Low Heart Rate Is Associated with Cerebral Pulsatility after TIA or Minor Stroke.

OBJECTIVE: Beta-blockers are beneficial in coronary artery disease but less so in stroke prevention and dementia, potentially due to reduced heart rate (HR). Cerebral pulsatility is strongly associated with cerebral small vessel disease (SVD) and may be increased by lower diastolic pressures resulting from longer cardiac cycles. METHODS: Patients 4-6 weeks after TIA or non-disabling stroke (Oxford Vascular Study) underwent 5 minutes continuous monitoring of blood pressure (BP), electrocardiogram (ECG), and middle cerebral artery flow velocity (transcranial ultrasound). Beat-to-beat relationships between HR, blood pressure and Gosling's pulsatility index (MCA-PI) are reported as beta-coefficients from general linear models for each individual. RESULTS: Across 759 patients, average MCA-PI during monitoring was associated with lower HR and diastolic BP (DBP) and greater systolic BP (SBP) (∆MCA-PI per 10 bpm/mmHg: -0.02, -0.04, 0.03, all p < 0.001), with HR particularly associated with low end-diastolic cerebral velocity (0.86, p = 0.014). Beat-to-beat HR was strongly associated with concurrent low DBP and high SBP, potentially mediating the association with greater beat-to-beat cerebral pulsatility (average ∆MCA-PI vs HR/DBP/SBP unadjusted: -0.062, -0.052, 0.0092; adjusted for concurrent BP: -0.039, -0.11, 0.041). The beat-to-beat association between HR and MCA-PI increased with age, beta-blockers, arterial stiffness, low HR (age > 70 + HR < 65 vs age < 70 + HR > 65: -0.081 vs -0.024, interaction p < 0.001), and severe SVD on MRI (age > 70 + severe vs age < 70 + none: -0.087 vs -0.047, interaction p = 0.03), with interactions between age, severe SVD, and low HR synergistically increasing MCA-PI. INTERPRETATION: Low HR is associated with greater cerebral pulsatility in patients with SVD, potentially mediated by lower diastolic blood flow and representing a novel potential treatment target. ANN NEUROL 2022;92:909-920.

Consistencies and Differences in Intermediate Physiological Phenotypes of Vascular Ageing between Ischaemic Stroke Aetiologies.

OBJECTIVE: Arterial stiffness, cerebral pulsatility, and beat-to-beat blood pressure variability partly mediate the relationship between hypertension and stroke, but it is unknown if these intermediate phenotypes of vascular ageing differ between stroke aetiologies. We therefore aimed to characterize differences in these intermediate cardiovascular phenotypes between patients presenting with strokes of different aetiologies. METHODS: In consecutive patients on best medical management 1 month after TIA or nondisabling stroke (Oxford Vascular Study), arterial stiffness (PWV) was measured by applanation tonometry (Sphygmocor), middle cerebral blood flow velocity, and pulsatility index (MCA-PI) were measured by transcranial ultrasound (TCD, DWL Doppler Box), and beat-to-beat BP variability was measured with a Finometer. Differences between patients with large artery (LAS), small vessel (SVD), cardioembolic (CE), or undetermined events were derived, including adjustment for cardiovascular risk factors. Relationships were characterized by mixed linear models. RESULTS: In 909 eligible patients, MCA-PI, PWV, and SBPV were all positively skewed. Mean values were greatest in LAS than CE and lowest in SVD (p < 0.001). However, after adjustment for age, sex, and risk factors, PI was greatest in LAS and lowest in CE stroke, whilst PWV was greatest in SVD and undetermined stroke (p < 0.001). In multivariate linear models, age was more strongly associated with PWV and PI in patients with small vessel stroke than other aetiologies, particularly under the age of 65, but SBPV was only weakly associated with demographic indices in all stroke subtypes. CONCLUSIONS: Intermediate cardiovascular phenotypes of vascular ageing had similar demographic associations between stroke aetiologies, but these were particularly strong in patients with small vessel stroke under the age of 65, implying a potential role of these phenotypes in increasing stroke risk in this patient group.

A Higher Grey Matter Density in the Amygdala and Midbrain Is Associated with Persistent Pain Following Total Knee Arthroplasty.

OBJECTIVE: The development of persistent pain following total knee arthroplasty (TKA) is common, but its underlying mechanisms are unknown. The goal of the study was to assess brain grey matter structure and its correlation with function of the nociceptive system in people with good and poor outcomes following TKA. SUBJECTS: Thirty-one people with LOW_PAIN (<3/10 on the numerical ratings scale [NRS]) at six months following TKA and 15 people with HIGH_PAIN (≥3/10 on the NRS) were recruited into the study. METHODS: Grey matter in key brain areas related to nociception was analyzed using voxel-based morphometry (VBM). Nociceptive facilitatory and inhibitory processes were evaluated using quantitative sensory testing (QST). QST scores and grey matter density in prespecified brain regions were compared between the LOW_PAIN and HIGH_PAIN groups. Regression analyses were used to analyze the associations between the grey matter and QST scores. RESULTS: There were no between-group differences in QST measures. In the VBM analysis, the HIGH_PAIN group had a higher grey matter density in the right amygdala, right nucleus accumbens, and in the periaqueductal grey (PAG), but lower grey matter density in the dorsal part of the left caudate nucleus. Grey matter density in the right amygdala and PAG correlated positively with temporal summation of pain. CONCLUSIONS: Persistent pain at six months after TKA is associated with a higher grey matter density in the regions involved in central sensitization and pain-related fear, which may contribute to the development of persistent pain after surgery.

Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial.

BACKGROUND: Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease. METHODS: We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated. FINDINGS: Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years [SD 9·9]) and 26 with CADASIL (53·1 years [7·0]) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10-4%/mm Hg [SE 20·1; 95% CI -37·6 to 41·2] for amlodipine; 16·7 × 10-4%/mm Hg [20·0; -22·3 to 55·8] for losartan; -7·1 × 10-4%/mm Hg [19·6; -45·5 to 31·1] for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10-4%/mm Hg [SE 27·5; 95% CI -38·3 to 69·7] for amlodipine; 19·4 × 10-4%/mm Hg [27·9; -35·3 to 74·2] for losartan; -23·9 × 10-4%/mm Hg [27·5; -77·7 to 30·0] for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (-39·6 × 10-4%/mm Hg [95% CI -72·5 to -6·6; p=0·019) and with losartan compared with atenolol (-43·3 × 10-4%/mm Hg [-74·3 to -12·3]; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake. INTERPRETATION: 4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research. FUNDING: EU Horizon 2020 programme.

White matter damage due to pulsatile versus steady blood pressure differs by vascular territory: A cross-sectional analysis of the UK Biobank cohort study.

Small vessel disease is associated with age, mean blood pressure (MAP) and blood pressure pulsatility (PP). We used data from the UK Biobank cohort study to determine the relative importance of MAP versus PP driving white matter injury within individual white matter tracts, particularly in the anterior and posterior vascular territory. The associations between blood pressure and diffusion indices in 27 major tracts were analysed using unadjusted and fully-adjusted general linear models and mixed-effect linear models. Blood pressure and neuroimaging data were available for 37,041 participants (mean age 64+/-7.5 years, 53% female). In unadjusted analyses, MAP and PP were similarly associated with diffusion indices in the anterior circulation. In the posterior circulation, the associations were weaker, particularly for MAP. In fully-adjusted analyses, MAP remained associated with all diffusion indices in the anterior circulation, independently of age. In the posterior circulation, the effect of MAP became protective. PP remained associated with greater mean diffusivity and extracellular free water diffusion in the anterior circulation and all diffusion indices in the posterior circulation. There was a significant interaction between PP and age. This implies discordant mechanisms for chronic white matter injury in different brain regions and potentially in the associated stroke risks.

Placebo's invisible brother: a restricted scoping review of the biomedical literature on the nocebo effect.

ABSTRACT: Placebos and their beneficial clinical and psychological effects are well-researched, but nocebo effects receive far less attention, despite being highly undesirable. The aim of this restricted scoping review was to examine how nocebo effects are represented in the biomedical literature and to identify the trends and gaps in existing knowledge. After searching 5 biomedical databases and 2 clinical trials registries (from their inception to December 23, 2020) for articles on nocebo effects or negative placebo effects, 1161 eligible publications were identified. The 2 main publication types were nonsystematic reviews (37.7%) and primary research studies (35.6%); only 85 publications (7.3%) were systematic reviews and meta-analyses. The nonsystematic reviews, many of them heavily opinion-based, may contribute to the amplification of narratives, attitudes, and beliefs about nocebo effects that do not objectively reflect the primary research. The primary research articles often used nocebo effects to explain results, rather than as the primary phenomenon under investigation. Most publications were concerned with both positive and negative placebo effects, rather than just nocebo effects. Over half of the abstracts were in the field of neurology, psychiatry, psychology, or neuroscience (52.8%). The nocebo effect was most frequently investigated in the context of pain. Studies were almost exclusively in adults and more often in healthy participants than in patients. In conclusion, in the biomedical literature, there is an overabundance of nonsystematic reviews and expert opinions and a lack of primary research and high-quality systematic reviews and meta-analyses specifically dealing with nocebo effects.

Blood Pressure Determinants of Cerebral White Matter Hyperintensities and Microstructural Injury: UK Biobank Cohort Study.

[Figure: see text].

A meta-analysis of temporal changes of response in the placebo arm of surgical randomized controlled trials: an update.

BACKGROUND: Temporal changes in the placebo arm of randomized controlled trials (RCTs) have not been thoroughly investigated, despite the fact that results of RCTs depend on the comparison between arms. METHODS: In this update of our earlier systematic review and meta-analysis, we set out to investigate the effect of assessment time and number of visits on the magnitude of change from baseline in the placebo arm of these trials. We used linear mixed-effects models to account for within-trial correlations. RESULTS: Across all 47 trials the magnitude of response in the placebo arm did not change with time (ß = -0.0070, 95% CI -0.024, 0.010) or visit (ß = -0.033, 95% CI -0.082, 0.017) and remained significantly different from baseline for at least 12 months or seven follow-up visits. Change in the placebo arm in trials with subjective outcomes was large (ß0 = 0.68, 95% CI 0.53, 0.82) and relatively constant across time (ß = -0.0042, 95% CI -0.024, 0.016) and visit (ß = -0.029, 95% CI -0.089, 0.031), whereas in trials with objective outcomes the response was smaller (ß0 = 0.28, 95% CI 0.11, 0.46) and diminished with time (ß = -0.030, 95% CI -0.050, -0.010), but not with visit (ß = -0.099, 95% CI -0.30, 0.11). For trials with assessed outcomes, there was no significant effect of time (ß = -0.0071, 95% CI -0.026, 0.011) or visit (ß = -0.032, 95% CI -0.33, 0.26); however, these results should be interpreted with caution due to the small number of studies, and high clinical heterogeneity between studies. In trials with pain as an outcome, the improvement was significant (ß0 = 0.91, 95% CI 0.75, 1.07), but there was no effect of time (ß = -0.013, 95% CI -0.06, 0.03) or visit (ß = -0.045, 95% CI -0.16, 0.069), and pain ratings remained significantly different from baseline for 12 months or seven visits. CONCLUSIONS: These results are consistent with our previous findings. In trials with subjective outcomes response in the placebo arm remains large and relatively constant for at least a year, which is interesting considering that this is an effect of a single application of an invasive procedure. The lack of effect of time and visit number on subjective outcomes raises further questions regarding whether the observed response is the result of placebo effect or the result of bias.

The magnitude and temporal changes of response in the placebo arm of surgical randomized controlled trials: a systematic review and meta-analysis.

BACKGROUND: Understanding changes in the placebo arm is essential for correct design and interpretation of randomized controlled trials (RCTs). It is assumed that placebo response, defined as the total improvement in the placebo arm of surgical trials, is large; however, its precise magnitude and properties remain to be characterized. To the best of our knowledge, the temporal changes in the placebo arm have not been investigated. The aim of this paper was to determine, in surgical RCTs, the magnitude of placebo response and how it is affected by duration of follow-up. METHODS: The databases of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched from their inception to 20 October 2015 for studies comparing the efficacy of a surgical intervention with placebo. Inclusion was not limited to any particular condition, intervention, outcome or patient population. The magnitude of placebo response was estimated using standardized mean differences (SMDs). Study estimates were pooled using random effects meta-analysis. Potential sources of heterogeneity were evaluated using stratification and meta-regression. RESULTS: Database searches returned 88 studies, but for 41 studies SMDs could not be calculated, leaving 47 trials (involving 1744 participants) eligible for inclusion. There were no temporal changes in placebo response within the analysed trials. Meta-regression analysis showed that duration of follow-up did not have a significant effect on the magnitude of the placebo response and that the strongest predictor of placebo response was subjectivity of the outcome. The pooled effect in the placebo arm of studies with subjective outcomes was large (0.64, 95% CI 0.5 to 0.8) and remained significantly different from zero regardless of the duration of follow-up, whereas for objective outcomes, the effect was small (0.11, 95% CI 0.04 to 0.26) or non-significant across all time points. CONCLUSIONS: This is the first study to investigate the temporal changes of placebo response in surgical trials and the first to investigate the sources of heterogeneity of placebo response. Placebo response in surgical trials was large for subjective outcomes, persisting as a time-invariant effect throughout blinded follow-up. Therefore, placebo response cannot be minimized in these types of outcomes through their appraisal at alternative time points. The analyses suggest that objective outcomes may be preferable as trial end-points. Where subjective outcomes are of primary interest, a placebo arm is necessary to control for placebo response.