Tag: cerebral blood flow

Assessment of dynamic cerebral blood flow changes during cognitive tasks in patients with post-COVID-19 syndrome

Abstract:

The objective of this study was to quantify the variability of cortical blood flow during cognitive load as an indicator of disease-related changes in cerebral capillary blood flow intermittency in patients with post-COVID-19 syndrome. The regulation of cerebral blood flow in the dorsolateral prefrontal cortex under cognitive load was examined using high-resolution functional near-infrared spectroscopy in 36 subjects including 12 patients with post-COVID-19 syndrome and two control groups [12 coronary artery disease patients matched for age and 12 young healthy individuals (CTRL)].

To induce cognitive load, a Flanker task and an N-back task were employed. The structure of temporal variability of local blood flow regulation was assessed using sample entropy at 17 channels spanning both brain hemispheres. The spatial variability of the regional blood flow pattern was evaluated using the coefficient of variation (CV) from sample entropies across all channels.

Results revealed a notable discrepancy in that patients with post-COVID-19 syndrome exhibited reduced temporal variability (lower sample entropy) but elevated spatial variability (higher CV) in comparison to coronary artery disease patients during cognitive load (P = 0.02). In the N-back task, the spatial variability increased from healthy individuals to coronary artery disease patients to patients with post-COVID-19 syndrome and was associated with longer reaction time and with lower accuracy.

The results confirmed that dynamic cerebral blood flow is altered in patients with post-COVID-19 syndrome, which may be related to fatigue during cognitive tasks. Sample entropy and CV values represent different aspects of blood flow regulation fluctuation. Their simultaneous analysis enabled a meaningful distinction between groups suggesting disease-related changes in brain haemodynamic. The presented method is therefore suitable for describing current states of cortical blood flow regulation and for documenting intervention results in patients with post-COVID-19 syndrome or patients with similar symptoms (e.g. myalgic encephalomyelitis/chronic fatigue syndrome).

Source: Kutz DF, Garbsch R, Mooren FC, Schmitz B, Voelcker-Rehage C. Assessment of dynamic cerebral blood flow changes during cognitive tasks in patients with post-COVID-19 syndrome. Brain Commun. 2026 Feb 10;8(1):fcag036. doi: 10.1093/braincomms/fcag036. PMID: 41728261; PMCID: PMC12917544. https://pmc.ncbi.nlm.nih.gov/articles/PMC12917544/ (Full text)

Shared autonomic phenotype of long COVID and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Introduction: Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are relatively common and disabling multisystem disorders that share overlapping features, including post-infectious onset and similar clinical manifestations such as brain fog, fatigue, muscle pain, and dysautonomia with orthostatic intolerance. These similarities suggest that Long COVID and ME/CFS may share common pathophysiological mechanisms, though the underlying mechanisms remain poorly understood, partly due to the difficulty in quantifying many of the symptoms.

Materials and methods: This retrospective study evaluated Long COVID and pre-COVID ME/CFS patients who completed autonomic testing between 2018 and 2023 at the Brigham and Women’s Faulkner Hospital Autonomic Laboratory. The evaluations included autonomic tests (Valsalva maneuver, deep breathing, tilt-table test, and sudomotor function) with capnography and transcranial Doppler monitoring of cerebral blood flow velocity (CBFv) in the middle cerebral artery, neuropathic assessment through skin biopsies for small fiber neuropathy (SFN), invasive cardiopulmonary exercise testing (ICPET), and laboratory analyses covering metabolic, inflammatory, autoimmune, and hormonal profiles.

Results: A total of 143 Long COVID and 170 ME/CFS patients were analyzed and compared to 73 healthy controls and 290 patients with hypermobile Ehlers-Danlos syndrome (hEDS). Tests revealed extensive similarities between Long COVID and ME/CFS, including reduced orthostatic CBFv (92%/88% in Long COVID/ME/CFS), mild-to-moderate widespread autonomic failure (95%/89%), presence of SFN (67%/53%), postural tachycardia syndrome (POTS) (22%/19%), neurogenic orthostatic hypotension (15%/15%) and preload failure (96%/92%, assessed in 25/66 Long COVID/ME/CFS). Patients with hEDS exhibited more severe peripheral neurodegeneration compared to the other groups. Laboratory tests did not distinguish between the conditions.

Conclusion: Both Long COVID and ME/CFS demonstrate dysregulation in cerebrovascular blood flow, autonomic reflexes, and small fiber neuropathy, suggesting that these conditions may share a common underlying pathophysiology. However, differing distributions of findings in patients with hEDS raise the question of whether these conditions represent distinct but overlapping syndromes or reflect a shared underlying pathway. Further research is required to clarify the relationship between these conditions and the potential underlying pathophysiological mechanisms.

Source: Novak P, Systrom DM, Witte A, Marciano SP, Felsenstein D, Milunsky JM, Milunsky A, Krier J, Fishman MC. Shared autonomic phenotype of long COVID and myalgic encephalomyelitis/chronic fatigue syndrome. PLoS One. 2026 Jan 23;21(1):e0341278. doi: 10.1371/journal.pone.0341278. PMID: 41576003. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0341278 (Full text)

Virus-induced endothelial senescence as a cause and driving factor for ME/CFS and long COVID: mediated by a dysfunctional immune system

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are two post-viral diseases, which share many common symptoms and pathophysiological alterations. Yet a mechanistic explanation of disease induction and maintenance is lacking. This hinders the discovery and implementation of biomarkers and treatment options, and ultimately the establishment of effective clinical resolution. Here, we propose that acute viral infection results in (in)direct endothelial dysfunction and senescence, which at the blood-brain barrier, cerebral arteries, gastrointestinal tract, and skeletal muscle can explain symptoms.

The endothelial senescence-associated secretory phenotype (SASP) is proinflammatory, pro-oxidative, procoagulant, primed for vasoconstriction, and characterized by impaired regulation of tissue repair, but also leads to dysregulated inflammatory processes. Immune abnormalities in ME/CFS and long COVID can account for the persistence of endothelial senescence long past the acute infection by preventing their clearance, thereby providing a mechanism for the chronic nature of ME/CFS and long COVID.

The systemic and tissue-specific effects of endothelial senescence can thus explain the multisystem involvement in and subtypes of ME/CFS and long COVID, including dysregulated blood flow and perfusion deficits. This can occur in all tissues, but especially the brain as evidenced by findings of reduced cerebral blood flow and impaired perfusion of various brain regions, post-exertional malaise (PEM), gastrointestinal disturbances, and fatigue.

Paramount to this theory is the affected endothelium, and the bidirectional sustainment of immune abnormalities and endothelial senescence. The recognition of endothelial cell dysfunction and senescence as a core element in the aetiology of both ME/CFS and Long COVID should aid in the establishment of effective biomarkers and treatment regimens.

Source: Nunes M, Kell L, Slaghekke A, Wüst RC, Fielding BC, Kell DB, Pretorius E. Virus-induced endothelial senescence as a cause and driving factor for ME/CFS and long COVID: mediated by a dysfunctional immune system. Cell Death Dis. 2026 Jan 9;17(1):16. doi: 10.1038/s41419-025-08162-2. PMID: 41513611; PMCID: PMC12789617. https://pmc.ncbi.nlm.nih.gov/articles/PMC12789617/ (Full text)

Autonomic phenotyping, brain blood flow control, and cognitive-motor-integration in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome: A pilot study

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the prolonged sequelae after COVID-19 (>3 months; Long COVID) have similar symptomology, are both associated with autonomic dysfunction, and a growing proportion of Long COVID patients are developing ME/CFS. We aimed to determine an autonomic phenotype of patients with ME/CFS vs Long COVID. We hypothesized that the groups would differ from controls yet be similar to one another.

We recruited sedentary controls (n = 10), mild/moderate ME/CFS patients (n = 12), and Long COVID patients (n = 9) to undergo 1) breathing 5 % CO2, 2) breathing 10 % O2, and 3) 5-minutes of 70° head-up tilt. Respiratory, hemodynamic, and cerebrovascular variables were measured throughout the 3 trials. Resting vascular function and cognitive-motor-integration were also assessed. ME/CFS and Long COVID were similar to the healthy controls and each other with regard to resting vascular function and the hemodynamic responses to hypoxia, hypercapnia, and head-up tilt (p > 0.05). However, in ME/CFS we observed a greater reduction of cerebrovascular resistance (p = 0.041) and impaired autoregulation (p = 0.042) during hypercapnia alongside impaired cognitive-motor integration (p < 0.02), and in Long COVID we observed reduced peripheral and end-tidal oxygen (p < 0.04) and less vagal withdrawal during tilt (p = 0.028).

Our findings suggest unique phenotypes when comparing ME/CFS and Long COVID whereby we have shown that Long COVID patients experience hypoxia while upright contributing to less vagal withdrawal, and ME/CFS patients experience impaired cerebrovascular control during potentially leading to reduced cognitive-motor integration. These differences could stem from disease severity/duration or some unique aspect of the COVID-19 virus.

Source: Badhwar S, Pereira TJ, Kerr K, Bray R, Tabassum F, Sergio L, Edgell H. Autonomic phenotyping, brain blood flow control, and cognitive-motor-integration in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome: A pilot study. Auton Neurosci. 2025 Oct 14;262:103358. doi: 10.1016/j.autneu.2025.103358. Epub ahead of print. PMID: 41138391. https://www.autonomicneuroscience.com/article/S1566-0702(25)00120-1/fulltext (Full text)

Mapping cerebral blood flow in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance: insights from a systematic review

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating condition with a large proportion of patients that experience orthostatic intolerance (OI). This systematic review aimed to assess whether cerebral blood flow (CBF) is reduced in ME/CFS and OI, and whether the presence of both conditions leads to an additional decline in CBF.

Methods: PubMed (from 1943), MEDLINE (from 1946), EMBASE (from 1947) and Cochrane were searched from inception to February 14th, 2025, using terms including “chronic fatigue syndrome”, “myalgic encephalomyelitis”, “orthostatic intolerance” and “cerebral blood flow”. Article selection required the following criteria: published in English; CBF measured in participants with either ME/CFS or OI, or both ME/CFS and OI combined. Quality assessment and risk of bias was assessed using the Newcastle-Ottawa Scale and the systematic review was conducted in accordance with the PRISMA 2020 guidelines.

Results: Of 14,928 articles, 118 were included, 26 (22.1%) of which studied CBF in ME/CFS alone, 81 (68.6%) in OI alone and 11 (9.3%) in both ME/CFS and OI. Overall, the articles included 9185 participants, with a mean age of 39.1 years (SD = 8.8), and 73.8% of participants were female. Studies found CBF was significantly reduced in 12 of the articles focused on ME/CFS and in 56 of those focused on OI; compared to controls. Additionally, in 4 out of 11 studies that examined both conditions, CBF was further reduced in participants suffering from both conditions compared to those with ME/CFS alone.

Conclusions: CBF is reduced in ME/CFS and OI alone and having both conditions comorbidly amplifies CBF reductions. Therefore, observing CBF changes in ME/CFS with and without OI may be important in monitoring disease severity. Despite this, few studies focus on the combination of ME/CFS and OI, and OI may be a confounding factor in CBF in a large portion of ME/CFS studies.

Source: Christopoulos EM, Tantanis D, Huang K, Schneider-Futschik EK, Gooley PR, Moneghetti KJ, Armstrong CW. Mapping cerebral blood flow in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance: insights from a systematic review. J Transl Med. 2025 Aug 26;23(1):963. doi: 10.1186/s12967-025-06954-w. PMID: 40859389. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06954-w (Full text)

The Relation Between Cardiac Output and Cerebral Blood Flow in ME/CFS Patients with a POTS Response During a Tilt Test

Abstract:

Background/Objectives: Orthostatic intolerance is prevalent in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and is caused by an abnormal reduction in cerebral blood flow (CBF). In healthy controls (HCs), CBF is regulated complexly, and cardiac output (CO) is an important determinant of CBF. A review in HC showed that a 30% reduction in CO results in a 10% reduction in CBF. In contrast, we showed in ME/CFS patients with a normal HR (HR) and blood pressure response during a tilt test that CO and CBF decreased to a similar extent. The relation between CO and CBF in ME/CFS patients with postural orthostatic tachycardia syndrome (POTS) is unknown.

Therefore, the aim of this study is to assess the relation between CBF and CO, in ME/CFS patients with POTS. The methods used in this retrospective study analyze this relation in a large group of patients. We also analyzed the influence of clinical data. A total of 260 ME/CFS patients with POTS underwent tilt testing with measurements of HR, BP, CBF, CO, and end-tidal PCO2. We measured CBF using extracranial Doppler flow velocity and vessel diameters obtained with a General Electric echo system, and suprasternal aortic flow velocities were measured using the same device. We recorded end-tidal PCO2 using a Nonin Lifesense device.

Results: End-tilt HR and the HR increase were significantly higher in the patients with a %CO reduction ≥ -15% than in the other group. End-tilt CO was higher and the %CO reduction was lower in patients with %CO reduction ≥ -15% than in the other group. CBF data (supine, end-tilt and the %CBF reduction) were not different between the two patient groups. The use of HR increases and %SV reductions were not as discriminative as the %CO reduction.

Conclusions: In ME/CFS patients with POTS during tilt testing with measurements of both the CO and the CBF, two different patterns were observed: (1) appr. two-thirds of patients had an almost 1:1 relation between the %CBF reduction and the %CO reduction. (2) Appr. one-third of patients showed a limited reduction in CO together with a substantial increase in HR. In these patients, there was no relation between the CO and CBF reduction. These data suggest the presence of a hyperadrenergic response.

Source: van Campen CLMC, Visser FC. The Relation Between Cardiac Output and Cerebral Blood Flow in ME/CFS Patients with a POTS Response During a Tilt Test. J Clin Med. 2025 May 22;14(11):3648. doi: 10.3390/jcm14113648. PMID: 40507411. https://www.mdpi.com/2077-0383/14/11/3648 (Full text)

Cerebral Blood Flow in Orthostatic Intolerance

Abstract:

Cerebral blood flow (CBF) is vital for delivering oxygen and nutrients to the brain. Many forms of orthostatic intolerance (OI) involve impaired regulation of CBF in the upright posture, which results in disabling symptoms that decrease quality of life. Because CBF is not easy to measure, rises in heart rate or drops in blood pressure are used as proxies for abnormal CBF. These result in diagnoses such as postural orthostatic tachycardia syndrome and orthostatic hypotension. However, in many other OI syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and long COVID, heart rate and blood pressure are frequently normal despite significant drops in CBF. This often leads to the incorrect conclusion that there is nothing hemodynamically abnormal in these patients and thus no explanation or treatment is needed. There is a need to measure CBF, as orthostatic hypoperfusion is the shared pathophysiology for all forms of OI. In this review, we examine the literature studying CBF dysfunction in various syndromes with OI and evaluate methods of measuring CBF including transcranial Doppler ultrasound, extracranial cerebral blood flow ultrasound, near infrared spectroscopy, and wearable devices.

Source: Khan MS, Miller AJ, Ejaz A, Molinger J, Goyal P, MacLeod DB, Swavely A, Wilson E, Pergola M, Tandri H, Mills CF, Raj SR, Fudim M. Cerebral Blood Flow in Orthostatic Intolerance. J Am Heart Assoc. 2025 Feb 3:e036752. doi: 10.1161/JAHA.124.036752. Epub ahead of print. PMID: 39895557. https://www.ahajournals.org/doi/10.1161/JAHA.124.036752 (Full text)

Tetrahydrobiopterin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Friend or Foe?

Abstract:

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a chronic multisystem disease characterized by severe muscle fatigue, pain, dizziness, and brain fog. The two most common symptoms are post-exertional malaise (PEM) and orthostatic intolerance (OI). ME/CFS patients with OI (ME+OI) suffer from dizziness or faintness due to a sudden drop in blood pressure while maintaining an upright posture. Clinical research has demonstrated that patients with OI display severe cardiovascular abnormalities resulting in reduced effective blood flow in the cerebral blood vessels. However, despite intense investigation, it is not known why the effective cerebral blood flow is reduced in OI patients. Based on our recent findings, we observed that tetrahydrobiopterin (BH4) metabolism was highly dysregulated in ME+OI patients. In the current review article, we attempted to summarize our recent findings on BH4 metabolism to shed light on the molecular mechanisms of OI.

Source: Rahman AFMT, Benko A, Bulbule S, Gottschalk CG, Arnold LA, Roy A. Tetrahydrobiopterin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Friend or Foe? Biomolecules. 2025 Jan 10;15(1):102. doi: 10.3390/biom15010102. PMID: 39858496; PMCID: PMC11763651. https://pmc.ncbi.nlm.nih.gov/articles/PMC11763651/ (Full text)

The Cardiac Output-Cerebral Blood Flow Relationship Is Abnormal in Most Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients with a Normal Heart Rate and Blood Pressure Response During a Tilt Test

Abstract:

Introduction: Orthostatic intolerance is highly prevalent in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and is caused by an abnormal reduction in cerebral blood flow (CBF). In healthy controls (HCs), the regulation of CBF is complex and cardiac output (CO) is an important determinant of CBF: a review showed that a 30% reduction in CO results in a 10% reduction in CBF. In previous and separate ME/CFS studies, we showed that CO and CBF decreased to a similar extent during tilt testing.

The aim of the study: to test the relationship between CBF and CO, which seems to be abnormal in ME/CFS patients and is different from that in HCs.

Methods: In this retrospective study we analyzed this relationship in a large group of patients. To compare the patient data with those of HCs, we focused on patients with a normal heart rate (HR) and blood pressure (BP) response to upright tilt. Also, the influence of clinical data was analyzed. A total of 534 ME/CFS patients and 49 HCs underwent tilt testing with measurements of HR, BP, CBF, CO, and end-tidal PCO2. To measure CBF, extracranial Doppler flow velocity and vessel diameters were obtained using a GE echo system. The same device was used to measure suprasternal aortic flow velocities. End-tidal PCO2 was recorded using a Nonin Lifesense device.

Results: In 46 (9%) patients, CO and CBF changes were in the normal range for HCs, and in 488 (91%) an abnormal CO and CBF reduction was found. In patients with abnormal CO and CBF reductions, the slope of the regression line of CO versus CBF reduction was almost 1. The multiple regression analysis of the latter group showed that the CO reduction for the most part predicted the CBF reduction, with a limited role for the PETCO2 reduction.

Conclusions: Two different patient groups with a normal HR and BP response during the tilt were identified: those with a CO and CBF in the normal range for HCs and those with an abnormal CO and CBF reduction during the tilt (91% of patients). In the latter group of patients, an almost 1:1 relationship between the CO and CBF reduction suggests the absence of compensatory vasodilation in the cerebral vasculature. This might indicate endothelial dysfunction in most ME/CFS patients and may have clinical and therapeutic implications.

Source: van Campen CLMC, Verheugt FWA, Rowe PC, Visser FC. The Cardiac Output-Cerebral Blood Flow Relationship Is Abnormal in Most Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients with a Normal Heart Rate and Blood Pressure Response During a Tilt Test. Healthcare (Basel). 2024 Dec 20;12(24):2566. doi: 10.3390/healthcare12242566. PMID: 39765993. https://www.mdpi.com/2227-9032/12/24/2566 (Full text)

Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI

Abstract:

Neurological symptoms are central to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), yet its underlying neurophysiological mechanisms remain elusive. We examined a neglected aspect of task-based functional MRI, focusing on how blood oxygenation level-dependent (BOLD) signals alter during cognitive tasks in ME/CFS.

This prospective observational study utilised MRI scans on ME/CFS participants and healthy controls (HCs) with sedentary lifestyles (ACTRN12622001095752). Participants completed two blocks of a Symbol Digit Modalities Test, with 30 trials per block split into two sets. The fMRI signal changes between blocks and sets were compared within and between groups. Thirty-four ME/CFS participants (38 years ± 10; 27 women) and 34 HCs (38 ± 10; 27 women), were evaluated.

In the second task block, ME/CFS participants exhibited increased activation in the right postcentral gyrus, contrasting with decreased activation in multiple regions in HCs. These results were further confirmed by significantly higher bilateral dynamic changes (2nd vs 1st set) in the motor, sensory and cognitive cortex in ME/CFS compared to HCs and significant correlations between those changes in the left primary motor cortex with fatigue severities. BOLD adaptation, potentially improving energy economy, was absent in ME/CFS, which may provide an underlying neurophysiological process in ME/CFS.

Source: Schönberg L, Mohamed AZ, Yu Q, Kwiatek RA, Del Fante P, Calhoun VD, Shan ZY. Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI. J Cereb Blood Flow Metab. 2024 Aug 7:271678X241270528. doi: 10.1177/0271678X241270528. Epub ahead of print. PMID: 39113421. https://journals.sagepub.com/doi/10.1177/0271678X241270528 (Full text)