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Neuroimage Clin
Neuroimage Clin
NeuroImage : Clinical
2213-1582
Elsevier

S2213-1582(24)00092-5
10.1016/j.nicl.2024.103653
103653
Regular Article
Beyond the Buzz: Cortical and subcortical brain changes in patients with pulsatile tinnitus
Remer Justin justin.remer@ucsf.edu
a⁎
Narsinh Kazim ab
Caton Travis c
Lamboy Alison a
Tu-Chan Adelyn d
Raj Ashish a
Amans Matthew R. ab
a UCSF Department of Diagnostic Radiology, United States
b UCSF Department of Neurosurgery, United States
c Mount Sinai Department of Neurosurgery, United States
d UCSF Department of Neurology, United States
⁎ Corresponding author at: UCSF Department of Diagnostic Radiology, 505 Parnassus Avenue, San Francisco CA 94143, United States. justin.remer@ucsf.edu
14 8 2024
2024
14 8 2024
43 10365314 4 2024
23 7 2024
6 8 2024
© 2024 Published by Elsevier Inc.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Highlights

• This is the first study to demonstrate significant differences in brain anatomy in a large cohort of patients with pulsatile tinnitus providing insight into the neurological sequale of this disease.

• Patients with pulsatile tinnitus exhibited significant decreases in cortical thickness in the anterior cingulate and entorhinal cortex, and decreased volume in the left putamen, compared to age-matched controls.

• Patients with pulsatile tinnitus demonstrated significant increased volume in frontal and occipital lobe structures, the cerebellum, hippocampi, and ventral pallidum.

• The observed structural differences in patient’s with PT occurred in brain regions related to auditory processing, and depression, which provides additional evidence of the psychiatric sequlae of PT.

• These findings emphasize the value in evaluating and treating this disease to prevent the observed neurologic implications.

Pulsatile tinnitus (PT) can be a debilitating condition characterized by rhythmic, heartbeat-synchronous sounds, which can severely impact patients’ quality of life. Understanding the neuroanatomical changes in PT patients may provide critical insights into the impacts of this condition. This study aimed to investigate potential differences in cortical and subcortical brain volume between adults with PT and age-matched controls (60 to 70 years of age). A retrospective, cross-sectional analysis of imaging and medical records was conducted, with data collected from January 2015 to December 2021. The study was conducted in a tertiary referral center with a specialized tinnitus clinic. A total of 135 adults diagnosed with PT and 135 age-matched controls were included. All participants were screened for PT and relevant medical history, with consecutive sampling used for selection. Cortical and subcortical brain volume differences between PT patients and controls were measured using Freesurfer. PT patients (n = 79, after exclusion of patients with inadequate imaging data) exhibited significant decreases in cortical thickness in the anterior cingulate and entorhinal cortex, and decreased volume in the left putamen, compared to age-matched controls (n = 135). PT patients also demonstrated significant increased volume in frontal and occipital lobe structures, the cerebellum, hippocampi, and ventral pallidum. In conclusion, our findings suggest that individuals with PT may have structural differences in brain regions related to auditory processing, and depression, which provides additional evidence of the psychiatric sequalae of PT. These findings demonstrate that there are neuroanatomical alterations in patients with PT, emphasizing the value in evaluating and treating this disease to prevent these neuroanatomical differences from developing.

Keywords

Pulsatile tinnitus
Brain Morphometry
MRI
Abbreviations

PT Pulsatile Tinnitus

MRI Magnetic Resonance Imaging
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pmc1 Introduction

Pulsatile tinnitus (PT) is characterized by a rhythmic or pulsating sound that is synchronous with the patient's heartbeat (Cummins et al., 2022, Cummins et al., 2022, Narsinh et al., 2022). Distinct from continuous tone tinnitus, PT is typically caused by abnormal blood flow (e.g. venous sinus stenosis including idiopathic intracranial hypertension, arterial stenoses in the head or neck, and shunting lesions such as dural arteriovenous fistulas), structural abnormalities in the head and neck (e.g. Various tumors, enlarged vestibular aqueduct), and neurogenic causes (essentially the nerve is “telling” the brain there is sound in the absence of external auditory stimulus) (Cummins et al., 2022, Cummins et al., 2022, Narsinh et al., 2022, Raz et al., 2022). Many of the causes of PT carry a risk of hemorrhagic or ischemic stroke, or even blindness (Raz et al., 2022). In addition to the physical harms of the underlying causes, PT is also highly linked to debilitating psychological impacts including debilitating depression, sleep disturbance, anxiety, difficulty with concentration and memory, and even suicidal ideation (Narsinh et al., 2022, Salazar et al., 2019).

Improvements in MRI technology including 1 mm isovoxel high resolution acquisition sequences are now frequently used in the diagnostic work up of patients with PT (Cummins et al., 2022). These techniques have enabled rigorous evaluate of subtle changes in brain structure, a field known as morphometry. Morphometric studies conducted on patients suffering from continuous tone (chronic) tinnitus have identified distinct modifications within specific brain regions (Aldhafeeri et al., 2012). This has facilitated an in-depth understanding of the continuous tone tinnitus and has shed light on potential neurological bridges linking tinnitus and psychiatric comorbidities (Salazar et al., 2019, Elgoyhen et al., 2015).

Although these advancements have significantly expanded our comprehension of morphometric alterations associated with continuous tone tinnitus, our knowledge regarding cortical and subcortical morphometric variations in PT patients remains limited (Liu et al., 2018). Given the different etiologies, natural history, and therapeutic approaches between PT and continuous tone tinnitus, it is imperative to explore the specific neuroanatomical correlates of PT. Our study aims to address this gap by examining differences in cortical and subcortical volume among a cohort of adults with PT, using age-matched controls as a reference. This will enable us to gain a better understanding of the neuroanatomical ramifications of this condition.

2 Methods

2.1 Study cohort

Patients in their 7th decade with PT, diagnosed by our multidisciplinary pulsatile tinnitus clinic, were enrolled in this IRB-approved retrospective analysis of imaging and medical records. Patients with history of prior head or neck surgery, or head trauma were excluded. Medical records were evaluated to gather demographic information, laterality of tinnitus (right, left, or bilateral), duration of PT, severity of PT (on a scale of 1 to 10, with 10 being the most severe), cognitive status, psychiatric co-morbidities, as well as past medical, surgical and family histories. If hearing loss was mentioned in their medical history, audiograms were evaluated and severity of hearing loss was further characterized. Race, age, and sex matched controls with normal neurocognitive testing and no history of prior head or neck surgery or trauma were gathered using the OASIS dataset (LaMontagne et al., 2019).

2.2 Image acquisition

MR data for all participants in the pulsatile tinnitus cohort was acquired using MPRAGE or BRAVO acquisition protocols on our institution’s 3.0 T or 1.5 T GE or Siemens scanners at 1.0 mm^3 voxel resolution. Acquisition matrix, and field of view were varied according to head size to maintain the same voxel resolution across all participants. Inclusion criteria demanded adequate image quality as adjudicated by a board-certified radiologist; patients with subpar image quality were omitted. Patients with imaging obtained at an outside institution were excluded from this cohort as well.

2.3 Data processing

Cortical volume was measured for 34 bilateral regions per cerebral hemisphere using the surface mesh based cortical modeling software package Freesurfer by employing the typical methodology (Fischl et al., 1999, Dale et al., 1999, Fischl, 2012). Images were visually inspected at each step in the procedure and manually edited using gcut (Ségonne et al., 2004) as needed to correct any improper skull stripping and remove any additional non-brain tissue from the analysis (https://freesurfer.net/fswiki/FsTutorial/SkullStripFix_freeview).

2.4 Statistical analysis

Demographic variables were compared using Chi-square tests. Differences in cortical and subcortical volume for each neuroanatomical location in each cerebral hemisphere were compared between groups using Welch’s T-tests assuming unequal distributions and unequal variance. Significant anatomical difference was defined as p < 0.001 corrected for each brain region tested using the Bonferroni correction (Weisstein, 2004) and images of significant neuroanatomical differences were generated using the BrainPainter software (Marinescu et al., 2019) (https://github.com/razvanmarinescu/brain-coloring). Percent differences in brain volume between the two groups were additionally calculated with as:Percent Difference = (Cortical Parameter Patients with PT – Cortical Parameter in Control Cohort)/Cortical Parameter in Control Cohort * 100

where Cortical Parameter can represents both cortical volume and cortical thickness for each of the 34 brain regions in each hemisphere. Confidence intervals for percent difference in each brain regions where calculated as well.

2.5 Results

135 patients were identified meeting including criteria from our local institution’s Pulsatile Tinnitus Clinic. 46 subjects were excluded due to inadequate image quality resulting a final cohort of 79 patients with PT and adequate magnetic resonance (MR) datasets for evaluation. The two cohorts were matched in terms of demographics (Table 1). 60 % of subjects were female and the ages were uniformly distributed between 60 and 70 years of age with an average age of 64. Amongst our pulsatile tinnitus cohort the average duration of PT was 4 years before being imaged, and the severity of pulsatile tinnitus was 6 on a scale from 1 to 10. In addition, 27 % of our PT cohort had clinically diagnosed major depressive disorder, 11 % had clinically diagnosed generalized anxiety. 4 patients had endorsed clinically significant hearing on their initial evaluation at PT clinic. These patients underwent further audiometry which demonstrated high frequency bilateral mild sensorineural hearing loss in 2 of those patients, high frequency unilateral moderate hearing loss in one patient and high frequency unilateral moderate to severe hearing loss in one patient. Four patients in our PT cohort had MRI evidence of a dural arterial venous fistula, thirteen patients had diagnosed IIH, and two patients had suspected IIH.Table 1 Participant demographics.

	Pulastile Tinnitus	Control Cohort	
Average age	64	66	
Gender			
Male	53	64	
Female	82	71	
Race			
White/Caucasian	107	105	
Black	5	27	
Asian	11	3	
Other	12	0	
Ethnicity			
Not Hispanic	122	135	
Hispanic	9	0	
Unknown	4	0	

Two patients from our PT cohort had mild cognitive impairment, and were referred for a formal comprehensive cognitive assessment.

Our investigation revealed multiple anatomical differences in both cortical and subcortical thickness and volume across both hemispheres in PT patients, as compared to the controls. Significant cortical thinning was identified after correction for multiple comparisons in the bilateral cingulate gyri including: the bilateral caudal anterior cingulate and the left rostral anterior cingulate; as well as the right entorhinal cortex (see Fig. 2). Additional regions, including the right posterior cingulate, right middle temporal gyrus, and left entorhinal cortex, exhibited evidence of cortical thinning within the pulsatile tinnitus cohort. However, these latter findings did not retain their statistical significance following correction for multiple comparisons.Fig. 3.Fig. 1 Whole brain statistical analysis displaying regions of increased cortical thickness in PT patients when compared to controls. Regions that are yellow signify p < 0.05 (significance uncorrected for multiple comparisons), regions that are orange correlate with P<0.01, and regions that are red significant p < 0.001 (significance after correction for multiple comparisons). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2 Whole brain statistical analysis displaying regions of decreased cortical thickness in PT patients when compared to controls. Regions that are yellow signify p < 0.05 (significance uncorrected for multiple comparisons), regions that are orange correlate with P<0.01, and regions that are red significant p < 0.001 (significance after correction for multiple comparisons). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3 Graph showing percent difference in cortical thickness and cortical volume in patients with pulsatile tinnitus when compared with healthy controls. The x-axis indicates each individual brain region analyzed, the y-axis for the first panel indicates percent difference in cortical thickness in patients with PT when compared with controls, and the y-axis in the second panel indicates percent difference in cortical volume in patients with PT when compared with controls. Positive percent difference signifies regions with increased subcortical volume in patients with PT and negative percent difference signifies regions with decreased subcortical volume in patients with PT. A * indicates regions where p < 0.05, ** indicates regions where p < 0.01, and *** indicates regions where p < 0.001 (significance after correction for multiple comparisons).

In the subcortical brain, the left putamen demonstrated significantly decreased volume in patients with PT (see Fig. 4). Moreover, we identified a trend of decreased volume in the nucleus accumbens within the pulsatile tinnitus cohort, although this finding did not withstand correction for multiple comparisons.Fig. 4 Graph showing percent difference in subcortical volume in patients with pulsatile tinnitus when compared with healthy controls. The x-axis indicates each individual brain region analyzed, the y-axis indicates percent difference in subcortical volume in patients with PT when compared with controls. Positive percent difference signifies regions with increased subcortical volume in patients with PT and negative percent difference signifies regions with decreased subcortical volume in patients with PT. A * indicates regions where p < 0.05, ** indicates regions where p < 0.01, and *** indicates regions where p < 0.001 (significance after correction for multiple comparisons).

Conversely, there are multiple cortical and subcortical brain regions that demonstrated significantly greater volume in patients with pulsatile tinnitus when compared to healthy controls after correction for multiple comparisons. In the cortex these included frontal lobe structures such as the bilateral frontal poles, and the bilateral medial orbitofrontal cortex, as well as occipital lobe structures such as the bilateral cuneus, and the bilateral pericalcarine cortex (see Fig. 1 and Supplementary Table 1). In the subcortical brain there was significantly greater volume in the bilateral ventral pallidum, bilateral cerebellum, bilateral hippocampi, and the corpus callosum (see Fig. 4 and Supplementary Table 1).

2.6 Discussion

The current study aimed to investigate the potential differences in brain volume between individuals with pulsatile tinnitus (PT) and healthy adults (control group). This is the first cross-sectional brain morphometric study in PT to demonstrate significant differences in brain anatomy between the two groups with predominantly decreased cortical thickness in the anterior cingulate, a region described to be critically involved in the attention control of sensory processing; (Weisstein, 2004, Marinescu et al., 2019) the entorhinal cortex a limbic structure that regulates the connections between the hippocampus and memory processing with the neocortex; (Crottaz-Herbette and Menon, 2006) and the putamen a region in the brain that has been implicated with depression (Haupt et al., 2009). Additionally, our results also revealed that patients with pulsatile tinnitus showed greater volume in frontal and occipital lobe structures as well in the cerebellum, regions with both cognitive and motor functions (Maass et al., 2015); as well as the hippocampi and ventral pallidum, subcortical structures involved in memory (Sacchet et al., 2017) and reward motivation (Buckner, 2013) respectively.

The neuroanatomical correlates of abnormal auditory processing in tinnitus are the subject of ongoing research and debate and it is unknown whether these findings are generalizable to patients with PT. In patients with continuous tone (i.e. non-pulsatile) tinnitus, the limbic system has been proposed to have a critical role in “noise cancellation” of tinnitus signals (Eichenbaum et al., 1992). Specifically patients with decreased ability for the nucleus accumbens to filter out unwanted noises relayed from the amygdala may exhibit a decreased ability in modulating the emotional perception of tinnitus and suffer from more severe symptoms (Eichenbaum et al., 1992, Smith et al., 2009). Patients in our PT cohort reinforce this theory by demonstrating decreased volume in the bilateral right greater then left nucleus accumbens (p = 0.004 and p = 0.018, respectively), however these results did not maintain significance after correction for multiple corrections.

In addition, studies using EEG have suggested abnormalities in the rostral anterior cingulate might be contributory in dysfunctional noise cancellation leading to increased perception of tinnitus (Rauschecker et al., 2010, Mühlau et al., 2006). Our results support the latter theory by demonstrating that patients with PT exhibit decreased thickness in both the caudal and rostral anterior cingulate, and increases in volume in additional limbic structures such as the orbitofrontal cortex, suggesting chronic changes in limbic system morphology Moreover, anatomical differences in these systems might further explain why patients with PT are more impacted by their symptoms.

While many studies explore differences in neuroanatomy in chronic tinnitus (Elgoyhen et al., 2015, Song et al., 2015), very little data exists looking at structural anatomical differences in patients with PT. One prior study revealed that younger patients (ages 24–53) with PT had decreased cortical volume in the left orbitofrontal cortex, the bilateral putamen, and right middle occipital gyrus, and significantly increased volumes in the bilateral superior temporal gyrus (Liu et al., 2018). Nevertheless, this prior study is limited by a wide age range and small sample size, decreasing statistical power. Our findings extend these results by revealing that changes in putamen persist in patients with pulsatile tinnitus in our older cohort and further demonstrate decreased thickness in the cingulate and entorhinal cortex as well as increased volume in the left pallidum and cerebellum. Future longitudinal studies are needed to analyze changes in brain anatomy across the entire range and look for differences in rates of change.

Previous studies have also shown changes in the auditory cortex and other sound processing regions in the brains of patients with continuous tone tinnitus (Song et al., 2015). For example decreased gray matter volume has been shown in the cingulate, superior, middle, and inferior temporal gyrus, and the superior, middle, and inferior frontal gyri in patients with continuous tone tinnitus when compared to healthy controls (Aldhafeeri et al., 2012). Similarly, other studies have reported changes in the functional connectivity of the auditory cortex in patients with continuous tone tinnitus, including increased connectivity between the auditory cortex and the limbic system (Eichenbaum et al., 1992). The current study of patients with PT found reduced thickness in the cingulate; however, our cohort also exhibited decreased thickness in the putamen and increased thickness in the hippocampi. Reasons for our additional anatomical differences are unclear; however, the similarities suggest that both patients with PT and continuous tone tinnitus both exhibit anatomical sequalae from pathologic auditory-limbic processing. Future studies can consider more direct comparisons in anatomy between patients with pulsatile tinnitus and continuous tone tinnitus.

As mentioned previously, our PT cohort demonstrated reduced volume in the left putamen. This result is of particular interest as prior research has suggested decreased putamen volume might be a potential biomarker for depressive disorders and a predictor of major depressive episodes (Cheng et al., 2020, Landgrebe et al., 2009). Our cohort had a high prevalence of depression (27 % of participants) and decreases in volume in the left putamen in our cohort might have relevant clinical implications. This finding could provide insights on how untreated PT can lead to depression and other psychiatric co-morbidities or how patients with co-morbid depression with PT might be more likely to present for treatment. Future studies will look towards correlating psychiatric co-morbidities in patients with PT with neuroanatomical abnormalities.

There are several potential limitations to our study which include age-related differences in brain volume, heterogeneity of pulsatile tinnitus etiology, sample size, and multiple comparisons. While the study aims to control for age while using a 10-year age range and by matching the patient and control groups, there may still be some differences in brain structure due to normal aging processes within this interval that could affect the results. Pulsatile tinnitus can be caused by a range of underlying conditions, and the sample in this study included patients with different etiologies. This heterogeneity may make it more difficult to interpret the results and identify specific patterns of brain structure changes associated with pulsatile tinnitus and future studies will look to stratify PT patients based on underlying etiology.

Another possible limitation of the study is the use of freesurfer for image processing/analysis, specifically the use of the current cortical segmentation atlas. While accurate and well validated for image analysis, using the freesurfer atlas limits evaluation of subtle differences in smaller/more specific brain regions and future studies can look at subdivisions of brain anatomy for more subtle results. Another limitation of this study involves the use of the Bonferroni correction. While effective in reducing reduce the risk of false positive findings, this correction can also make it more difficult to detect true positive findings, particularly if the differences between the groups are small. Another limitation of this study we only examined brain structure and did not assess brain function. Brain volume and thickness while essential measures to understand neuropathology are only one facet of the multiple imaging modalities available. For further studies we hope to explore differences in functional metrics in pulsatile tinnitus patients with use of fMRI and microstructural differences with DTI. Overall, it is important to consider these potential limitations when interpreting the results of this study and considering the implications for future research.

The use of the OASIS dataset as a control group in our study is acknowledged as a limitation, particularly because it does not include measures of hearing ability. This is a significant concern because subtle changes in hearing, can influence neuroimaging results and there is a concern that findings may inadvertently reflect correlates of hearing changes rather than tinnitus itself. Future studies should aim to include detailed audiometric assessments for both PT patients and control groups.

For this study a specific cohort of patients, 60–70 years of age was selected for the analysis. The reason for this decision was to first control for age a variable in differences in brain anatomy. As brain structure and function can change significantly with age, narrowing the age range of study participants limits the influence of age-related variability on the results. Second, there is a lack of research in pulsatile tinnitus focusing specifically on this age group. Expanding the understanding of tinnitus in this age range will fill a gap in the current literature, potentially leading to a better understanding of the morphometric implications of PT. Third, this age group made up a substantial component of patients who presented to our institution’s pulsatile tinnitus clinic. By only looking at adults within a specific age range for this cross-sectional analysis, it would be of interest for future studies to see if these findings are generalizable to other age groups as well as if the observed differences in brain volume change over time in longitudinal analyses.

In conclusion, our findings suggest that individuals with PT may have structural differences in brain regions related to auditory processing, and depression, which provides additional evidence of the psychiatric sequalae of PT. These findings demonstrate that there are neuroanatomical aberrations in patients with PT, emphasizing the value in evaluating and treating this disease to prevent these neuroanatomical differences from developing.

CRediT authorship contribution statement

Justin Remer: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Kazim Narsinh: Writing – review & editing, Project administration, Investigation, Data curation. Travis Caton: Writing – review & editing, Resources, Investigation, Data curation. Alison Lamboy: Writing – review & editing, Data curation. Adelyn Tu-Chan: Data curation. Ashish Raj: Writing – review & editing, Supervision, Methodology, Formal analysis, Conceptualization. Matthew R. Amans: Writing – review & editing, Supervision, Investigation, Funding acquisition, Data curation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A Supplementary data

The following are the Supplementary data to this article:Supplementary Data 1

Supplementary Table 1: Statistical analysis comparing differences in cortical thickness, cortical volume, and subcortical volume between patients with pulsatile tinnitus and healthy controls. The table shows the results of a two-tailed t-test comparing the control cohort and the pulsatile tinnitus (PT) cohort for various brain regions. The “Brain_region” column lists the specific brain regions that were analyzed, with subsequent column showing the associated p-values. The “control_mean” and “control_std” columns show the mean and standard deviation of the control cohort for each brain region, respectively, while the “PT_mean” and “PT_std” columns show the same information for the PT cohort. The “Confidence Interval” column shows the 95% confidence interval for the mean difference between the two groups.

Data availability

Data will be made available on request.

Acknowledgements

Research reported in this publication was supported by Peer Reviewed Medical Research Program of the 10.13039/100000005 Department of Defense under award number PR201091 .

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.nicl.2024.103653.
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