The scalability of common paradigms for assessment of cognitive function: A functional transcranial Doppler study.

Cognitive paradigms induce changes in cerebral blood flow (CBF) associated with increased metabolic demand, namely neurovascular coupling (NVC). We tested the hypothesis that the effect of complexity and duration of cognitive paradigms will either enhance or inhibit the NVC response. Bilateral CBF velocity (CBFV) in the middle cerebral arteries (MCAs) via transcranial Doppler ultrasound (TCD), blood pressure (BP), electrocardiogram (ECG) and end-tidal CO2 (EtCO2) of 16 healthy participants (aged 21-71 years) were simultaneously recorded at rest and during randomized paradigms of different complexities (naming words beginning with P-,R-,V- words and serial subtractions of 100-2,100-7,1000-17), and durations (5s, 30s and 60s). CBFV responses were population mean normalized from a 30-s baseline period prior to task initiation. A significant increase in bilateral CBFV response was observed at the start of all paradigms and provided a similar pattern in most responses, irrespective of complexity or duration. Although significant inter-hemispherical differences were found during performance of R-word and all serial subtraction paradigms, no lateralisation was observed in more complex naming word tasks. Also, the effect of duration was manifested at late stages of 100-7, but not for other paradigms. CBFV responses could not distinguish different levels of complexity or duration with a single presentation of the cognitive paradigm. Further studies of the ordinal scalability of the NVC response are needed with more advanced modelling techniques, or different types of neural stimulation.

Age-related differences in cerebrovascular responses to cognitive stimulation using a novel method.

Aging is associated with a number of alterations to cerebrovascular function. We aimed to investigate the effect of age on cerebrovascular responses to cognitive stimulation using an objective two-parameter method.Previously derived from a large data-set (135 healthy participants) were applied to a task-activated dataset of 69 healthy participants in five different task conditions. Cumulative response rate (CRR) was calculated as the sum of responses across tasks and hemispheres.There was a significant effect of age (adjusted odds ratio: 1.02 (95% confidence interval: 1.01, 1.04), p = 0.016). There was also a significant effect of task (p = 0.002), but there was no significant interaction between age and task (p = 0.37). Increasing age was associated with increased CRR (adjusted odds ratio: 1.04 (95% confidence interval: 1.01, 1.07), p = 0.009).Using an objective two-parameter method, healthy older adults had increased cerebrovascular responses to cognitive testing.

The Interaction of Dynamic Cerebral Autoregulation and Neurovascular Coupling in Cognitive Impairment.

BACKGROUND: Dynamic cerebral autoregulation (dCA) remains intact in both ageing and dementia, but studies of neurovascular coupling (NVC) have produced mixed findings. OBJECTIVE: We investigated the effects of task-activation on dCA in healthy older adults (HOA), and patients with mild cognitive impairment (MCI) and Alzheimer's Disease (AD). METHODS: Resting and task-activated data from thirty HOA, twenty-two MCI, and thirty-four AD were extracted from a database. The autoregulation index (ARI) was determined at rest and during five cognitive tasks from transfer function analysis. NVC responses were present where group-specific thresholds of cross-correlation peak function and variance ratio were exceeded. Cumulative response rate (CRR) was the total number of positive responses across five tasks and two hemispheres. RESULTS: ARI differed between groups in dominant (p=0.012) and non-dominant (p=0.042) hemispheres at rest but not during task-activation (p=0.33). ARI decreased during language and memory tasks in HOA (p=0.002) but not in MCI or AD (p=0.40). There was a significant positive correlation between baseline ARI and CRR in all groups (r=0.26, p=0.018), but not within sub-groups. CONCLUSION: dCA efficiency was reduced in task-activation in healthy but not cognitively impaired participants. These results indicate differences in neurovascular processing in healthy older adults relative to cognitively impaired individuals.

COHmax: an algorithm to maximise coherence in estimates of dynamic cerebral autoregulation.

OBJECTIVE: The reliability of dynamic cerebral autoregulation (dCA) parameters, obtained with transfer function analysis (TFA) of spontaneous fluctuations in arterial blood pressure (BP), require statistically significant values of the coherence function. A new algorithm (COHmax) is proposed to increase values of coherence by means of the automated, selective removal of sub-segments of data. APPROACH: Healthy subjects were studied at baseline (normocapnia) and during 5% breathing of CO2 (hypercapnia). BP (Finapres), cerebral blood flow velocity (CBFV, transcranial Doppler), end-tidal CO2 (EtCO2, capnography) and heart rate (ECG) were recorded continuously during 5 min in each condition. TFA was performed with sub-segments of data of duration (SEGD) 100 s, 50 s or 25 s and the autoregulation index (ARI) was obtained from the CBFV response to a step change in BP. The area-under-the curve (AUC) was obtained from the receiver-operating characteristic (ROC) curve for the detection of changes in dCA resulting from hypercapnia. MAIN RESULTS: In 120 healthy subjects (69 male, age range 20-77 years), CO2 breathing was effective in changing mean EtCO2 and CBFV (p < 0.001). For SEGD = 100 s, ARI changed from 5.8 ± 1.4 (normocapnia) to 4.0 ± 1.7 (hypercapnia, p < 0.0001), with similar differences for SEGD = 50 s or 25 s. Depending on the value of SEGD, in normocapnia, 15.8% to 18.3% of ARI estimates were rejected due to poor coherence, with corresponding rates of 8.3% to 13.3% in hypercapnia. With increasing coherence, 36.4% to 63.2% of these could be recovered in normocapnia (p < 0.001) and 50.0% to 83.0% in hypercapnia (p < 0.005). For SEGD = 100 s, ROC AUC was not influenced by the algorithm, but it was superior to corresponding values for SEGD = 50 s or 25 s. SIGNIFICANCE: COHmax has the potential to improve the yield of TFA estimates of dCA parameters, without introducing a bias or deterioration of their ability to detect impairment of autoregulation. Further studies are needed to assess the behaviour of the algorithm in patients with different cerebrovascular conditions.

Neuroimaging Outcomes in Studies of Cognitive Training in Mild Cognitive Impairment and Early Alzheimer's Disease: A Systematic Review.

BACKGROUND: Cognitive Training (CT) has demonstrated some benefits to cognitive and psychosocial function in Mild Cognitive Impairment (MCI) and early dementia, but the certainty related to those findings remains unclear. Therefore, understanding the mechanisms by which CT improves cognitive functioning may help to understand the relationships between CT and cognitive function. The purpose of this review was to identify the evidence for neuroimaging outcomes in studies of CT in MCI and early Alzheimer's Disease (AD). METHODS: Medline, Embase, Web of Science, PsycINFO, CINAHL, and The Cochrane Library were searched with a predefined search strategy, which yielded 1778 articles. Studies were suitable for inclusion where a CT program was used in patients with MCI or AD, with a structural or functional Magnetic Resonance Imaging (MRI) outcome. Studies were assessed for quality using the Downs and Black criteria. RESULTS: A total of 19 studies met the inclusion criteria. Quality of the included studies was variable and there was significant heterogeneity for studies included in this review. Task activation was generally increased post-training, but functional connectivity was both increased and decreased after training. Results varied by diagnosis, type of CT program, and brain networks examined. No effects were seen on hippocampal volumes post-training, but cortical thickening and increased grey matter volumes were demonstrated. CONCLUSIONS: CT resulted in variable functional and structural changes in dementia, and conclusions are limited by heterogeneity and study quality. Larger, more robust studies are required to correlate these findings with clinical benefits from CT.

An objective method to identify non-responders in neurovascular coupling testing.

BACKGROUND: Neurovascular coupling (NVC) can be assessed using transcranial Doppler (TCD) measured task-activation of cerebral blood flow velocity (CBFv). However, not all individuals show consistent responses. The aim of this study was to develop a robust, objective, method to identify non-responders to task-activation. NEW METHOD: Using five-minute seated resting (non-stimulated), bilateral CBFv data from 135 healthy participants, the cross-correlation function peak (CCF) between the population coherent average and each individual was obtained for a randomly selected segment of data (40 s) for both hemispheres (n = 270). The variance ratio (VR) was calculated by comparing the variance in CBFv data pre- and post-random mark. The 90th percentile for non-stimulated data was used to determine the upper confidence limit of normal variation in the CCF peak value (0.53), and VR (2.59). These criteria were then applied to task-activated CBFv from 69 healthy participants for five cognitive tasks (attention, verbal fluency, language, visuospatial, memory). RESULTS: Data were accepted as responders if either CCF ≥ 0.53 or VR ≥ 2.59. The number of cases accepted as responders for each task were as follows: attention, 54-59 (78-86 %); verbal fluency, 42-48 (60-70 %); language, 51-53 (74-77 %); visuospatial, 54 (78 %); memory, 40-47 (58-68 %). COMPARISON WITH EXISTING METHOD: Currently, there are no objective criteria for the identification of non-responders in studies of NVC. This is a new method to objectively classify non-responders to task-activation. CONCLUSIONS: Using a large sample of resting CBFv data, we have set objective criteria to differentiate between responders and non-responders in task activation protocols.

Chasing the evidence: the influence of data segmentation on estimates of dynamic cerebral autoregulation.

OBJECTIVE: Transfer function analysis (TFA) of dynamic cerebral autoregulation (dCA) requires smoothing of spectral estimates using segmentation of the data (SD). Systematic studies are required to elucidate the potential influence of SD on dCA parameters. APPROACH: Healthy subjects (HS, n = 237) and acute ischaemic stroke patients (AIS, n = 98) were included. Cerebral blood flow velocity (CBFV, transcranial Doppler ultrasound) was recorded supine at rest with continuous arterial blood pressure (BP, Finometer) for a minimum of 5 min. TFA was performed with durations SD = 100, 50 or 25 s and 50% superposition to derive estimates of coherence, gain and phase for the BP-CBFV relationship. The autoregulation index (ARI) was estimated from the CBFV step response. Intrasubject reproducibility was expressed by the intraclass correlation coefficient (ICC). MAIN RESULTS: In HS, the ARI, coherence, gain, and phase (low frequency) were influenced by SD, but in AIS, phase (very low frequency) and ARI were not affected. ICC was excellent (>0.75) for all parameters, for both HS and AIS. For SD = 100 s, ARI was different between HS and AIS (mean ± sdev: 5.70 ± 1.61 vs 5.1 ± 2.0; p < 0.01) and the significance of this difference was maintained for SD = 50 s and 25 s. Using SD = 100 s as reference, the rate of misclassification, based on a threshold of ARI ⩽ 4, was 6.3% for SD = 50 s and 8.1% for SD = 25 s in HS, with corresponding values of 11.7% and 8.2% in AIS patients, respectively. SIGNIFICANCE: Further studies are warranted with SD values lower than the recommended standard of SD = 100 s, to explore possibilities of improving the reproducibility, sensitivity and prognostic value of TFA parameters used as metrics of dCA.

Assessment of cerebral autoregulation in stroke: A systematic review and meta-analysis of studies at rest.

Dynamic cerebral autoregulation (dCA) has been shown to be impaired in cerebrovascular diseases, but there is a lack of consistency across different studies and the different metrics that have been proposed for assessment. We performed a systematic review and meta-analyses involving assessment of dCA in ischemic and hemorrhagic stroke. Thirty-three articles describing assessment of dCA with transfer function analysis (TFA) were included, with meta-analyses performed for derived parameters of gain, phase and autoregulation index (ARI). A total of 1233 patients were pooled from 12 studies on acute ischemic stroke (AIS) and two studies on intracerebral hemorrhage (ICH). In comparison with controls, TFA phase of AIS was significantly reduced (nine studies), in both hemispheres (P < 0.0001). TFA gain provided inconsistent results, with reduced values in relation to controls, for both hemispheres. The ARI (six studies) was reduced compared to controls, in both hemispheres (P < 0.005). In ICH, gain showed higher values compared to controls for the unaffected (P = 0.01), but not for the affected hemisphere. Meta-analyses in AIS have demonstrated that phase and the ARI index can show highly significant differences in comparison with healthy controls, while ICH have been limited by the scarcity of studies and the diversity of units adopted for gain.

Can we use short recordings for assessment of dynamic cerebral autoregulation? A sensitivity analysis study in acute ischaemic stroke and healthy subjects.

OBJECTIVE: It is unclear whether the duration of recordings influences estimates of dynamic cerebral autoregulation (dCA). Therefore, we performed a retrospective study of the effects of reducing recording durations on dCA estimates; with the potential to inform recording duration for reliable estimates in challenging clinical populations. APPROACH: Seventy-eight healthy control subjects and 79 acute ischaemic stroke (AIS) patients were included. Cerebral blood flow (CBF) velocity was recorded with transcranial Doppler (TCD) and continuous blood pressure (BP) with a Finapres device. The autoregulation index (ARI), derived with transfer function analysis (TFA), was calculated for recording durations at one-minute intervals between 1 and 5 min using the same starting point of each recording. MAIN RESULTS: Though recording duration did not affect the overall ARI value, when compared to control subjects, AIS patients had significantly lower ARI values for durations between 3 and 5 min (p  < 0.0001), but not 1 and 2 min. The intraclass correlation coefficient of all participants, for reproducibility of the five recording durations, was 0.69. AIS patients classified as having impaired cerebral autoregulation (CA; ARI ⩽ 4) at 5 min, had a 7.1% rate of false negatives for both 4 and 3 min recordings, reaching 42.9% for 1 min recording. The percentage of false-positives also increased with reduced recording durations (from 0% at 5 to 16.2% at 1 min). SIGNIFICANCE: Reducing recording durations from 5 to 3 min can still provide reliable estimates of ARI, and may facilitate CA studies in potentially medically unstable AIS patients, as well as in other patient groups.

Correlation between Decreased Parasympathetic Activity and Reduced Cerebrovascular Reactivity in Patients with Lacunar Infarct.

Reduced cerebrovascular reactivity (CVR) was found in patients with recent lacunar infarct. However, its mechanisms were controversial. The breath holding maneuver as a vasodilatory stimulus is clinically useful for an estimation of cerebrovasomotor reactivity in well co-operative patients. Patients with lacunar infarct have no higher cortical dysfunction and remain well co-operation. The breath holding maneuver is feasible and safe to perform in patients with lacunar infarct. Autonomic nervous system regulates systemic vascular activity. Regulation of autonomic function to cerebrovascular reactivity has been reported in the literature. We examined the correlation between autonomic functions with frequency and nonlinear heart rate variability (HRV) and cerebrovascular reactivity in patients with lacunar infarct by application of breath holding maneuver. Fifteen patients with lacunar infarct (8 women, age 65.6 ± 13.61) and 16 healthy controls (11 women, age 27.33 ± 3.85) were continuously monitored at baseline before maneuver (basal phase), during CVR induction (experimental phase) with breath holding maneuver and after maneuver (recovery phase), for arterial blood pressure (ABP), electrocardiography (EKG), mean cerebral blood flow velocity (mCBFV) of middle cerebral arteries (MCA) by transcranial doppler (TCD). The short term-one minute HRV was analyzed from EKG signals for low frequency (LF)/ high frequency (HF) ratio, nonlinear of standard deviation 1 (SD1), standard deviation 2 (SD2), cardiac Sample Entropy (SampEn) and Shannon Entropy. Significant increasing in mCBFV, LF/HF ratio, SD2/SD1, Shannon Entropy and inversely decreasing SampEn during breath holding maneuver compared with baseline were found in both groups (p<0.05). The trend of cerebrovascular reactivity is similar in both groups. However, there were differences of mCBFV, systolic blood pressure (SysBP) in the whole phases (basal, experiment and recovery) between patients and controls (p<0.05). Less scattered signals of SD1 with low value in patient group were illustrated from Poincaré (p<0.05). This indicated less degree of parasympathetic drive in the patients compared to the controls. Moreover, significant positive correlation between systolic bloods pressure and mCBFV in patients suggests impact of autonomic control and cerebral blood flow on the patho-physiological mechanism of vasodilatation, triggered by hypercapnia from breath holding maneuver in patients with lacunar infarct. Reduction of cerebrovascular reactivity in patients with lacunar infarct may relate with decreased parasympathetic activity. Further study is required to demonstrate whether these findings mean mechanisms of lacunar infarct or the effect of hypertensive response.

Risk factors for carotid stenosis in Thai patients with ischemic stroke/TIA.

We looked for risk factors for significant carotid stenosis (CS) in patients with ischemic stroke. We included all patients treated for an ischemic stroke/transient ischemic attack (TIA) and had a carotid duplex done from August 2006 to November 2008. A total of 458 patients were included. Significant CS of the extracranial internal carotid artery and the common carotid artery were found in 10.9% (50 of 458 patients). Age (≥65 years old) was the independent risk factor for CS (OR 4.0, P < .0001). The patients with a CS had more history of coronary artery disease (12% vs 8%, P = .32), prior ischemic stroke (18% vs 11%, P = .17), atrial fibrillation (10% vs 5%, P = .19), and smoking (28% vs 24%, P = .18) compared with the patients without CS. The evaluation of the carotid arteries should be recommended in patients with ischemic stroke/TIA, especially in the older ones (≥65 years old).