Whole-brain Cerebral Blood Flow Research Articles

Spatiotemporal cerebral blood flow dynamics underlies emergence of the limbic-sensorimotor-association cortical gradient in human infancy

Infant cerebral blood flow (CBF) delivers nutrients and oxygen to fulfill brain energy consumption requirements for the fastest period of postnatal brain development across the lifespan. However, organizing principle of whole-brain CBF dynamics during infancy remains obscure. Leveraging a unique cohort of 100+ infants with high-resolution arterial spin labeled MRI, we find the emergence of the cortical hierarchy revealed by the highest-resolution infant CBF maps available to date. Infant CBF across cortical regions increases in a biphasic pattern featured by initial rapid and subsequently slower rate, and break-point ages increasing along the limbic-sensorimotor-association cortical gradient. Increases in CBF in sensorimotor cortices are associated with enhanced language and motor skills, and frontoparietal association cortices with cognitive skills. The study discovers emergence of the hierarchical limbic-sensorimotor-association cortical gradient in infancy and offers standardized reference of infant brain CBF and insight into the physiological basis of cortical specialization and real-world infant developmental functioning.

Spatiotemporal cerebral blood flow dynamics underlies emergence of the limbic-sensorimotor-association cortical gradient in human infancy.

Infant cerebral blood flow (CBF) delivers nutrients and oxygen to fulfill brain energy consumption requirements for the fastest period of postnatal brain development across the lifespan. However, organizing principle of whole-brain CBF dynamics during infancy remains obscure. Leveraging a unique cohort of 100+ infants with high-resolution arterial spin labeled MRI, we found the emergence of the cortical hierarchy revealed by the highest-resolution infant CBF maps available to date. Infant CBF across cortical regions increased in a biphasic pattern with initial rapid and sequentially slower rate, with break-point ages increasing along the limbic-sensorimotor-association cortical gradient. Increases in CBF in sensorimotor cortices were associated with enhanced language and motor skills, and frontoparietal association cortices for cognitive skills. The study discovered emergence of the hierarchical limbic-sensorimotor-association cortical gradient in infancy, and offers standardized reference of infant brain CBF and insight into the physiological basis of cortical specialization and real-world infant developmental functioning.

Arterial Spin Labeling Magnetic Resonance Imaging for Acute Disorders of Consciousness in the Intensive Care Unit

BackgroundTo investigate patients with disorders of consciousness (DoC) for residual awareness, guidelines recommend quantifying glucose brain metabolism using positron emission tomography. However, this is not feasible in the intensive care unit (ICU). Cerebral blood flow (CBF) assessed by arterial spin labeling magnetic resonance imaging (ASL-MRI) could serve as a proxy for brain metabolism and reflect consciousness levels in acute DoC. We hypothesized that ASL-MRI would show compromised CBF in coma and unresponsive wakefulness states (UWS) but relatively preserved CBF in minimally conscious states (MCS) or better.MethodsWe consecutively enrolled ICU patients with acute DoC and categorized them as being clinically unresponsive (i.e., coma or UWS [≤ UWS]) or low responsive (i.e., MCS or better [≥ MCS]). ASL-MRI was then acquired on 1.5 T or 3 T. Healthy controls were investigated with both 1.5 T and 3 T ASL-MRI.ResultsWe obtained 84 ASL-MRI scans from 59 participants, comprising 36 scans from 35 patients (11 women [31.4%]; median age 56 years, range 18–82 years; 24 ≤ UWS patients, 12 ≥ MCS patients; 32 nontraumatic brain injuries) and 48 scans from 24 healthy controls (12 women [50%]; median age 50 years, range 21–77 years). In linear mixed-effects models of whole-brain cortical CBF, patients had 16.2 mL/100 g/min lower CBF than healthy controls (p = 0.0041). However, ASL-MRI was unable to discriminate between ≤ UWS and ≥ MCS patients (whole-brain cortical CBF: p = 0.33; best hemisphere cortical CBF: p = 0.41). Numerical differences of regional CBF in the thalamus, amygdala, and brainstem in the two patient groups were statistically nonsignificant.ConclusionsCBF measurement in ICU patients using ASL-MRI is feasible but cannot distinguish between the lower and the upper ends of the acute DoC spectrum. We suggest that pilot testing of diagnostic interventions at the extremes of this spectrum is a time-efficient approach in the continued quest to develop DoC neuroimaging markers in the ICU.

A 3D pseudo-continuous arterial spin labeling study of altered cerebral blood flow correlation networks in mild cognitive impairment and Alzheimer's disease.

To investigate the abnormalities of the three-dimensional pseudo-continuous arterial spin labeling (3D PCASL) based cerebral blood flow (CBF) correlation networks in mild cognitive impairment (MCI) and Alzheimer's disease (AD). 3D PCASL images of 53 cognitive normal (CN) subjects, 43 subjects with MCI, and 30 subjects with AD were acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Whole-brain CBF maps were calculated using PCASL and proton density-weighted images (PDWI). The 246 regional CBF values, including the cortex and subcortex, were obtained after registering the Brainnetome Atlas to the individual CBF maps. The Pearson correlation coefficient between every two regions across subjects was calculated to construct the CBF correlation network. Then the topologies of CBF networks with regard to global properties (global network efficiency, clustering coefficient, characteristic path length, and small-world properties), hub regions, nodal properties (betweenness centrality, BC), and connections were compared among CN, MCI, and AD. Significant changes in the global and nodal properties were observed in the permutation tests, and connections with significant differences survived after the z-statistic and false discovery rate (FDR) correction. The CBF correlation networks of CN, MCI, and AD all showed small-world properties. Compared with CN, global efficiency decreased significantly in AD. Significant differences in nodal properties and a loss of hub regions are noted in the middle temporal lobe in both MCI and AD. In the frontal lobe, BC is reduced in MCI while it is increased in the occipital lobe in AD. The identified altered hub regions with significant differences in MCI and AD were mainly distributed in the hippocampus and entorhinal cortex. In addition, disrupted hub regions in AD with significantly decreased connections were mainly found in the precuneus/posterior cingulate cortex (PCC) and hippocampus-cortical cortex. Noninvasive 3D PCASL-based CBF correlation networks are capable of showing changes in topological organization in subjects with MCI and AD, and the observed disruption in the topological organization may underlie cognitive decline in MCI and AD.

Diurnal variation of cerebral blood flow in healthy humans under normal entrained conditions.

The presence of a circadian cycle of cerebral blood flow may have implications for the occurrence of daily variations in cerebrovascular events in humans, but how cerebral blood flow varies throughout the day and its mechanism are still unclear. The study aimed to explore the diurnal variation of cerebral blood flow in healthy humans and its possible mechanisms. Arterial spin labelling images were collected at six time-points (09:00 hours, 13:00 hours, 17:00 hours, 21:00 hours, 01:00 hours, 05:00 hours) from 18 healthy participants (22-39 years old; eight females) to analyse diurnal variations in cerebral blood flow. Resting heart rate and blood pressure at six time-points and blood indicators (20-hydroxyeicosatetraenoic acid, epoxyeicosatrienoic acids, prostaglandin E2, noradrenaline and nitric oxide) related to cerebral vascular tone at two time-points (09:00 hours and 21:00 hours) were collected to analyse possible influences on diurnal variations in cerebral blood flow. From 21:00 hours to 05:00 hours, parietal cortical relative cerebral blood flow tended to increase, while frontal cortical and cerebellar relative cerebral blood flow tended to decrease. There was a time-dependent negative correlation between parietal cortical relative cerebral blood flow and resting heart rate, whereas there was a time-dependent positive correlation between cerebellar relative cerebral blood flow and resting heart rate. The change of parietal cortical relative cerebral blood flow was positively correlated with the change of nitric oxide. There was also a time-dependent positive correlation between mean arterial pressure and mean whole-brain cerebral blood flow. The findings indicated that parietal cortical relative cerebral blood flow and frontal cortical/cerebellar relative cerebral blood flow showed roughly opposite trends throughout the day. The diurnal variations in relative cerebral blood flow were regional-specific. Diurnal variation of nitric oxide and neurogenic regulation may be potential mechanisms for diurnal variation in regional relative cerebral blood flow.

Assessing cerebrovascular reactivity (CVR) in rhesus macaques (Macaca mulatta) using a hypercapnic challenge and pseudo-continuous arterial spin labeling (pCASL)

Cerebrovascular reactivity (CVR) is a measure of cerebral small vessels’ ability to respond to changes in metabolic demand and can be quantified using magnetic resonance imaging (MRI) coupled with a vasoactive stimulus. Reduced CVR occurs with neurodegeneration and is associated with cognitive decline. While commonly measured in humans, few studies have evaluated CVR in animal models. Herein, we describe methods to induce hypercapnia in rhesus macaques (Macaca mulatta) under gas anesthesia to measure cerebral blood flow (CBF) and CVR using pseudo-continuous arterial spin labeling (pCASL). Fifteen (13 M, 2 F) adult rhesus macaques underwent pCASL imaging that included a baseline segment (100% O2) followed by a hypercapnic challenge (isoflurane anesthesia with 5% CO2, 95% O2 mixed gas). Relative hypercapnia was defined as an end-tidal CO2 (ETCO2) ≥5 mmHg above baseline ETCO2. The mean ETCO2 during the baseline segment of the pCASL sequence was 34 mmHg (range: 23–48 mmHg). During this segment, mean whole-brain CBF was 51.48 ml/100g/min (range: 21.47–77.23 ml/100g/min). Significant increases (p<0.0001) in ETCO2 were seen upon inspiration of the mixed gas (5% CO2, 95% O2). The mean increase in ETCO2 was 8.5 mmHg and corresponded with a mean increase in CBF of 37.1% (p<0.0001). The mean CVR measured was 4.3%/mmHg. No anesthetic complications occurred as a result of the CO2 challenge. Our methods were effective at inducing a state of relative hypercapnia that corresponds with a detectable increase in whole brain CBF using pCASL MRI. Using these methods, a CO2 challenge can be performed in conjunction with pCASL imaging to evaluate CBF and CVR in rhesus macaques. The measured CVR in rhesus macaques is comparable to human CVR highlighting the translational utility of rhesus macaques in neuroscience research. These methods present a feasible means to measure CVR in comparative models of neurodegeneration and cerebrovascular dysfunction.

Blood-brain barrier breakdown in COVID-19 ICU survivors: an MRI pilot study.

Coronavirus disease 2019 (COVID-19) results in severe inflammation at the acute stage. Chronic neuroinflammation and abnormal immunological response have been suggested to be the contributors to neuro-long-COVID, but direct evidence has been scarce. This study aims to determine the integrity of the blood-brain barrier (BBB) in COVID-19 intensive care unit (ICU) survivors using a novel MRI technique. COVID-19 ICU survivors (n=7) and age and sex-matched control participants (n=17) were recruited from June 2021 to March 2023. None of the control participants were hospitalized due to COVID-19 infection. The COVID-19 ICU survivors were studied at 98.6 ± 14.9 days after their discharge from ICU. A non-invasive MRI technique was used to assess the BBB permeability to water molecules, in terms of permeability surface area-product (PS) in the units of mL/100 g/min. PS was significantly higher in COVID-19 ICU survivors (p=0.038) when compared to the controls, with values of 153.1 ± 20.9 mL/100 g/min and 132.5 ± 20.7 mL/100 g/min, respectively. In contrast, there were no significant differences in whole-brain cerebral blood flow (p=0.649) or brain volume (p=0.471) between the groups. There is preliminary evidence of a chronic BBB breakdown in COVID-19 survivors who had a severe acute infection, suggesting a plausible contributor to neurological long-COVID symptoms.

The effects of nicotine use during adolescence and young adulthood on gray matter cerebral blood flow estimates.

Nicotine and tobacco product (NTP) use remains prevalent in adolescence/young adulthood. The effects of NTPs on markers of brain health during this vulnerable neurodevelopmental period remain largely unknown. This report investigates associations between NTP use and gray matter cerebral blood flow (CBF) in adolescents/young adults. Adolescent/young adult (16-22 years-old) nicotine users (NTP; N = 99; 40 women) and non-users (non-NTP; N = 95; 56 women) underwent neuroimaging sessions including anatomical and optimized pseudo-continuous arterial spin labeling scans. Groups were compared on whole-brain gray matter CBF estimates and their relation to age and sex at birth. Follow-up analyses assessed correlations between identified CBF clusters and NTP recency and dependence measures. Controlling for age and sex, the NTP vs. non-NTP contrast revealed a single cluster that survived thresholding which included portions of bilateral precuneus (voxel-wise alpha < 0.001, cluster-wise alpha < 0.05; ≥7 contiguous voxels). An interaction between NTP group contrast and age was observed in two clusters including regions of the left posterior cingulate (PCC)/lingual gyrus and right anterior cingulate cortex (ACC): non-NTP exhibited positive correlations between CBF and age in these clusters, whereas NTP exhibited negative correlations between CBF and age. Lower CBF from these three clusters correlated with urine cotinine (rs=-0.21 - - 0.16; ps < 0.04) and nicotine dependence severity (rs=-0.16 - - 0.13; ps < 0.07). This is the first investigation of gray matter CBF in adolescent/young adult users of NTPs. The results are consistent with literature on adults showing age- and nicotine-related declines in CBF and identify the precuneus/PCC and ACC as potential key regions subserving the development of nicotine dependence.

OR31-03 Testosterone Gender-affirming Hormonal Therapy Is Associated With Decreased Cerebral Blood Flow In Transgender Teens

Abstract Disclosure: S. Cote: None. K. Fathy: None. S. Lenet: None. O. Espinosa-Bentancourt: None. E. Lavallee: None. E. Croteau: None. D. Rottembourg: None. J. Lepage: None. K. Whittingstall: None. There is increasing demand for gender-affirming hormonal therapy (GAHT) in recent years, with increased access to GAHT for transgender teenagers. While it is well documented that psychological outcomes and quality of life improve after GAHT, it remains unclear how cerebrovascular physiology changes with GAHT. Therefore, this study aimed to investigate the effects of testosterone GAHT on cerebral microvascular and macrovascular physiology in teenage transgender men receiving GAHT. Six teenage transgender men were referred by their endocrinologist prior to the start of GAHT. Participants visited the research center before GAHT (session 1) and between 3 to 9 months into their GHAT (session 2). At each visit, participants completed a non-contrast-enhanced magnetic resonance imaging (MRI) protocol. This protocol assessed the macrovasculature using time-of-flight magnetic resonance angiography to visualize cerebral arteries and estimate diameters of the Circle of Willis and 2D-Phase Contrast to estimate large artery blood velocity. The microvasculature was assessed using pseudo-Continuous Arterial Spin Labelling, which estimates cerebral blood flow (CBF). Paired-sample t-tests were performed between sessions to determine if arterial diameters, CBF and blood velocity change with GAHT. Whole-brain CBF significantly decreased with GAHT between session 1 and session 2 (CBFS1=69.15 +/- 5.85 ml/100g/min; CBFS2=59.30 +/- 8.11 ml/100g/min; t=3.19, p=0.02, df=5). The average percent change in CBF was -9.85%, and the largest decrease experienced by a participant was -20.44%. Note that even though CBF decreased, average whole-brain CBF for all participants remained in a healthy range. We observed no significant change in large artery blood velocity or arterial lumen diameters of the Circle of Willis after starting GAHT. Our results suggest that GAHT influences the brain’s microvasculature. As women tend to have higher CBF than men, the reduction in CBF likely reflects a masculinization of the brain with GAHT. Without EEG to probe neuronal activity, it is difficult to determine if the change is due to decreased neuronal activity or a structural and/or functional change in the microvasculature. Considering that little is known about the long-term effects of GAHT on the brain, these results highlight the need to better understand how hormonal states impact human cerebrovascular physiology and how it may relate to risk for cerebrovascular disease and neurological disorders. Presentation: Sunday, June 18, 2023

Association of Cerebral Hemodynamics and Anemia on Processing Speed in Adults with Sickle Cell Disease.

Compared to healthy controls, adult patients with Sickle Cell Disease (SCD) are anemic, and therefore have higher cardiac output and Cerebral Blood Flow (CBF) to maintain brain oxygenation. They also demonstrate comparatively more cognitive deficits due to either overt strokes or silent cerebral ischemia. However, there are few correlative studies between CBF and cognitive deficits, specifically processing speed in SCD. Such studies are important to develop biomarkers of central brain processing and ischemia for diagnosis, prognosis, and evaluating the effectiveness of potential interventions. This pilot cross-sectional study tested the hypotheses that adults with SCD and elevated CBF demonstrate lower central brain processing speed than controls on average and that CBF is inversely correlated with processing speed. We conducted a pilot cross-sectional study to assess the relation-ships between CBF, central brain processing speed, and hemoglobin levels in asymptomatic adults with SCD and controls from an urban academic medical center. MRI acquisitions at 3T consisted of 2D phase-contrast quantitative arteriograms (Qflow) of the bilateral internal carotid and vertebral arteries and 3D pseudo-continuous arterial spin labeling (pCASL) of the brain. Participants were patients with SCD (hemoglobin [Hb]SS, [Hb] SBetaThal°, or [Hb]SC) aged 22-52 years of African American descent (N=7) or community controls (Hb AA) (n=3). Processing speed was assessed as an in-direct functional marker of ischemia using a recommended test from the NIH Toolbox for Assessment of Neurological and Behavioral Function, the Pattern Comparison Processing Speed Test. t-tests were used to compare means of CBF, hemoglobin, and cognition between SCD patients and healthy controls. Among SCD patients only multivariate correla-tions were used to evaluate relationships between brain perfusion in specific brain regions vs. processing speed and CBF. The significance level was set at p≤0.05. Adults with SCD reported higher CBF compared to healthy con-trols (72.15±28.90 vs. 47.23±12.30 ml/min/100g, p=0.04), and lower hemoglobin concentration (8.64±2.33 vs. 13.33±0.58, p=0.001). Heart rate in SCD patients was higher than in controls (86.29±1.37 vs. 74.00±2.10, p=0.04). Patients with SCD demonstrated lower processing speed (96.14±21.04 vs.123±13.74, p=0.02) than controls. Among adult patients with SCD, perfusion in specific regions of the brain showed an inverse relationship with processing speed, as did whole-brain CBF (p=0.0325). These findings, although from a small sample, lend a degree of validity to the claim that processing speed is slower in people with SCD than in controls and that CBF is significantly higher in SCD patients com-pared to controls. The results also lend credence to the finding that the degree of processing speed deficiencies among adults with SCD is correlated with the degree of elevated CBF, which is known to correspond with the degree of anemia associated with SCD.

Altered resting-state neurovascular coupling in patients with pontine infarction

The risk for motor and cognitive impairment is increased in patients with chronic pontine infarction (PI). In this study, we attempted to explore the alterations of neurovascular coupling (NVC) in order to understand the neural basis of behavioral impairment after PI. Three-dimensional pseudo-continuous arterial spin labeling (3D-pcASL) and resting-state functional magnetic resonance imaging (rs-fMRI) were applied in 49 patients with unilateral PI (left-sided, n = 26; right-sided, n = 23) and 30 matched normal subjects to assess whole-brain cerebral blood flow (CBF) and functional connectivity strength (FCS). We evaluated NVC in each subject by calculating the correlation coefficient between the whole-brain CBF and FCS (CBF-FCS coupling) and the ratio between voxel-wise CBF and FCS (CBF/FCS ratio). The FCS maps were then divided into long-range and short-range FCS to identify the influence of connection distance. The results indicated that the CBF-FCS coupling in the whole-brain level was significantly interrupted in PI patients, and the CBF/FCS ratio in cognition-related brain regions was abnormal. Distance-dependent results demonstrated that PI had a more serious effect on long-range neurovascular coupling. Correlation analysis revealed that the changes in neurovascular coupling were correlated with working memory scores. These findings imply that disruption of neurovascular coupling in the remote-infarction brain regions may underlie the impaired cognitive functions in chronic PI.

Cerebral blood flow in patients recovered from mild COVID-19.

Cerebral hypoperfusion has been described in both severe and mild forms of symptomatic Coronavirus Disease 2019 (COVID-19) infection. The purpose of this study was to investigate global and regional cerebral blood flow (CBF) in asymptomatic COVID-19 patients. Cases with mild COVID-19 infection and age-, sex-, and race-matched healthy controls were drawn from the Aging Brain Consortium at The University of South Carolina data repository. Demographics, risk factors, and data from the Montreal Cognitive Assessment were collected. Mean CBF values for gray matter (GM), white matter (WM), and the whole brain were calculated by averaging CBF values of standard space-normalized CBF image values falling within GM and WM masks. Whole brain region of interest-based analyses were used to create standardized CBF maps and explore differences between groups. Twenty-eight cases with prior mild COVID-19 infection were compared with 28 controls. Whole-brain CBF (46.7±5.6 vs. 49.3±3.7, p=.05) and WM CBF (29.3±2.6 vs. 31.0±1.6, p = .03) were noted to be significantly lower in COVID-19 cases as compared to controls. Predictive models based on these data predicted COVID-19 group membership with a high degree of accuracy (85.2%, p<.001), suggesting CBF patterns are an imaging marker of mild COVID-19 infection. In this study, lower WM CBF, as well as widespread regional CBF changes identified using quantitative MRI, was found in mild COVID-19 patients. Further studies are needed to determine the reliability of this newly identified COVID-19 brain imaging marker and determine what drives these CBF changes.

Alteration of intracranial blood perfusion in temporal lobe epilepsy, an arterial spin labeling study

BackgroundA critical necessity before surgical resection in mesial temporal lobe epilepsy (mTLE) is lateralizing the seizure focus in the temporal lobe. This study aimed to investigate the differences in perfusion pattern changes in right and left mTLE. Methods42 mTLE patients (22 left and 20 right mTLE) and 14 controls were surveyed with pulsed arterial spin labeling at 3.0 T. The mean cerebral blood flow (CBF) and asymmetry index (AI) were calculated in the bilateral temporal lobe, amygdala, hippocampus, parahippocampus, and nine bilateral vascular territories ROIs. The alterations in whole-brain CBF were identified using statistical parametric mapping (SPM). ResultsCBF decreased in ipsilateral sides in both epilepsy subcohorts, with right mTLE showing a significant difference in most ROIs while left mTLE exhibiting no significant change. CBF comparison of left mTLE and controls showed a significant drop in ROI analysis in left middle temporal and left intermediate posterior cerebral artery and in AI analysis in parahippocampus, distal anterior cerebral artery, distal middle cerebral artery, and intermediate anterior cerebral artery. CBF hypoperfusion was seen in ROI analysis in the left intermediate anterior cerebral artery, left middle temporal, right middle temporal, left superior temporal in the right mTLE compared to controls. Left mTLE CBF differed significantly from right mTLE CBF in right distal middle cerebral artery ROI and AI of proximal middle cerebral artery. ConclusionOur result revealed that mTLE affects extratemporal regions and both mTLE subcohorts with different perfusion patterns, which may enhance the performance of preoperative MRI assessment in lateralization procedures.

Abstract 109: Regional Cerebral Hypoperfusion In Patients Recovered From Mild COVID-19

Background: Cerebral hypoperfusion have been described in both severe and mild forms of symptomatic coronavirus disease 2019 (COVID-19) infection. The purpose of this study was to investigate global and regional gray matter (GM) and white matter (WM) cerebral blood flow (CBF) in asymptomatic COVID-19 infection patients compared with age-gender-race matched controls. Methods: Cases with mild COVID-19 infection and age-gender-race matched healthy controls, were drawn from the ABC@UofSC data repository. Demographics, risk factors and data from the Montreal Cognitive Assessment (MOCA score) were collected within a week of magnetic resonance imaging (MRI) perfusion image acquisition using pseudo-continuous arterial spin labeling. Mean CBF values for GM, WM and whole brain were calculated by averaging CBF values of standard space normalized CBF image values falling within GM and WM masks. Whole-brain, region of interest (ROI) based analyses were used to create standardized cerebral blood flow maps and further explore differences between the two groups. Results: Twenty-eight cases with prior mild COVID-19 infection were compared with 28 age-, gender-, race-matched controls. The MOCA score was similar between cases and controls. Whole-brain CBF (46.7±5.6 vs. 49.3±3.7, p=0.05), GM-specific CBF (64.2±8.9 vs. 67.6±6.0, p=0.10), and WM-specific CBF (29.3±2.6 vs. 31.0±1.6, p=0.03) were noted to be lower in COVID-19 cases as compared to controls. Further analysis identified several brain regions with lower CBF than the CONTROL group colors representing Z-scores shown in the figure. Predictive models based on these data predicted COVID-19 group membership with a high degree of accuracy (85.2%) suggesting CBF patterns as a key imaging marker of mild infection. Conclusion: In this study, lower white matter CBF, as well as widespread regional CBF changes identified using quantitative MRI, were found in patients recovered from mild to moderate COVID-19 infection.

Cerebral blood flow changes induced by high-frequency repetitive transcranial magnetic stimulation combined with cognitive training in Alzheimer's disease.

Hypoperfusion of the posterior cingulate cortex (PCC) and precuneus has consistently been reported in patients with Alzheimer's disease (AD). Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (COG) is effective in alleviating the symptoms of patients with mild AD. This study investigated the effects of rTMS-COG therapy on cerebral blood flow (CBF), with a special interest in the PCC/precuneus, and whether observed CBF changes are associated with changes in neuropsychological assessments in AD. Twenty-one patients with mild or moderate AD were randomly divided into real rTMS (n = 11) and sham treatment (n = 10) groups, both combined with COG. Neuro-navigated 10 Hz rTMS was used to stimulate the left dorsolateral prefrontal cortex (DLPFC) and then the left lateral temporal lobe (LTL) for 20 min each day for 4 weeks in the real rTMS group. All patients with AD underwent neuropsychological assessment, pseudo-continuous arterial spin labeling, and structural 3D T1-weighted MRI before treatment (T0), immediately after treatment (T1), and 4 weeks after treatment (T2). CBF in the precuneus, PCC, and stimulation targets at the region-of-interest (ROI) level, as well as whole-brain CBF changes at the voxel level, were compared between the two groups at three timepoints. rTMS-COG therapy revealed significant group × time interactions for the Mini-Mental State Examination (F = 5.339, p = 0.023, η2 = 0.433) and activities of daily living (F = 5.409, p = 0.039, η2 = 0.436) scores. The regional CBF in the precuneus showed a significant group × time interaction (F = 5.833, p = 0.027, η2 = 0.593). For voxel-level analysis, a significant group main effect was found in the left limbic lobe cluster, with the maximal peak in the left parahippocampus (p < 0.001, uncorrected, peak at [-16 -8 -24]). Simple effects analysis indicated that rTMS-COG therapy induced a decrease in CBF in the precuneus at T1 (p = 0.007) and an increase in the left parahippocampus at T2 (p=0.008). CBF decrease in the precuneus was correlated with better cognitive function immediately after treatment (T1) (r =-0.732, p=0.025). Neuropsychological assessments showed immediate and long-term effects on cognitive function and activities of daily living after rTMS-COG therapy. CBF changes induced by high-frequency rTMS-COG therapy are region-dependent, showing immediate effects in the precuneus and long-term effects in the left parahippocampus. These results provide imaging evidence to understand the underlying neurobiological mechanism for the application of rTMS-COG in AD.

Effects of Physical Exercise Training on Cerebral Blood Flow Measurements: A Systematic Review of Human Intervention Studies.

The aim of this systematic review was to examine the effects of physical exercise training on cerebral blood flow (CBF), which is a physiological marker of cerebrovascular function. Relationships between training-induced effects on CBF with changes in cognitive performance were also discussed. A systematic search was performed up to July 2022. Forty-five intervention studies with experimental, quasi-experimental, or pre-post designs were included. Sixteen studies (median duration: 14weeks) investigated effects of physical exercise training on CBF markers using magnetic resonance imaging, 20 studies (median duration: 14weeks) used transcranial Doppler ultrasound, and eight studies (median duration: 8weeks) used near-infrared spectroscopy. Studies using magnetic resonance imaging observed consistent increases in CBF in the anterior cingulate cortex and hippocampus, but not in whole-brain CBF. Effects on resting CBF-measured with transcranial Doppler ultrasound and near-infrared spectroscopy-were variable, while middle cerebral artery blood flow velocity increased in some studies following exercise or hypercapnic stimuli. Interestingly, concomitant changes in physical fitness and regional CBF were observed, while a relation between training-induced effects on CBF and cognitive performance was evident. In conclusion, exercise training improved cerebrovascular function because regional CBF was changed. Studies are however still needed to establish whether exercise-induced improvements in CBF are sustained over longer periods of time and underlie the observed beneficial effects on cognitive performance.

ASL MRI informs blood flow to chronic stroke lesions in patients with aphasia.

Introduction: Response to post-stroke aphasia language rehabilitation is difficult to anticipate, mainly because few predictors can help identify optimal, individualized treatment options. Imaging techniques, such as Voxel-based Lesion Symptom Mapping have been useful in linking specific brain areas to language behavior; however, further development is required to optimize the use of structural and physiological information in guiding individualized treatment for persons with aphasia (PWA). In this study, we will determine if cerebral blood flow (CBF) mapped in patients with chronic strokes can be further used to understand stroke-related factors and behavior. Methods: We collected perfusion MRI data using pseudo-Continuous Arterial Spin Labeling (pCASL) using a single post-labeling delay of 2,200ms in 14 chronic PWA, along with high-resolution structural MRI to compute maps of tissue damage using Tissue Integrity Gradation via T2w T1w Ratio (TIGR). To quantify the CBF in chronic stroke lesions, we tested at what point spatial smoothing should be applied in the ASL analysis pipeline. We then related CBF to tissue damage, time since stroke, age, sex, and their respective cross-terms to further understand the variability in lesion CBF. Finally, we assessed the feasibility of computing multivariate brain-behavior maps using CBF and compared them to brain-behavior maps extracted with TIGR MRI. Results: We found that the CBF in chronic stroke lesions is significantly reduced compared to its homologue grey and white matter regions. However, a reliable CBF signal (although smaller than expected) was detected to reveal a negative relationship between CBF and increasing tissue damage. Further, the relationship between the lesion CBF and age, sex, time since stroke, and tissue damage and cross-terms suggested an aging-by-disease interaction. This relationship was strongest when smoothing was applied in the template space. Finally, we show that whole-brain CBF relates to domain-general visuospatial functioning in PWA. The CBF-based brain-behavior maps provide unique and complementary information to structural (lesion-based) brain-behavior maps. Discussion: Therefore, CBF can be detected in chronic stroke lesions using a standard pCASL MRI acquisition and is informative at the whole-brain level in identifying stroke rehabilitation targets in PWAs due to its relationship with demographic factors, stroke-related factors, and behavior.

Altered cerebral blood flow in patients with spinocerebellar degeneration.

ObjectivesSpinocerebellar degeneration (SCD) comprises a multitude of disorders with sporadic and hereditary forms, including spinocerebellar ataxia (SCA). Except for progressive cerebellar ataxia and structural atrophy, hemodynamic changes have also been observed in SCD. This study aimed to explore the whole-brain patterns of altered cerebral blood flow (CBF) and its correlations with disease severity and psychological abnormalities in SCD via arterial spin labeling (ASL).MethodsThirty SCD patients and 30 age- and sex-matched healthy controls (HC) were prospectively recruited and underwent ASL examination on a 3.0T MR scanner. The Scale for Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS) scores were used to evaluate the disease severity in SCD patients. Additionally, the status of anxiety, depression and sleep among all patients were, respectively, evaluated by the Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS) and Self-Rating Scale of Sleep (SRSS). We compared the whole-brain CBF value between SCD group and HC group at the voxel level. Then, the correlation analyses between CBF and disease severity, and psychological abnormalities were performed on SCD group.ResultsCompared with HC, SCD patients demonstrated decreased CBF value in two clusters (FWE corrected P < 0.05), covering bilateral dentate and fastigial nuclei, bilateral cerebellar lobules I-IV, V and IX, left lobule VI, right lobule VIIIb, lobules IX and X of the vermis in the cerebellar Cluster 1 and the dorsal part of raphe nucleus in the midbrain Cluster 2. The CBF of cerebellar Cluster 1 was negatively correlated with SARA scores (Spearman’s rho = –0.374, P = 0.042) and SDS standard scores (Spearman’s rho = –0.388, P = 0.034), respectively. And, the CBF of midbrain Cluster 2 also had negative correlations with SARA scores (Spearman’s rho = –0.370, P = 0.044) and ICARS scores (Pearson r = –0.464, P = 0.010).ConclusionThe SCD-related whole-brain CBF changes mainly involved in the cerebellum and the midbrain of brainstem, which are partially overlapped with the related function cerebellar areas of hand, foot and tongue movement. Decreased CBF was related to disease severity and depression status in SCD. Therefore, CBF may be a promising neuroimaging biomarker to reflect the severity of SCD and suggest mental changes.

The longitudinal evolution of cerebral blood flow in children with tuberous sclerosis assessed by arterial spin labeling magnetic resonance imaging may be related to cognitive performance.

To study longitudinal changes in tuber and whole-brain perfusion in children with tuberous sclerosis complex (TSC) using arterial spin labeling (ASL) perfusion MRI and correlate them with pathological EEG slow wave activity and neurodevelopmental outcomes. Retrospective longitudinal cohort study of 13 children with TSC, 3 to 6 serial ASL-MRI scans between 2 months and 7 years of age (53 scans in total), and an EEG examination performed within 2 months of the last MRI. Tuber cerebral blood flow (CBF) values were calculated in tuber segmentation masks, and tuber:cortical CBF ratios were used to study tuber perfusion. Logistic regression analysis was performed to identify which initial tuber characteristics (CBF value, volume, location) in the first MRI predicted tubers subsequently associated with EEG slow waves. Whole-brain and lobar CBF values were extracted for all patient scans and age-matched controls. CBF ratios were compared in patients and controls to study longitudinal changes in whole-brain CBF. Perfusion was reduced in tubers associated with EEG slow waves compared with other tubers. Low tuber CBF values around 6 months of age and large tuber volumes were predictive of tubers subsequently associated with EEG slow waves. Patients with severe developmental delay had more severe whole-brain hypoperfusion than those with no/mild delay, which became apparent after 2 years of age and were not associated with a higher tuber load. Dynamic changes in tuber and brain perfusion occur over time. Perfusion is significantly reduced in tubers associated with EEG slow waves. Whole-brain perfusion is significantly reduced in patients with severe delay. • Tubers associated with EEG slow wave activity were significantly more hypoperfused than other tubers, especially after 1 year of age. • Larger and more hypoperfused tubers at 6 months of age were more likely to subsequently be associated with pathological EEG slow wave activity. • Patients with severe developmental delay had more extensive and severe global hypoperfusion than those without developmental delay.

Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease

AbstractChildren with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (−19.4 mL/100 g/min) and OEF (−8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, −0.9 mL/100 g/min; P = .024; OEF, −3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.