral carotid artery stenosis. We applied an abrupt boxcar change in PCO2 and monitored S. We convolved the PCO2 with a set of first-order exponential functions whose time constant τ was increased in 2-second intervals between 2 and 100 seconds. The τ corresponding to the best fit between S and the convolved PCO2 was used to score the speed of response. Additionally, the slope of the regression between S and the convolved PCO2 represents the steady-state CVR (ssCVR). We found that both prolongations of τ and reductions in ssCVR (compared with the reference atlas) were associated with the reductions in CVR on the side of the lesion. τ and ssCVR are respectively the dynamic and static components of measured CVR.

Areas of reduced CVR precede the progression from NAWM to WMH, suggesting that hemodynamic impairment may contribute to the pathogenesis and progression of age-related white matter disease. Ann Neurol 2016;80:277-285.

PurposeTo evaluate the relationship between both dynamic and steady-state measures of cerebrovascular reactivity (CVR) and the progression of age-related white matter disease.MethodsBlood oxygen level-dependent (BOLD) MRI CVR scans were acquired from forty-five subjects (age range: 50–90 years, 25 males) with moderate to severe white matter disease, at baseline and one-year follow-up. To calculate the dynamic (τ) and steady-state (ssCVR) components of the BOLD signal response, the PETCO2 signal waveform was convolved with an exponential decay function. The τ corresponding to the best fit between the convolved PETCO2 and BOLD signal defined the speed of response, and the slope of the regression between the convolved PETCO2 and BOLD signal defined ssCVR. ssCVR and τ were compared between normal-appearing white matter (NAWM) that remains stable over time and NAWM that progresses to white matter hyperintensities (WMHs).ResultsIn comparison to contralateral NAWM, NAWM that progressed to WMH had significantly lower ssCVR values by mean (SD) 46.5 (7.6)%, and higher τ values by 31.9 (9.6)% (both P < 0.01).ConclusionsVascular impairment in regions of NAWM that progresses to WMH consists not only of decreased magnitude of ssCVR, but also a pathological decrease in the speed of vascular response. These findings support the association between cerebrovascular dysregulation and the development of WMH.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Ketamine is an N-methyl-d-aspartate receptor antagonist that reduces temporal summation of pain and modulates antinociception. Ketamine infusions can produce significant relief of neuropathic pain, but the treatment is resource intensive and can be associated with adverse effects. Thus, it is crucial to select patients who might benefit from this treatment. The authors tested the hypothesis that patients with enhanced temporal summation of pain and the capacity to modulate pain via the descending antinociceptive brain pathway are predisposed to obtain pain relief from ketamine. Methods Patients with refractory neuropathic pain (n = 30) and healthy controls underwent quantitative sensory testing and resting-state functional magnetic resonance imaging and then completed validated questionnaires. Patients then received outpatient intravenous ketamine (0.5 to 2 mg · kg−1 · h−1; mean dose 1.1 mg · kg−1 · h−1) for 6 h/day for 5 consecutive days. Pain was assessed 1 month later. Treatment response was defined as greater than or equal to 30% pain relief (i.e., reduction in pain scores). We determined the relationship between our primary outcome measure of pain relief with pretreatment temporal summation of pain and with brain imaging measures of dynamic functional connectivity between the default mode network and the descending antinociceptive brain pathway. Results Approximately 50% of patients achieved pain relief (mean ± SD; Responders, 61 ± 35%; Nonresponders, 7 ± 14%). Pretreatment temporal summation was associated with the effect of ketamine (ρ = −0.52, P = 0.003) and was significantly higher in Responders (median [25th, 75th] = 200 [100, 345]) compared with Nonresponders (44 [9, 92]; P = 0.001). Pretreatment dynamic connectivity was also associated with the clinical effect of ketamine (ρ = 0.51, P = 0.004) and was significantly higher in Responders (mean ± SD, 0.55 ± 0.05) compared with Nonresponders (0.51 ± 0.03; P = 0.006). Finally, the dynamic engagement of the descending antinociceptive system significantly mediated the relationship between pretreatment pain facilitation and pain relief (95% CI, 0.005 to 0.065). Conclusions These findings suggest that brain and behavioral measures have the potential to prognosticate and develop ketamine-based personalized pain therapy.