Cerebral blood flow alterations in non-auditory tinnitus: implications for cerebral venous congestion pathophysiology

Abstract

Background

Cerebral venous congestion (CVC), including internal jugular vein stenosis (IJVS) and cerebral venous sinus stenosis (CVSS), can impair venous drainage, leading to secondary reductions in cerebral blood flow (CBF) and neurological symptoms such as non-auditory tinnitus (NAT). While arterial spin labeling (ASL) primarily measures arterial perfusion, it also provides insights into global perfusion changes in venous pathologies. This study investigates CBF alterations in CVC patients, particularly those with NAT.

Methods

A cross-sectional study was conducted with 87 participants, including 34 NAT+ patients, 17 NAT- patients, and 36 healthy controls (HC). Multi-delay pseudo-continuous ASL was used to quantify whole-brain and regional CBF based on the anatomical automatic labeling atlas version 3 (AAL3v1), adjusted for arterial transit time. Group differences in CBF were assessed, and correlations with clinical variables were analyzed, including tinnitus duration, sleep quality, anxiety, depression, and cognitive function.

Results

Patients in the NAT+ group exhibited significant CBF reductions in the left hemisphere, cerebrum, and specific regions, including the insula, paracentral lobule, and precentral gyrus, compared to those in the NAT- and HC groups. Reduced CBF in NAT+ patients was correlated with longer tinnitus duration, poorer sleep quality, and worse depression scores. Further analysis revealed that the affected regions were part of the attention, sensorimotor, default mode, and cerebellar networks.

Conclusion

This study identified a distinct pattern of cerebral perfusion alterations in patients with CVC, particularly those with NAT. The findings highlight characteristic regional reductions in CBF associated with impaired venous outflow, offering new insights into the venous pathophysiological mechanisms underlying NAT. Moreover, reduced CBF was found to be associated with clinical symptoms such as sleep disturbances and emotional dysregulation. These findings support a link between venous pathology and altered cerebral perfusion patterns with symptom correlations, warranting confirmation in larger and longitudinal cohorts.

Supplementary Information

The online version contains supplementary material available at 10.1007/s11682-026-01144-8.

Introduction

Cerebral venous congestion (CVC), including internal jugular vein stenosis (IJVS) and cerebral venous sinus stenosis (CVSS), is characterized by impaired venous outflow due to external compression, intraluminal narrowing, or structural abnormalities (Anand et al., 2022; Association, 2023; Han et al., 2015, 2019). In healthy individuals, cerebral blood flow (CBF) autoregulation relies on the dynamic balance between arterial inflow and venous outflow (Association, 2023; Miller et al., 2024). However, venous outflow obstruction can disrupt this equilibrium, leading to hemodynamic disturbances, increased intracranial pressure, blood-brain barrier dysfunction, and cerebrospinal fluid dysregulation. These alterations may ultimately result in regional cerebral perfusion deficits and neurovascular dysfunction, contributing to a spectrum of neurological symptoms (Baidina et al., 2015; Beggs et al., 2014; Itrat et al., 2006; Muller et al., 2016; Rashad et al., 2018; Zivadinov & Chung, 2013).

Recent studies, including those from Xuanwu Hospital, have shown that non-auditory tinnitus (NAT) is a common symptom of CVC, affecting > 60% of IJVS and ~ 50% of CVSS patients (Bai et al. 2019a, b, 2020; Zhou et al., 2018b). This high prevalence suggests that NAT may serve as a distinguishing feature of non-thrombotic venous outflow disorders. Distinct from auditory tinnitus, NAT manifests as intracranial noise (e.g., “cicada-like”) unrelated to cochlear pathology (Bai et al. 2021; Tang et al. 2019; Zhou et al. 2018a). In CVC patients, NAT often co-occurs with symptoms such as sleep disturbances, headaches, vision problems, cognitive decline, and autonomic dysfunction (Vega-Moreno et al., 2021; Zhou et al., 2019). Whether NAT is associated with more severe clinical symptoms remains uncertain, and the exact mechanisms underlying NAT have yet to be elucidated.

Previous research has confirmed that patients with pulsatile tinnitus (PT) and transverse sinus stenosis exhibit significantly reduced CBF in gray matter, white matter, and across the entire brain (Li et al. 2021a, b). In one reported case, stent implantation to relieve transverse sinus stenosis in a patient with pulsatile tinnitus led to normalized cerebral perfusion, as confirmed by post-surgical single-photon emission computed tomography (SPECT) imaging (Ding et al., 2020). Additionally, some patients with CVC experience immediate and even complete resolution of NAT following surgical intervention, with sustained improvement during follow-up (Bai et al., 2020; Wang et al., 2021; Yang et al., 2019; Zhou et al., 2019). These findings suggest that venous outflow impairment may contribute to NAT through its impact on cerebral perfusion, yet the specific neurovascular mechanisms remain unclear. Moreover, patients with sigmoid sinus diverticulum and PT have been reported to exhibit increased CBF in the left inferior parietal lobule, which positively correlates with tinnitus handicap inventory (THI) scores (Li et al., 2021b). In animal studies using the internal jugular vein ligation model to mimic CVC-induced tinnitus, abnormally elevated metabolic activity has been observed in several brain regions, including the prefrontal cortex, amygdala, hippocampus, and cerebellum (Wei et al., 2024), supporting the hypothesis that non-auditory regions involved in emotion, cognition, and sensory integration may be particularly vulnerable to venous-induced neurovascular dysfunction. Together, these clinical and preclinical findings indicate that venous outflow obstruction may not only alter global cerebral perfusion but also exert regionally selective effects on brain areas with high metabolic demand and functional specialization. Regions such as the prefrontal cortex and cerebellum—implicated in emotion, attention, and sensory integration—appear especially vulnerable to perfusion disturbances in the setting of venous congestion. This regional vulnerability may be attributed to both anatomical features of venous drainage pathways and the intrinsic perfusion sensitivity of functional networks such as the default mode and limbic systems. Notably, this pattern of selective neurovascular susceptibility aligns with the central perceptual nature of NAT, which is believed to arise from multisensory integration circuits rather than dysfunction of the auditory pathway alone. Identifying these region-specific perfusion alterations may therefore help elucidate the neurovascular mechanisms underlying CVC-related NAT and its associated symptoms.

Arterial spin labeling (ASL), a non-invasive MRI technique, enables quantitative assessment of CBF across the brain, providing insight into metabolic and neuronal activity that is tightly coupled with perfusion dynamics (Li et al., 2020). Multi-delay ASL further refines perfusion measurements by estimating arterial transit time (ATT) through multiple post-labeling delays, correcting for inter-individual and regional variations in blood arrival times. This ATT-corrected CBF measurement minimizes bias related to prolonged arterial arrival times and enhances the accuracy of perfusion quantification. Therefore, we applied ASL to comprehensively capture localized perfusion alterations associated with venous pathology.

To investigate the impact of CVC on cerebral perfusion, this study employed a background-suppressed 3D GRASE multi-delay pseudo-continuous ASL (pCASL) sequence with five post-labeling delay points. We systematically compared the spatial patterns of CBF changes and their clinical relevance among distinct CVC subgroups. Specifically, we examined whole-brain and regional CBF differences among patients with CVC and non-auditory tinnitus (NAT+), those with CVC but without NAT (NAT−), and healthy controls (HC). The primary objective is to determine whether venous outflow impairment alters perfusion patterns in both auditory and non-auditory brain regions and to explore the associations between perfusion abnormalities and clinical symptoms.

Methods

Study design and participants

This cross-sectional study was conducted at Xuanwu Hospital, Capital Medical University, from May 2023 to January 2024, and written informed consent was obtained from all participants. The study protocol was approved by the Ethics Committee of Xuanwu Hospital, Capital Medical University (ID: [2022]029). The research adhered to the principles outlined in the Declaration of Helsinki.

We included patients with CVC who met the following criteria: [1] Age between 18 and 65 years, right-handed; [2] Radiologically confirmed IJVS or transverse sinus stenosis (TVSS), diagnosed based on contrast-enhanced MR venography (CE-MRV), CT venography (CTV), or digital subtraction angiography (DSA). All images were independently reviewed by two experienced neuroradiologists blinded to clinical grouping. IJVS was defined as a ≥ 50% reduction in diameter at the narrowest point of the internal jugular vein, compared to the adjacent upstream segment on the same imaging plane (axial or sagittal). In addition to the degree of narrowing, we required the presence of prominent venous collaterals, such as paraspinal or vertebral plexuses, to confirm the hemodynamic significance of the lesion. Morphologically, the stenotic segment typically exhibited a focal, hourglass-like appearance (Bai et al. 2019a; Jayaraman et al. 2012; Wang et al. 2022). TVSS was diagnosed when one of the following criteria was met: (a) bilateral transverse sinus filling defects, or (b) unilateral transverse sinus hypoplasia with a contralateral focal stenosis showing ≥ 50% luminal narrowing, compared with an adjacent normal segment within the same slice (Association 2023; Bai et al. 2019a). In addition to quantitative narrowing, we also considered qualitative features of stenosis, such as segmental sinus wall collapse, absence of a definable sinus lumen on one or more contiguous slices, and proximal post-stenotic dilatation (Morris et al., 2017). Representative imaging examples of TVSS and IJVS based on CE-MRV and CTV are shown in Fig. 1; [3] Normal bilateral hearing, confirmed by audiometric tests showing an average threshold < 25 dB HL at 0.5 kHz, 1 kHz, 2 kHz, 4 kHz, and 8 kHz (Lv et al., 2015); [4] Voluntary provision of written informed consent.

Fig. 1.

Representative CE-MRV and CTV images showing transverse sinus stenosis (TVSS) and internal jugular vein stenosis (IJVS) in patients with cerebral venous congestion. A CE-MRV shows a right-sided transverse sinus filling defect (red arrow), with compensatory development of the occipital sinus draining into the sigmoid sinus. Notably, post-stenotic dilatation is observed at the proximal segment of the right transverse sinus. B CTV demonstrates interruption of contrast opacification at the transverse–sigmoid sinus junction on the non-dominant side, and marked narrowing at the corresponding junction on the right dominant side (red arrows). C CE-MRV reveals bilateral internal jugular vein stenosis at the J3 segment (red arrows), with typical "hourglass-like" focal narrowing. D CE-MRV displays bilateral IJVS with prominent collateral venous pathways (red arrow), including tortuous paraspinal and vertebral venous plexuses, reflecting compensatory outflow

Patients with CVC were further divided into the NAT+ group and the non-NAT (NAT-) group based on the presence of NAT. The NAT+ group included patients who had experienced continuous or intermittent, non-pulsatile tinnitus for ≥ 6 months, with no evidence of peripheral auditory pathology or hearing loss. Non-auditory tinnitus was defined based on: (a) patient-reported perception of centrally located or diffuse ringing/buzzing not synchronized with heartbeat; (b) normal audiological and otoscopic examination; and (c) exclusion of cochlear or middle ear pathology. The NAT- group consisted of patients with confirmed CVC but without any history of tinnitus or auditory symptoms.

The HC group was composed of age-, sex-, and education-matched right-handed individuals with no imaging or clinical evidence of CVC and no significant hearing loss on audiometric testing.

Participants were excluded if they had any of the following: [1] significant neurological disorders, including intracranial tumors, brain infections, demyelinating or neurodegenerative diseases, ischemic stroke, cerebral venous thrombosis; [2] history of traumatic brain injury or any head trauma affecting venous structures; [3] significant otologic conditions, such as ear trauma, Ménière’s disease, or acoustic neuroma; [4] severe systemic illnesses, including major organ dysfunction (e.g., liver cirrhosis, renal failure, or significant thyroid dysfunction); [5] cardiovascular diseases, including uncontrolled hypertension (defined as SBP ≥ 160 mmHg or DBP ≥ 100 mmHg), atrial fibrillation, history of myocardial infarction, congestive heart failure (NYHA class III–IV), or significant carotid artery stenosis (≥ 50%); [6] metabolic disorders, including uncontrolled diabetes mellitus (HbA1c ≥ 7.5%), hyperlipidemia (LDL ≥ 4.14 mmol/L or triglycerides ≥ 6.2 mmol/L), or morbid obesity (BMI ≥ 40 kg/m²); [7] psychiatric disorders or behavioral disturbances impacting study participation; [8] recent history (within 3 months) of substance abuse or use of medications affecting neuropsychological assessments; [9] contraindications for MRI or allergy to contrast agents; [10] any other condition deemed by the investigators to potentially interfere with study results.

Clinical data collection

For eligible participants, data collection included: general demographics (sex, age, education years), primary sites of CVC identified through clinical diagnosis and imaging, and NAT severity assessed using a visual analog scale (VAS) and an adapted tinnitus handicap inventory (THI). Audiometric results were recorded. Common symptoms were evaluated using the Headache Impact Test-6 (HIT-6), Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), and Pittsburgh Sleep Quality Index (PSQI). Cognitive assessments were conducted with the Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), and the Auditory Verbal Learning Test (AVLT), covering immediate recall, delayed recall, and recognition.

Imaging data acquisition

All imaging data were acquired using a Siemens 3.0T MRI scanner (Prisma) within 24 h of clinical assessments.

The imaging protocol included structural magnetic resonance imaging (MRI) and ASL. Structural images were obtained using a magnetization-prepared rapid acquisition gradient echo (MPRAGE) sequence. The imaging parameters were as follows. Repetition time (TR) = 2530 ms, echo time (TE) = 2.98 ms, inversion time (TI) = 1100 ms, flip angle (FA) = 7°, matrix = 512 × 448, field of view (FOV) = 256 × 256 mm, slice thickness = 1.0 mm, inter-slice gap = 0.5 mm, number of slices = 192, and total scan time = 5 min 58 s. Perfusion images were acquired using a background-suppressed 3D GRASE multi-delay pCASL sequence with post-labeling delays of 500, 1000, 1500, 2000, and 2500 ms. The imaging parameters included: TR = 4100 ms, TE = 31.68 ms, FA = 120°, matrix = 64 × 64, FOV = 224 × 224 mm, slice thickness = 3.5 mm, inter-slice gap = 1.75 mm, number of slices = 40, and total scan time = 7 min 11 s.

During preparation, participants’ heads were stabilized with foam pads inside the coil to minimize motion, and earplugs were provided to reduce noise. Participants were instructed to remain still, relaxed, and awake throughout the scan to minimize movement artifacts.

Quantitative assessment of cerebral blood flow

The pCASL data were processed using CereFlow software (Anying Technology Co., Ltd., Beijing, China). The following steps were performed: First, pairwise subtraction between label and control images was performed, followed by averaging for each post-labeling delay (PLD) to compute ∆M(i). Using ∆M(i) and weighting factors w(i) = 0.5/1.0/1.5/2.0/2.5 s, the weighted delay (WD) was calculated using the following formula:

1

The relationship between WD and arterial transit time (ATT) was then applied to convert WD to ATT (Dai et al., 2012). Corrected cerebral blood flow (cCBF) was then calculated based on the ATT. The M0 images and perfusion maps were registered to the T1-weighted image space, which was further aligned to the Montreal Neurological Institute 152 (MNI152) standard brain template, with the anatomical automatic labeling atlas version 3 (AAL3v1) mapped to the T1 images (Rolls et al., 2020). Finally, the mean cCBF for each region defined by the AAL3v1 atlas was computed.

Statistical analysis

Statistical analyses were performed using SPSS version 27.0 and GraphPad Prism version 9.5. Categorical variables were analyzed using the chi-square test. For continuous variables, normality was tested first; if normal distribution and homogeneity of variance were confirmed, one-way analysis of variance (ANOVA) followed by post hoc testing was applied. Non-parametric tests were used when assumptions of normality or homogeneity were not met. Post hoc analyses were adjusted using the Bonferroni correction. For multiple comparisons of cCBF across the three groups, false discovery rate (FDR) correction was applied. Partial correlation analyses, controlling for age, sex, and years of education, were conducted to assess the relationship between cCBF differences in brain regions and clinical data. Statistical significance was defined as P < 0.05. We visualized the data using GraphPad Prism version 9.5 and MRIcroGL software.

Results

Demographic analysis

A total of 87 participants were included after applying exclusion criteria to investigate the cerebral perfusion changes associated with CVC, particularly focusing on their characteristic symptom—NAT. The cohort consisted of 34 NAT+ patients, 17 NAT- patients, and 36 HC volunteers (Fig. S1, Supplementary Information). Demographic and clinical data analysis revealed no statistically significant differences among the NAT+, NAT-, and HC groups in terms of age, sex, years of education, or average bilateral hearing thresholds (P > 0.05, Table 1). The average tinnitus duration in the NAT+ group was 4.89 years, with a mean THI score of 52.82, indicating moderate severity (grade 3). Clinical assessments showed significant differences in sleep quality, memory, and anxiety and depression scores among the groups (P < 0.05, Table 1–1). The NAT+ group had significantly higher PSQI scores (9.09 ± 3.18) compared to the HC (6.37 ± 5.58) and NAT- (6.06 ± 3.80) groups, indicating poorer sleep quality. Both NAT + and NAT- groups exhibited higher SAS, SDS, HAMA, and HAMD scores than the HC group, although none reached the threshold for moderate or severe anxiety or depression. Cognitive assessments showed lower scores in the NAT + and NAT- groups compared to HC, with the most significant declines observed in the NAT+ group, particularly in MoCA and immediate and delayed recall components of the AVLT.

Table 1.

Demographic and clinical characteristics

	NAT+ (n = 34)	NAT- (n = 17)	HC (n = 36)	P
Age (years)	45.15 ± 12.870	49.47 ± 9.715	50.31 ± 9.52	0.183
Sex (Male: Female)	15/19	3/14	11/25	0.151
Years of education	15.76 ± 2.450	15.41 ± 3.55	14.58 ± 3.57	0.417
IJVS/n	25/34	13/17	-	0.820
Average hearing level (left, dBHL)	14.76 ± 4.89	16.45 ± 6.06	16.98 ± 8.28	0.572
Average hearing level (right, dBHL)	15.51 ± 5.17	18.25 ± 7.77	16.25 ± 7.88	0.420
Tinnitus duration (years)	4.89 ± 5.32	-	-
Tinnitus VAS score	6.15 ± 2.36	-	-
THI score	52.82 ± 27.04	-	-
HIT-6 score	21.47 ± 28.11	29.35 ± 32.49	-	0.277
PSQI score	9.09 ± 3.18ab	6.06 ± 3.80c	6.37 ± 5.58c	0.004
MMSE score	29.10 ± 1.14	29.13 ± 1.13	29.40 ± 0.98	0.403
MoCA score	26.48 ± 2.59a	27.27 ± 1.58	27.97 ± 1.82c	0.022
AVLT-IR score	25.06 ± 7.13a	27.07 ± 5.65	30.77 ± 9.40c	0.028
AVLT-DR score	9.77 ± 3.01a	10.07 ± 2.34	11.43 ± 2.64c	0.039
AVLT-REC score	12.71 ± 2.41	12.60 ± 1.88	13.11 ± 1.89	0.553
SAS score	43.93 ± 9.39a	43.36 ± 13.53a	32.85 ± 9.43bc	0.001
SDS score	46.54 ± 11.77a	44.84 ± 15.89a	34.72 ± 11.50bc	0.005
HAMA score	5.15 ± 3.40a	5.00 ± 4.57a	1.65 ± 2.09bc	< 0.001
HAMD score	14.96 ± 8.34a	11.20 ± 10.13a	4.85 ± 5.82bc	< 0.001

Data are presented as mean ± standard deviation

HC Healthy control, NAT+ With non-auditory tinnitus, NAT- without non-auditory tinnitus, IJVS Internal jugular venous stenosis, VAS Visual analog scale, THI Tinnitus handicap inventory, HIT-6 Headache impact test-6, PSQI Pittsburgh sleep quality index, MMSE Mini-mental state examination, MoCA Montreal cognitive assessment, AVLT Auditory verbal learning test, IR immediate recall; DR: delayed recall; REC: long-term delayed recognition; SAS: self-rating anxiety scale; SDS: self-rating depression scale; HAMA: Hamilton anxiety scale; HAMD: Hamilton depression scale

^a indicates a significant difference compared to the HC group; ^b indicates a significant difference compared to the NAT- group; ^c indicates a significant difference compared to the NAT+ group

The level of significance was set at P < 0.05

Whole-brain CBF changes in cerebral venous congestion and subgroups

To assess cerebral perfusion characteristics in patients with CVC, cCBF adjusted by ATT was calculated and compared among the three groups. The analysis encompassed both hemispheres (including the cerebrum and cerebellum), as well as individual assessments of the cerebrum, cerebellum, and brain lobes. Significant differences in cCBF were identified in the left hemisphere, cerebrum, temporal lobe, parietal lobe, and bilateral frontal lobes (Fig. 2). Post hoc analysis further demonstrated that the NAT+ group exhibited notably lower cCBF in these regions compared to the HC group, with the most substantial reduction observed in the left hemisphere.

Fig. 2.

Whole-Brain CBF Distribution in Patients and Healthy Controls. A Differences in cCBF were observed in the left hemisphere, cerebrum, temporal lobe, frontal lobe, and parietal lobe; B Differences in cCBF were noted in the right frontal lobe. Note: cCBF, corrected cerebral blood flow; WB, Whole Brain; Cb, Cerebrum; Cbl, Cerebellum; TL, Temporal Lobe; FL, Frontal Lobe; PL, Parietal Lobe; OL, Occipital Lobe; HC, healthy control; NAT+, with non-auditory tinnitus; NAT-, without non-auditory tinnitus. *P < 0.05

Regional CBF changes in cerebral venous congestion and subgroups

To further investigate whether there were regional cCBF differences among the three groups, the whole brain was divided into 170 regions using the AAL3v1 atlas, and comparisons were made across groups. Multiple comparison corrections revealed significant differences in cCBF across numerous brain regions (FDR-corrected, P < 0.05, Table 2). These regions included areas within the sensorimotor network (left precentral gyrus [PreCG], postcentral gyrus [PoCG], right supplementary motor area [SMA], and bilateral paracentral lobules [PCL]); attention network (left opercular part of the inferior frontal gyrus [IFGoperc] and triangular part of the inferior frontal gyrus [IFGtriang]); default mode network (bilateral middle cingulate gyrus and parahippocampal cingulate gyrus [DCG], and right pregenual anterior cingulate cortex [ACCpre]); subcortical network (bilateral olfactory cortex [OLF]); auditory network (left insula [INS]); and visual network (left middle occipital gyrus [MOG]). Additionally, significant cCBF differences were observed in the left cerebellar hemisphere VIII [CRBL8], bilateral cerebellar hemispheres IX [CRBL9], and right locus coeruleus [LC] (FDR-corrected, P < 0.05, Table 2). No statistically significant cCBF differences were found in other brain regions (FDR-corrected, P > 0.05).

Table 2.

Intergroup Differences in cCBF Among Cerebral Venous Congestion Groups and Healthy Controls Unit: ml·100 g^− 1·min^− 1

Brain Region	NAT+ (mean ± SD)	NAT- (mean ± SD)	HC (mean ± SD)	FDR-corrected P-value
Left IFGoperc	46.31 ± 5.19	46.46 ± 9.26	54.24 ± 10.83	0.030
Left IFGtriang	43.36 ± 5.93	44.93 ± 8.86	52.01 ± 12.30	0.030
Right SMA	40.61 ± 6.54	42.30 ± 8.60	48.51 ± 10.30	0.032
Left OLF	43.61 ± 11.43	49.73 ± 43.61	52.82 ± 12.10	0.033
Right OLF	43.52 ± 10.40	50.98 ± 11.62	52.04 ± 12.31	0.045
Left DCG	55.57 ± 6.44	54.09 ± 10.40	63.81 ± 13.75	0.045
Right DCG	46.98 ± 6.95	45.81 ± 9.21	55.25 ± 11.17	0.030
Left INS	43.97 ± 4.50	45.30 ± 8.27	50.95 ± 9.92	0.017
Left PreCG	40.89 ± 6.69	41.03 ± 8.23	48.00 ± 10.69	0.032
Left PoCG	41.46 ± 6.82	42.38 ± 8.78	48.62 ± 11.21	0.033
Left MOG	45.99 ± 7.75	49.40 ± 8.67	55.13 ± 13.91	0.045
Left PCL	43.06 ± 6.60	45.03 ± 8.77	51.95 ± 14.25	0.048
Right PCL	40.82 ± 6.30	43.04 ± 8.75	48.32 ± 10.92	0.033
Left CRBL8	28.37 ± 7.43	35.63 ± 7.31	35.35 ± 10.84	0.017
Left CRBL9	36.99 ± 12.43	48.47 ± 11.93	49.48 ± 17.75	0.033
Right CRBL9	36.33 ± 12.08	45.79 ± 9.80	47.71 ± 15.14	0.045
Right ACCpre	40.79 ± 6.81	41.79 ± 7.76	48.54 ± 12.08	0.032
Right LC	34.03 ± 9.70	44.91 ± 13.39	43.42 ± 16.46	0.048

NAT+ With non-auditory tinnitus, NAT- Without non-auditory tinnitus, cCBF Corrected cerebral blood flow, FDR False discovery rate, PreCG Precentral gyrus, IFGoperc Opercular part of the inferior frontal gyrus, IFGtriang Triangular part of the inferior frontal gyrus, DCG Middle cingulate gyrus and parahippocampal cingulate gyrus, ACCpre Pregenual anterior cingulate cortex, LC Locus coeruleus, OLF Olfactory cortex, CRBL8 Cerebellar hemisphere VIII, CRBL9 Cerebellar hemisphere IX, INS Insula, MOG Middle occipital gyrus, PoCG Postcentral gyrus, PCL Paracentral lobule, SMA Supplementary motor area

Post hoc comparisons (Bonferroni-corrected) indicated that, compared to the HC group, the NAT+ group showed significantly lower cCBF in the left INS, bilateral PCL, left PoCG, left MOG, right SMA, and left OLF (P < 0.05, Fig. 3). Patients with CVC (both NAT + and NAT- groups) exhibited significant cCBF reductions in the left opercular and triangular parts of the left IFGoperc, IFGtriang, PreCG, bilateral DCG, and right ACCpre (P < 0.05, Fig. 4). Moreover, the NAT+ group showed lower cCBF in the right OLF, left CRBL8, bilateral CRBL9, and right LC compared to the HC and NAT- groups (P < 0.05, Fig. 5).

Fig. 3.

Brain Regions with Significant cCBF Differences Between the NAT+ and HC Groups. A Post hoc analysis showing the distribution of brain regions with significant cCBF differences between the NAT+ and HC groups. B Compared to the HC group, the NAT+ group showed significantly lower cCBF in the L-INS (P = 0.001), L-PCL (P = 0.004), R-PCL (P = 0.002), L-PoCG (P = 0.002), L-MOG (P = 0.003), R-SMA (P = 0.001), and L-OLF (P = 0.002), with results corrected using the Bonferroni method. Note: cCBF, corrected cerebral blood flow; HC, healthy control; NAT+, with non-auditory tinnitus; NAT-, without non-auditory tinnitus; INS, insula; MOG, middle occipital gyrus; PoCG, postcentral gyrus; PCL, paracentral lobule; SMA, supplementary motor area; OLF, olfactory cortex; L, left; R, right

Fig. 4.

Brain Regions with Significant cCBF Differences in NAT+ and NAT- Groups Compared to HC. A Post hoc analysis showing the distribution of brain regions with significant cCBF differences in patients with CVC (NAT+ or NAT- groups) compared to the HC group. B Compared to the HC group, patients with cerebral venous congestion (NAT+ or NAT- groups) showed significantly lower cCBF in the L-IFGtriang, L-IFGoperc, L-PreCG, bilateral DCG, and ACCpre (P < 0.05), with results corrected using the Bonferroni method. Note: cCBF, corrected cerebral blood flow; HC, healthy control; NAT+, with non-auditory tinnitus; NAT-, without non-auditory tinnitus; PreCG, precentral gyrus; IFGoperc, opercular part of the inferior frontal gyrus; IFGtriang, triangular part of the inferior frontal gyrus; DCG, middle cingulate gyrus and parahippocampal cingulate gyrus; ACCpre, pregenual anterior cingulate cortex; L, left; R, right

Fig. 5.

Brain Regions with Reduced cCBF in the NAT+ Group Compared to NAT- and HC. A Post hoc analysis showing the distribution of brain regions where the NAT+ group had lower cCBF compared to the NAT- and HC groups. B Compared to the HC and NAT- groups, the NAT+ group showed significantly lower cCBF in the ROLF,L-CRBL8, bilateral CRBL9, and R-LC (P < 0.05). Note: cCBF, corrected cerebral blood flow; HC, healthy control; NAT+, with non-auditory tinnitus; NAT-, without non-auditory tinnitus; LC, locus coeruleus; OLF, olfactory cortex; CRBL8, cerebellar hemisphere VIII; CRBL9, cerebellar hemisphere IX; L, left; R, right

Correlation analysis between CBF changes in cerebral venous congestion and clinical symptoms

Partial correlation analysis was conducted with age, sex, and years of education as covariates. In patients with CVC (combined NAT + and NAT- groups), cCBF values in brain regions showing significant differences compared to the HC group were analyzed for correlations with clinical data. A negative correlation was observed between cCBF in the right DCG and PSQI insomnia scores (r = − 0.343, P = 0.015; Fig. S2, Supplementary Information), indicating a small-to-moderate effect size.

In the NAT+ group, cCBF values of regions with differences compared to the other two groups were analyzed for correlations with clinical data. As shown in Fig. 6, cCBF in the right ACCpre was positively correlated with tinnitus duration (r = 0.429, P = 0.011, Fig. 6A), reflecting a moderate effect size. In contrast, cCBF in the left CRBL9 was negatively correlated with tinnitus duration (r = -0.385, P = 0.025, Fig. 6B), also indicating a moderate effect.

Fig. 6.

Correlations Between CBF and Clinical Variables in the NAT+ Group. A, B cCBF in the pregenual anterior cingulate cortex (ACCpre) and cerebellar hemisphere IX (CRBL9) was positively (r = 0.429, P = 0.011) and negatively (r = -0.385, P = 0.025) correlated with tinnitus duration, respectively (R-ACCpre and L-CRBL9). C, D cCBF in the paracentral lobule (PCL) was negatively correlated with HIT-6 scores (L-PCL: r = -0.367, P = 0.033; R-PCL: r = -0.357, P = 0.038). E, F cCBF in the dorsal cingulate gyrus (DCG) and ACCpre showed negative correlations with PSQI scores (R-DCG: r = -0.394, P = 0.021; R-ACCpre: r = -0.411, P = 0.016). G-J cCBF in the insula (INS), middle occipital gyrus (MOG), PCL, and cerebellar hemisphere VIII (CRBL8) was negatively correlated with HAMD scores (L-INS: r = -0.403, P = 0.046; L-MOG: r = -0.470, P = 0.015; L-PCL: r = -0.495, P = 0.010; L-CRBL8: r = -0.431, P = 0.028). Note: NAT+, with non-auditory tinnitus; CBF, cerebral blood flow; HIT-6, Headache Impact Test-6; PSQI, Pittsburgh Sleep Quality Index; HAMD, Hamilton Depression Scale; ACCpre, pregenual anterior cingulate cortex; CRBL, cerebellar hemisphere; DCG, middle cingulate gyrus and parahippocampal cingulate gyrus; INS, insula; MOG, middle occipital gyrus; PCL, paracentral lobule; L, left; R, right

Additionally, in the NAT+ group, cCBF in the L-PCL (r = -0.367, P = 0.033, Fig. 6C) and R-PCL (r = -0.357, P = 0.038, Fig. 6D) was negatively correlated with HIT-6 scores, both representing small-to-moderate effect sizes. CBF in the right DCG (r = -0.394, P = 0.021, Fig. 6E) and ACCpre (r = -0.411, P = 0.016, Fig. 6F) showed weak to moderate negative correlations with PSQI scores. CBF in the left INS, MOG, PCL, and CRBL8 was negatively correlated with HAMD depression scores (Fig. 6G-I); although the exact effect sizes were modest, these associations were statistically significant (P < 0.05).

Discussion

This study is the first to apply background-suppressed 3D GRASE multi-delay pCASL with five post-labeling time points to explore CBF changes at the whole-brain and voxel levels in patients with IJVS and CVSS. The findings demonstrate significant, lateralized reductions in CBF among CVC patients, with the most pronounced decreases observed in NAT+ patients compared to NAT- and HC groups. Notable perfusion deficits were identified in regions such as the IFG, PreCG, DMN, and CRBL, areas known for their roles in sensory integration, attention regulation, and cognitive processing. These CBF reductions suggest potential involvement in the development of symptoms such as tinnitus, cognitive decline, and emotional disturbances. The more prominent perfusion reductions observed in NAT+ patients support an association between altered cerebral perfusion and clinical manifestations, and raise the possibility that venous outflow impairment may relate to neurovascular dysregulation.

Whole-brain CBF changes and clinical relevance

This study found that patients with CVC, including IJVS and CVSS, exhibited significant reductions in CBF in the left hemisphere, cerebrum, temporal lobes, parietal lobes, and bilateral frontal lobes compared to HC. These results are consistent with prior reports of global CBF reductions associated with CVC(Garaci et al., 2012). For example, patients with impaired extracranial venous drainage have been shown to experience decreased brain perfusion (Zamboni et al., 2016), which can improve significantly or even normalize following stenting or surgical correction (Bai et al., 2020; Wang et al., 2021; Yang et al., 2019; Zhou et al., 2019).

Previous studies often relied on invasive techniques, such as SPECT or dynamic susceptibility contrast MR. These modalities are limited by semi-quantitative assessments or region-of-interest-based approaches. To address these limitations, our study employed non-invasive ASL to quantify whole-brain and regional CBF, providing a more comprehensive and quantitative alternative to traditional perfusion imaging methods.

Although ASL primarily measures arterial perfusion, prior studies have demonstrated its utility in evaluating global cerebral perfusion changes in conditions involving vascular dysfunction, including venous congestion (Li et al. 2021a, b). CVC can impair cerebral venous drainage, leading to disturbed blood flow distribution and impaired autoregulation. These changes may manifest as reduced perfusion detectable by ASL. Therefore, while ASL does not directly assess venous outflow impairment, it provides indirect yet valuable insights into the impact of venous dysfunction on cerebral perfusion. The reductions in CBF observed in this study may be interpreted within a hemodynamic hypothesis in which TVSS or IJVS is associated with elevated venous pressure and a reduced inflow of oxygenated arterial blood, potentially imposing downstream microvascular disruption and manifesting as decreased perfusion on ASL (Beggs, 2017; Ding et al., 2020). Correspondingly, symmetrical periventricular white matter hyperintensities on T2-weighted imaging have been described in patients with CVC, and are commonly interpreted as reflecting chronic hypoperfusion and/or microvascular vulnerability (Bai et al. , 2019b; Zhou et al. 2019).

Furthermore, the combination of multi-delay ASL with cCBF has been validated for its accuracy in measuring perfusion, especially in cases involving vascular stenosis or occlusion (Amemiya et al., 2022; Yan et al., 2023). This technical advantage enabled us to detect perfusion deficits with greater specificity and sensitivity. By capturing changes in CBF due to venous outflow restrictions, ASL provides insight into how compromised venous drainage may reduce cerebral blood supply and contribute to the symptoms observed in NAT+ patients.

In our study, patients in the NAT+ group exhibited more pronounced CBF reductions across affected regions compared to the NAT- and HC groups, suggesting that tinnitus may be associated with more pronounced perfusion impairment in the context of CVC. However, alternative explanations should also be considered, including differences in central symptom burden, affective modulation, and network-level alterations that may influence CBF independent of venous outflow obstruction, and these contributions cannot be disentangled in the present cross-sectional design. Notably, the observed CBF reductions predominantly affected the left hemisphere, while symmetric decreases were limited to the bilateral frontal lobes. This may reflect the predominance of left-sided stenosis in our sample, aligning with the affected side in NAT+ patients. We hypothesize that perfusion deficits initially localize to the stenotic side and gradually extend with disease progression. Further studies including patients with right-sided or bilateral stenosis are warranted to validate this lateralization pattern.

Voxel-level CBF changes in key brain regions

Voxel-level CBF analysis demonstrated significant perfusion reductions in specific brain networks in patients with CVC. The most robust reductions, shared by both NAT + and NAT− patients relative to HC, involve the attention network (left IFGoperc and IFGtriang), the sensorimotor network (left PreCG), and core DMN nodes (bilateral DCG and right ACCpre). In the NAT+ subgroup, additional decreases extend to the auditory network (left INS), sensorimotor regions (bilateral PCL and left PoCG, with right SMA), the visual network (left MOG), and subcortical regions (OLF), and NAT+-specific candidate regions include the cerebellum (left CRBL8 and bilateral CRBL9) and right LC. Overall, these results indicate that CVC-related hypoperfusion involves both auditory and non-auditory systems, prominently engaging attention, sensorimotor, default-mode, and cerebellar circuits; however, the additional changes observed in the NAT+ subgroup are exploratory and require further replication.

The frontal lobe plays a key role in cognitive and emotional functions and is a central component of the attention network. Within this region, the IFG is a hub for regulating higher-order cognitive functions, such as emotion, memory, and daily activities (Hu et al., 2022), and is closely associated with neurodegenerative diseases and aging (Martersteck et al., 2020). Emerging evidence suggests that the IFG is involved in abnormal auditory processing (Seydell-Greenwald et al., 2012). For example, chronic tinnitus patients exhibit reduced CBF in the prefrontal cortex (Xu et al., 2021), accompanied by disrupted functional connectivity (Schmidt et al., 2013), suggesting that changes in prefrontal CBF may be a key feature of chronic tinnitus. Furthermore, neuronal activity in the bilateral IFG has been correlated with tinnitus duration (Lv et al., 2015), implicating the IFG in the persistence of auditory symptoms.

The PreCG, part of the posterior frontal cortex, supports sensorimotor processing and has been increasingly linked to auditory perception and cognitive control, including attention and executive function (Corbetta et al., 2002). Several studies have reported reduced functional connectivity between the PreCG and the thalamus or insula in individuals with tinnitus or deafness (X. M. Xu et al. 2019a; Zhang et al. 2015). Decreased CBF in the PreCG has also been reported in patients with sudden sensorineural hearing loss (Chen et al., 2022b). These alterations may contribute to cognitive and attentional deficits observed in auditory disorders (Chen et al., 2022b; Xia et al. 2020). In our study, CVC patients showed lower MoCA and AVLT scores, along with higher levels of anxiety and depression. These cognitive and emotional abnormalities may be associated with perfusion deficits in the IFG and PreCG, which could disrupt neuronal activity and functional brain networks, thereby exacerbating broader neuropsychological symptoms. However, the cross-sectional design precludes causal inference, and symptom expression is likely multifactorial.

The DMN, which includes the posterior and anterior cingulate cortices, medial prefrontal and temporal cortices, precuneus, and inferior parietal lobule, plays a vital role in internally directed thought, self-referential processing, and suppression of irrelevant stimuli during rest. In this study, decreased CBF in the right DCG and ACCpre—two core nodes of the DMN—was statistically associated with poorer sleep quality. Poor sleep quality has previously been associated with reduced myelin in the posterior cingulate cortex (Toschi et al., 2021) and disrupted white matter integrity in the anterior cingulate (Kocevska et al., 2019; Lee et al., 2022). Within a neurovascular coupling framework, reduced perfusion may co-occur with sleep-related brain dysfunction. However, the observed association between cCBF and insomnia-related scores is of modest magnitude. Accordingly, links to microstructural changes remain hypothesis-generating and require confirmation with complementary sequences such as diffusion- or myelin-sensitive imaging.

In addition to its role in sleep, the DMN—particularly the cingulate cortex—has also been implicated in auditory perception abnormalities such as tinnitus (Xia et al., 2020). PET studies have shown increased perfusion and metabolism in the posterior cingulate cortex in chronic tinnitus patients, possibly reflecting compensatory plasticity (Plewnia et al., 2007; Verger et al., 2017). In contrast, DTI and fMRI data suggest reduced white matter integrity and disrupted connectivity in the cingulate cortex of patients with tinnitus or hearing loss (An et al., 2023; Chen et al., 2020; Xie et al., 2024), further linking structural and functional abnormalities in the DMN to tinnitus persistence. Decreased CBF in ACCpre may weaken its top-down inhibitory control over sensory cortices, particularly the auditory cortex, consistent with previous models of tinnitus centralization (Lan et al., 2022). According to the predictive coding framework, the brain continuously generates internal predictions to interpret sensory inputs. In the absence of auditory afferent input, internally retrieved auditory representations may be misperceived as external signals (De Ridder et al., 2021). Under normal conditions, the DMN is thought to suppress irrelevant internal noise. However, hypoperfusion in ACCpre may impair this filtering function, allowing abnormal auditory processing and tinnitus maintenance (Lee et al., 2020). In our study, the moderate positive correlation between right ACCpre CBF and tinnitus duration may reflect heterogeneity in stage-dependent responses, compensatory processes, or individual differences in symptom adaptation. Importantly, the directionality and mechanistic meaning of this association remain uncertain.

The cerebellum, although traditionally not considered part of the auditory pathway, is increasingly recognized for its role in sensory integration, cognitive processing, and auditory modulation (Baumann et al., 2015; Nguyen et al., 2017; Xiao Min Xu et al., 2019b). Cerebellar perfusion abnormalities have also been observed in various neurological and psychiatric conditions, underscoring its sensitivity to network-level disruptions (Delvecchio et al., 2022; Meng et al., 2023; Sato et al., 2022). In the context of auditory pathology, studies have directly linked cerebellar perfusion changes to tinnitus and related disorders. For example, Osaki et al. reported decreased blood flow in the right cerebellar posterior lobe during tinnitus suppression in non-pulsatile tinnitus patients (Osaki et al., 2005), and similar abnormalities have been noted in misophonia (Mirz et al., 2000). Animal research using manganese-enhanced MRI has also implicated the paraflocculus as a potential generator in noise-induced tinnitus models (Brozoski et al., 2017). In our study, NAT+ patients showed more pronounced CBF reductions in multiple cerebellar regions, and left CRBL9 CBF was statistically associated with tinnitus duration in a negative direction. These findings align with our previous study in a CVC rat model (Wei et al., 2024), which showed increased FDG uptake in the cerebellum during subacute and chronic phases, accompanied by GABA reduction and abnormal synaptic profiles, suggesting impaired inhibitory modulation. Behavioral testing further revealed tinnitus-like deficits in gap-prepulse inhibition of the acoustic startle (GPIAS), which were positively correlated with cerebellar GABA levels. Together, these findings support a potential link between cerebellar dysfunction and tinnitus under conditions of chronic venous congestion. Nevertheless, the observed effects in our study are modest, and whether cerebellar hypoperfusion has clinically meaningful value for tinnitus persistence remains to be established.

In addition to prominent tinnitus, patients with CVC in our study frequently reported symptoms such as headache, mild anxiety, depressive mood, and sleep disturbances, particularly in the NAT+ subgroup. Correlation analyses revealed that lower CBF in regions including the DCG, PCL, INS, MOG, and CRB was associated with higher HIT-6, HAMD, and PSQI scores, though the effect size was small to moderate. Decreased CBF has been proposed as a marker of synaptic dysfunction and disrupted brain connectivity (Chen et al., 2011). Neuroimaging studies have demonstrated activation and abnormal functional connectivity of the PCL in migraine patients (Wei et al., 2020; Xiong et al., 2024), and structural, functional, or perfusion abnormalities in the INS, MOG, PCL, and cerebellum have been widely reported in neuropsychiatric disorders such as anxiety, depression, and sleep disturbances (Ambrosi et al., 2017; C. Chen et al. 2022a; Cheng et al. 2022; Hu et al. 2023; Marwood et al. 2018; Teng et al. 2018; Xu et al. 2023). Moreover, anxiety and depressive symptoms are commonly observed in patients with tinnitus or migraine (Chen et al., 2024; Luo et al., 2025; Yu et al., 2023), which aligns with the clinical profile of CVC patients with NAT in our study. Taken together, these observations may reflect a complex interplay between venous congestion–induced perfusion alterations and broader neuropsychological manifestations, potentially influenced by unmeasured factors such as psychological responses to chronic illness, medication use, and individual coping mechanisms.

Limitations

This study has several limitations. First, the sample size is relatively small and group sizes are uneven, which may limit statistical power as well as generalizability. Second, we did not quantitatively assess the severity of CVC. Further analyses are needed to confirm whether factors such as lesion location, stenosis degree, and disease duration correlate with the extent of regional perfusion deficits. Third, given the cross-sectional design and the generally small-to-moderate effect sizes in symptom-related analyses, the directionality and clinical significance of the observed associations cannot be established, and unmodeled contributors to NAT may influence CBF independent of venous outflow obstruction. Fourth, although FDR/Bonferroni corrections were applied, extensive regional testing in a limited and unbalanced cohort increases the risk of false-positive findings. Therefore, regional CBF patterns should be considered hypothesis-generating until replicated in larger, balanced samples. Moreover, although ASL is effective for evaluating perfusion changes related to venous outflow impairment, it does not directly measure venous hemodynamics. Integrating venous-specific techniques, such as phase-contrast MRI or Doppler ultrasound, would help further elucidate the relationship between venous outflow impairment and cerebral hemodynamics. Finally, the comparison of CBF changes in patients before and after venous intervention, along with the establishment of a longitudinal follow-up cohort, is needed to clarify the relationship between clinical symptoms, cerebral perfusion, and the underlying venous pathology.

Conclusion

This study provides critical insights into the impact of non-thrombotic CVC on cerebral perfusion in patients with NAT. Using background-suppressed 3D GRASE multi-delay pCASL, we observe that CVC is accompanied by significant perfusion reductions across the attention, sensorimotor, DMN, and cerebellar networks, which are more prominent when NAT is present. While these results support a relationship between venous congestion and altered perfusion patterns, future longitudinal and interventional studies are required to further clarify the clinical meaning of these perfusion findings.

Supplementary Information

Below is the link to the electronic supplementary material.

Authors’ contributions

L.L., C.Z., and X.J. conceptualized the study. M.J. drafted the original manuscript. M.J., H.L., W.Z., Y.Z. and C.Z. conducted the investigation. L.L. was responsible for methodology and data curation. R.M. and J.D. reviewed and edited the manuscript. L.L. and X.J. acquired funding. All authors have read and agreed to the published version of the manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Beijing Natural Science Foundation (7254366), the National Natural Science Foundation of China (82027802), and Science and Technology Innovation Service Capacity Building Project of Beijing Municipal Education Commission (11000023T000002157177).

Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The study protocol was approved by the Ethics Committee of Xuanwu Hospital, Capital Medical University (ID: [2022]029). The research adhered to the principles outlined in the Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study.

Competing interests

The authors declare no competing interests.